Adding KIT Inhibitor Dasatinib (DAS) to Chemotherapy Overcomes the Negative Impact of KIT Mutation/over-Expression in Core Binding Factor (CBF) Acute Myeloid Leukemia (AML): Results from CALGB 10801 (Alliance)
Authors: Marcucci Guido , Geyer Susan , Zhao Weiqiang , Caroll Andrew J , Bucci Donna , Uy Geoffrey L. , Blum William , Pardee Timothy , Wetzler Meir , Stock Wendy , Kolitz Jonathan E. , Eisfeld Ann-Kathrin , Bloomfield Clara D. , Stone Richard M. , Larson Richard A. 
Published: October 2019

In AML, t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22) and corresponding molecular rearrangements RUNX1/RUNX1T1 and CBFB/MYH11 (each involving a gene encoding a subunit of CBF) predict for favorable outcome in patients (pts) receiving consolidation with high-dose cytarabine (HiDAC) after achievement of complete remission (CR). However, 40-45% of these pts relapse. The subset of CBF AML pts harboring gain-of function mutations in the KIT gene (25%) and others overexpressing wild type (wt) KIT have inferior outcomes. Therefore, inhibiting KIT with DAS is a rational therapeutic strategy in CBF AML.

We provide updated results (median follow-up 21.3 months (mo); range: 1.8-32.3 mo) for CALGB 10801, a phase II trial that combined DAS with standard chemotherapy for newly diagnosed with CBF AML pts. Enrollment required confirmation of CBF AML by the Alliance Molecular Pathology central lab using RT-PCR and Sanger sequencing-based assays for RUNX1/RUNX1T1 or CBFB/MYH11. Positive pts received induction chemotherapy with cytarabine (C) 200 mg/m2/day continuous intravenous (IV) infusion d (d) 1-7, daunorubicin (DNR) 60 mg/m2/d IV bolus d 1-3 and DAS 100 mg/d PO d 8-21. Pts with residual disease (>5% blasts) on d 21 were re-induced with same doses of C d1-5, DNR d1-3 and DAS d6-19. Pts who achieved CR received consolidation with HiDAC 3000 mg/m2 over 3 hours (if <60 years (yr) old) or 1000 m/m2 (if older) q12h on d1,3,5 and DAS 100 mg/d PO on d6-26 x 4 courses. Pts in CR after consolidation received DAS 100mg/d PO x 12 mo. The primary goals of this study were to ensure the safety of the combination and a CR rate not inferior to historical controls.

Between April 2011 and January 2013, we screened 779 pts and 61 adult CBF AML pts were enrolled. Two pts were excluded from these analyses – one had no follow-up information and one was not molecularly eligible. Median age was 51 yr (range: 19-85 yrs); 14 pts (24%) were older (>60 yr). Fifty-two% of patients were male; 76% were Caucasian. Of the 59 pts, 65% were CBFB/MYH11-positive and 35% were RUNX1/RUNX1T1-positive; 18% of the 56 who were molecularly evaluable harbored KIT-mutated (mut). Treatment (tx) began on average 4 d from molecular diagnosis (range: 0-11 d). Seven pts are still undergoing tx; 4 pts died on tx (2 older), 9 (4 older) had an adverse event (AE) requiring tx interruption, and 8 refused to complete the tx (mainly DAS maintenance).

Observed AEs were those expected with C and DNR (hematologic and non-hematologic) and with DAS (nausea, liver toxicity, pleural effusions). Only 2 and 3 pts had gr4 pleural effusions or increased liver function tests, respectively. Gr 5 AEs included respiratory failure (1) and sepsis (2). Three pts died during induction (2 older CBFB/MYH11 and 1 younger RUNX1/RUNX1T1). One pt died from sepsis during consolidation in CR (CBFB/MYH11, 48 yr). The 30-d survival rate was 97% overall (98% in younger and 93% in older pts).

The outcomes of all pts and molecular subsets are summarized in the Table.

Table Clinical outcomes All (n=59) Younger (n= 45) Older (n= 14) RUNX1/RUNX1T1 (n= 20) CBFB/MYH11 (n= 38) KIT-wt (n=46 ) KIT-mut(n=10 ) CR* (%) 90 93 79 90 89 89 90 Relapseº (%) 17 13 29 20 16 17 20 2-yr DFS# (%) 72 74 65 79 67 72 70 2-yr OS¶ (%) 87 96 61 85 89 86 90 *CR, complete remission; º Relapse rate at any time #DFS, disease-free survival, ¶OS, overall survival

These updated results suggest that 1) rapid molecular screening and treatment-protocol allocation for CBF AML are feasible within a cooperative group, 2) DAS+chemotherapy is tolerable in CBF AML pts of all ages, 3) clinical outcomes for CBF pts receiving DAS+chemotherapy remain at least comparable to those historically observed in CBF pts who received chemotherapy alone; 4) older CBF AML pts seem to benefit from this intensive approach; 5) among pts treated with DAS+chemotherapy, outcomes of KIT-mut pts seem similar to those of KIT-wt pts (see Figure), although we recognize the limitations with relatively small numbers. Pts on CALGB 10801 continue to be followed for survival endpoints. Overall, these results support the continued evaluation of KIT inhibitors in CBF AML through prospective randomized trials but emphasize that further outcome enhancements in this disease subset could be achieved via the use of additional rationally targeted agents.

Figure 1 Figure 1.

Disclosures

Stock: Sigma-Tau: Membership on an entity's Board of Directors or advisory committees, Research Funding. Larson:Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy.