US7727968B2 - Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome - Google Patents
Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome Download PDFInfo
- Publication number
- US7727968B2 US7727968B2 US11/811,626 US81162607A US7727968B2 US 7727968 B2 US7727968 B2 US 7727968B2 US 81162607 A US81162607 A US 81162607A US 7727968 B2 US7727968 B2 US 7727968B2
- Authority
- US
- United States
- Prior art keywords
- amount
- daunorubicin
- cytarabine
- days
- per day
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 54
- 201000003793 Myelodysplastic syndrome Diseases 0.000 title claims abstract description 44
- 206010000830 Acute leukaemia Diseases 0.000 title claims abstract description 34
- 238000002648 combination therapy Methods 0.000 title description 13
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims abstract description 100
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 claims abstract description 98
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims abstract description 94
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims abstract description 93
- 229960000684 cytarabine Drugs 0.000 claims abstract description 92
- 229960000975 daunorubicin Drugs 0.000 claims abstract description 89
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims abstract description 60
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 36
- 238000002560 therapeutic procedure Methods 0.000 claims description 31
- 230000006698 induction Effects 0.000 claims description 25
- 238000001802 infusion Methods 0.000 claims description 20
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 claims description 15
- 229960003109 daunorubicin hydrochloride Drugs 0.000 claims description 15
- 238000001990 intravenous administration Methods 0.000 claims description 13
- 229940045799 anthracyclines and related substance Drugs 0.000 abstract description 29
- 231100000433 cytotoxic Toxicity 0.000 abstract description 28
- 230000001472 cytotoxic effect Effects 0.000 abstract description 28
- 239000002718 pyrimidine nucleoside Substances 0.000 abstract description 25
- 150000003834 purine nucleoside derivatives Chemical class 0.000 abstract description 22
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract description 21
- 150000001875 compounds Chemical class 0.000 abstract description 16
- 229930195731 calicheamicin Natural products 0.000 description 21
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 21
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 20
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 20
- -1 pitarubicin Chemical compound 0.000 description 15
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 13
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 13
- 230000000118 anti-neoplastic effect Effects 0.000 description 13
- 229960000908 idarubicin Drugs 0.000 description 13
- 239000003814 drug Substances 0.000 description 12
- 229960001156 mitoxantrone Drugs 0.000 description 12
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- 229960000390 fludarabine Drugs 0.000 description 11
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 11
- 238000011084 recovery Methods 0.000 description 11
- AMNAZJFEONUVTD-QJHHURCWSA-N (2s,3s,4s,5r,6r)-6-(4-amino-2-oxopyrimidin-1-yl)-4,5-dihydroxy-3-[[(2r)-3-hydroxy-2-[[2-(methylamino)acetyl]amino]propanoyl]amino]oxane-2-carboxamide Chemical compound O1[C@H](C(N)=O)[C@@H](NC(=O)[C@@H](CO)NC(=O)CNC)[C@H](O)[C@@H](O)[C@@H]1N1C(=O)N=C(N)C=C1 AMNAZJFEONUVTD-QJHHURCWSA-N 0.000 description 10
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 10
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 10
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 10
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 10
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 10
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 10
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 10
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 10
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 10
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 10
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 10
- 229930189413 Esperamicin Natural products 0.000 description 10
- FEACDOXQOYCHKU-UHFFFAOYSA-N Gougerotin Natural products CNCC(=O)NC1=NC(=O)N(C=C1)C2OC(C(O)C(NC(=O)C(N)CO)C2O)C(=O)N FEACDOXQOYCHKU-UHFFFAOYSA-N 0.000 description 10
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 10
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 10
- 229960004176 aclarubicin Drugs 0.000 description 10
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 10
- 229950000242 ancitabine Drugs 0.000 description 10
- 229960002756 azacitidine Drugs 0.000 description 10
- 229950004398 broxuridine Drugs 0.000 description 10
- 229960004117 capecitabine Drugs 0.000 description 10
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 10
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 10
- 229950001725 carubicin Drugs 0.000 description 10
- 229960002436 cladribine Drugs 0.000 description 10
- 229960003603 decitabine Drugs 0.000 description 10
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 10
- 229950005454 doxifluridine Drugs 0.000 description 10
- 229960004679 doxorubicin Drugs 0.000 description 10
- 229950011487 enocitabine Drugs 0.000 description 10
- 229960001904 epirubicin Drugs 0.000 description 10
- 229960000961 floxuridine Drugs 0.000 description 10
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 10
- 229960005277 gemcitabine Drugs 0.000 description 10
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 10
- 229950002676 menogaril Drugs 0.000 description 10
- LWYJUZBXGAFFLP-OCNCTQISSA-N menogaril Chemical compound O1[C@@]2(C)[C@H](O)[C@@H](N(C)C)[C@H](O)[C@@H]1OC1=C3C(=O)C(C=C4C[C@@](C)(O)C[C@H](C4=C4O)OC)=C4C(=O)C3=C(O)C=C12 LWYJUZBXGAFFLP-OCNCTQISSA-N 0.000 description 10
- 229950009266 nogalamycin Drugs 0.000 description 10
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 10
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 10
- 229960002340 pentostatin Drugs 0.000 description 10
- 229950010131 puromycin Drugs 0.000 description 10
- 229960001674 tegafur Drugs 0.000 description 10
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 10
- FVRDYQYEVDDKCR-DBRKOABJSA-N tiazofurine Chemical compound NC(=O)C1=CSC([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 FVRDYQYEVDDKCR-DBRKOABJSA-N 0.000 description 10
- 229960003723 tiazofurine Drugs 0.000 description 10
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 10
- 229960003962 trifluridine Drugs 0.000 description 10
- 229960000653 valrubicin Drugs 0.000 description 10
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 10
- 229960000641 zorubicin Drugs 0.000 description 10
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 10
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 9
- 231100000599 cytotoxic agent Toxicity 0.000 description 9
- LJQQFQHBKUKHIS-WJHRIEJJSA-N esperamicin Chemical compound O1CC(NC(C)C)C(OC)CC1OC1C(O)C(NOC2OC(C)C(SC)C(O)C2)C(C)OC1OC1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)C(OC3OC(C)C(O)C(OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)C2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-WJHRIEJJSA-N 0.000 description 9
- 230000001965 increasing effect Effects 0.000 description 9
- 230000004083 survival effect Effects 0.000 description 9
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 9
- 101710112752 Cytotoxin Proteins 0.000 description 8
- 210000001185 bone marrow Anatomy 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 239000002619 cytotoxin Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 7
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 238000002512 chemotherapy Methods 0.000 description 7
- 231100000304 hepatotoxicity Toxicity 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 229960003087 tioguanine Drugs 0.000 description 7
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 7
- 230000008901 benefit Effects 0.000 description 6
- 238000009093 first-line therapy Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000001976 improved effect Effects 0.000 description 5
- 208000032839 leukemia Diseases 0.000 description 5
- 230000007056 liver toxicity Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 4
- 238000010322 bone marrow transplantation Methods 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 238000012937 correction Methods 0.000 description 4
- 230000002559 cytogenic effect Effects 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 229940107841 daunoxome Drugs 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 4
- 229960005420 etoposide Drugs 0.000 description 4
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 4
- 208000018645 hepatic veno-occlusive disease Diseases 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 3
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 3
- 235000009421 Myristica fragrans Nutrition 0.000 description 3
- 208000009527 Refractory anemia Diseases 0.000 description 3
- 208000012346 Venoocclusive disease Diseases 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940034982 antineoplastic agent Drugs 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 210000003969 blast cell Anatomy 0.000 description 3
- 238000004820 blood count Methods 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 229940070968 depocyt Drugs 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000002489 hematologic effect Effects 0.000 description 3
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 3
- 230000011132 hemopoiesis Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000011368 intensive chemotherapy Methods 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 239000001115 mace Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 210000005259 peripheral blood Anatomy 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- VNTHYLVDGVBPOU-QQYBVWGSSA-N (7s,9s)-9-acetyl-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 VNTHYLVDGVBPOU-QQYBVWGSSA-N 0.000 description 2
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 2
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 description 2
- 206010065553 Bone marrow failure Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 102000003951 Erythropoietin Human genes 0.000 description 2
- 108090000394 Erythropoietin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010019851 Hepatotoxicity Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010072684 Refractory cytopenia with unilineage dysplasia Diseases 0.000 description 2
- WPDOZYZAJKUVRZ-NRYSMURASA-N S-[(2R,3S,4S,6S)-6-[[(2R,3S,4S,5R,6R)-5-[(2S,4S,5S)-5-[acetyl(ethyl)amino]-4-methoxyoxan-2-yl]oxy-4-hydroxy-6-[[(2S,5Z,9R)-9-hydroxy-12-(methoxycarbonylamino)-13-[2-(methyltrisulfanyl)ethylidene]-11-oxo-2-bicyclo[7.3.1]trideca-1(12),5-dien-3,7-diynyl]oxy]-2-methyloxan-3-yl]amino]oxy-4-hydroxy-2-methyloxan-3-yl] 4-[(2S,3R,4R,5S,6S)-3,5-dihydroxy-4-methoxy-6-methyloxan-2-yl]oxy-5-iodo-2,3-dimethoxy-6-methylbenzenecarbothioate Chemical compound CCN([C@H]1CO[C@H](C[C@@H]1OC)O[C@@H]1[C@@H](O)[C@H](NO[C@H]2C[C@H](O)[C@H](SC(=O)c3c(C)c(I)c(O[C@@H]4O[C@@H](C)[C@H](O)[C@@H](OC)[C@H]4O)c(OC)c3OC)[C@@H](C)O2)[C@@H](C)O[C@H]1O[C@H]1C#C\C=C/C#C[C@]2(O)CC(=O)C(NC(=O)OC)=C1C2=CCSSSC)C(C)=O WPDOZYZAJKUVRZ-NRYSMURASA-N 0.000 description 2
- 108010029180 Sialic Acid Binding Ig-like Lectin 3 Proteins 0.000 description 2
- 102000001555 Sialic Acid Binding Ig-like Lectin 3 Human genes 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000009108 consolidation therapy Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 229940105423 erythropoietin Drugs 0.000 description 2
- 150000002337 glycosamines Chemical class 0.000 description 2
- 230000007686 hepatotoxicity Effects 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 206010028537 myelofibrosis Diseases 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 238000011301 standard therapy Methods 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 238000011476 stem cell transplantation Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000003319 supportive effect Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 101100002068 Bacillus subtilis (strain 168) araR gene Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 241001227713 Chiron Species 0.000 description 1
- 206010008583 Chloroma Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- GUGHGUXZJWAIAS-QQYBVWGSSA-N Daunorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 GUGHGUXZJWAIAS-QQYBVWGSSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 206010018687 Granulocytopenia Diseases 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 206010019842 Hepatomegaly Diseases 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 1
- FHFHNVHRVKQQHN-UHFFFAOYSA-N Islandicin Chemical group C1=CC=C2C(=O)C3=C(O)C(C)=CC(O)=C3C(=O)C2=C1O FHFHNVHRVKQQHN-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 206010064912 Malignant transformation Diseases 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000187722 Micromonospora echinospora Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 1
- 208000033833 Myelomonocytic Chronic Leukemia Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 206010033661 Pancytopenia Diseases 0.000 description 1
- 208000007541 Preleukemia Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 206010041660 Splenomegaly Diseases 0.000 description 1
- 241000220254 Streptomyces coeruleorubidus Species 0.000 description 1
- 241000187081 Streptomyces peucetius Species 0.000 description 1
- 102000036693 Thrombopoietin Human genes 0.000 description 1
- 108010041111 Thrombopoietin Proteins 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 description 1
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 description 1
- 208000012634 Venoocclusive liver disease Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 101150044616 araC gene Proteins 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 206010003074 arachnoiditis Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- 208000027119 bilirubin metabolic disease Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 1
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 230000018486 cell cycle phase Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000012829 chemotherapy agent Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 201000010902 chronic myelomonocytic leukemia Diseases 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 229940047120 colony stimulating factors Drugs 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 238000011441 consolidation chemotherapy Methods 0.000 description 1
- 238000007596 consolidation process Methods 0.000 description 1
- 229940077926 cytarabine liposome injection Drugs 0.000 description 1
- 208000024389 cytopenia Diseases 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 238000011393 cytotoxic chemotherapy Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960003334 daunorubicin citrate Drugs 0.000 description 1
- 229940052372 daunorubicin citrate liposome Drugs 0.000 description 1
- WPJRFCZKZXBUNI-HCWXCVPCSA-N daunosamine Chemical compound C[C@H](O)[C@@H](O)[C@@H](N)CC=O WPJRFCZKZXBUNI-HCWXCVPCSA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000000925 erythroid effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 208000036796 hyperbilirubinemia Diseases 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229940090044 injection Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000036212 malign transformation Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 201000005987 myeloid sarcoma Diseases 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 208000003476 primary myelofibrosis Diseases 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 231100000279 safety data Toxicity 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 208000016595 therapy related acute myeloid leukemia and myelodysplastic syndrome Diseases 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000133 toxic exposure Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 229940117972 triolein Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
Definitions
- Methods of treatment and pharmaceutical combinations are provided for the treatment of acute leukemia, in particular, acute myelogenous leukemia and myelodysplastic syndrome.
- the methods of treatment and pharmaceutical combinations employ an anti-CD33 cytotoxic conjugate in combination with at least one compound selected from the group consisting of an anthracycline and a pyrimidine or purine nucleoside analog, in particular, gemtuzumab ozogamicin, daunorubicin, and cytarabine.
- Acute leukemia is typically a rapidly progressing leukemia characterized by replacement of normal bone marrow by blast cells of a clone arising from malignant transformation of a hematopoietic stem cell.
- ALL acute lymphoblastic leukemia
- AML acute myelogenous leukemia
- ALL is the most common malignancy in children, but also occurs in adolescents and has a second, lower peak in adults.
- AML also know as acute myeloid leukemia and acute myelocytic leukemia, is the more common acute leukemia in adults and its incidence increases with age, but AML also occurs in children.
- the primary goal of treatment is to achieve complete remission, with resolution of abnormal clinical features, return to normal blood counts and normal hematopoiesis in the bone marrow with ⁇ 5% blast cells, a neutrophil count of >1,000-1,500, a platelet count of >100,000, and disappearance of the leukemic clone; however, the drug regimens for treating ALL and AML have differed.
- the Merck Manual Sec. 11, Ch. 138 (17 th ed. 1999); Estey, E., Cancer (2001) 92(5): 1059-1073.
- Initial therapy aims at inducing remission. Treatment of AML differs most from ALL in that patients with AML respond to fewer drugs and have a high rate of relapse.
- AML AML-associated leukemic clones
- Induction of remission is usually possible with intensive chemotherapy.
- Complete remission has been stated to be achievable in up to 80% of younger patients and about 50% of older patients (who form the majority of those with AML), but patients suffer severe neutropenia during induction and remission rate is to some extent dependent upon the standard of supportive care.
- Remission rates are lower in those with adverse prognostic factors such as poor performance status, AML secondary to myelodysplasia or antineoplastics, high white cell count, features of multidrug resistance, and unfavorable cytogenetics.
- Established regimens are based on cytarabine, a pyrimidine nucleoside analog, with the anthracycline daunorubicin.
- the first successful regimens also included thioguanine, which is still used by some medical centers, although the majority opinion is that it gives no additional advantage and thioguanine has been dropped from most induction protocols.
- daunorubicin alternatives include idarubicin and mitoxantrone.
- Etoposide has been added to induction protocols of cytarabine and daunorubicin with improved results in younger patients.
- the basic induction regimen for treatment of AML includes administration of cytarabine by continuous intravenous (IV) infusion for 7 days, with an anthracycline such as daunorubicin or idarubicin given IV for 3 days during this time, usually in the first three days.
- IV intravenous
- an anthracycline such as daunorubicin or idarubicin given IV for 3 days during this time, usually in the first three days.
- This widely used regimen for the treatment of AML is known as a 3+7 regimen and produces complete remission rates of 60-80%.
- the induction regimen may be repeated, usually up to a total of three times, to achieve remission.
- a bone marrow analysis is done on after fourteen days from the completion of the last induction regimen. If the bone marrow has been cleaned out, i.e., there is a complete response, then the physician will wait until the patient's peripheral blood counts recover before administering another induction regimen. If the bone marrow analysis shows that disease is still present, i.e., there is a partial or minimal response, then the induction regimen will be repeated without waiting for the patient's peripheral blood counts to recover.
- the waiting period between induction regimens is therefore twenty-eight to thirty-five days for a complete responder, and fourteen to twenty-one days for partial and minimal responders.
- the standard induction therapy of cytarabine and daunorubicin does not produce a good response rate, typically ⁇ 40%, and the prognosis is poor for these patients.
- consolidation therapy a second treatment regimen using the same drugs or other drugs to knock out the disease, known as consolidation therapy, may be employed.
- consolidation therapy a second treatment regimen using the same drugs or other drugs to knock out the disease.
- a high percentage of patients suffer from relapse, even in series with intensive post-remission consolidation chemotherapy. De Nully Brown, P., et al., Leukemia (1997) 11:37-41.
- gemtuzumab ozogamicin Another drug used in the treatment of AML is gemtuzumab ozogamicin (Mylotarg®).
- Gemtuzumab ozogamicin was approved in May 2000 in the United States of America for the treatment of AML in patients in first relapse who are 60 years old or older and not considered candidates for other cytotoxic chemotherapy.
- Gemtuzumab ozogamicin is administered as a two-hour IV infusion in a dose of 9 mg/m 2 . A second dose may be administered fourteen days later. While many patients receiving gemtuzumab ozogamicin have achieved complete remission, a significant number of patients have had a delay in platelet recovery or incomplete platelet recovery. Physician's Desk Reference (56 th ed. 2002).
- gemtuzumab ozogamicin Combination therapies with gemtuzumab ozogamicin have been tried with limited success.
- gemtuzumab ozogamicin was administered to elderly patients previously untreated for AML by 2-hour IV infusion at a dose of 9 mg/m 2 on day 1 and 15, with MICE (mitoxantrone, cytarabine and etoposide) being given for one or two courses within seven days from the response assessment to gemtuzumab ozogamicin (between day 28 and 35 following the last infusion).
- MICE mitoxantrone, cytarabine and etoposide
- Significant non-hematologic adverse events included, among others, VOD (6%), arrhythmia (6%), and infection (24%).
- AML 9503 the patient received two “pulses” of chemotherapy each consisting of 2 gm/m 2 of
- the complete remission rate for AML 9503 was 30% and for AML 9798 was 40%.
- the chemotherapy was changed to add a single dose of gemtuzumab ozogamicin in an amount of 9 mg/m 2 three days prior to the first pulse of chemotherapy, two of four such treated patients with refractory AML entered complete remission.
- Preisler, H, D., et al. “Synergistic Antileukemia Effects of Mylotarg and Chemotherapy in AML,” Blood (2001) 98:193b.
- H-DAT 3+10 regimen (daunorubicin 45 mg/m 2 days 1, 3, 5; cytarabine 400 mg/m 2 bd days 1-10; thioguanine 100 mg/m 2 bd days 1-10) with gemtuzumab ozogamicin (3 or 6 mg/m 2 given as a 2-hour infusion on day 1).
- gemtuzumab ozogamicin 3 or 6 mg/m 2 given as a 2-hour infusion on day 1).
- the second course given was H-DAT 3+8 with the same gemtuzumab ozogamicin dose as in course 1.
- gemtuzumab ozogamicin While both the 3 mg/m 2 and 6 mg/m 2 doses of gemtuzumab ozogamicin were tolerated in these two regimens, increased liver toxicity was seen when gemtuzumab ozogamicin was given at 6 mg/m 2 in the first course and it was decided to thereafter use 3 mg/m 2 of gemtuzumab ozogamicin in courses 1 and 2.
- H-DAT 3+10 (daunorubicin 50 mg/m 2 daily by slow IV push on days 1, 3, 5; cytarabine 200 mg/m 2 IV push bd days 1-10; thioguanine 100 mg/m 2 bd oral days 1-10) or S-DAT 3+10 (daunorubicin 50 mg/m 2 daily by slow IV push on days 1, 3, 5; cytarabine 100 mg/m 2 IV push bd days 1-10; thioguanine 100 mg/m 2 bd oral days 1-10) with 3 or 6 mg/m 2 gemtuzumab ozogamicin as induction therapy.
- H-DAT 3+8 did not give gemtuzumab ozogamicin in an amount of 3 mg/m 2 .
- Consolidation therapy consisted of MACE (MACE: Amsacarine 100 mg/m 2 daily by one hour infusion (in 5% dextrose on days 1-5); cytarabine 200 mg/m 2 by daily continuous IV infusion days 1-5, Etoposide 100 mg/m 2 daily by one hour IV infusion days 1-5) chemotherapy with or without gemtuzumab ozogamicin in an amount of 3 mg/m 2 .
- MACE Amsacarine 100 mg/m 2 daily by one hour infusion (in 5% dextrose on days 1-5); cytarabine 200 mg/m 2 by daily continuous IV infusion days 1-5, Etoposide 100 mg/m 2 daily by one hour IV infusion days 1-5) chemotherapy with or without gemtuzumab ozogamicin in an amount of 3 mg/m 2 .
- gemtuzumab ozogamicin can be given with H-DAT 3+10 in course 1 and in course 3 with MACE, but that two courses of gemtuzumab ozogamicin in induction or an increase of the dose of gemtuzumab ozogamicin to 6 mg/m 2 is associated with increased toxicity and not recommended. Burnett, A. K. and Kell, J., “The Feasibility of Combining Immunoconjugate and Chemotherapy in AML,” Hematology J. (June 2002) Vol. 3, supp. 1, p. 156.
- gemtuzumab ozogamicin was given to de novo and relapsed/refractory AML patients >60 years old in a combination therapy with cytarabine.
- Six patients were treated with cytarabine by continuous infusion in an amount of 100 mg/m 2 /day on days 1 to 7 and gemtuzumab ozogamicin in an amount of 6 mg/m 2 on days 1 and 15. While the combination was well tolerated, four patients died.
- gemtuzumab ozogamicin was administered on days 1 and 8 in an amount of 6 mg/m 2 on day 1 and 4 mg/m 2 on day 8. Of seven patients who were treated, three achieved complete remission.
- phase I/II study was developed in the United States of America combining gemtuzumab ozogamicin with cytarabine and daunorubicin. The phase I portion of the study began in October 2000 and a preliminary report was published at the 43 rd American Society of Hematology Annual Meeting electronically on Nov. 6, 2001 and in print on Nov. 7, 2001.
- the combination was well tolerated, no dose-limiting toxicity (DLT) was observed, and two patients achieved a remission.
- the efficacy of the combination of cytarabine 100 mg/m 2 /day, daunorubicin 45 mg/m 2 , and gemtuzumab ozogamicin 6 mg/m 2 could not be determined based on the limited number of patients enrolled in the phase I portion of the study or the efficacy of this combination compared to the efficacy of standard chemotherapy for AML.
- Myelodysplastic syndrome is a group of syndromes (preleukemia, refractory anemias, Ph-negative chronic myelocytic leukemia, chronic myelomonocytic leukemia, agnogenic myeloid metaplasia) commonly seen in patients >50 years old. Its incidence is unknown, but it is increasing, probably in part due to the increasing proportion of elderly in the population and an increase in treatment-associated leukemias. Exposure to benzene and radiation may be related to its development. In the preleukemic phase of some of the secondary leukemias (e.g., after drug or toxic exposure), altered and defective cellular production may be seen with diagnostic features of myelodysplasia. The Merck Manual , Sec. 11, Ch. 138 (17 th ed. 1999).
- MDS is characterized by clonal proliferation of hematopoietic cells, including erythroid, myeloid, and megakaryocytic forms.
- the bone marrow is normal or hypercellular, and ineffective hematopoiesis causes variable cytopenias, the most frequent being anemia.
- the disordered cell production is also associated with morphologic cellular abnormalities in marrow and blood. Extramedullary hematopoiesis may occur, leading to hepatomegaly and splenomegaly.
- Myelofibrosis is occasionally present at diagnosis or may develop during the course of MDS.
- the MDS clone is unstable and tends to progress to AML.
- the prognosis of a patient with MDS is highly dependent on FAB classification and on any associated disease. Patients with refractory anemia or refractory anemia with sideroblasts are less likely to progress to the more aggressive forms and may die of unrelated causes.
- the Merck Manual Sec. 11, Ch. 138 (17 th ed. 1999).
- cytokine therapy erythropoietin to support red blood center needs, granulocyte colony-stimulating factor to manage severe symptomatic granulocytopenia, and, when available, thrombopoietin for severe thrombocytopenia
- Allogeneic bone marrow transplantation is not recommended for patients >50 years old.
- Colony-stimulating factors e.g., granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor
- increase neutrophil counts and erythropoietin increases RBC production in 20 to 25% of cases, but survival advantage has not been shown.
- Response of MDS to AML chemotherapy is similar to that of AML, after age and karyotype are considered.
- the Merck Manual Sec. 11, Ch. 138 (17 th ed. 1999).
- a combination therapy employing an anti-CD33 cytotoxic conjugate in combination with an anthracycline and a pyrimidine or purine nucleoside analog, in particular, gemtuzumab ozogamicin, daunorubicin, and cytarabine, respectively, a significant improvement in efficacy compared to the combination therapy of daunorubicin and cytarabine or to gemtuzumab ozogamicin alone.
- the present invention provides a method of treating acute leukemia or MDS comprising administering to a patient in need of said treatment an anti-CD33 cytotoxic conjugate in combination with at least one compound selected from the group consisting of an anthracycline and a pyrimidine or purine nucleoside analog in an amount effective to ameliorate the symptoms of said acute myelogenous leukemia or said myelodysplastic syndrome.
- the acute leukemia being treated is preferably AML.
- the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin.
- the anthracycline is selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin.
- the pyrimidine or purine nucleoside analog is selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin.
- the present invention further provides a method of treatment of a patient having acute leukemia or MDS, comprising administering to the patient: (a) gemtuzumab ozogamicin in an amount of about 3 mg/m 2 to about 9 mg/m 2 per day; (b) daunorubicin, preferably daunorubicin hydrochloride, in an amount of about 45 mg/m 2 to about 60 mg/m 2 per day; and (c) cytarabine in an amount of about 100 mg/m 2 to about 200 mg/m 2 per day.
- the gemtuzumab ozogamicin is in an amount of about 6 mg/m 2 per day.
- the daunorubicin preferably daunorubicin hydrochloride, is in an amount of 45 mg/m 2 per day.
- the cytarabine is in an amount of 100 mg/m 2 per day.
- the present invention further provides a method of treating acute leukemia or MDS syndrome comprising administering to a patient in need of treatment thereof: (a) gemtuzumab ozogamicin in an amount of about 3 mg/m 2 to 9 mg/m 2 for one day; (b) daunorubicin in an amount of about 45 mg/m 2 to 60 mg/m 2 per day for three days; and (c) cytarabine in an amount of about 100 mg/m 2 to 200 mg/m 2 per day for at least seven days.
- the daunorubicin is administered on the first three days that cytarabine is administered, preferably in an amount of 45 mg/m 2 per day.
- the cytarabine is administered for ten days, more preferably for seven days, and preferably in an amount of 100 mg/m 2 per day.
- the gemtuzumab ozogamicin is administered to the patient on the fourth day that cytarabine is administered to the patient, preferably in an amount of 6 mg/m 2 .
- the cytarabine is administered by continuous infusion
- the daunorubicin preferably daunorubicin hydrochloride
- the gemtuzumab ozogamicin is administered by 2-hour infusion.
- the present invention further provides a pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or MDS comprising: (a) an anti-CD33 cytotoxic conjugate, wherein the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin; (b) an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin; and (c) a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine
- the present invention further provides a pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or MDS comprising gemtuzumab ozogamicin in an amount of about 3 mg/m 2 to about 9 mg/m 2 per day, preferably 6 mg/m 2 per day, daunorubicin, preferably daunorubicin hydrochloride, in an amount of about 45 mg/m 2 to about 60 mg/m 2 per day, preferably 45 mg/m 2 per day, and cytarabine in an amount of about 100 mg/m 2 to about 200 mg/m 2 per day, preferably 100 mg/m 2 per day.
- the present invention further provides a method of treating acute leukemia or MDS comprising:
- a) administering a first course of therapy to a patient in need of treatment comprising (i) administering an anti-CD33 cytotoxic conjugate for one day, wherein the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin; (ii) administering an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin for up to three days; and (iii) administering a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostat
- a second course of therapy comprising: (i) administering an anti-CD33 cytotoxic conjugate for one day, wherein the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin; (ii) administering an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin for up to three days; and (iii) administering a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostat
- (c) administering a third course of therapy to a patient in need of treatment comprising: (i) administering an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin for up to three days; and (ii) administering a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin for up to ten
- the present invention further provides a method of treating acute leukemia or MDS comprising:
- a) administering a first course of therapy to a patient in need of treatment comprising (i) gemtuzumab ozogamicin in an amount of about 3 mg/m 2 to about 9 mg/m 2 , preferably 6 mg/m 2 , per day for one day; (ii) daunorubicin in an amount of about 45 mg/m 2 to about 60 mg/m 2 , preferably 45 mg/m 2 , per day for up to three days; and (iii) cytarabine in an amount of about 100 mg/m 2 to about 200 mg/m 2 , preferably 100 mg/m 2 , per day for up to ten days;
- (b) administering a second course of therapy to a patient in need of treatment comprising: (i) gemtuzumab ozogamicin in an amount of about 3 mg/m 2 to about 9 mg/m 2 , preferably 6 mg/m 2 , per day for one day; (ii) daunorubicin in an amount of about 45 mg/m 2 to about 60 mg/m 2 , preferably 45 mg/m 2 , per day for up to three days; and (iii) cytarabine in an amount of about 100 mg/m 2 to about 200 mg/m 2 , preferably 100 mg/m 2 , per day for up to ten days; and
- a third course of therapy comprising: (i) daunorubicin in an amount of about 45 mg/m 2 to about 60 mg/m 2 , preferably 45 mg/m 2 , per day for up to three days; and (ii) cytarabine in an amount of about 100 mg/m 2 to about 200 mg/m 2 , preferably 100 mg/m 2 , per day for up to ten days.
