Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome

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.

What is claimed is:  
     
         1 . A method of treating acute leukemia or myelodysplastic syndrome 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 leukemia or said myelodysplastic syndrome.  
     
     
         2 . The method of  claim 1 , wherein the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin.  
     
     
         3 . The method of  claim 1 , wherein the anthracycline is selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin.  
     
     
         4 . The method of  claim 1 , wherein 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.  
     
     
         5 . A method of treating acute leukemia or myelodysplastic syndrome comprising administering to a patient in need of treatment thereof: 
 (a) gemtuzumab ozogamicin in an amount of about 3 mg/m 2  to about 9 mg/m 2  per day;    (b) daunorubicin 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.    
     
     
         6 . The method according to  claim 5 , wherein the amount of gemtuzumab ozogamicin is 6 mg/m 2  per day.  
     
     
         7 . The method according to  claim 5 , wherein the daunorubicin is daunorubicin hydrochloride.  
     
     
         8 . The method according to  claim 5  or  7 , wherein the amount of daunorubicin is 45 mg/m 2  per day.  
     
     
         9 . The method according to  claim 5 , wherein the amount of cytarabine is 100 mg/m 2  per day.  
     
     
         10 . A method of treating acute leukemia or myelodysplastic 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.    
     
     
         11 . The method according to  claim 10 , wherein the daunorubicin is administered to the patient on the first three days that cytarabine is administered to the patient.  
     
     
         12 . The method according to  claim 10  or  11 , wherein the gemtuzumab ozogamicin is administered to the patient on the fourth day that cytarabine is administered to the patient.  
     
     
         13 . The method according to  claim 10 , wherein the cytarabine is administered for ten days.  
     
     
         14 . The method according to  claim 12 , 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.  
     
     
         15 . The method according to  claim 12 , wherein the cytarabine is administered in an amount of 100 mg/m 2 /day, the daunorubicin is administered in an amount of 45 mg/m 2 , and the gemtuzumab ozogamicin is administered in an amount of 6 mg/m 2 .  
     
     
         16 . The method according to  claim 10 , wherein the daunorubicin is daunorubicin hydrochloride.  
     
     
         17 . A pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or myelodysplastic syndrome 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.    
     
     
         18 . A pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or myelodysplastic syndrome comprising gemtuzumab ozogamicin in an amount of about 3 mg/m 2  to about 9 mg/m 2 , daunorubicin in an amount of about 45 mg/m 2  to about 60 mg/m 2 , and cytarabine in an amount of about 100 mg/m 2  to about 200 mg/m 2 .  
     
     
         19 . The pharmaceutical combination of  claim 18 , wherein the daunorubicin is daunorubicin hydrochloride.  
     
     
         20 . The pharmaceutical combination of  claim 18  wherein the gemtuzumab ozogamicin is in an amount of about 6 mg/m 2 .  
     
     
         21 . The pharmaceutical combination of  claim 18  or  19 , wherein the daunorubicin is in an amount of about 45 mg/m 2 .  
     
     
         22 . The pharmaceutical combination of  claim 18 , wherein the cytarabine is in an amount of 100 mg/m 2 .  
     
     
         23 . A pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or myelodysplastic syndrome comprising gemtuzumab ozogamicin in an amount of 6 mg/m 2 , daunorubicin in an amount of 45 mg/m 2 , and cytarabine in an amount of 100 mg/m 2 .  
     
     
         24 . A method of treating acute leukemia or MDS comprising administering at least one course of therapy to a patient in need of treatment comprising: 
 (a) 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;    (b) 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    (c) 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.    
     
     
         25 . The method of  claim 24 , wherein at least two courses of therapy are administered to the patient.  
     
     
         26 . The method of  claim 24  or  25 , wherein the final course of therapy administered to the patient comprises: 
 (a) 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  
 (b) 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.  
 
     
     
         27 . 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.    
     
     
         28 . A method of treating acute myelogenous leukemia or myelodysplastic syndrome 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  per day for one day;  
 (ii) daunorubicin in an amount of about 45 mg/m 2  to about 60 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  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  per day for one day;  
 (ii) daunorubicin in an amount of about 45 mg/m 2  to about 60 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  per day for up to ten days;  
   (c) administering a third course of therapy to a patient in need of treatment comprising: 
 (i) daunorubicin in an amount of about 45 mg/m 2  to about 60 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  per day for up to ten days.  
   
     
     
         29 . A method of treating acute myelogenous leukemia or myelodysplastic syndrome comprising: 
 (a) administering a first course of therapy to a patient in need of treatment comprising: 
 (i) gemtuzumab ozogamicin in an amount of 6 mg/m 2  per day for one day;  
 (ii) daunorubicin in an amount of 45 mg/m 2  per day for up to three days; and  
 (iii) cytarabine in an amount of 100 mg/m 2  200 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 6 mg/m 2  per day for one day;  
 (ii) daunorubicin in an amount of 45 mg/m 2  to per day for up to three days; and  
 (iii) cytarabine in an amount of 100 mg/m 2  per day for up to ten days;  
   (c) administering a third course of therapy to a patient in need of treatment comprising: 
 (i) daunorubicin in an amount of 45 mg/m 2  per day for up to three days; and  
 (ii) cytarabine in an amount of 100 mg/m 2  per day for up to ten days.