Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia

Abstract

We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362).

Conflict of interest statement

RTM discloses honoraria from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics; Board of Directors membership at Novartis Pharmaceuticals Corporation; consultancies with Incyte and Juno Therapeutics; and patents and royalties from Athersys, Inc; as an OHSU employee who provided and received payment for consultancy services to Novartis Pharmaceuticals Corporation, this potential conflict of interest has been reviewed and managed by OHSU. ML discloses consultancy with Novartis Pharmaceuticals Corporation, Astellas, and Daiichi Sankyo; research funding from Novartis Pharmaceuticals Corporation, Astellas, and Fujifilm; and honoraria from Novartis Pharmaceuticals Corporation. MMP discloses advisory board membership with Stemline. BLS discloses consultancy with Acceleron, Incyte, Agios, Celgene, and Alexion and research funding from Novartis Pharmaceuticals Corporation and Celgene. SRM has nothing to disclose. AD discloses consultancies with Kite Therapeutics and Novartis Pharmaceuticals Corporation. SDR has nothing to disclose. DDHK discloses consultancies with Novartis Pharmaceuticals Corporation, Bristol-Meyers Squibb, Paladin, and Pfizer and honoraria and research funding from Novartis Pharmaceuticals Corporation and Bristol-Meyers Squibb. DH and TR have nothing to disclose. KH discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Regeneron Pharmaceuticals, Inc. GB and DP disclose employment with Novartis Pharmaceuticals Corporation. PR discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Target CW. HFF discloses honoraria from Pfizer and Sanofi and speakers’ bureau membership with Sanofi.

Figures

Fig. 1. CONSORT diagram.

AE adverse event, alloHSCT allogeneic hematopoietic stem cell transplant, SOC, standard of care. aA single patient might have had >1 reason for screen failure. bEarly termination due to work schedule conflicts. cPatients lost to follow-up (n = 2), early termination due to hospitalization at outside facility (n = 1), and early termination due to large travel distance (n = 1).

Fig. 2. Outcomes after alloHSCT.

Kaplan–Meier curves of A RFS by treatment arm at 18 months after undergoing alloHSCT and B OS by treatment arm at 24 months after undergoing alloHSCT. Blue, midostaurin + SOC; red, SOC. Tick marks indicate censoring of data. alloHSCT allogeneic hematopoietic stem cell transplant, HR hazard ratio, OS overall survival, RFS relapse-free survival, SOC standard of care. aMedian RFS was not reached. bLog-rank P value. cMedian OS was not reached.

Fig. 3. Correlation between exploratory biomarker analyses and clinical outcomes.

A Median FLT3 ligand levels and B median P-FLT3 levels relative to baseline and concurrent combined levels of midostaurin and its metabolites in patients who received midostaurin + SOC. Median P-FLT3 levels were 70% of baseline at C3D1. C RFS and D OS at 24 months after alloHSCT in patients who received midostaurin + SOC stratified by P-FLT3 level (<70% vs >70%). C cycle; D day; FLT3, fms-like tyrosine kinase 3; M midostaurin, P-FLT3 phosphorylated FLT3, OS overall survival, RFS relapse-free survival, SOC standard of care. aFor this analysis, RFS was defined as time from transplant to relapse or death from any cause. bLog-rank P value vs SOC (n = 28). cPatients who reached C3D1 and received midostaurin + SOC (n = 28) were stratified according to FLT3 inhibition levels above or below the median (median P-FLT3, 70%). FLT3 inhibition was higher in patients with P-FLT3 levels <70% of baseline. dP-FLT3 > 70% includes patients with missing P-FLT3 at C3D1.