- This invention provides advantageous pharmaceutical combinations and methods of treatment for acute leukemia, such as AML, and for myelodysplastic syndrome (MDS) which employ an anti-CD33 cytotoxic conjugate, an anthracycline, and a pyrimidine or purine nucleoside analog.
- the method of treatments and pharmaceutical combinations described herein provide a better rate of complete remission and improved quality of life in such patients than the standard 3+7 regimen of daunorubicin and cytarabine.
- a preferred embodiment employing gemtuzumab ozogamicin, daunorubicin, and cytarabine provides a higher rate of complete remission than the standard 3+7 regimen of daunorubicin and cytarabine.
- the patients to be treated with the methods of treatment and pharmaceutical combinations provided herein are those who have been untreated for acute leukemia such as AML and are being treated de novo, those who are being treated with induction therapy, those who are being treated with consolidation therapy, those who are being treated after one or more relapses, and those who have MDS.
- composition used in the present invention is an anti-CD33 cytotoxic conjugate in which an anti-CD33 antibody is conjugated with a cytotoxic antitumor or antibiotic, such as a calicheamicin isolated from fermentation of a bacterium, Micromonospora echinospora ssp. calichensis , or an esperamicin.
- a cytotoxic antitumor or antibiotic such as a calicheamicin isolated from fermentation of a bacterium, Micromonospora echinospora ssp. calichensis , or an esperamicin.
- Calicheamicins are described in U.S. Pat. Nos. 4,970,198; 5,037,651; and 5,079,233.
- Esperamicins are described in U.S. Pat. Nos. 4,675,187; 4,539,203; 4,554,162; and 4,837,206.
- the antibody portion of the conjugate binds specifically to the CD33 antigen, a sialic acid-dependent adhesion protein found on the surface of leukemic blasts and immature normal cells of myelomonocytic lineage, but not on normal hematopoietic stem cells, and acts as a targeting unit to deliver the cytotoxic agent to these targeted cells.
- This antibody is linked to the calicheamicin or esperamicin. When N-acetyl-gamma calicheamicin is used, it is preferred to link the antibody by a bifunctional linker.
- Such conjugates and methods for making them are described in U.S. Pat. Nos. 5,733,001; 5,739,116; 5,767,285; 5,877,296; 5,606,040; 5,712,374; and 5,714,586, which are incorporated by reference herein in their entirety.
- a preferred form of the anti-CD33 cytotoxic conjugate for use in the present invention is gemtuzumab ozogamicin, a chemotherapy agent composed of a recombinant humanized IgG4, kappa antibody conjugated with calicheamicin.
- Gemtuzumab ozogamicin is available commercially as Mylotarg® (Wyeth Pharmaceuticals, Philadelphia, Pa.). The antibody portion of gemtuzumab ozogamicin binds specifically to the CD33 antigen.
- Gemtuzumab ozogamicin contains amino acid sequences of which approximately 98.3% are of human origin.
- the constant region and framework regions contain human sequences while the complementarity-determining regions are derived from a murine antibody (p67.6) that binds CD33.
- This antibody is linked to N-acetyl-gamma calicheamicin via a bifunctional linker.
- Gemtuzumab ozogamicin has approximately 50% of the antibody loaded with 4-6 moles calicheamicin per mole of antibody. The remaining 50% of the antibody is not linked to the calicheamicin derivative.
- Gemtuzumab ozogamicin has a molecular weight of 151 to 153 kDa.
- Gemtuzumab ozogamicin and methods for making it are described in U.S. Pat. Nos. 5,733,001; 5,739,116; 5,767,285; 5,877,296; 5,606,040; 5,712,374; and 5,714,586, which are incorporated by reference herein in their entirety.
- gemtuzumab ozogamicin When given as a single agent therapy for the treatment of AML, the recommended dose of gemtuzumab ozogamicin is 9 mg/m 2 , administered as a two-hour intravenous infusion.
- the recommended treatment course with gemtuzumab ozogamicin alone has been a total of two doses with fourteen days between the doses.
- gemtuzumab ozogamicin is given in an amount ranging from about 3 mg/m 2 to 9 mg/m 2 per day.
- calicheamicin When calicheamicin is loaded onto the antibody, there is approximately 27 ⁇ g calicheamicin/mg protein.
- a 9 mg/m 2 dose of gemtuzumab ozogamicin is equivalent to 243 ⁇ g calicheamicin/m 2 protein.
- a 6 mg/m 2 dose of gemtuzumab ozogamicin is equivalent to 162 ⁇ g calicheamicin/m 2 protein.
- a 3 mg/m 2 dose of gemtuzumab ozogamicin is equivalent to 81 ⁇ g calicheamicin/m 2 protein.
- composition used in the present invention is an anthracycline, an anticancer agent consisting of 3 moieties: a pigmented aglycone, an amino sugar, and a lateral chain.
- Anthracyclines include doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin. See Merck Index (13 th ed. 2001).
- a preferred anthracycline for use in the present invention is daunorubicin.
- Daunorubicin also known as daunomycin, is an anthracycline cytotoxic antibiotic of the rhodomycin group obtained from Streptomyces peucetius , which is used in the treatment of acute leukemia. Stedman's Medical Dictionary (27 th ed. 2002). Daunorubicin has a 4-ring anthracycline moiety linked by a glycosidic bond to daunosamine, an amino sugar.
- Daunorubicin may also be isolated from Streptomyces coeruleorubidus and has the following chemical name: (8S-cis)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-(alpha)-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. Daunorubicin is usually given as the hydrochloride, but doses are expressed in terms of the base.
- daunorubicin hydrochloride the hydrochloride salt of daunorubicin.
- Daunorubicin hydrochloride is available commercially as Cerubidine® (Bedford Laboratories, Bedford Ohio). It may be described with the chemical name of (1 S,3 S)-3-Acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1-naphthacenyl 3-amino-2,3,6-trideoxy-(alpha)-L-lyxo-hexopyranoside hydrochloride.
- daunorubicin hydrochloride used as a single agent, has produced complete remission rates of 40 to 50%, and in combination with cytarabine, has produced complete remission rates of 53 to 65%. Physician's Desk Reference (56 th ed. 2002).
- daunorubicin is given daily for three days in an amount of 30 to 45 mg/m 2 by intravenous infusion for two to three days.
- daunorubicin is given daily in an amount of 50 mg/m 2 for three days.
- Daunorubicin is also available commercially in a daunorubicin citrate liposome injection as DaunoXome® (Gilead Sciences, Inc., Foster City, Calif.).
- DaunoXome® contains an aqueous solution of the citrate salt of daunorubicin encapsulated within lipid vesicles (liposomes) composed of a lipid bilayer of distearoylphosphatidylcholine and cholesterol (2:1 molar ratio), with a mean diameter of about 45 nm.
- the lipid to drug weight ratio is 18.7:1 (total lipid:daunorubicin base), equivalent to a 10:5:1 molar ratio of distearoylphosphatidylcholine:cholesterol:daunorubicin.
- Each vial of DaunoXome® contains daunorubicin citrate equivalent to 50 mg of daunorubicin base, encapsulated in liposomes consisting of 704 mg distearoylphosphatidylcholine and 168 mg cholesterol.
- the liposomes encapsulating daunorubicin are dispersed in an aqueous medium containing 2,125 mg sucrose, 94 mg glycine, and 7 mg calcium chloride dihydrate in a total volume of 25 ml/vial.
- the pH of the dispersion is between 4.9 and 6.0.
- DaunoXome® is administered intravenously over a 60 minute period at a dose of 40 mg/m 2 , with doses repeated every two weeks.
- a third composition used in the present invention is a pyrimidine nucleoside analog or a purine nucleoside analog.
- nucleoside analogs are cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin. See Merck Index (13 th ed. 2001).
- a preferred pyrimidine nucleoside analog used in the present invention is cytarabine, which is also known as arabinosylcytosine (aC, araC), arabinocytidine, or arabinofuranosylcytosine.
- cytarabine is 4-amino-1-(beta)-D-arabinofuranosyl-2(1H)-pyrimidinone, also known as cytosine arabinoside (C 9 H 13 N 3 O 5 , molecular weight 243.22). Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phase of cell division.
- cytarabine is given in an amount of 100-200 mg/m 2 daily for five to ten days by constant intravenous infusion, usually for seven days. Cytarabine can be given in an amount of 100 mg/m 2 body-surface twice daily by rapid intravenous injection. However, cytarabine can be given in amounts of up to 3 g/m 2 daily. In high-dose regimens, cytarabine is given in doses of up to 3 g/m 2 by intravenous infusion for every 12 hours for up to six days.
- Cytarabine is also available commercially in a cytarabine liposome injection as DEPOCYT® (Chiron Corporation, Emeryville, Calif.).
- DepoCyt® is a sterile, injectable suspension of the antimetabolite cytarabine, encapsulated into multivesicular lipid-based particles. Each vial contains 50 mg of cytarabine.
- Cytarabine, the active ingredient is present at a concentration of 10 mg/ml and is encapsulated in the particles.
- Inactive ingredients at their respective approximate concentrations are cholesterol, 4.1 mg/ml; triolein, 1.2 mg/ml; dioleoylphosphatidylcholine (DOPC), 5.7 mg/ml; and dipalmitoylphosphatidylglycerol (DPPG), 1.0 mg/ml.
- the pH of the product falls within the range from 5.5 to 8.5.
- DepoCyt® is administered intrathecally.
- the present invention provides several methods for treating acute leukemia or MDS.
- a patient is given an anti-CD33 cytotoxic conjugate in combination with at least one compound selected from the group consisting of an anthracycline and a pyrimidine or purine nucleoside analog in an amount effective to ameliorate the symptoms of the acute leukemia, such as AML, or MDS.
- the cytotoxin in the anti-CD33 cytotoxic conjugate is a calicheamicin or an esperamicin.
- the anthracycline is preferably selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin.
- the pyrimidine or purine nucleoside analog is preferably selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercid.
- the cytotoxin in the anti-CD33 conjugate is a calicheamicin
- the anthracycline is daunorubicin or daunorubicin hydrochloride
- the pyrimidine nucleoside analog is cytarabine.
- a patient having acute leukemia or MDS is given gemtuzumab ozogamicin in an amount of about 3 mg/m 2 to about 9 mg/m 2 per day; daunorubicin, preferably daunorubicin hydrochloride, in an amount of about 45 mg/m 2 to about 60 mg/m 2 per day; and cytarabine in an amount of about 100 mg/m 2 to about 200 mg/m 2 per day.
- the gemtuzumab ozogamicin is given in an amount of about 6 mg/m 2 per day.
- the daunorubicin, preferably daunorubicin hydrochloride is preferably given in an amount of 45 mg/m 2 per day.
- the cytarabine is preferably given in an amount of 100 mg/m 2 per day.
- a patient having acute leukemia or MDS is given gemtuzumab ozogamicin in an amount of about 3 mg/m 2 to 9 mg/m 2 for one day; daunorubicin in an amount of about 45 mg/m 2 to 60 mg/m 2 per day for three days; and cytarabine in an amount of about 100 mg/m 2 to 200 mg/m 2 per day for at least seven days.
- the daunorubicin is administered on the first three days that cytarabine is administered, and is preferably given in an amount of 45 mg/m 2 per day.
- the cytarabine is preferably administered for ten days, more preferably for seven days, and is preferably given in an amount of 100 mg/m 2 per day.
- the gemtuzumab ozogamicin is preferably administered to the patient on the fourth day that cytarabine is administered to the patient, and is preferably given in an amount of 6 mg/m 2 .
- the cytarabine is administered by continuous infusion
- the daunorubicin, preferably daunorubicin hydrochloride is administered by intravenous bolus
- the gemtuzumab ozogamicin is administered by 2-hour infusion.
- compositions for enhanced induction of remission in a patient having acute leukemia or MDS are also provided by the present invention.
- One such pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or MDS comprises an anti-CD33 cytotoxic conjugate, an anthracycline, and a pyrimidine or purine nucleoside analog.
- the cytotoxin in the anti-CD33 cytotoxic conjugate may be selected from the group consisting of a calicheamicin and an esperamicin.
- the anthracycline may be selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin.
- the pyrimidine or purine nucleoside analog may be selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin.
- Another pharmaceutical combination comprises gemtuzumab ozogamicin in an amount of about 3 mg/m 2 to about 9 mg/m 2 per day, preferably 6 mg/m 2 per day, daunorubicin, preferably daunorubicin hydrochloride, in an amount of about 45 mg/m 2 to about 60 mg/m 2 per day, preferably 45 mg/m 2 per day, and cytarabine in an amount of about 100 mg/m 2 to about 200 mg/m 2 per day, preferably 100 mg/m 2 per day.
- a single course of combination therapy comprises administering to the patient a therapeutically effective amount of an anti-CD33 cytotoxic conjugate, together with one or more chemotherapeutic agents, such as anthracycline, and a pyrimidine or purine nucleoside analog.
- chemotherapeutic agents such as anthracycline, and a pyrimidine or purine nucleoside analog.
- the present invention also provides treatment regimens in which multiple courses of combination therapy, which include an anti-CD33 cytotoxic conjugate and other chemotherapeutic agents, are administered. Such treatment regimens may be administered from at least two to five courses of treatment, depending upon the drugs being administered, the severity of the disease, and the condition of the patient.
- a patient having acute leukemia or MDS is given three courses of therapy.
- the patient is given an anti-CD33 cytotoxic conjugate for one day; an anthracycline for up to three days; and a pyrimidine or purine nucleoside analog for up to ten days.
- the cytotoxin in the anti-CD33 cytotoxic conjugate may be selected from the group consisting of a calicheamicin and an esperamicin.
- the anthracycline may be selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin.
- the pyrimidine or purine nucleoside analog may be selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin.
- the first course of therapy is repeated as a second course of therapy in which the patient is given an anti-CD33 cytotoxic conjugate for one day, an anthracycline for up to three days, and a pyrimidine or purine nucleoside analog for up to ten days.
- a third course of therapy may be given to the patient which comprises the administration to the patient of an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin for up to three days, and a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin for up to ten days.
- an anthracycline selected from the
- a patient is given a first course of therapy comprising gemtuzumab ozogamicin in an amount of about 3 mg/m 2 to about 9 mg/m 2 , preferably 6 mg/m 2 , per day for one day; daunorubicin in an amount of about 45 mg/m 2 to about 60 mg/m 2 , preferably 45 mg/m 2 , per day for up to three days; and cytarabine in an amount of about 100 mg/m 2 to about 200 mg/m 2 , preferably 100 mg/m 2 , per day for up to ten days.
