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The outcome in CBF-AML [AML with t(8;21)(q22;q22) or inv(16)(p13.1q22) or t(16;16)(p13.1;q22)] has been largely improved by using repetitive cycles of high-dose cytarabine (HiDAC) for postremission treatment. However, still only half of the CBF-AML patients (pts) have a favorable long term outcome, indicating the need for improved therapeutic approaches. Dasatinib (DAS) is a multikinase inhibitor with activity against the KIT kinase, which is highly expressed in CBF-AML and mutated in around one third of the cases. In preclinical studies DAS inhibited growth and survival of AML progenitor cells, enhanced the sensitivity to chemotherapy and induced in vitro differentiation of AML cells (Dos Santos et al., Blood 2013; Fang et al., PLoS One 2013). Anecdotally, DAS also induced differentiation of blasts in an AML patient with t(8;21) after single-drug treatment (Chevalier et al., Leukemia 2010).

The primary endpoint in the open-label AMLSG 11-08 study (NCT00850382) was to assess the feasibility of DAS after intensive induction and postremission chemotherapy, and as single agent in 1-year maintenance therapy in pts with newly diagnosed CBF-AML.

Adults [≥18 years (yrs)] with CBF-AML received induction with daunorubicin (60 mg/m²/d, d1-3) and cytarabine (200 mg/m²/d, d1-7); DAS 100 mg/d was added on days 8-21; pts with partial remission could receive a second induction cycle. Pts achieving a complete remission (CR) or CR with incomplete hematologic recovery (CRi), were intended to receive four cycles of HiDAC [cytarabine 3 g/m² (in pts >60 yrs 1 g/m²) q12h, d1,3,5); DAS 100 mg/d was added on days 6-28 of each cycle. Maintenance with DAS 100 mg/d was continued for 1 year after completion of chemotherapy or until relapse.

Eighty-nine pts [median age 48.5 yrs; males, n=47; t(8;21), n=37; inv(16), n=52] were included in the study. The median baseline WBC in AML with t(8;21) and inv(16) was 9.2 Giga (G)/l and 34.1 G/l, respectively. The current median follow-up is 2.9 yrs. The overall CR/CRi rate was 93% (83/89); CR/CRi rate in AML with t(8;21) and inv(16) was 94% and 92%, respectively. Overall, there were 2 cases with refractory disease and 5 cases with early/hypoplastic death. The median time until recovery of neutrophils (>0.5 G/l) and platelets (>20 G/l) after induction cycles was 27d and 23d, respectively, and after the consolidation cycles 22d and 21d, respectively. To date, a total of 64 serious adverse events (SAEs) with suspected causal relationship to DAS have been reported. Among them the most frequent SAEs were infection-related (n=23); they only rarely occurred during maintenance phase (n=2). Pleural/pericardial effusion and liver toxicity CTC ≥3° was reported in 11% (10/89) and 10% (9/89) of the pts, respectively. There was no significant difference in event-free (EFS) and relapse-free survival between AML with t(8;21) and inv(16), but overall survival (OS) was superior (P=.04) in AML with inv(16) (OS at 3-yrs: 80.5% vs 63.4%). When compared with an AMLSG historical control group, there was an improvement in EFS (P=.04), but so far not for OS (P=.4).

There was no unexpected excess in toxicity by the addition of DAS to intensive induction and postremission therapy as well as of single-agent maintenance. The preliminary data indicate efficacy of the treatment when compared to historical controls. Based on the favorable toxicity profile and the encouraging efficacy data, a confirmatory phase III trial with DAS (AMLSG 21-13; NCT02013648) has been initiated.