Combination of Dasatinib with Conventional Chemotherapy Is Associated with a High Response Rate in High Risk Acute Myeloid Leukemia (AML)

Background:  High risk AML patients (pts) have poor outcome with low complete remission (CR) rate and long term survival despite intensive chemotherapy.

Tyrosine kinases play an important role in AML pathogenesis. Pre-clinical studies performed in our center (Blood. 2013 122:1900) have shown that Src family tyrosine kinases (SFK) including Lyn, Hck and Fgr are abnormally activated in AML compared to normal hematopoietic stem cell and progenitor cells. Other studies have shown that the c-Kit receptor is over-activated in a subset of AML pts and contributes to abnormal leukemia cell growth. We further show that the small molecule SFK and c-Kit inhibitor dasatinib reduces proliferation and survival of AML stem and progenitor cells. Importantly, dasatinib enhances the sensitivity of AML stem and progenitor cells to chemotherapeutic agents by inhibiting Akt signaling, increasing mdm2 phosphorylation and enhancing p53 activity in AML cells. Based on this data we conducted a phase I/II clinical study of the combination of dasatinib with conventional cytarabine-idarubicin (“7+3”)-based induction chemotherapy in high-risk AML.

Methods: Between September 20013 and July 2015, 18 adult AML pts were enrolled in the study. Eligibility criteria were high-risk AML, age >18 years, and suitability for intensive therapy. High risk AML was defined by one of the following criteria: older age (> 60 yrs), poor-risk cytogenetic and molecular abnormalities (ELN criteria), secondary disease (AML evolving from myelodysplasia or myeloproliferative neoplasm), therapy related (t-AML), or relapsed/refractory.

This Phase I study used a 3 + 3 dose escalation design for dasatinib while keeping a fixed dose of cytarabine and idarubicin (cytarabine 200 mg/m² CIV days 1-7, idarubicin 12 mg/m² IV days 1-3).  Dasatinib was started at a dose of 70 mg (dose level 1; DL-1) days 1-7, and escalated to 100 mg orally days 1-7 (DL 1). Pts who failed to achieve CR received second re-induction with the same regimen. Pts who achieved CR received consolidation high dose cytarabine and/or allogeneic stem cell transplantation (SCT) based on donor availability.

Results: Of the 18 pts enrolled on the study, 7 pts (39%) had secondary AML, 5 pts (28%) relapsed AML, 2 pts (11%) t-AML, and 4 (22%) were newly diagnosed older AML pts (one with complex karyotype, one with trisomy 8 and one cytogenetically normal with FTL3-ITD). The median age of all pts was 62 yrs (range 27-73). Of the 18 pts, 13 pts are currently evaluable for response; of which 10 (77%) achieved CR/Cri.  Of the 5 non-evaluable pts, one pt withdrew from study after 2 days of therapy, one pt was taken off study after 3 days due to cytarabine neurotoxicity, one pt died of intracranial hemorrhage before the day 14 bone marrow biopsy, one pt had therapy interrupted secondary to pneumonia and sepsis, and one is still receiving therapy. None of the pts required more than one induction to achieve CR. Of the 10 pts who achieved CR/Cri, 8 patients went on to receive allogeneic SCT. As expected, the most commonly reported grade 3 and 4 adverse events (AE) were anemia 50%, thrombocytopenia 44%, neutropenia 38%, and fatigue 27%.  The most common grade 1-2 AE were GI toxicities 61% and rash 33%.

Correlative studies performed on blood samples obtained from pts on day 3 after initiation of treatment (n=9) demonstrated significant decrease in of SRC activity (as indicated by reduction in phospho-SRC  levels on immunoblotting, 0.52±0.11 of control, p=0.01),  and increased expression of p53-target genes as evaluated by Q-RT-PCT [including Puma (16.2±6.9 fold, p=0.015), P21 (4.9±1.1 fold, p=0.004),  DR5 (3.4±0.9, p=0.004), Bax (3.7±0.9 fold, p=0.001) and HDM2 (2.1±0.5, p=0.02)].

Conclusion: Combination of dasatinib with conventional “7+3” induction chemotherapy is feasible in high-risk AML and leads to higher CR rate compared to historical data without increase in toxicity rate, allowing more pts to receive allogeneic transplantation. Correlative laboratory studies are consistent with pre-clinical studies suggesting that this combination is associated with significant inhibition of SRC activity and enhanced activation of p53-target genes.