- a second course of therapy is given to the patient comprising gemtuzumab ozogamicin in an amount of about 3 mg/m 2 to about 9 mg/m 2 , preferably 6 mg/m 2 , per day for one day; daunorubicin in an amount of about 45 mg/m 2 to about 60 mg/m 2 , preferably 45 mg/m 2 , per day for up to three days; and cytarabine in an amount of about 100 mg/m 2 to about 200 mg/m 2 , preferably 100 mg/m 2 , per day for up to ten days.
- a third course of therapy may be administered to the patient comprising daunorubicin in an amount of about 45 mg/m 2 to about 60 mg/m 2 , preferably 45 mg/m 2 , per day for up to three days, and cytarabine in an amount of about 100 mg/m 2 to about 200 mg/m 2 , preferably 100 mg/m 2 , per day for up to ten days.
- the surprising and unexpected result disclosed herein is the ability of the anti-CD33 cytotoxic conjugate, the anthracycline, and the pyrimidine or purine nucleoside analog to act synergistically in the treatment of various symptoms associated with acute leukemia or MDS.
- Synergistically is used herein to refer to a situation where the benefit conveyed by the administration of these antineoplastic compositions in combination is greater than the algebraic sum of the effects resulting from the separate administration of the components of the combination.
- the combination treatment of an anti-CD33 cytotoxic conjugate, an anthracycline, and an pyrimidine or purine nucleoside analog is synergistic with respect to treating acute leukemia and increasing the efficacy as measured by complete remission.
- This combined treatment has the advantage of achieving the same result with a lower dose of the anti-CD33 cytotoxic conjugate, thereby reducing any toxic effect from the conjugate, providing an improved quality of life, and increasing the chances for survival of the patient.
- the individual patient will be monitored in a manner deemed appropriate by the treating physician.
- the combination therapy agents described herein may be administered with immunosuppressive agents, potentiators and side-effect relieving agents as deemed necessary by the treating physician.
- the dosages of the agents used in accordance with the invention may vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in complete remission as previously defined.
- An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. It is especially advantageous to formulate compositions of these antineoplastic compounds in dosage unit form for ease of administration and uniformity of dosage.
- Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated, each unit containing a predetermined quantity of anti-neoplastic compounds calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like which are compatible with the active ingredient and with the mode of administration and other ingredients of the formulation and not deleterious to the recipient.
- compositions of this invention which are found in the combination may also include, depending on the formulation desired, pharmaceutically-acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration.
- the diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological saline, Ringer's solution, dextrose solution, and Hank's solution.
- the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like. Effective amounts of such diluent or carrier will be those amounts which are effective to obtain a pharmaceutically acceptable formulation in terms of solubility of components, or biological activity, and the like.
- each antineoplastic compound may be incorporated with a sterile injectable solution.
- the sterile injectable solution may be prepared by incorporating the antineoplastic compound in the required amount in an appropriate pharmaceutically acceptable carrier, with various other ingredients, followed by filtered sterilization.
- each may be prepared by incorporating the additional antineoplastic compound into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated herein.
- each may be prepared by incorporating a powder of the additional antineoplastic compound and, optionally, any additional desired ingredient from a previously sterile-filtered solution thereof, wherein the powder is prepared by any suitable technique (e.g., vacuum drying and freeze drying).
- any suitable technique e.g., vacuum drying and freeze drying.
- Supplementary active ingredients can also be incorporated into the compositions.
- the specific dose of the antineoplastic compound is calculated according to the approximate body weight or surface area of the patient.
- determining the appropriate dosage can include the stage of the acute myelogenous leukemia or myelodysplastic syndrome (de novo or relapse), the severity of the disease, the route of administration and the age, sex and medical condition of the patient. Further refinement of the calculations necessary to determine the appropriate dosage for treatment involving each of the herein-mentioned formulations is routinely made by those skilled in the art. Dosages can also be determined through the use of known assays for determining dosages used in conjunction with appropriate dose-response data. Thus, for example, it is within the scope of the invention that doses of the antineoplastic compounds used in the present invention for treating acute myelogenous leukemia or myelodysplastic syndrome can be varied to achieve a desired therapeutic effect.
- the antineoplastic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixers, suspensions, syrups, wafers and the like, or it may be incorporated directly with the food in the diet.
- the tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; or a flavoring agent such as peppermint, oil of wintergreen or cherry or orange flavoring.
- a binder such as gum tragacanth, acacia, corn starch or gelatin
- excipients such as dicalcium phosphate
- a disintegrating agent such as corn starch, alginic acid and the like
- a lubricant such as magnesium stearate
- a sweetening agent such as sucrose, lactose or saccharin
- a flavoring agent such as peppermint, oil of wintergreen or cherry or orange flavoring
- tablets, pills or capsules may be coated with shellac, sugar or both.
- any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
- the antineoplastic compound may be incorporated into a sustained-release preparation and formulation. The amount of the antineoplastic compound in such therapeutically useful composition is such that a suitable dosage will be obtained.
- phase 1 ⁇ 2 study was developed in the United States of America to combine gemtuzumab ozogamicin with cytarabine and daunorubicin.
- Patients with relapsed, refractory, or de novo AML were enrolled in phase 1 from October 2000 through November 2001.
- the maximum tolerated dose was determined to be cytarabine 100 mg/m 2 /day by continuous infusion on days 1 through 7, daunorubicin 45 mg/m 2 by intravenous bolus on days 1 through 3, and gemtuzumab ozogamicin 6 mg/m 2 by 2-hour infusion on day 4.
- the phase 2 portion of the study was open to enrollment on November 2001 and 42 of the planned 45 patients have been enrolled to date.
- the median time to recover ANC to ⁇ 1500/ ⁇ L was 38 days and platelets to ⁇ 100,000/ ⁇ L was 30 days. Patients have been followed for too short a time to determine duration of remission (median follow-up 193 days).
- the feasibility of combining gemtuzumab ozogamicin with intensive chemotherapy for induction and/or consolidation was evaluated in 67 patients in a safety study in the United Kingdom prior to the start of the Medical Research Center AML15 trial.
- the aim was to combine gemtuzumab ozogamicin with chemotherapy planned in the trial, (DAT; Daunorubicin, AraC, Thioguanine, or DA; Daunorubicin AraC; or FLAG-IDA; Fludarabine, AraC, G-CSF, Idarubicin) as course 1.
- Course 1 was given using gemtuzumab ozogamicin in an amount of 3 mg/m 2 on day 1 of chemotherapy in 55 patients.
- the median time to ANC recovery (1 ⁇ 10 9 /l) was 27 days (range 9-54) and platelets >100 ⁇ 10 9 /l was 30 (range 21-48) which is within the mean+ISD of the 720 patients treated with H-DAT alone in the MRC AML12 trial.
- Non-hemopoietic toxicity was confined to the liver.
- a possible contributory factor was the inclusion of Thioguanine.
- 22 developed Grade 3 or 4 liver toxicity compared with 1 for 16 recipients of non-Thioguanine schedules.
- the overall survival of all patients receiving gemtuzumab ozogamicin in a dose of 3 mg/m 2 with course 1 at 6 months is 73% and at 12 months is 68%.
- the 6 month survival is 91%.
Abstract
Methods of treatment and pharmaceutical combinations are provided for the treatment of acute leukemia, such as acute myelogenous leukemia, and myelodysplastic syndrome. The methods of treatment and pharmaceutical combinations employ an anti-CD33 cytotoxic conjugate in combination with at least one compound selected from the group consisting of an anthracycline and a pyrimidine or purine nucleoside analog. Preferred methods of treatment and pharmaceutical combinations employ gemtuzumab ozogamicin, daunorubicin, and cytarabine.
Description
This application is a continuation of U.S. application Ser. No. 10/700,650 filed on Nov. 4, 2003, now abandoned which claims the benefit under 35 U.S.C. §119(e) of U.S. provisional application No. 60/424,156 filed on Nov. 6, 2002, the entire disclosures of which are hereby incorporated by reference.
Methods of treatment and pharmaceutical combinations are provided for the treatment of acute leukemia, in particular, acute myelogenous leukemia and myelodysplastic syndrome. The methods of treatment and pharmaceutical combinations employ an anti-CD33 cytotoxic conjugate in combination with at least one compound selected from the group consisting of an anthracycline and a pyrimidine or purine nucleoside analog, in particular, gemtuzumab ozogamicin, daunorubicin, and cytarabine.
Acute leukemia is typically a rapidly progressing leukemia characterized by replacement of normal bone marrow by blast cells of a clone arising from malignant transformation of a hematopoietic stem cell. There are two types of acute leukemias, acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). ALL is the most common malignancy in children, but also occurs in adolescents and has a second, lower peak in adults. AML, also know as acute myeloid leukemia and acute myelocytic leukemia, is the more common acute leukemia in adults and its incidence increases with age, but AML also occurs in children. For both types of acute leukemias, the primary goal of treatment is to achieve complete remission, with resolution of abnormal clinical features, return to normal blood counts and normal hematopoiesis in the bone marrow with <5% blast cells, a neutrophil count of >1,000-1,500, a platelet count of >100,000, and disappearance of the leukemic clone; however, the drug regimens for treating ALL and AML have differed. The Merck Manual, Sec. 11, Ch. 138 (17th ed. 1999); Estey, E., Cancer (2001) 92(5): 1059-1073. Initial therapy aims at inducing remission. Treatment of AML differs most from ALL in that patients with AML respond to fewer drugs and have a high rate of relapse.
Patients with AML who achieve a complete remission live longer than patients who do not, and only patients who achieve complete remission are potentially cured if their complete remission remains for at least three years. Estey, E., Cancer (2001) 92(5): 1059, 1060. Remission induction rates in patients with AML range from 50 to 85%, with patients older than 50 years, and especially those older than 65 years, less likely to achieve remission. Long-term disease-free survival occurs in a low percentage of patients, 20-40%, and increases to 40-50% in younger patients treated with bone marrow transplants. Patients with secondary AML have a poor prognosis. The Merck Manual, Sec. 11, Ch. 138 (17th ed. 1999).
Treatment of AML is problematic because normal stem-cell precursors are sensitive to the agents used, and therapy aimed at myeloid leukemic clones results in destruction of part of the normal stem-cell pool. Induction of remission is usually possible with intensive chemotherapy. Complete remission has been stated to be achievable in up to 80% of younger patients and about 50% of older patients (who form the majority of those with AML), but patients suffer severe neutropenia during induction and remission rate is to some extent dependent upon the standard of supportive care. Remission rates are lower in those with adverse prognostic factors such as poor performance status, AML secondary to myelodysplasia or antineoplastics, high white cell count, features of multidrug resistance, and unfavorable cytogenetics. Löwenberg, B., et al., N. Engl. J. Med. (1999) 341:1051-62; Correction. ibid.; 1484. The greatest unmet medical need is in AML patients over 70 years of age. For these elderly AML patients, complete remission may be difficult to obtain, but an increased benefit in their quality of life is a treatment goal to be achieved.
Established regimens are based on cytarabine, a pyrimidine nucleoside analog, with the anthracycline daunorubicin. Löwenberg, B., et al., N. Engl. J. Med. (1999) 341:1051-62; Correction. ibid.; 1484; Burnett, A. K. & Eden O. B., Lancet (1997) 349:270-275; Hiddemann, W., et al., J. Clin. Oncol. (1999) 17:3569-76. The first successful regimens also included thioguanine, which is still used by some medical centers, although the majority opinion is that it gives no additional advantage and thioguanine has been dropped from most induction protocols. Alternatives to daunorubicin include idarubicin and mitoxantrone. Löwenberg, B., et al., N. Engl. J. Med. (1999) 341:1051-62; Correction. ibid.; 1484. Etoposide has been added to induction protocols of cytarabine and daunorubicin with improved results in younger patients.
The basic induction regimen for treatment of AML includes administration of cytarabine by continuous intravenous (IV) infusion for 7 days, with an anthracycline such as daunorubicin or idarubicin given IV for 3 days during this time, usually in the first three days. The Merck Manual, Sec. 11, Ch. 138 (17th ed. 1999). This widely used regimen for the treatment of AML is known as a 3+7 regimen and produces complete remission rates of 60-80%. De Nully Brown, P., et al., Leukemia (1997) 11:37-41. Treatment usually results in significant myelosuppression, often for long periods before marrow recovery. Other adverse events from these two drugs include chemical arachnoiditis, myocardial toxicity, and neurotoxicity. The induction regimen may be repeated, usually up to a total of three times, to achieve remission. Before repeating the induction regimen, a bone marrow analysis is done on after fourteen days from the completion of the last induction regimen. If the bone marrow has been cleaned out, i.e., there is a complete response, then the physician will wait until the patient's peripheral blood counts recover before administering another induction regimen. If the bone marrow analysis shows that disease is still present, i.e., there is a partial or minimal response, then the induction regimen will be repeated without waiting for the patient's peripheral blood counts to recover. The waiting period between induction regimens is therefore twenty-eight to thirty-five days for a complete responder, and fourteen to twenty-one days for partial and minimal responders. For patients with relapsed AML, the standard induction therapy of cytarabine and daunorubicin does not produce a good response rate, typically <40%, and the prognosis is poor for these patients.
After remission is achieved, a second treatment regimen using the same drugs or other drugs to knock out the disease, known as consolidation therapy, may be employed. However, a high percentage of patients suffer from relapse, even in series with intensive post-remission consolidation chemotherapy. De Nully Brown, P., et al., Leukemia (1997) 11:37-41.
The current trend is towards the use of more intensive induction regimens. Use of high-dose cytarabine in doses of up to 3 g/m2 every twelve hours for up to six days per day (with daunorubicin and etoposide) has been reported to improve the duration of first remission and disease-free survival compared with standard doses of cytarabine. Bishop, J. F., et al., Blood (1996) 87:1710-1717. Equally the timing of induction cycles may be important: intensive timing (where the second cycle was given 10 days after the first) has improved disease-free survival, despite more toxicity-related deaths, compared with the standard interval of 14 days or more. Woods, W. G., et al., Blood (1996) 87:4979-4989.
Once remission is induced, further treatment (post remission therapy) is essential in preventing relapse. Löwenberg, B., et al., N. Engl. J. Med. (1999) 341:1051-62; Correction. ibid.; 1484; Burnett, A. K. & Eden O. B., Lancet (1997) 349:270-275; Hiddemann, W., et al., J. Clin. Oncol. (1999) 17:3569-76. Options include further chemotherapy, or allogeneic or autologous bone marrow transplantation. Long-term survival of about 50% may be possible with these options when used in patients in first remission. However, which option to use is controversial. The most successful chemotherapy regimens use high-dose cytarabine for up to 4 courses, and appear to be comparable to bone marrow transplantation in terms of survival. Mayer, R. J. et al., N. Engl. J. Med. (1994) 331:896-903; Cassileth, P. A., et al., N. Engl. J. Med. (1998) 339:1649-1656. Consequently, some advocate a policy of intensive post remission chemotherapy, reserving transplantation for subsequent relapse, particularly for patients with favorable cytogenetics. Edenfield, W. J. & Gore, S. D., Semin. Oncol. (1999) 26:21-34.
