Combination Treatment with Imatinib and Mitoxantrone/Etoposide Is a Suitable Preparative Regimen before Allogeneic Transplantation in Patients with Myeloid Blast Crisis of Chronic Myeloid Leukemia.

In advanced BCR-ABL-positive leukemia, combination of chemotherapy with imatinib is expected to result in better reduction of leukemia cell load and may delay or offset clonal selection of resistant leukemia cells, thus improving the survival. We carried out a prospective phase I/II combination trial for patients (pts) with myeloid blast crisis of chronic myelogenous leukemia (CML). Pts were treated with imatinib+mitoxantrone/etoposide in four cohorts starting from mitoxantrone 10mg/m²/d and etoposide 100 mg/m²/d for 2 or 3 consecutive days and start of imatinib 600mg/d from day 15 (coh. 1 and 2) or from day 1 (coh. 3 and 4, respectively). After hematologic reconstitution following the cytopenic phase, cytarabine was administered at a dose of 10mg/m²/d s.c. in addition to imatinib as maintenance treatment.

A total of 16 pts (8 m, 8 f) are available for analysis, median age 59 years (range 37–74). All pts who received more intensive induction treatment (coh. 3 and 4, n=7) achieved a hematologic response (HR). In contrast, HR was achieved in 6 of 9 pts treated in coh. 1 and 2. The induction treatment was well tolerated with a treatment-related mortality rate of 12.5% (1 intracranial hemorrhage in coh. 1, and 1 pneumonia in coh. 4).

A median of 8 (2–18) red blood cell concentrates and a median of 5 (1–8) platelet concentrates were required. Antibiotic treatment for febrile episodes was administered for a median of 10d (0–38). Of note, CTC grade 3 or grade 4 mucositis did not occur. Pts who received imatinib on day 1 (coh. 3–4) had a longer duration of severe leukopenia (WBC <1/nl) with a median of 19 days (0–23) vs. 2 (0–14) but without increase of infection incidence.

Six pts who achieved HR received an allogeneic stem cell transplantation with myeloablative conditioning. Three of 6 transplanted patients are alive and in complete cytogenetic remission at 735, 723, and 279 days after initiation of study treatment. Two patients died of transplant-related complications (GvHD and sepsis), 1 patient died from hematologic relapse. Of 10 pts who received only conventional treatment, 1 (coh. 1) is still alive and in a complete cytogenetic remission at day 1280 after initiation of study treatment. Median survival of transplanted pts was 486 days, and 142 days in the group with conventional treatment only (p=0.078).

We conclude that the combination of mitoxantrone/etoposide and imatinib is a well tolerated induction protocol with mild non-hematological toxicity even in older patients. Eligible pts have an advantage from an allogeneic stem cell transplantation following response to the induction treatment.