A Phase I/II Dose Escalating Study of Daunorubicin Combined with Imatinib Mesylate and Cytarabine as Induction Therapy for Chronic Myelogenous Leukaemia in Myeloid Blast Crisis. Preliminary Results of the AFR01 Trial.

The prognosis of patients (pts) with chronic myelogenous leukaemia (CML) in blast crisis (BC) remains poor. Despite better result with imatinib mesylate (IM), overall hematologic response rates with IM alone are about 50% including 13% of pts reaching complete hematologic remission (CHR). Response duration is short and median survival is 6 to 7 months. Daunorubicin and cytarabine are 2 major drugs for acute myeloblastic leukaemia and have additive or synergistic in vitro effects with IM, depending of the cell line studied. We therefore planned a dose escalating study in an attempt to assess the safety and the efficacy of IM associated with chemotherapy. We combined fixed doses of IM (600 mg daily started 3 days before chemotherapy) and cytarabine (100 mg/m² per day as a continuous IV infusion D1 to D7) with increasing dosages of daunorubicin (cohort 1: no daunorubicin, cohorts 2, 3 and 4 : 15, 30 and 45 mg/m²/day D1 to D3 respectively). G-CSF was administered from D9 until haematological recovery. No PK analysis were performed in this study. Unacceptable toxicities were defined as aplasia duration ≥ 45 days and/or unusual grade 3/4 toxicities. Lowest Toxic Dose was defined as the occurence of unacceptable toxicities in ≥2/6 pts per cohort. Maximum Tolerated Dose defined the recommended dose i.e dose level at which 1 or less than 1 unacceptable toxicity occured in 6 pts. Pts aged ≥18 years with CML myeloid BC were eligible if not previously exposed to IM (n=6 pts evaluable for toxicity in each cohort). 20 pts (median age 55 range 29–74) have been enrolled, 19 pts being evaluable (1 pt with lymphoid BC was excluded). Median follow up is 9 months. Grade 3 to 4 non haematological toxicities were hepatitis not related to IM (n=1, dose level 1), spleen pain (n=1, dose level 2), hyperbilirubinemia (n=1, dose level 2) and skin rash (n=1, dose level 3). All responding pts had a neutrophil recovery before D45 (median duration of neutropenia 16 days, range 1–44); one pt in cohort 3 experienced a thrombocytopenia (< 100 G/l) for longer than 45 days leading to recommend the 30 mg/sq dosage of daunorubicin for the further pts included in the study. CHR was achieved in 45% (n=9) of cases, including 5 pts in complete cytogenetic response(CCR). Median CHR duration was 5 months (range 0,5–16+ months). 1 pt received allogenic bone marrow transplantation in CR. During this first part of the trial 10 deaths were recorded with a 12 months estimated survival of 52% (95%CI: 26–77): 2 deaths were due to disease progression; 3 occurred early in the course of the disease ( 2 CNS haemorrhage and 1 after splenectomy ); 3 after achieving initial hematologic response ( 1 relapse, 1 septic shock, 1 hepatitis) 2 because of refractory relapse after achieving initial CCR.

Imatinib combined with the classical 3 + 7 induction protocol produce a high rate of haematological remissions in myeloid BC pts. Daunorubicin dosage should be tapered to 30 mg/m² per day to avoid excessive toxicity. Additional pts are currently under treatment with this dosage in order to confirm this recommendation. An update of this trial will be presented.