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document
Clofarabine ± fludarabine with once daily i.v . busulfan as pretransplant conditioning therapy for advanced myeloid leukemia and MDS . Although a combination of i.v . busulfan ( Bu ) and fludarabine ( Flu ) is a safe , reduced-toxicity conditioning program for acute myelogenous leukemia/myelodysplastic syndromes ( AML/MDS ) , recurrent leukemia posttransplantation remains a problem . To enhance the conditioning regimen 's antileukemic effect , we decided to supplant Flu with clofarabine ( Clo ) , and assayed the interactions of these nucleoside analogs alone and in combination with Bu in Bu-resistant human cell lines in vitro . We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu . We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation ( allo-SCT ) . Patients were adaptively randomized as follows : Arm I-Clo : Flu 10:30 mg/m ( 2 ) , Arm II-20:20 mg/m ( 2 ) , Arm III-30:10 mg/m ( 2 ) , and Arm IV-single-agent Clo at 40 mg/m ( 2 ) . The nucleoside analog ( s ) were/was infused over 1 hour once daily for 4 days , followed on each day by Bu , infused over 3 hours to a pharmacokinetically targeted daily area under the curve ( AUC ) of 6000 μMol-min ± 10 % . Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days . There were 32 males and 19 females , with a median age of 45 years ( range : 6-59 ) . Nine patients had chronic myeloid leukemia ( CML ) ( BC : 2 , second AP : 3 , and tyrosine-kinase inhibitor refractory first chronic phase [ CP ] : 4 ) . Forty-two patients had AML : 14 were induction failures , 8 in first chemotherapy-refractory relapse , 7 in untreated relapse , 3 in second or subsequent relapse , 4 were in second complete remission ( CR ) , and 3 in second CR without platelet recovery ( CRp ) , 2 were in high-risk CR1 . Finally , 1 patient was in first CRp . Graft-versus-host disease ( GVHD ) prophylaxis was tacrolimus and mini-methorexate ( MTX ) , and those who had an unrelated or 1 antigen-mismatched donor received low-dose rabbit-ATG ( Thymoglobulin™ ) . All patients engrafted . Forty-one patients had active leukemia at the time of transplant , and 35 achieved CR ( 85 % ) . Twenty of the 42 AML patients and 5 of 9 CML patients are alive with a projected median overall survival ( OS ) of 23 months . Marrow and blood ( T cell ) chimerism studies at day +100 revealed that both in the lower-dose Clo groups ( groups 1+2 ) and the higher-dose Clo groups ( groups 3+4 ) , the patients had a median of 100 % donor ( T cell ) -derived DNA . There has been no secondary graft failure . In the first 100 days , 1 patient died of pneumonia , and 1 of liver GVHD . We conclude that ( 1 ) Clo ± Flu with i.v . Bu as pretransplant conditioning is safe in high-risk myeloid leukemia patients ; ( 2 ) clofarabine is sufficiently immunosuppressive to support allo-SCT in myeloid leukemia ; and ( 3 ) the median OS of 23 months in this high-risk patient population is encouraging . Additional studies to evaluate the antileukemic efficacy of Clo ± Flu with i.v . Bu as pretransplant conditioning therapy are warranted .
47778
Intervention_Pharmacological
Clofarabine ± fludarabine
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Intervention_Pharmacological
busulfan
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Intervention_Pharmacological
i.v . busulfan ( Bu )
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Intervention_Pharmacological
fludarabine ( Flu )
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Intervention_Pharmacological
clofarabine ( Clo )
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Intervention_Pharmacological
I-Clo : Flu
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Intervention_Pharmacological
IV-single-agent Clo
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Outcome_Mortality
with a projected median overall survival
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Outcome_Physical
Marrow and blood ( T cell )
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Outcome_Adverse-effects
secondary graft failure
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Outcome_Other
Bu as pretransplant conditioning is safe in high-risk myeloid leukemia patients ;
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Outcome_Other
clofarabine is sufficiently immunosuppressive
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Outcome_Other
evaluate the antileukemic efficacy
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Outcome_Other
Bu as pretransplant conditioning therapy are warranted