Another drug used in the treatment of AML is gemtuzumab ozogamicin (Mylotarg®). Gemtuzumab ozogamicin was approved in May 2000 in the United States of America for the treatment of AML in patients in first relapse who are 60 years old or older and not considered candidates for other cytotoxic chemotherapy. Gemtuzumab ozogamicin is administered as a two-hour IV infusion in a dose of 9 mg/m2. A second dose may be administered fourteen days later. While many patients receiving gemtuzumab ozogamicin have achieved complete remission, a significant number of patients have had a delay in platelet recovery or incomplete platelet recovery. Physician's Desk Reference (56th ed. 2002). Hepatic venoocclusive disease (VOD), which is potentially fatal, has occurred in patients who have undergone stem cell transplantation after gemtuzumab ozogamicin therapy. Tack, D. K. et al., Bone Marrow Transplantation (2001) 28(9):895-897. It was also reported in July 2001 that patients receiving gemtuzumab ozogamicin who did not undergo stem cell transplantation developed as much as a 10% increased risk of developing significant hepatotoxicity and possible morbidity and mortality, although most of these patients received gemtuzumab ozogamicin in previously untested combinations or outside the approved labeled use. Giles, F. J., et al., Cancer (2001) 92(2):406-413. Like the standard cytarabine-daunorubicin induction therapy, the response rate of patients with relapsed AML to gemtuzumab ozogamicin therapy can be <40%.
Combination therapies with gemtuzumab ozogamicin have been tried with limited success. In one study, gemtuzumab ozogamicin was administered to elderly patients previously untreated for AML by 2-hour IV infusion at a dose of 9 mg/m2 on day 1 and 15, with MICE (mitoxantrone, cytarabine and etoposide) being given for one or two courses within seven days from the response assessment to gemtuzumab ozogamicin (between day 28 and 35 following the last infusion). Significant non-hematologic adverse events included, among others, VOD (6%), arrhythmia (6%), and infection (24%). At the end of the whole induction program, thirteen patients were in complete remission (38.2%) and 3 achieved a complete remission with incomplete platelet recovery (8.8%) for an overall response rate of 47%, not an improvement over existing therapies for AML. Amadori, S., et al., “Sequential Administration of Gemtuzumab Ozogamicin (GO) and Intensive Chemotherapy for Remission Induction in Previously Untreated Patients with AML over the Age of 60: Interim Results of the EORTC Leukemia Group AML-15A Phase II Trial,” Blood (2001) 98:587a.
In another study, patients with poor prognosis AML (>70 years age, myelodysplasia, leukemia developing after toxic exposure) were either treated under a protocol designated “AML 9503” in which the patient received two “pulses” of chemotherapy each consisting of 2 gm/m2 of cytarabine (a high dose of cytarabine) administered at time=0 and time=12 hours and mitoxantrone in an amount of 35 mg/m2 immediately after the second cytarabine dose, with the second “pulse” being given 96 hours later, or were treated under a protocol designated “AML 9798” in which the patient received two “pulses” of chemotherapy each consisting of 2 gm/m2 of cytarabine administered at time=0 and time=12 hours and mitoxantrone in an amount of 35 mg/m2 immediately after the second cytarabine dose, with the second “pulse” being given 96 hours later, followed by administration of amifostine. The complete remission rate for AML 9503 was 30% and for AML 9798 was 40%. When the chemotherapy was changed to add a single dose of gemtuzumab ozogamicin in an amount of 9 mg/m2 three days prior to the first pulse of chemotherapy, two of four such treated patients with refractory AML entered complete remission. Preisler, H, D., et al., “Synergistic Antileukemia Effects of Mylotarg and Chemotherapy in AML,” Blood (2001) 98:193b.
In a feasibility study, patients <60 years of age received H-DAT 3+10 regimen (daunorubicin 45 mg/m2 days 1, 3, 5; cytarabine 400 mg/m2 bd days 1-10; thioguanine 100 mg/m2 bd days 1-10) with gemtuzumab ozogamicin (3 or 6 mg/m2 given as a 2-hour infusion on day 1). The second course given was H-DAT 3+8 with the same gemtuzumab ozogamicin dose as in course 1. While both the 3 mg/m2 and 6 mg/m2 doses of gemtuzumab ozogamicin were tolerated in these two regimens, increased liver toxicity was seen when gemtuzumab ozogamicin was given at 6 mg/m2 in the first course and it was decided to thereafter use 3 mg/m2 of gemtuzumab ozogamicin in courses 1 and 2. Kell, J. W., et al., “Effects of Mylotarg™ (Gemtuzumab Ozogamicin, GO) in Combination with Standard Induction Chemotherapy in the Treatment of Acute Myeloid Leukaemia (AML): A Feasibility Study,” Blood (2001) 98:123a-124a.
In a further study, patients <60 years of age were given H-DAT 3+10 (daunorubicin 50 mg/m2 daily by slow IV push on days 1, 3, 5; cytarabine 200 mg/m2 IV push bd days 1-10; thioguanine 100 mg/m2 bd oral days 1-10) or S-DAT 3+10 (daunorubicin 50 mg/m2 daily by slow IV push on days 1, 3, 5; cytarabine 100 mg/m2 IV push bd days 1-10; thioguanine 100 mg/m2 bd oral days 1-10) with 3 or 6 mg/m2 gemtuzumab ozogamicin as induction therapy. A second course of H-DAT 3+8 (daunorubicin 50 mg/m2 daily by slow IV push on days 1, 3, 5; cytarabine 200 mg/m2 IV push bd days 1-8; thioguanine 100 mg/m2 bd oral days 1-10) or S-DAT 3+8 (daunorubicin 50 mg/m2 daily by slow IV push on days 1, 3, 5; cytarabine 100 mg/m2 IV push bd days 1-8; thioguanine 100 mg/m2 bd oral days 1-10) was given with or without gemtuzumab ozogamicin in an amount of 3 mg/m2. Consolidation therapy consisted of MACE (MACE: Amsacarine 100 mg/m2 daily by one hour infusion (in 5% dextrose on days 1-5); cytarabine 200 mg/m2 by daily continuous IV infusion days 1-5, Etoposide 100 mg/m2 daily by one hour IV infusion days 1-5) chemotherapy with or without gemtuzumab ozogamicin in an amount of 3 mg/m2. Patients who received gemtuzumab ozogamicin in courses 1 and 2 had delayed hematological recovery and VOD, one of whom died. The 6 mg/m2 dose of gemtuzumab ozogamicin was also associated with increased liver toxicity. It was concluded that 3 mg/m2 gemtuzumab ozogamicin can be given with H-DAT 3+10 in course 1 and in course 3 with MACE, but that two courses of gemtuzumab ozogamicin in induction or an increase of the dose of gemtuzumab ozogamicin to 6 mg/m2 is associated with increased toxicity and not recommended. Burnett, A. K. and Kell, J., “The Feasibility of Combining Immunoconjugate and Chemotherapy in AML,” Hematology J. (June 2002) Vol. 3, supp. 1, p. 156.
In another preliminary study to assess safety and efficacy, gemtuzumab ozogamicin was given to de novo and relapsed/refractory AML patients >60 years old in a combination therapy with cytarabine. Six patients were treated with cytarabine by continuous infusion in an amount of 100 mg/m2/day on days 1 to 7 and gemtuzumab ozogamicin in an amount of 6 mg/m2 on days 1 and 15. While the combination was well tolerated, four patients died. To reduce the duration of myelosuppression following induction therapy, gemtuzumab ozogamicin was administered on days 1 and 8 in an amount of 6 mg/m2 on day 1 and 4 mg/m2 on day 8. Of seven patients who were treated, three achieved complete remission. Durrant, S., et al., Proc. Amer. Soc. Clin. Oncol. (2002) 21:271a.
To assess the safety and efficacy of gemtuzumab ozogamicin as part of combination therapy for AML, a phase I/II study was developed in the United States of America combining gemtuzumab ozogamicin with cytarabine and daunorubicin. The phase I portion of the study began in October 2000 and a preliminary report was published at the 43rd American Society of Hematology Annual Meeting electronically on Nov. 6, 2001 and in print on Nov. 7, 2001. DeAngelo, D., et al., “Preliminary Report of the Safety and Efficacy of Gemtuzumab Ozogamicin (Mylotarg®) Given in Combination with Cytarabine and Daunorubicin in Patients with Acute Myeloid Leukemia”, Blood (2001) 98:199(b). That report described the treatment of three patients, one with de novo AML and two with relapsed/refractory AML, with cytarabine in an amount of 100 mg/m2/day by continuous infusion on days 1 to 7, daunorubicin in an amount of 45 mg/m2 on days 1 to 3, and gemtuzumab ozogamicin in an amount of 6 mg/m2 on day 4 (dosage group 1). The combination was well tolerated, no dose-limiting toxicity (DLT) was observed, and two patients achieved a remission. Three patients with relapsed/refractory AML then were enrolled in the next dosage group in which the dose of gemtuzumab ozogamicin was escalated to 9 mg/m2 (dosage group 2), with the combination well tolerated, but all three patients were nonresponders. Six additional patients, three with de novo AML and three with relapsed/refractory AML, were enrolled at the dosage level of 9 mg/m2. Therapy was again well tolerated, and no DLT was observed. There were, however, 2 episodes of grade 3 non-drug-related elevations of ALT/AST and 2 episodes of grade 4 non-drug-related dyspnea. All 3 patients with de novo AML achieved remission and recovered both an ANC >1500/L and platelets >100,000/L on days 26, 28, and 36, respectively. Patients then were enrolled in the next dosage group in which the cytarabine dose was increased to 200 mg/m2/day (dosage group 3). Infusion of the combination therapy was well tolerated, but DLT was observed in four of six patients enrolled in this group with one patient with refractory AML developing hepatic VOD soon after completing induction therapy and dying on day 28. Another patient with de novo AML died of cardiac arrest on day 24 and also had reversible grade 3 elevation of ALT. In light of the foregoing results, it was concluded that six additional patients would be enrolled in dosage group 1 to expand the safety data, and if the combination of cytarabine 100 mg/m2/day, daunorubicin 45 mg/m2, and gemtuzumab ozogamicin 6 mg/m2 would be found to be well tolerated in this expanded group, then the phase II portion of the study would begin and approximately 45 patients with de novo AML would be enrolled. DeAngelo, D., et al., supra. The efficacy of the combination of cytarabine 100 mg/m2/day, daunorubicin 45 mg/m2, and gemtuzumab ozogamicin 6 mg/m2 could not be determined based on the limited number of patients enrolled in the phase I portion of the study or the efficacy of this combination compared to the efficacy of standard chemotherapy for AML.
Myelodysplastic syndrome (MDS) is a group of syndromes (preleukemia, refractory anemias, Ph-negative chronic myelocytic leukemia, chronic myelomonocytic leukemia, agnogenic myeloid metaplasia) commonly seen in patients >50 years old. Its incidence is unknown, but it is increasing, probably in part due to the increasing proportion of elderly in the population and an increase in treatment-associated leukemias. Exposure to benzene and radiation may be related to its development. In the preleukemic phase of some of the secondary leukemias (e.g., after drug or toxic exposure), altered and defective cellular production may be seen with diagnostic features of myelodysplasia. The Merck Manual, Sec. 11, Ch. 138 (17th ed. 1999).
MDS is characterized by clonal proliferation of hematopoietic cells, including erythroid, myeloid, and megakaryocytic forms. The bone marrow is normal or hypercellular, and ineffective hematopoiesis causes variable cytopenias, the most frequent being anemia. The disordered cell production is also associated with morphologic cellular abnormalities in marrow and blood. Extramedullary hematopoiesis may occur, leading to hepatomegaly and splenomegaly. Myelofibrosis is occasionally present at diagnosis or may develop during the course of MDS. The MDS clone is unstable and tends to progress to AML. The prognosis of a patient with MDS is highly dependent on FAB classification and on any associated disease. Patients with refractory anemia or refractory anemia with sideroblasts are less likely to progress to the more aggressive forms and may die of unrelated causes. The Merck Manual, Sec. 11, Ch. 138 (17th ed. 1999).
There is no established treatment for MDS. Therapy is supportive with RBC transfusions, platelet transfusions for bleeding, and antibiotic therapy for infection. In some patients, cytokine therapy (erythropoietin to support red blood center needs, granulocyte colony-stimulating factor to manage severe symptomatic granulocytopenia, and, when available, thrombopoietin for severe thrombocytopenia) can serve as important hematopoietic support. Allogeneic bone marrow transplantation is not recommended for patients >50 years old. Colony-stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor) increase neutrophil counts, and erythropoietin increases RBC production in 20 to 25% of cases, but survival advantage has not been shown. Response of MDS to AML chemotherapy is similar to that of AML, after age and karyotype are considered. The Merck Manual, Sec. 11, Ch. 138 (17th ed. 1999).
Thus, there is a need for an improved treatment for patients with acute leukemia or myelodysplastic syndrome which will produce a higher rate of complete remission, thereby increasing the survival prospects of such patients. It has been surprisingly been found that a combination therapy employing an anti-CD33 cytotoxic conjugate in combination with an anthracycline and a pyrimidine or purine nucleoside analog, in particular, gemtuzumab ozogamicin, daunorubicin, and cytarabine, respectively, a significant improvement in efficacy compared to the combination therapy of daunorubicin and cytarabine or to gemtuzumab ozogamicin alone.
The present invention provides a method of treating acute leukemia or MDS comprising administering to a patient in need of said treatment an anti-CD33 cytotoxic conjugate in combination with at least one compound selected from the group consisting of an anthracycline and a pyrimidine or purine nucleoside analog in an amount effective to ameliorate the symptoms of said acute myelogenous leukemia or said myelodysplastic syndrome. The acute leukemia being treated is preferably AML.
In a preferred embodiment, the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin.
In another preferred embodiment, the anthracycline is selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin.
In another preferred embodiment, the pyrimidine or purine nucleoside analog is selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin.
The present invention further provides a method of treatment of a patient having acute leukemia or MDS, comprising administering to the patient: (a) gemtuzumab ozogamicin in an amount of about 3 mg/m2 to about 9 mg/m2 per day; (b) daunorubicin, preferably daunorubicin hydrochloride, in an amount of about 45 mg/m2 to about 60 mg/m2 per day; and (c) cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2 per day.
In a preferred embodiment, the gemtuzumab ozogamicin is in an amount of about 6 mg/m2 per day.
In another preferred embodiment, the daunorubicin, preferably daunorubicin hydrochloride, is in an amount of 45 mg/m2 per day.
In another preferred embodiment, the cytarabine is in an amount of 100 mg/m2 per day.
The present invention further provides a method of treating acute leukemia or MDS syndrome comprising administering to a patient in need of treatment thereof: (a) gemtuzumab ozogamicin in an amount of about 3 mg/m2 to 9 mg/m2 for one day; (b) daunorubicin in an amount of about 45 mg/m2 to 60 mg/m2 per day for three days; and (c) cytarabine in an amount of about 100 mg/m2 to 200 mg/m2 per day for at least seven days.
