The c-kit (CD117) receptor is expressed on > 10% blasts in 64% of de novo AMLs and mediates proliferation and anti-apoptotic effects. High c-kit levels correlate with a shorter time to relapse and decreased overall survival (OS). Imatinib mesylate (IM), a c-kit inhibitor, has activity against relapsed/refractory AML. The primary objective of this study was to determine whether adding maintenance IM for 1 yr after completion of standard induction (IT) and post-remission therapy (PRT) in patients (pts) with newly diagnosed c-kit+ AML improves relapse-free survival (RFS) compared to historical controls. Secondary objectives included: (1) assessing the feasibility of this approach; (2) evaluating outcomes based on c-kit expression (c-kit mean fluorescent intensity [MFI]); (3) determining whether c-kit expression correlates with AF1q gene and/or multi-drug resistance (MDR) gene expression.
Pts were treated at Cleveland Clinic, Duke, Roswell Park, and University Hospitals of Cleveland from 2008 to 2012. IM was supplied by Novartis. Eligibility criteria included: pts age ≥ 18 yrs, AML in first complete remission (CR1), ≥ 20% c-kit+ blasts at diagnosis (dx), ECOG performance status 0–2. Cytogenetics (CG) were classified by CALGB 8461. Pts must have received IT (7+3 [continuous infusion cytarabine (C) and an anthracycline] or ADE [C, daunorubicin, etoposide]) and PRT (≥ 1 course for pts > 60 yrs; ≥ 2 courses for pts < 60 yrs). CR status was confirmed by bone marrow analysis prior to study enrollment. MDR expression was analyzed by immunohistochemistry on diagnostic samples (n=19); AF1q gene expression was analyzed by RT-PCR on RNA from available diagnostic pt samples (n=9) as previously described (Tse et al. Blood 2004; 104: 3058–63). C-kit MFI was calculated as the mean channel number (MCN) of the blasts/MCN autofluorescence using a CD45/orthogonal light scatter gate to isolate blasts. All pts received IM 600 mg/day for 12 months (mos) unless they experienced toxicity or disease progression. Dose modifications were made for Grades 2–4 non-hematologic toxicity and Grades 3–4 neutropenia and thrombocytopenia. Pts remaining off IM for > 4 wks were removed from treatment. Cumulative dose intensity was defined as the proportion of the total optimum dose administered over time.
Thirty-three pts were enrolled, with 32 pts having complete data. The median age was 54 yrs (range 19–81), median WBC at dx 22.13 K/μL (1.55–98.44), median peripheral blood blasts at dx 23.6% (range 0–85), and 44% were male. CG risk included: 47% (15) good, 31% (10) intermediate, and 22% (7) poor. The median c-kit % was 79.9, and median c-kit MFI 39.8 (range 6.5–120.1). Median AF1q expression was 9.59 (range 1.83–161.8.5). Eighty-four percent of pts had moderate or high levels of MDR expression (GSTP1, MDR1, LRP1, and/or MRP1); almost half (47%) had high expression. The majority of pts (74%, n=20) received PRT with high dose C (3 g/m2/dose × 6 doses/cycle). Pts received IM for a median of 4.0 mos (range 0.1–12.2), and the median daily dose was 600 mg. Twelve pts (38%) were dose reduced to 400 mg. Forty-five percent (13/29) of pts experienced grade 3 reactions possibly related to treatment, with the majority (31%) being myelosuppression. The most commonly reported adverse events were Grade 1/2 nausea and vomiting (72%), edema (59%), and fatigue (41%). Twelve pts (38%) discontinued treatment for adverse events. The median RFS survival is 18.8 mos, with a median follow-up of 19.1 mos (range 6.4–37.2). Estimated 2-yr OS is 62% ± 10%. Predictors of RFS included: age, WBC at dx, % peripheral blasts at dx, and CG risk. Dose intensity of IM did not correlate with outcome. AF1q and MDR expression did not correlate with c-kit MFI; although the number of pts with AF1q data was small. Of note, neither c-kit MFI nor AF1q expression were prognostic in this subset of pts treated with IM. With the exception of LRP1 expression (p=0.03), there was no correlation of MDR expression with RFS.
Previous studies have demonstrated that c-kit MFI > 20.3 is an independent adverse prognostic factor for RFS and OS (median RFS 10.7 months). Considering the high c-kit MFI of pts in this study, the outcomes using IM maintenance are encouraging, and suggest that further study of this approach is warranted. Given the toxicities observed, reducing the dose of IM to 400 mg in the maintenance setting may be better tolerated.
Advani:Novartis: Research Funding. Rizzieri:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kalaycio:Novartis: Research Funding, Speakers Bureau. Maciejewski:Novartis: Research Funding.
Asterisk with author names denotes non-ASH members.