Among the prognostic cytogenetic and molecular aberrations in AML, t(8;21)(q22;q22) and inv(16)(p13q22) and their corresponding molecular rearrangements RUNX1/RUNX1T1 and CBFB/MYH11 (each involving a gene encoding a protein chain of the key transctiption factor CBF), predict for a favorable outcome in pts receiving consolidation with high-dose cytarabine (HiDAC) after achievement of complete remission (CR). However, approximately 40% of these pts eventually relapse. Approximately 25% of CBF AML pts carry gain-of function mutations in the KIT gene. These mutations result in a constitutively active tyrosine kinase (TK) that contributes to aggressive leukemia growth, and is associated with unfavorable outcome. In addition, CBF AML pts with wild type KIT overexpress this protein, and this is also associated with an inferior outcome. Therefore, inhibiting KIT with DAS is a rational therapeutic strategy in CBF AML.

We report here on a phase II trial that combined DAS with standard chemotherapy for CBF AML. Enrollment required molecular confirmation of CBF AML by the Alliance Molecular Pathology central lab using RT-PCR and Sanger sequencing-based assays. Overall, 779 patients were screened for CBF; 69 were found to be CBF-positive and 61 were subsequently enrolled. Newly diagnosed RUNX1/RUNX1T1 or CBFB/MYH11-positive pts received induction chemotherapy with cytarabine (C) 200 mg/m2/day continuous intravenous (IV) infusion on days 1-7, daunorubicin (DNR) 60 mg/m2/d IV bolus on days 1-3 and DAS 100 mg/d PO on days 8-21. Pts with residual disease (>5% blasts) on day 21 after first induction received a re-induction treatment with same doses of C on days 1-5, DNR on days 1-3 and DAS on days 6-19. Pts who achieved CR received consolidation therapy with HiDAC 3000 mg/m2 over 3 hours (if <60 yrs old) or 1000 m/m2 (if older) q12h on days 1,3,5 and DAS 100 mg/d PO on days 6-26 x 4 courses. Pts who remained in CR after consolidation treatments received continuation treatment with DAS 100mg/d PO x 12 months. The primary goal of this study was to insure that the CR rate and survival during induction were not inferior to historical outcomes.

Between April 2011 and January 2013, we completed the planned accrual of 61 adult CBF AML pts. Median age was 51 years (yrs; range: 19.6 to 85 yrs), and 15 pts (24%) were older (>60 yrs). Half of pts were male (51%) and a majority were Caucasian (75%). Of all 61 pts, 65% were CBFB/MYH11-positive and 35% were RUNX1/RUNX1T1-positive. Treatment was started on average 4 days from molecular diagnosis (range: 0 to 11 days). To date, 51% of pts are still undergoing treatment; 4 pts died on treatment (2 older), 7 (4 older) had an adverse event requiring treatment interruption, and 6 refused to complete the treatment (mainly the continuation component). Observed toxicities were those expected with C and DNR (hematologic and non-hematologic) and with DAS (nausea, liver toxicity). 55 pts are currently evaluable for treatment-related toxicity. The most common grade 4 toxicities were sepsis (5), acute kidney injury (3), and respiratory failure (3). Grade 5 toxicities included respiratory failure (1) and sepsis (2). Two of these pts died during induction (respiratory failure, sepsis); both were older and CBFB/MYH11. One pt died from sepsis during consolidation in CR (CBFB/MYH11, 48 yrs). The 30-day survival rate was 97% (95% CI: 89% to 99.6%) overall (98% in younger and 93% in older pts).

Of 59 pts currently evaluable for response, 54 (92% of all pts; 96% younger and 80% older) achieved CR. Of the 5 patients who failed to achieve CR, 2 had RUNX1/RUNX1T1 and 3 had CBFB/MYH11. Among the 54 CR pts, no younger pt has relapsed, while 2 older pts with CBFB/MYH11 have relapsed. The median follow-up (f/u) was 11.2 months (range: 1.2 to 23.2 mos.). The 1-yr DFS and OS rates were respectively 90% and 87% for all pts; 97% and 95% for younger pts, and 63% and 62% for older pts, respectively.

Early results from this study show that 1) rapid screening for CBF AML is feasible within a cooperative group, 2) DAS plus chemotherapy in CBF AML pts is tolerable including in older pts, and 3) the initial clinical outcomes are at least comparable to those historically observed in this patient population. Patients continue to be followed for survival endpoints. Molecular characterization for KIT mutations and expression levels of marrow and blood blasts is ongoing and will be correlated with toxicity and clinical outcome.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

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