In a preferred embodiment, the daunorubicin is administered on the first three days that cytarabine is administered, preferably in an amount of 45 mg/m2 per day.
In another preferred embodiment, the cytarabine is administered for ten days, more preferably for seven days, and preferably in an amount of 100 mg/m2 per day.
In another preferred embodiment, the gemtuzumab ozogamicin is administered to the patient on the fourth day that cytarabine is administered to the patient, preferably in an amount of 6 mg/m2.
In another preferred embodiment, the cytarabine is administered by continuous infusion, the daunorubicin, preferably daunorubicin hydrochloride, is administered by intravenous bolus, and the gemtuzumab ozogamicin is administered by 2-hour infusion.
The present invention further provides a pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or MDS comprising: (a) an anti-CD33 cytotoxic conjugate, wherein the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin; (b) an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin; and (c) a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin.
The present invention further provides a pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or MDS comprising gemtuzumab ozogamicin in an amount of about 3 mg/m2 to about 9 mg/m2 per day, preferably 6 mg/m2 per day, daunorubicin, preferably daunorubicin hydrochloride, in an amount of about 45 mg/m2 to about 60 mg/m2 per day, preferably 45 mg/m2 per day, and cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2 per day, preferably 100 mg/m2 per day.
The present invention further provides a method of treating acute leukemia or MDS comprising:
(a) administering a first course of therapy to a patient in need of treatment comprising (i) administering an anti-CD33 cytotoxic conjugate for one day, wherein the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin; (ii) administering an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin for up to three days; and (iii) administering a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin for up to ten days;
(b) administering a second course of therapy to a patient in need of treatment comprising: (i) administering an anti-CD33 cytotoxic conjugate for one day, wherein the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin; (ii) administering an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin for up to three days; and (iii) administering a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin for up to ten days; and
(c) administering a third course of therapy to a patient in need of treatment comprising: (i) administering an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin for up to three days; and (ii) administering a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin for up to ten days.
The present invention further provides a method of treating acute leukemia or MDS comprising:
(a) administering a first course of therapy to a patient in need of treatment comprising (i) gemtuzumab ozogamicin in an amount of about 3 mg/m2 to about 9 mg/m2, preferably 6 mg/m2, per day for one day; (ii) daunorubicin in an amount of about 45 mg/m2 to about 60 mg/m2, preferably 45 mg/m2, per day for up to three days; and (iii) cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2, preferably 100 mg/m2, per day for up to ten days;
(b) administering a second course of therapy to a patient in need of treatment comprising: (i) gemtuzumab ozogamicin in an amount of about 3 mg/m2 to about 9 mg/m2, preferably 6 mg/m2, per day for one day; (ii) daunorubicin in an amount of about 45 mg/m2 to about 60 mg/m2, preferably 45 mg/m2, per day for up to three days; and (iii) cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2, preferably 100 mg/m2, per day for up to ten days; and
(c) administering a third course of therapy to a patient in need of treatment comprising: (i) daunorubicin in an amount of about 45 mg/m2 to about 60 mg/m2, preferably 45 mg/m2, per day for up to three days; and (ii) cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2, preferably 100 mg/m2, per day for up to ten days.
This invention provides advantageous pharmaceutical combinations and methods of treatment for acute leukemia, such as AML, and for myelodysplastic syndrome (MDS) which employ an anti-CD33 cytotoxic conjugate, an anthracycline, and a pyrimidine or purine nucleoside analog. The method of treatments and pharmaceutical combinations described herein provide a better rate of complete remission and improved quality of life in such patients than the standard 3+7 regimen of daunorubicin and cytarabine. Surprisingly, a preferred embodiment employing gemtuzumab ozogamicin, daunorubicin, and cytarabine provides a higher rate of complete remission than the standard 3+7 regimen of daunorubicin and cytarabine.
The patients to be treated with the methods of treatment and pharmaceutical combinations provided herein are those who have been untreated for acute leukemia such as AML and are being treated de novo, those who are being treated with induction therapy, those who are being treated with consolidation therapy, those who are being treated after one or more relapses, and those who have MDS.
One composition used in the present invention is an anti-CD33 cytotoxic conjugate in which an anti-CD33 antibody is conjugated with a cytotoxic antitumor or antibiotic, such as a calicheamicin isolated from fermentation of a bacterium, Micromonospora echinospora ssp. calichensis, or an esperamicin. Calicheamicins are described in U.S. Pat. Nos. 4,970,198; 5,037,651; and 5,079,233. Esperamicins are described in U.S. Pat. Nos. 4,675,187; 4,539,203; 4,554,162; and 4,837,206. The antibody portion of the conjugate binds specifically to the CD33 antigen, a sialic acid-dependent adhesion protein found on the surface of leukemic blasts and immature normal cells of myelomonocytic lineage, but not on normal hematopoietic stem cells, and acts as a targeting unit to deliver the cytotoxic agent to these targeted cells. This antibody is linked to the calicheamicin or esperamicin. When N-acetyl-gamma calicheamicin is used, it is preferred to link the antibody by a bifunctional linker. Such conjugates and methods for making them are described in U.S. Pat. Nos. 5,733,001; 5,739,116; 5,767,285; 5,877,296; 5,606,040; 5,712,374; and 5,714,586, which are incorporated by reference herein in their entirety.
A preferred form of the anti-CD33 cytotoxic conjugate for use in the present invention is gemtuzumab ozogamicin, a chemotherapy agent composed of a recombinant humanized IgG4, kappa antibody conjugated with calicheamicin. Gemtuzumab ozogamicin is available commercially as Mylotarg® (Wyeth Pharmaceuticals, Philadelphia, Pa.). The antibody portion of gemtuzumab ozogamicin binds specifically to the CD33 antigen. Gemtuzumab ozogamicin contains amino acid sequences of which approximately 98.3% are of human origin. The constant region and framework regions contain human sequences while the complementarity-determining regions are derived from a murine antibody (p67.6) that binds CD33. This antibody is linked to N-acetyl-gamma calicheamicin via a bifunctional linker. Gemtuzumab ozogamicin has approximately 50% of the antibody loaded with 4-6 moles calicheamicin per mole of antibody. The remaining 50% of the antibody is not linked to the calicheamicin derivative. Gemtuzumab ozogamicin has a molecular weight of 151 to 153 kDa. Gemtuzumab ozogamicin and methods for making it are described in U.S. Pat. Nos. 5,733,001; 5,739,116; 5,767,285; 5,877,296; 5,606,040; 5,712,374; and 5,714,586, which are incorporated by reference herein in their entirety. When given as a single agent therapy for the treatment of AML, the recommended dose of gemtuzumab ozogamicin is 9 mg/m2, administered as a two-hour intravenous infusion. The recommended treatment course with gemtuzumab ozogamicin alone has been a total of two doses with fourteen days between the doses. In the combination therapy of the present invention, gemtuzumab ozogamicin is given in an amount ranging from about 3 mg/m2 to 9 mg/m2 per day.
U.S. Pat. No. 5,773,001, in col. 62, lines 37-46, and Example 112, describes dosage amounts of calicheamicin conjugates, including gemtuzumab ozogamicin, based on calicheamicin equivalents, i.e., 10 μg calicheamicin/m2 protein, as compared to the clinical dose description based on mg/m2 body-surface. When calicheamicin is loaded onto the antibody, there is approximately 27 μg calicheamicin/mg protein. A 9 mg/m2 dose of gemtuzumab ozogamicin is equivalent to 243 μg calicheamicin/m2 protein. A 6 mg/m2 dose of gemtuzumab ozogamicin is equivalent to 162 μg calicheamicin/m2 protein. A 3 mg/m2 dose of gemtuzumab ozogamicin is equivalent to 81 μg calicheamicin/m2 protein.
Another composition used in the present invention is an anthracycline, an anticancer agent consisting of 3 moieties: a pigmented aglycone, an amino sugar, and a lateral chain. Anthracyclines include doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin. See Merck Index (13th ed. 2001).
A preferred anthracycline for use in the present invention is daunorubicin. Daunorubicin, also known as daunomycin, is an anthracycline cytotoxic antibiotic of the rhodomycin group obtained from Streptomyces peucetius, which is used in the treatment of acute leukemia. Stedman's Medical Dictionary (27th ed. 2002). Daunorubicin has a 4-ring anthracycline moiety linked by a glycosidic bond to daunosamine, an amino sugar. Daunorubicin may also be isolated from Streptomyces coeruleorubidus and has the following chemical name: (8S-cis)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-(alpha)-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. Daunorubicin is usually given as the hydrochloride, but doses are expressed in terms of the base.
A preferred form of daunorubicin used in the present invention is daunorubicin hydrochloride, the hydrochloride salt of daunorubicin. Daunorubicin hydrochloride is available commercially as Cerubidine® (Bedford Laboratories, Bedford Ohio). It may be described with the chemical name of (1 S,3 S)-3-Acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1-naphthacenyl 3-amino-2,3,6-trideoxy-(alpha)-L-lyxo-hexopyranoside hydrochloride. Its molecular formula is C27H29NO10.HCl with a molecular weight of 563.99. In the treatment of adult acute nonlymphocytic leukemia, such as AML and ALL, daunorubicin hydrochloride, used as a single agent, has produced complete remission rates of 40 to 50%, and in combination with cytarabine, has produced complete remission rates of 53 to 65%. Physician's Desk Reference (56th ed. 2002). Typically, daunorubicin is given daily for three days in an amount of 30 to 45 mg/m2 by intravenous infusion for two to three days. In high-dose regimens, daunorubicin is given daily in an amount of 50 mg/m2 for three days.
Daunorubicin is also available commercially in a daunorubicin citrate liposome injection as DaunoXome® (Gilead Sciences, Inc., Foster City, Calif.). DaunoXome® contains an aqueous solution of the citrate salt of daunorubicin encapsulated within lipid vesicles (liposomes) composed of a lipid bilayer of distearoylphosphatidylcholine and cholesterol (2:1 molar ratio), with a mean diameter of about 45 nm. The lipid to drug weight ratio is 18.7:1 (total lipid:daunorubicin base), equivalent to a 10:5:1 molar ratio of distearoylphosphatidylcholine:cholesterol:daunorubicin. Each vial of DaunoXome® contains daunorubicin citrate equivalent to 50 mg of daunorubicin base, encapsulated in liposomes consisting of 704 mg distearoylphosphatidylcholine and 168 mg cholesterol. The liposomes encapsulating daunorubicin are dispersed in an aqueous medium containing 2,125 mg sucrose, 94 mg glycine, and 7 mg calcium chloride dihydrate in a total volume of 25 ml/vial. The pH of the dispersion is between 4.9 and 6.0. DaunoXome® is administered intravenously over a 60 minute period at a dose of 40 mg/m2, with doses repeated every two weeks.
A third composition used in the present invention is a pyrimidine nucleoside analog or a purine nucleoside analog. Representative of such nucleoside analogs are cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin. See Merck Index (13th ed. 2001).
A preferred pyrimidine nucleoside analog used in the present invention is cytarabine, which is also known as arabinosylcytosine (aC, araC), arabinocytidine, or arabinofuranosylcytosine. Chemically, cytarabine is 4-amino-1-(beta)-D-arabinofuranosyl-2(1H)-pyrimidinone, also known as cytosine arabinoside (C9H13N3O5, molecular weight 243.22). Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phase of cell division. It is a compound of arabinose and cytosine that inhibits the biosynthesis of DNA and is used as a chemotherapeutic agent because of its antiviral and tumor-growth-inhibiting properties. Typically, cytarabine is given in an amount of 100-200 mg/m2 daily for five to ten days by constant intravenous infusion, usually for seven days. Cytarabine can be given in an amount of 100 mg/m2 body-surface twice daily by rapid intravenous injection. However, cytarabine can be given in amounts of up to 3 g/m2 daily. In high-dose regimens, cytarabine is given in doses of up to 3 g/m2 by intravenous infusion for every 12 hours for up to six days.
Cytarabine is also available commercially in a cytarabine liposome injection as DEPOCYT® (Chiron Corporation, Emeryville, Calif.). DepoCyt® is a sterile, injectable suspension of the antimetabolite cytarabine, encapsulated into multivesicular lipid-based particles. Each vial contains 50 mg of cytarabine. Cytarabine, the active ingredient, is present at a concentration of 10 mg/ml and is encapsulated in the particles. Inactive ingredients at their respective approximate concentrations are cholesterol, 4.1 mg/ml; triolein, 1.2 mg/ml; dioleoylphosphatidylcholine (DOPC), 5.7 mg/ml; and dipalmitoylphosphatidylglycerol (DPPG), 1.0 mg/ml. The pH of the product falls within the range from 5.5 to 8.5. DepoCyt® is administered intrathecally.
The present invention provides several methods for treating acute leukemia or MDS. In one method, a patient is given an anti-CD33 cytotoxic conjugate in combination with at least one compound selected from the group consisting of an anthracycline and a pyrimidine or purine nucleoside analog in an amount effective to ameliorate the symptoms of the acute leukemia, such as AML, or MDS. Preferably, the cytotoxin in the anti-CD33 cytotoxic conjugate is a calicheamicin or an esperamicin. The anthracycline is preferably selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin. The pyrimidine or purine nucleoside analog is preferably selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercid. Most preferred is that the cytotoxin in the anti-CD33 conjugate is a calicheamicin, the anthracycline is daunorubicin or daunorubicin hydrochloride, and the pyrimidine nucleoside analog is cytarabine.
In another method of treatment, a patient having acute leukemia or MDS is given gemtuzumab ozogamicin in an amount of about 3 mg/m2 to about 9 mg/m2 per day; daunorubicin, preferably daunorubicin hydrochloride, in an amount of about 45 mg/m2 to about 60 mg/m2 per day; and cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2 per day. Preferably, the gemtuzumab ozogamicin is given in an amount of about 6 mg/m2 per day. The daunorubicin, preferably daunorubicin hydrochloride, is preferably given in an amount of 45 mg/m2 per day. The cytarabine is preferably given in an amount of 100 mg/m2 per day.
In another method of treatment, a patient having acute leukemia or MDS is given gemtuzumab ozogamicin in an amount of about 3 mg/m2 to 9 mg/m2 for one day; daunorubicin in an amount of about 45 mg/m2 to 60 mg/m2 per day for three days; and cytarabine in an amount of about 100 mg/m2 to 200 mg/m2 per day for at least seven days. Preferably, the daunorubicin is administered on the first three days that cytarabine is administered, and is preferably given in an amount of 45 mg/m2 per day. The cytarabine is preferably administered for ten days, more preferably for seven days, and is preferably given in an amount of 100 mg/m2 per day. The gemtuzumab ozogamicin is preferably administered to the patient on the fourth day that cytarabine is administered to the patient, and is preferably given in an amount of 6 mg/m2. In a preferred embodiment, the cytarabine is administered by continuous infusion, the daunorubicin, preferably daunorubicin hydrochloride, is administered by intravenous bolus, and the gemtuzumab ozogamicin is administered by 2-hour infusion.
