An Open-Label, Phase I Study of Dasatinib in Combination with Decitabine in Patients (Pts) with Accelerated or Blastic Phase Chronic Myeloid Leukemia (CML)

Background: Current treatment for advanced phase CML remains unsatisfactory. Dasatinib induces major cytogenetic response (MCyR) in 31% and 37% of pts with imatinib-resistant or -intolerant accelerated (AP) and blast phase (BP), respectively (Cortes 2007). Hypermethylation is associated with disease progression in CML. In pts with imatinib-refractory CML-AP and CML-BP, low dose decitabine induced MCyR in 12% and 17% of pts, respectively, with similar rates achieved combining decitabine with imatinib (Issa 2005, Oki 2007). The reported synergy between imatinib and decitabine depends upon residual sensitivity to imatinib (La Rosee 2004). We investigated whether improved responses might be achieved through synergy between dasatinib, a 2^nd generation tyrosine kinase inhibitor (TKI) and decitabine.

Methods: Pts age 18 years or older with CML-AP, CML-BP, or Philadelphia chromosome (+) acute myeloid leukemia (Ph+AML) were enrolled in this phase 1 study regardless of previous TKI therapy. Pts were assigned to 2 schedules using a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). The starting schedule was decitabine 10mg/m² daily for 10 days and dasatinib 100 mg orally daily (schedule A), and decitabine 20mg/m² daily for 10 days with dasatinib 100 mg (schedule B). The next dose level (target dose) was decitabine 10mg/m² daily for 10 days (schedule A) or 20 mg/m² daily for 10 days (schedule B) with dasatinib 140 mg orally daily. The primary objective was to determine the MTD of the combination. The secondary objectives are to determine the rate of overall hematologic response (OHR) (2 cycles required to be evaluable for response), response duration (RD), overall survival (OS), and toxicity profile. OHR includes complete hematologic response (CHR), no evidence of leukemia (NEL), and minor hematologic response (MiHR). CHR is defined as normal WBC, no blasts or promyelocytes in peripheral blood (PB), ANC ≥1x10⁹/L, platelets >100 x10⁹/L, PB basophils < 5%, ≤ 5% blasts in bone marrow (BM), and no extra-medullary disease. NEL is the same criteria as CHR except for platelets between ≥ 20 x10⁹/L and <100x10⁹/L or ANC between ≥ 0.5x10⁹/L and < 1x10⁹/L. MiHR is defined as <15% blasts in PB and BM, <30% blasts + promyelocytes in BM and PB, <20% basophils in PB, and no extra-medullary disease.

Results: A total of 15 pts were enrolled (2 AP, 11 BP, 2 Ph+AML); 13 were evaluable for response. The remaining 2 pts were not evaluable for response since they did not complete 2 cycles of therapy as defined in the protocol, due to drug toxicity (n=1) and insurance issues (n=1). Eleven pts had received prior TKI therapy with a median of 1 TKI per pt (range, 1-4). Two pts had a kinase domain mutation (V299L, E255K); one other patient had a 162 bp deletion. No DLT was observed at the starting dose level for either schedule. The MTD was thus established at decitabine 10mg/m² and dasatinib 140 mg at which 1 of 6 pts treated experienced dose-limiting toxicity (DLT) in the form of grade 3 heart failure considered possibly related to dasatinib. Pts received a median of 2 treatment cycles (range 1-10) and 2 pts are still receiving study therapy. Nine (69%) pts achieved OHR (4 CHR, 2NEL, 3 MiHR). A MCyR was achieved by 38% (5/13). In addition, 1 pt achieved MCyR after stem cell transplantation (SCT) (CHR with DAC + dasatinib prior to SCT). Median duration of OHR was not reached (RD for each of the 9 pts was 4, 1, 31+, 2, 3, 1, 18+, 2+, 3+ months, respectively). Median OS was 12 months (95% CI: 2.3- not reached). A total of nine (60%) pts died, all due to disease progression. Two pts have ongoing complete cytogenetic response with combination therapy (for 7+ and 10+ cycles, respectively). The remaining 4 surviving pts all received SCT. Two of them had achieved MCyR, 1 CHR, and 1 MiHR with DAC + dasatinib prior to SCT. Grade 3-4 nonhematological toxicity was reported in 13 (87%) pts, most frequent toxicities being infections (27%), bleeding (20%), and acute renal failure (20%).

Conclusion: Combination therapy with decitabine and dasatinib is well tolerated and active in advanced phase CML. A phase 2 portion of the study has opened now to determine the efficacy of this combination and whether there is a difference in outcome by treatment schedule.