Clofarabine, Cytarabine And Mitoxantrone (CLAM) for relapsed or refractory acute myeloid leukaemia - interim results of a prospective phase 2 study

Abstract

Background In unselected patients with acute myeloid leukaemia (AML) in first relapse or refractory to primary daunorubicin / cytarabine therapy, complete response (CR) rate is merely 20 - 30%. In patients < 60-years old, CR rates of about 55% may be achieved. Aims We tested in a multicenter prospective phase 2 study the efficacy and safety of clofarabine, cytarabine and mitoxantrone (CLAM) in AML patients in first relapse or refractory to first-line daunorubicin / cytarabine induction therapy. Methods Consenting patients aged 18 to 65 years in first relapse or refractory to first-line dose-intensified daunorubicin / cytarabine were recruited. Bone marrow pathology and karyotype at diagnosis and relapse were centrally reviewed. Next-generation sequencing of a myeloid panel of 67 genes was performed. Re-induction CLAM comprised clofarabine (40mg/m2/day, days 1-5), cytarabine (750mg/m2/day, days 1-5) and mitoxantrone (12mg/m2/day, days 3-5). Bone marrow assessment was done on day 28 using standard criteria. Treatment toxicity was evaluated using the Eastern Cooperative Oncology Group Common Toxicity Criteria (ECOG-CTC). Survivals were determined using Kaplan Meier method. The primary outcome was the response on day 28. Secondary outcomes included treatment toxicity, leukaemia-free and overall survivals. Results In this interim analysis, 24 patients (14 men, 10 women) with a median age of 44.5 (19-66) years were treated. Karyotypic and genetic profiles were: normal karyotype (N=8) (NPM1 mutant, N=1; FLT3-WT, N=8), t(8;21)(q22;22) (N=4) (KIT D816V mutant, N=1), inv(16)(p13.2;q22)/t(16;16)(p13.2;q22) (N=1) (KIT D816V mutant, N=1), inv(3)(q21;q26) (N=5), del (11)(q23) (N=2), t(9;11)(p21;q23) (N=1), trisomy 13 (N=1), near-tetraploidy (N=1), and complex karyotype (N=1). Twenty patients (83.3%) responded (CR, N=16; CR with incomplete hematopoietic recovery, N=4). Eight responding patients underwent allogeneic haematopoietic stem cell transplantation. Grade 3/4 haematologic toxicity was seen in all patients. Grade 1/2 and grade 3/4 hepatotoxicity was observed in 17 (70.8%) and 2 (8.3%) patients respectively. Grade 1/2 rash was observed in 4 patients (20%). Cardiotoxicity or treatment-related mortality was not seen. With a median of follow-up of 4 (1-32) months, 6 patients relapsed. The 12-month overall and leukaemia-free survivals were 81.7% and 66.8% respectively. Conclusion CLAM resulted in a high CR rate for AML in first relapse or refractory to first-line induction therapy, which was associated with an acceptable toxicity profile.