Pharmaceutical combinations for enhanced induction of remission in a patient having acute leukemia or MDS are also provided by the present invention. One such pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or MDS comprises an anti-CD33 cytotoxic conjugate, an anthracycline, and a pyrimidine or purine nucleoside analog. The cytotoxin in the anti-CD33 cytotoxic conjugate may be selected from the group consisting of a calicheamicin and an esperamicin. The anthracycline may be selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin. The pyrimidine or purine nucleoside analog may be selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin.
Another pharmaceutical combination comprises gemtuzumab ozogamicin in an amount of about 3 mg/m2 to about 9 mg/m2 per day, preferably 6 mg/m2 per day, daunorubicin, preferably daunorubicin hydrochloride, in an amount of about 45 mg/m2 to about 60 mg/m2 per day, preferably 45 mg/m2 per day, and cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2 per day, preferably 100 mg/m2 per day.
The nature of acute leukemias and myelodysplastic syndrome calls for the administration of intensive chemotherapy to induce remission in patients having these diseases. In one embodiment of the present invention, a single course of combination therapy comprises administering to the patient a therapeutically effective amount of an anti-CD33 cytotoxic conjugate, together with one or more chemotherapeutic agents, such as anthracycline, and a pyrimidine or purine nucleoside analog. The present invention also provides treatment regimens in which multiple courses of combination therapy, which include an anti-CD33 cytotoxic conjugate and other chemotherapeutic agents, are administered. Such treatment regimens may be administered from at least two to five courses of treatment, depending upon the drugs being administered, the severity of the disease, and the condition of the patient.
In another method of treatment of the present invention, a patient having acute leukemia or MDS is given three courses of therapy. In the first course of therapy, the patient is given an anti-CD33 cytotoxic conjugate for one day; an anthracycline for up to three days; and a pyrimidine or purine nucleoside analog for up to ten days. The cytotoxin in the anti-CD33 cytotoxic conjugate may be selected from the group consisting of a calicheamicin and an esperamicin. The anthracycline may be selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin. The pyrimidine or purine nucleoside analog may be selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin. The first course of therapy is repeated as a second course of therapy in which the patient is given an anti-CD33 cytotoxic conjugate for one day, an anthracycline for up to three days, and a pyrimidine or purine nucleoside analog for up to ten days. A third course of therapy may be given to the patient which comprises the administration to the patient of an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin for up to three days, and a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin for up to ten days.
In another such method of treatment of acute leukemia or MDS, a patient is given a first course of therapy comprising gemtuzumab ozogamicin in an amount of about 3 mg/m2 to about 9 mg/m2, preferably 6 mg/m2, per day for one day; daunorubicin in an amount of about 45 mg/m2 to about 60 mg/m2, preferably 45 mg/m2, per day for up to three days; and cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2, preferably 100 mg/m2, per day for up to ten days. A second course of therapy is given to the patient comprising gemtuzumab ozogamicin in an amount of about 3 mg/m2 to about 9 mg/m2, preferably 6 mg/m2, per day for one day; daunorubicin in an amount of about 45 mg/m2 to about 60 mg/m2, preferably 45 mg/m2, per day for up to three days; and cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2, preferably 100 mg/m2, per day for up to ten days. A third course of therapy may be administered to the patient comprising daunorubicin in an amount of about 45 mg/m2 to about 60 mg/m2, preferably 45 mg/m2, per day for up to three days, and cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2, preferably 100 mg/m2, per day for up to ten days.
The surprising and unexpected result disclosed herein is the ability of the anti-CD33 cytotoxic conjugate, the anthracycline, and the pyrimidine or purine nucleoside analog to act synergistically in the treatment of various symptoms associated with acute leukemia or MDS. Synergistically” is used herein to refer to a situation where the benefit conveyed by the administration of these antineoplastic compositions in combination is greater than the algebraic sum of the effects resulting from the separate administration of the components of the combination. As shown in the Examples below, the combination treatment of an anti-CD33 cytotoxic conjugate, an anthracycline, and an pyrimidine or purine nucleoside analog is synergistic with respect to treating acute leukemia and increasing the efficacy as measured by complete remission. This combined treatment has the advantage of achieving the same result with a lower dose of the anti-CD33 cytotoxic conjugate, thereby reducing any toxic effect from the conjugate, providing an improved quality of life, and increasing the chances for survival of the patient.
As with the use of other chemotherapeutic drugs, the individual patient will be monitored in a manner deemed appropriate by the treating physician. The combination therapy agents described herein may be administered with immunosuppressive agents, potentiators and side-effect relieving agents as deemed necessary by the treating physician.
In therapeutic applications, the dosages of the agents used in accordance with the invention may vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in complete remission as previously defined. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. It is especially advantageous to formulate compositions of these antineoplastic compounds in dosage unit form for ease of administration and uniformity of dosage. “Dosage unit form” as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated, each unit containing a predetermined quantity of anti-neoplastic compounds calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like which are compatible with the active ingredient and with the mode of administration and other ingredients of the formulation and not deleterious to the recipient.
The pharmaceutical compositions of this invention which are found in the combination may also include, depending on the formulation desired, pharmaceutically-acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like. Effective amounts of such diluent or carrier will be those amounts which are effective to obtain a pharmaceutically acceptable formulation in terms of solubility of components, or biological activity, and the like.
For parenteral therapeutic administration, each antineoplastic compound may be incorporated with a sterile injectable solution. The sterile injectable solution may be prepared by incorporating the antineoplastic compound in the required amount in an appropriate pharmaceutically acceptable carrier, with various other ingredients, followed by filtered sterilization. In the case of dispersions, each may be prepared by incorporating the additional antineoplastic compound into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated herein. In the case of sterile injectable solutions, each may be prepared by incorporating a powder of the additional antineoplastic compound and, optionally, any additional desired ingredient from a previously sterile-filtered solution thereof, wherein the powder is prepared by any suitable technique (e.g., vacuum drying and freeze drying). The use of such media and agents is well known in the art (see for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990), Mack Publishing Co., Easton, Pa. 18042, pages 1435-1712, the disclosure of which is hereby incorporated by reference). Supplementary active ingredients can also be incorporated into the compositions. The specific dose of the antineoplastic compound is calculated according to the approximate body weight or surface area of the patient. Other factors in determining the appropriate dosage can include the stage of the acute myelogenous leukemia or myelodysplastic syndrome (de novo or relapse), the severity of the disease, the route of administration and the age, sex and medical condition of the patient. Further refinement of the calculations necessary to determine the appropriate dosage for treatment involving each of the herein-mentioned formulations is routinely made by those skilled in the art. Dosages can also be determined through the use of known assays for determining dosages used in conjunction with appropriate dose-response data. Thus, for example, it is within the scope of the invention that doses of the antineoplastic compounds used in the present invention for treating acute myelogenous leukemia or myelodysplastic syndrome can be varied to achieve a desired therapeutic effect.
If oral therapeutic administration is an option, the antineoplastic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixers, suspensions, syrups, wafers and the like, or it may be incorporated directly with the food in the diet. The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; or a flavoring agent such as peppermint, oil of wintergreen or cherry or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to material of the type described herein, a liquid carrier. Various other materials may be present as a coating or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the antineoplastic compound may be incorporated into a sustained-release preparation and formulation. The amount of the antineoplastic compound in such therapeutically useful composition is such that a suitable dosage will be obtained.
It is understood that the foregoing detailed description and the following examples are illustrative only and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments, which will be apparent to those skilled in the art, may be made without departing from the spirit and scope of the present invention. Further, all patents, patent applications, and publications cited herein are incorporated herein by reference.
To assess the safety and efficacy of gemtuzumab ozogamicin as part of a combination therapy for AML, a phase ½ study was developed in the United States of America to combine gemtuzumab ozogamicin with cytarabine and daunorubicin. Patients with relapsed, refractory, or de novo AML were enrolled in phase 1 from October 2000 through November 2001. The maximum tolerated dose was determined to be cytarabine 100 mg/m2/day by continuous infusion on days 1 through 7, daunorubicin 45 mg/m2 by intravenous bolus on days 1 through 3, and gemtuzumab ozogamicin 6 mg/m2 by 2-hour infusion on day 4. The phase 2 portion of the study was open to enrollment on November 2001 and 42 of the planned 45 patients have been enrolled to date.
A detailed safety and efficacy evaluation was performed on the first 19 patients treated with this combination induction regimen and subsequently followed for at least 28 days. There were sixteen men and three women enrolled with a median age of 46 years (range, 20 to 60). One, ten, and three patients were categorized in favorable-, intermediate- and poor-risk cytogenetic groups, respectively. Cytogenetic analysis was not available for five patients. Seventeen patients had baseline bone marrow leukemic blast cell determinations with a median blast percentage of 60% Combination therapy was well tolerated and all nineteen patients completed the planned induction therapy.
Three patients (16%) reported NCI grade 3 fever/chills on the day of gemtuzumab ozogamicin infusion. The incidence of grade 3 AST/ALT elevation was 16%; no grade 3 or 4 hyperbilirubinemia was reported. There were no cases of hepatic veno-occlusive disease/sinusoidal obstruction syndrome. The incidence of grade 3 or 4 infections was 32%. The early treatment mortality rate was 0%. Four patients required re-induction for residual AML with cytarabine and daunorubicin on approximately day 15. One of these patients was taken off study and given re-induction with a high-dose cytarabine (HDAC)-containing regimen on study day 15 and was not evaluable for efficacy.
Fifteen of 18 patients (83%) achieved a complete remission (CR) characterized by the absence of AML blasts from the peripheral blood, no extramedullary AML, ≦5% marrow blasts in a marrow with >20% cellularity, and recovery of peripheral counts to absolute neutrophil count (ANC)≧1500/μL and platelets to ≧100,000/μL. No patients were reported to have complete remission with incomplete platelet recovery (CRp). Of the three non-remission patients, 2 had progressive disease and 1 achieved a marrow remission but required radiation therapy for a residual chloroma. Among CR patients, the median time to recover ANC to ≧1500/μL was 38 days and platelets to ≧100,000/μL was 30 days. Patients have been followed for too short a time to determine duration of remission (median follow-up 193 days).
The combination of cytarabine 100 mg/m2/day, daunorubicin 45 mg/m2, and gemtuzumab ozogamicin 6 mg/m2 was well tolerated with low hepatotoxicity and resulted in an increase in the CR rate to 83%. Historical control data from the Southwest Oncology Group (SWOG) shows a 60% CR rate with standard therapy of 100 mg/m2/day of cytarabine for seven days and 45 mg/m2 of daunorubicin for three days. The combination of cytarabine 100 mg/m2/day, daunorubicin 45 mg/m2, and gemtuzumab ozogamicin 6 mg/m2 resulted in a markedly improved rate of CR compared to standard therapy.
The feasibility of combining gemtuzumab ozogamicin with intensive chemotherapy for induction and/or consolidation was evaluated in 67 patients in a safety study in the United Kingdom prior to the start of the Medical Research Center AML15 trial. The aim was to combine gemtuzumab ozogamicin with chemotherapy planned in the trial, (DAT; Daunorubicin, AraC, Thioguanine, or DA; Daunorubicin AraC; or FLAG-IDA; Fludarabine, AraC, G-CSF, Idarubicin) as course 1. Course 1 was given using gemtuzumab ozogamicin in an amount of 3 mg/m2 on day 1 of chemotherapy in 55 patients. Thirty-three patients received gemtuzumab ozogamicin with DAT. Eight patients received gemtuzumab ozogamicin with DA. Fourteen patients received gemtuzumab ozogamicin with FLAG-Ida. Of the 55 patients treated, 41 (85%) entered complete remission with course 1 broken down as follows: (19) DAT=26/32; (2) DA=7/8; and (3) FLAG-Ida=8/8. Prior experience in a separate trial designated MRC AML12 where 720 patients were treated with H-DAT alone in course 1, 64% of those patients achieved complete remission. In the present study, the median time to ANC recovery (1×109/l) was 27 days (range 9-54) and platelets >100×109/l was 30 (range 21-48) which is within the mean+ISD of the 720 patients treated with H-DAT alone in the MRC AML12 trial. Non-hemopoietic toxicity was confined to the liver. Overall the maximum toxicity was Grade 1=5 patients, Grade 2=22 patients, Grade 3=13 patients and Grade 4=10 patients. Of the Grade 3 and 4 toxicities, 7 were felt to be definitely associated with gemtuzumab ozogamicin therapy. A possible contributory factor was the inclusion of Thioguanine. Of the 39 recipients where Thioguanine was included in the schedules, 22 developed Grade 3 or 4 liver toxicity compared with 1 for 16 recipients of non-Thioguanine schedules.
Nine additional patients received H-DAT with 6 mg/m2 gemtuzumab ozogamicin and 8 patients achieved complete remission with course 1. Hematological recovery was not prolonged, but 3 patients developed Grade 3 or 4 liver toxicity of whom 2 developed a VOD-like syndrome from which both recovered. A 6 mg/m2 dose of gemtuzumab ozogamicin was not considered feasible.
Fifteen patients received gemtuzumab ozogamicin in a dose of 3 mg/m2 with courses 1 and 2 (DAT 3+10 and DAT 3+8). ANC recovery was delayed in 5 patients and platelet recovery in 11, and both in 5 patients. Grade 3 or 4 liver toxicity was seen in 3 cases of whom 2 developed a VOD-like syndrome.
Seventeen patients received gemtuzumab ozogamicin in a dose of 3 mg/m2 with chemotherapy in course 3 with MACE (MACE: Amsacarine, AraC, Etoposide, or high dose AraC). Only one patient developed greater than Grade 2 liver toxicity. Twelve patients received induction in course 1 with gemtuzumab ozogamicin in a dose of 3 mg/m2 and course 3 with gemtuzumab ozogamicin in a dose of 3 mg/m2. This appears to be feasible but further study of this regimen is ongoing.
The overall survival of all patients receiving gemtuzumab ozogamicin in a dose of 3 mg/m2 with course 1 at 6 months is 73% and at 12 months is 68%. For the patient receiving non-Thioguanine induction with 3 mg/m2 of gemtuzumab ozogamicin, the 6 month survival is 91%.
Claims (20)
1. A method of treating acute leukemia or myelodysplastic syndrome consisting essentially of administering to a patient in need of treatment thereof: (a) gemtuzumab ozogamicin in an amount of about 3 mg/m2 to about 9 mg/m2 per day; (b) daunorubicin in an amount of about 45 mg/m2 to about 60 mg/m2 per day; and (c) cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2 per day.
