NEW ORLEANSRates of complete remission were promising in patients with FLT3-ITD-positive acute myeloid leukemia (AML) when midostaurin was added to intensive induction therapy, especially in those with unfavorable FLT3-ITD characteristics, investigators reported at the 55th American Society of Hematology Annual Meeting and Exposition.

In the ongoing single-arm phase 2 AMLSG 16-10 trial, Sabine Kayser, MD, of the Department of Internal Medicine III at the University Hospital of Ulm, in Ulm, Germany, and colleagues are evaluating pharmacodynamic activity of the multi-targeted kinase inhibitor, midostaurin (PKC412), measured as inhibition of degree of phosphorylated FLT3 (pFLT3) in correlation to co-medication and outcome data.

Activating mutations in the receptor tyrosine kinase FLT3 occur in approximately 30% of patients with AML, “implicating FLT3 as a potential target for kinase inhibitor therapy,” they noted.

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Midostaurin has shown potent activity against FLT3, both as a single agent and in combination with intensive chemotherapy. “Besides its mere presence, the allelic ratio as well as internal tandem duplication (ITD) insertion site within the FLT3 gene had been reported as prognostic factors in FLT3-ITD positive AML,” Dr. Kayser noted. “Furthermore, pharmacokinetic analyses revealed clinically important interactions between potent CYP3A4 inhibitors, such as azoles, and midostaurin.”

The presence of FLT3-ITD is analyzed by Genescan-based fragment-length analysis, with an allelic ratio greater than 0.05 required to be FLT3-ITD-positive, the investigators stated. Patients receive induction therapy of daunorubicin 60 mg/m2, days 1 to 3, and cytarabine 200 mg/m2 continuously on days 1 to 7. Midostaurin 50 mg twice daily is administered from day 8 onwards until 48 hours prior to initiation of the next treatment cycle.

For consolidation therapy, patients proceed to allogeneic hematopoietic stem cell transplantation (HSCT) as first priority; however, if allogeneic HSCT is not possible, they receive three cycles of age-adapted high-dose cytarabine in combination with midostaurin from day 6 onwards. All patients are scheduled to receive maintenance therapy for 1 year.

To show an improvement in event-free survival from 25% after 2 years to 37.5%, a total sample size of 142 patients is planned. Recruitment started in June 2012 and the last patient is planned for March 2014. Plasma inhibitory activity assay (PIA) for pFLT3 is measured at day 15 of induction therapy, the end of each treatment cycle, and every 3 months during maintenance therapy.

To date, 107 adults with newly diagnosed FLT3-ITD-positive AML have been included in the study; those with acute promyelocytic leukemia are ineligible. Median age is 54 years (range, 20 to 69 years).

PIA has been performed in 37 patients during induction therapy. “Median pFLT3 inhibition after 1 week of midostaurin intake measured on day 15 of cycle 1 (C1D15) was 57.5% (range, 14.2%-93.7%), with two of 31 patients showing inhibition [greater than] 85%,” they reported. At the end of the first induction cycle (C1end), median inhibition was 60.3% (range, 0%-99.8%), with six of 37 patients having inhibition greater than 85%.

Co-medication with azoles was present in seven of 23 patients at C1D15 and in 13 of 28 patients at C1end. No significant difference was observed in pFLT3 inhibition either on C1D15 (P = 0.79) or at C1end (P = 0.70) between patients on (median pFLT3 inhibition: 52.5%) or off (median pFLT3 inhibition: 57.5%) azoles.

Response to induction therapy according to the allelic ratio (n = 74) was 67% (10/15) in the first quartile, 93% (14/15) in the second, 79% (22/28) in the third, and 75% (12/16) in the fourth quartile. Refractory disease was 20% (3/15) in the first, none in the second, 10.5% (3/28) in the third, and 25% (4/16) in the fourth quartile. The early death rate was 13% (2/15) in the first, 7% (1/15) in the second, 10.5% (3/28) in the third, and none in the fourth quartile.

“In first analyses, there was no difference in pFLT3 inhibition in patients achieving complete remission (n=30) as compared to those with refractory disease (n = 3; P = 0.99),” Dr. Kayser noted. The investigators noted this contrasts with previously published data from three historical trials without a FLT3 inhibitor, which showed that high allelic ratio was associated with low complete remission rates.

In this ongoing trial, complete remission rates remained high (81.5%) despite a high allelic ratio above the median (> 0.58). “In addition, we did not see a negative prognostic impact of ITD insertion site within the tyrosine kinase domain of the FLT3 gene (P = 0.99),” Dr. Kayser concluded.

Analyses are currently ongoing that include measurement of FLT3 ligand levels and evaluation of midostaurin pharmacokinetics.