Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome

Abstract

We investigated the combination of midostaurin and azacitidine (AZA) in patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). Patients received AZA 75 mg m(-2) on days 1-7 and midostaurin 25 mg bid (in cohort 1 of phase I) or 50 mg bid (in cohort 2 of Phase I and in Phase II) orally on day 8-21 during the first cycle and continuously thereafter. Fourteen patients were enrolled in the phase I and 40 in the phase II. Overall response rate was 26%. The median remission duration (RD) was 20 weeks and was significantly longer in patients with FLT3 mutations not previously exposed to other FLT3 inhibitors (P = 0.05) and in patients not previously transplanted (P = 0.01). Thirty-two (59%) patients have died, all of complications related to disease progression. G3-4 nonhematological toxicity was reported in 38 (70%) patients, most frequently infections (56%), ejection fraction reduction (11%), and diarrhea or nausea/vomiting (9% each). The combination of midostaurin and AZA is an effective and safe regimen in patients with AML and high-risk MDS. Patients with FLT3 mutations but not previously exposed to other FLT3 inhibitors and patients not previously transplanted derived the greatest benefit. Further studies with this combination are warranted.

Figure 1

Bone marrow and peripheral blood blast change. A. Median change in bone marrow blasts at time of best response to therapy. Thirty-eight patients had a reduction in BM blasts from median 57% (range, 9–93%) to 13% (range, 2–63%) and 25 (53%) patients had a ≥50% reduction. Ten patients had stable or increasing BM blasts from 38% (range, 7–68%) to 48% (range, 34–89%). B. Median change in peripheral blasts at time of best response to therapy. Forty-seven (96%) patients had a reduction in peripheral blasts from a median at baseline of 41 % (range, 1–100%) to a median of 1% (range, 0–98%) and 41 (84%) patients had a reduction ≥50%. Two patients had a stable/worsening peripheral blood disease, with an increase from to 2% to 4%, and from 51 to 52%, respectively.

Figure 2

Pharmacokinetics of midostaurin and its metabolites during cycle 1. Midostaurin and the metabolites levels rose rapidly over one week of treatment. Then the concentrations of midostaurin and CGP62221 reached steady state, whereas concentrations of CGP52421 continued to increase.

Figure 3

Plasma Inhibitory Assay (PIA). A. Plasma was collected prior to therapy and on day 15. Molm14 cells were exposed for 1 hour to the plasma samples, followed by lysis and immunoblot analysis for phosphorylated FLT3 (upper gels) and total FLT3 (lower gels). Shown are the results from three different patients on the study. B. Densitometric analysis compared the day 15 sample to the pretreatment sample. The mean level of FLT phosphorylation (49%, range 21–74%) is shown relative to baseline. P-FLT3, phosphorylated FLT3.

Figure 4

Response duration (RD) among 14 patients responsive to therapy. A. A longer RD was observed for patients with FLT3 mutations previously unexposed to other FLT3 inhibitors (31 vs 16 weeks, p=0.05). B. A longer RD was observed for patients who had not previously received a SCT (31 vs 6 weeks, p=0.01). RD, response duration; n, number; U/E, previously unexposed/exposed to other FLT3 inhibitors; SCT, stem cell transplant; +, mutated.