Combined Chemotherapy (daunorubicin + cytarabine) and Dasatinib as Salvage Therapy of Chronic Myeloid Leukemia (CML) in Myeloid Blast Crisis, a Pilot Study.

Abstract 2195

Poster Board II-172

The results of the treatment of blast crisis CML remain still disappointing with poor overall survival rates, despite the introduction of imatinib (IM) in the therapeutic arsenal of Ph+ leukemias. This compound alone provides 24% of overall initial hematologic responses in myeloid blast crisis (MBC) IM-naive patients (pts), with 7 months of median overall survival rates. Dasatinib remains disappointing with 34% of major hematological responses (MaHRs, Cortes, Blood, 2007) in IM-resistant pts. The combination of IM to daunorubicin (3 days) and cytarabine (7 days) AML schedule (“3+7”) might improve responses and survival rates with 55.5 % of complete remissions (CR) and a median overall survival of 15.9 months (B. Deau, submitted).

In this preliminary pilot study, we proposed to test the combination of daunorubicin + cytarabine to dasatinib in MBC CML in order to improve outcome. Fifteen patients have been enrolled [8M, 7F, median age at diagnosis 45 (28-64) years]. Prior to enrollment, 5 pts were in chronic phase (CP), 2 in accelerated phase (AccP) on IM. Eight pts were in MBC at diagnosis, and IM-naive. Additional chromosomal abnormalities (ACA) were present at diagnosis in 5 pts [+8 (2 pts), +21 (2 pts), t(3;21) (1 pt), add(1) (1 pt), complex abnormalities (1 pt), variant Ph (2 pts)]. For CP pts Sokal index was low for 2, intermediate for 1, unknown for 2, and none had any additional chromosomal abnormality at diagnosis. One patient had an e1a2 transcript, others a M-BCR transcript. Nine pts/15 had IM prior to combined therapy [best responses to IM prior to MBC were for 5 pts in CP: 3 complete hematologic remissions (CHR), 2 major molecular responses (MMR), for 2 pts in AccP: 2 CHR, for 2 in MBC: 1 complete cytogenetic remission (CCR) and 1 hematologic response (HR)]. In these 9 pts, 1 developed IM hematologic resistance in CP, 5 cytogenetic resistance, 1 molecular progression, and 2 entered MBC. Nine were screened for BCR-ABL mutations and only one was harboring a G250E mutation. The median interval between IM start and progression to MBC was 27 (1.1-65) months. Only 2 pts were exposed to dasatinib prior to combined therapy.

At MBC, 7/15 pts had ACA, 10/15 screened were unmutated, 3 mutated (G250E, and 2 unknown). The pts received a median dose of 60 mg/m²/d of daunorubicin 3 days + a median dose of 200 mg/m²/d of cytarabine for 7 days and a median dose of 140 mg/d of dasatinib starting at day 1. Eight pts/15 had G-CSF after induction chemotherapy as planned by the study, for a median of 18 (5-28) days. The induction chemotherapy was well tolerated with no pleural effusions or other particular toxicities. A median of 37 days of neutropenia (<0.5 G/l) and 27 days of thrombocytopenia (<20 G/l) since day 1 were observed, and a median of 8 (3-38) RBC transfusions and 10 (4-45) platelets transfusions were necessary. One patient remained aplastic until allogeneic transplantation. No particular infection occurred. Complete remission (CR) was obtained in 8/15 and non evidence of leukemia in 3/15 resulting in a MaHR rate of 73%. The median BCR-ABL/ABL (IS) ratio was 6 (0.04-62)% and CCR was documented in 3/15 pts. Six pts had various courses of consolidation therapy (dasatinib in all cases + anthracyclin + cytarabine in 5). Ten pts/15 could be referred for allogeneic stem cell transplantation (5 MUD, 1 haplo-identical, 3 cord blood, 1 related, 6 conventional, 4 reduced intensity). The median delay between day 1 combined therapy and transplant was 5 (2.9-5.4) months. In evaluable pts, acute GVHD did not occur in 4 pts (1 grade 2, 4 unknown). At 3 months post-transplant 4/8 evaluable pts were in CHR, 3 in complete molecular remission, 2 in CCR. With a median follow-up since combined chemotherapy of 8 (1-20.9) months, 6/15 (40%) pts are alive (4 in CMR, 2 in MMR). The median overall survival (OS) since MBC onset was 12.3 months as shown in figure 1 (dashed lines are 95% CI), but did not significantly differ between transplanted and untransplanted patients (12.3 vs 4.8 months respectively, p=0.604) in this small series of pts heterogeneously transplanted. In addition the OS was not different between pts previously submitted to IM or not (p=0.87).

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This strategy provides encouraging initial results compared to TKIs alone, without specific toxicity, however, it does not translate into survival improvement, but might still represent a suitable preparative regimen for allogeneic transplant whenever it is possible.