Photo © ASCO/Danny Morton 2017
Lobby of McCormick Place during ASCO 2017
CHICAGO—Next generation sequencing (NGS) has shown that the FLT3 inhibitor gilteritinib can produce deep molecular responses in a subset of patients with acute myeloid leukemia (AML), according to new research.
Gilteritinib is a highly selective FLT3/AXL inhibitor that is active against FLT3-ITD and FLT3-D835 mutations, but minimal residual disease (MRD) had not systematically been assessed previously in AML patients treated with potent FLT3 inhibitors.
Investigators believed that MRD evaluation in these patients could serve as a useful marker of FLT3 inhibitor efficacy. They therefore conducted an exploratory analysis of a subset of AML patients treated with gilteritinib on the Chrysalis study.
Jessica K. Altman, MD, of the Robert H. Lurie Cancer Center of Northwestern University in Chicago, Illinois, presented the findings at the ASCO 2017 Annual Meeting (abstract 7003).
Chrysalis study: Efficacy and survival
The phase 1/2 Chrysalis study examined the tolerability and antileukemic activity of once daily gilteritinib in a FLT3-ITD-enriched relapsed/refractory AML population of approximately 250 patients.
Overall, gilteritinib was well tolerated and had consistency and potent FLT3 inhibition at doses of >80 mg/day.
The maximum tolerated dose was 300 mg/day. Dose-limiting toxicities were diarrhea and liver function abnormalities.
The greatest overall response rate was 52% and the longest median overall survival (OS) duration was 31 weeks, observed in patients at doses >80 mg/day.
The composite complete remission (CR) rate, comprised of CR, CR with incomplete count recovery (Cri), and CR with incomplete platelet recovery (CRp), was 41%.
The median OS was 31 weeks, and median duration of response 20 weeks.
“Survival probabilities demonstrated that the overall survival for patients who received 80 mg of gilteritinib was higher than those who received less than 80 mg,” Dr Altman said.
Molecular response assessment
Dr Altman then presented the molecular response assessment.
The investigators included all FLT3-ITD mutated patients enrolled in the gilteritinib 120 and 200 mg/day dose cohorts and had bone marrow aspirates available at baseline and at 1 or more additional time points.
“The group I’m reporting on,” Dr Altman explained, “comprises 51% of all FLT3-ITD mutated patients treated at these 2 dose levels.”
FLT3-ITD and total FLT3 alleles were quantified by a novel NGS assay using an Illumina® sequencing platform. Read depth of at least 100,000 reads per sample were implemented.
“Evaluation of MRD was exploratory and it was not prespecified in the study,” Dr Altman noted.
Hence, the investigators defined a molecular response as an ITD signal ratio—FLT3-ITD : FLT3 total—of <10-2.
They defined major molecular response (MMR) as an ITD signal ratio of <10-3, and negative MRD status as <10-4.
Patient characteristics
Baseline characteristics of the 80 patients in the MRD analysis group were similar to those of the entire Chrysalis study population.
Median age was 61 years (range, 23 – 86) and the patients were heavily pretreated: 35% had 3 or more prior lines of AML therapy, and 28% had received a prior FLT3 inhibitor. About a third had prior allogeneic hematopoietic stem cell transplant.
Molecular response
Median OS in this cohort was 32.6 weeks, very similar to the entire study population.
Twenty patients (25%) achieved a molecular response, 18 (23%) an MMR, and 13 (16%) were MRD negative.
The median time to achieve a minimum ITD signal ratio was 8.2 weeks (range, 3.7 – 64).
And molecular response correlated with improved OS.
“The 20 patients who achieved a molecular response had a median overall survival of 59.6 weeks,” Dr Altman said, “which is statistically significantly different and I think clinically different than those who did not attain a molecular response.”
Patients who did not achieve a molecular response had a median overall survival of 28.4 weeks.
“As you could predict,” she added, “the molecular response was greater in those who attained a complete remission than those who had a CRp or Cri.”
Investigators observed similar results in patients who achieved an MMR, using the the cutoff point of 10-3.
“When we stratified by MRD negative status,” she said, “which was an ITD signal ratio of 10-4 or better, there’s clear separation of the Kaplan Meier curves for OS in this cohort again.”
Dr Altman pointed out that this was the first clinical trial to demonstrate that patients with AML treated with a FLT3 inhibitor can attain a molecular response.
“Also, and importantly, there is now a sensitive and specific assay for the detection of minimal residual disease in FLT3-ITD mutated patients and it has the potential to be widely adopted across trials and in clinical practice.”
MRD is prospectively being evaluated in 2 gilteritinib phase 3 maintenance studies.
The trial was sponsored by Astellas Pharma Global Development, Inc.