2. The method according to claim 1 , wherein the amount of gemtuzumab ozogamicin is 6 mg/m2 per day.
3. The method according to claim 1 , wherein the daunorubicin is daunorubicin hydrochloride.
4. The method according to claim 1 or 3 , wherein the amount of daunorubicin is 45 mg/m2 per day.
5. The method according to claim 1 , wherein the amount of cytarabine is 100 mg/m2 per day.
6. A method of treating acute leukemia or myelodysplastic syndrome consisting essentially of administering to a patient in need of treatment thereof: (a) gemtuzumab ozogamicin in an amount of about 3 mg/m2 to 9 mg/m2 for one day; (b) daunorubicin in an amount of about 45 mg/m2 to 60 mg/m2 per day for three days; and (c) cytarabine in an amount of about 100 mg/m2 to 200 mg/m2 per day for at least seven days.
7. The method according to claim 6 , wherein the daunorubicin is administered to the patient on the first three days that cytarabine is administered to the patient.
8. The method according to claim 6 or 7 , wherein the gemtuzumab ozogamicin is administered to the patient on the fourth day that cytarabine is administered to the patient.
9. The method according to claim 6 , wherein the cytarabine is administered for ten days.
10. The method according to claim 8 , wherein the cytarabine is administered by continuous infusion, the daunorubicin is administered by intravenous bolus, and the gemtuzumab ozogamicin is administered by 2-hour infusion.
11. The method according to claim 8 , wherein the cytarabine is administered in an amount of 100 mg/m2/day, the daunorubicin is administered in an amount of 45 mg/m2, and the gemtuzumab ozogamicin is administered in an amount of 6 mg/m2.
12. The method according to claim 6 , wherein the daunorubicin is daunorubicin hydrochloride.
13. A pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or myelodysplastic syndrome consisting essentially of gemtuzumab ozogamicin in an amount of about 3 mg/m2 to about 9 mg/m2, daunorubicin in an amount of about 45 mg/m2 to about 60 mg/m2, and cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2.
14. The pharmaceutical combination of claim 13 , wherein the daunorubicin is daunorubicin hydrochloride.
15. The pharmaceutical combination of claim 13 wherein the gemtuzumab ozogamicin is in an amount of about 6 mg/m2.
16. The pharmaceutical combination of claim 13 or 14 , wherein the daunorubicin is in an amount of about 45 mg/m2.
17. The pharmaceutical combination of claim 13 , wherein the cytarabine is in an amount of 100 mg/m2.
18. A pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or myelodysplastic syndrome consisting essentially of gemtuzumab ozogamicin in an amount of 6 mg/m2, daunorubicin in an amount of 45 mg/m2, and cytarabine in an amount of 100 mg/m2.
19. A method of treating acute myelogenous leukemia or myelodysplastic syndrome consisting essentially of: (a) administering a first course of therapy to a patient in need of treatment consisting essentially of: (i) gemtuzumab ozogamicin in an amount of about 3 mg/m2 to about 9 mg/m2 per day for one day; (ii) daunorubicin in an amount of about 45 mg/m2 to about 60 mg/m2 per day for up to three days; and (iii) cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2 per day for up to ten days; (b) administering a second course of therapy to a patient in need of treatment consisting essentially of: (i) gemtuzumab ozogamicin in an amount of about 3 mg/m2 to about 9 mg/m2 per day for one day; (ii) daunorubicin in an amount of about 45 mg/m2 to about 60 mg/m2 per day for up to three days; and (iii) cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2 per day for up to ten days; and (c) administering a third course of therapy to a patient in need of treatment consisting essentially of: (i) daunorubicin in an amount of about 45 mg/m2 to about 60 mg/m2 per day for up to three days; and (ii) cytarabine in an amount of about 100 mg/m2 to about 200 mg/m2 per day for up to ten days.
20. A method of treating acute myelogenous leukemia or myelodysplastic syndrome consisting essentially of: (a) administering a first course of therapy to a patient in need of treatment consisting essentially of: (i) gemtuzumab ozogamicin in an amount of 6 mg/m2 per day for one day; (ii) daunorubicin in an amount of 45 mg/m2 per day for up to three days; and (iii) cytarabine in an amount of 100 mg/m2 to about 200 mg/m2 per day for up to ten days; (b) administering a second course of therapy to a patient in need of treatment consisting essentially of: (i) gemtuzumab ozogamicin in an amount of 6 mg/m2 per day for one day; (ii) daunorubicin in an amount of 45 mg/m2 to per day for up to three days; and (iii) cytarabine in an amount of 100 mg/m2 per day for up to ten days; and (c) administering a third course of therapy to a patient in need of treatment consisting essentially of: (i) daunorubicin in an amount of 45 mg/m2 per day for up to three days; and (ii) cytarabine in an amount of 100 mg/m2 per day for up to ten days.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/811,626 US7727968B2 (en) | 2002-11-06 | 2007-06-11 | Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US42415602P | 2002-11-06 | 2002-11-06 | |
US10/700,650 US20040152632A1 (en) | 2002-11-06 | 2003-11-04 | Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome |
US11/811,626 US7727968B2 (en) | 2002-11-06 | 2007-06-11 | Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/700,650 Continuation US20040152632A1 (en) | 2002-11-06 | 2003-11-04 | Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome |
Publications (2)
Publication Number | Publication Date |
---|---|
US20070269430A1 US20070269430A1 (en) | 2007-11-22 |
US7727968B2 true US7727968B2 (en) | 2010-06-01 |
Family
ID=32775823
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/700,650 Abandoned US20040152632A1 (en) | 2002-11-06 | 2003-11-04 | Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome |
US11/811,626 Expired - Fee Related US7727968B2 (en) | 2002-11-06 | 2007-06-11 | Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/700,650 Abandoned US20040152632A1 (en) | 2002-11-06 | 2003-11-04 | Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome |
Country Status (1)
Country | Link |
---|---|
US (2) | US20040152632A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019139921A1 (en) | 2018-01-09 | 2019-07-18 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
US11034667B2 (en) | 2017-01-09 | 2021-06-15 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
US11584733B2 (en) | 2017-01-09 | 2023-02-21 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
US11594403B1 (en) * | 2014-12-03 | 2023-02-28 | Biodesix Inc. | Predictive test for prognosis of myelodysplastic syndrome patients using mass spectrometry of blood-based sample |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8404716B2 (en) | 2002-10-15 | 2013-03-26 | Celgene Corporation | Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine |
US11116782B2 (en) | 2002-10-15 | 2021-09-14 | Celgene Corporation | Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine |
US8404717B2 (en) * | 2002-10-15 | 2013-03-26 | Celgene Corporation | Methods of treating myelodysplastic syndromes using lenalidomide |
EP1629119A2 (en) * | 2003-04-29 | 2006-03-01 | Wyeth | Methods for diagnosing aml and mds by differential gene expression |
WO2005011598A2 (en) * | 2003-07-31 | 2005-02-10 | University Of South Florida | Leukemia treatment method and composition |
WO2005014004A1 (en) * | 2003-08-08 | 2005-02-17 | Novartis Ag | Combinations comprising staurosporines |
ES2344899T3 (en) * | 2003-09-25 | 2010-09-09 | Astellas Pharma Inc. | ANTITUMORAL AGENT UNDERSTANDING A HISTONE DEACETILASE INHIBITOR AND A TOPOISOMERASE II INHIBITOR. |
EP1796689A4 (en) * | 2004-09-20 | 2009-01-14 | British Columbia Cancer Agency | Free or liposomal gemcitabine alone or in combination with free or liposomal idarubicin |
WO2006050075A2 (en) * | 2004-10-29 | 2006-05-11 | Regents Of The University Of California | Method of increasing efficacy of tumor cell killing using combinations of anti-neoplastic agents |
EP1848994A2 (en) * | 2005-02-16 | 2007-10-31 | Wyeth | Methods and systems for diagnosis, prognosis and selection of treatment of leukemia |
CA2667808A1 (en) * | 2006-11-02 | 2008-05-15 | Seattle Genetics, Inc. | Methods of treating neoplastic, autoimmune and inflammatory diseases |
CN101578113B (en) | 2007-01-11 | 2015-04-22 | 诺和诺德公司 | Anti-KIR antibodies, formulations, and uses thereof |
KR20100014441A (en) * | 2007-02-16 | 2010-02-10 | 셀라토 파마슈티칼즈, 인코포레이티드 | Fixed drug ratios for treatment of hematopoietic cancers and proliferative disorders |
EP2211870A1 (en) * | 2007-11-01 | 2010-08-04 | Celgene Corporation | Cytidine analogs for treatment of myelodysplastic syndromes |
JP2016536361A (en) * | 2013-11-06 | 2016-11-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Pharmaceutical formulation comprising CD33 antibody and demethylating agent |
US10034872B2 (en) | 2014-08-22 | 2018-07-31 | Celgene Corporation | Methods of treating multiple myeloma with immunomodulatory compounds in combination with antibodies |
US11027021B2 (en) | 2016-03-15 | 2021-06-08 | Seagen Inc. | Combinations of PBD-based antibody drug conjugates with Bcl-2 inhibitors |
EP3463463A4 (en) | 2016-06-03 | 2020-01-15 | Seattle Genetics, Inc. | Combination of cd33 antibody drug conjugates with chemotherapeutic agents |
WO2017214433A1 (en) | 2016-06-09 | 2017-12-14 | Seattle Genetics, Inc. | Combinations of pbd-based antibody drug conjugates with flt3 inhibitors |
CA3087346A1 (en) * | 2018-01-08 | 2019-07-11 | Actinum Pharmaceuticals, Inc. | Combination immunotherapy and chemotherapy for the treatment of a hematological malignancy |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5744460A (en) | 1996-03-07 | 1998-04-28 | Novartis Corporation | Combination for treatment of proliferative diseases |
US5773001A (en) * | 1994-06-03 | 1998-06-30 | American Cyanamid Company | Conjugates of methyltrithio antitumor agents and intermediates for their synthesis |
US20020103141A1 (en) | 1998-12-23 | 2002-08-01 | Mckearn John P. | Antiangiogenic combination therapy for the treatment of cancer |
-
2003
- 2003-11-04 US US10/700,650 patent/US20040152632A1/en not_active Abandoned
-
2007
- 2007-06-11 US US11/811,626 patent/US7727968B2/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5773001A (en) * | 1994-06-03 | 1998-06-30 | American Cyanamid Company | Conjugates of methyltrithio antitumor agents and intermediates for their synthesis |
US5744460A (en) | 1996-03-07 | 1998-04-28 | Novartis Corporation | Combination for treatment of proliferative diseases |
US20020103141A1 (en) | 1998-12-23 | 2002-08-01 | Mckearn John P. | Antiangiogenic combination therapy for the treatment of cancer |
Non-Patent Citations (6)
Title |
---|
Elihu H. Estey, et al., Gemtuzumab Ozogamicin With or Without Interleukin 11 in Patients 65 Years of Age or Older With Untreated Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome: Comparison With Idarubicin Plus Continuous-Infusion, High-Dose Cytosine Arabinoside, Blood, vol. 99(12), pp. 4343-4349, Jun. 2002. |
G. Garcia-Manero, et al, Myelodyplastic Syndromes Acute Myeloid Leukemia, Haematologica, vol. 87(8): 804-807 Aug. 2002. |
Kell et al (Blood (2201) 98-123a-124), 2001. * |
Lowenberg et al (New Journal of Medicine, vol. 341, pp. 1051-1062, 1999. * |
Mark H. Beers and Robert Berkow, The Merck Manual, Seventeenth Edition, Sec. 11, Ch. 138, pp. 945-955, (1999). |
R. Berkow et al, The Merck Manual, Sixteenth Edition, pp. 1243-1244. Merck Research Laboratories, Rahway, NJ.(1992). |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11594403B1 (en) * | 2014-12-03 | 2023-02-28 | Biodesix Inc. | Predictive test for prognosis of myelodysplastic syndrome patients using mass spectrometry of blood-based sample |
US11034667B2 (en) | 2017-01-09 | 2021-06-15 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
EP4046989A1 (en) | 2017-01-09 | 2022-08-24 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
US11584733B2 (en) | 2017-01-09 | 2023-02-21 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
WO2019139921A1 (en) | 2018-01-09 | 2019-07-18 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
Also Published As
Publication number | Publication date |
---|---|
US20040152632A1 (en) | 2004-08-05 |
US20070269430A1 (en) | 2007-11-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7727968B2 (en) | Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome | |
AU2010201113A1 (en) | Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome | |
Seiter | Toxicity of the topoisomerase II inhibitors | |
AU773506B2 (en) | Antitumour synergistic composition | |
Fleischhack et al. | IDA‐FLAG (idarubicin, fludarabine, cytarabine, G‐CSF), an effective remission‐induction therapy for poor‐prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a phase II trial | |
CN110869029A (en) | Combination cancer therapy | |
Arlin et al. | Phase I-II Trial of Mitoxantrone in Acute Leukemia¹, 2 | |
CZ20003493A3 (en) | Antitumor composition containing synergetically active combination of anthracycline derivative with camptothecin derivative | |
Rowe et al. | Aclacinomycin A and etoposide (VP-16-213): an effective regimen in previously treated patients with refractory acute myelogenous leukemia | |
Lee et al. | Diaziquone given as a continuous infusion is an active agent for relapsed adult acute nonlymphocytic leukemia | |
Chisesi et al. | A phase II study of idarubicin (4-demethoxydaunorubicin) in advanced myeloma | |
RU2338535C2 (en) | Combined therapy for treatment of acute leukemia and myelodisplastic syndrome | |
Case Jr et al. | Phase I–II trial of high-dose Epirubicin in patients with lymphoma | |
Frenette et al. | Granulocyte‐macrophage colony stimulating factor (GM‐CSF) priming in the treatment of elderly patients with acute myelogenous leukemia | |
CN101259129A (en) | Combined treatment for acute leukemia and myelodysplastisches syndrom | |
Paciucci et al. | Sequential intermediate‐dose cytosine arabinoside and mitoxantrone for patients with relapsed and refractory acute myelocytic leukemia | |
Reiser et al. | DIZE (dexamethasone, idarubicin, and continuous infusion of ifosfamide and etoposide): an effective and well-tolerated new regimen for patients with relapsed lymphoma | |
Greenberg et al. | Treatment of myelodysplastic syndromes with daily oral idarubicin. A phase I–II study | |
WO1993021938A1 (en) | Methods for treating cancer using high-dose epirubicin | |
Parikh et al. | High-dose cytosine arabinoside plus etoposide as initial treatment for acute myeloid leukaemia: a single centre study | |
Saşmaz et al. | The results of treatment with idarubicin in childhood acute nonlymphoblastic leukemia | |
Horikoshi et al. | The value of oral cytarabine ocfosfate and etoposide in the treatment of refractory and elderly AML patients | |
Larrea et al. | Carboplatin plus cytarabine in the treatment of high-risk acute myeloblastic leukemia | |
Thomas et al. | Intensive chemotherapy with mitoxantrone administered as a single injection in patients with high-risk acute myeloid leukemia: results of the EMA 2000 trial | |
US6265385B1 (en) | Topoisomerase II poison and bis-dioxopiperazine derivative combination therapy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
REMI | Maintenance fee reminder mailed | ||
LAPS | Lapse for failure to pay maintenance fees | ||
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20140601 |