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Targeted Agent Improves Survival in FLT3-Positive Acute Myeloid Leukemia

— OS, EFS improved versus historical controls with addition of midostaurin to chemotherapy

MedpageToday

ATLANTA -- Adding a targeted drug to intensive chemotherapy significantly improved outcomes in FLT3-mutated acute myeloid leukemia (AML) versus historical controls treated with induction chemotherapy and allogeneic stem-cell transplantation (ASCT).

Patients who received the FLT3 inhibitor midostaurin (Rydapt) plus chemotherapy, followed by ASCT and a year of maintenance midostaurin, had almost 50% improvement in event-free survival (EFS) and overall survival (OS) as compared with a historical cohort. Complete response (CR) rate, median EFS, and median OS were 74.9%, 13.6 months, and 36.2 months, respectively.

The magnitude of improvement with the addition of midostaurin was similar in patients ages 18-60 and 61-70, reported Hartmut Döhner, MD, of University Hospital Ulm in Germany, during the American Society of Hematology meeting.

"In comparison to a historical control cohort, the addition of midostaurin to intensive chemotherapy led to a significant improvement in event-free and overall survival, as well as in response rates, in both younger and older patients with AML and FLT3-ITD [internal tandem duplications]," Döhner said in his summary. "Multivariate analysis using propensity score weighting and covariate adjustment identified treatment with midostaurin and presence of NPM1 mutation as favorable prognostic factors, whereas older age, higher white blood cell count, and a trend in FLT3-ITD allelic ration greater than 0.5 were significant unfavorable factors."

"In sensitivity analyses with allogeneic stem-cell transplant, the treatment effect of midostaurin remained significant. Midostaurin was well tolerated, with vascular events, metabolism and nutrition disorders, and a trend in cardiac events occurring more frequently in older patients."

FLT3-ITDs occur in 10-25% of newly diagnosed AML and generally confer , particularly ITDs with a high allelic ratio and without NPM1 mutation. In the trial, the addition of midostaurin to intensive chemotherapy and midostaurin maintenance after ASCT led to improved EFS and OS in patients ages 18-59 with FLT3-mutated AML.

Building on the previous results, the AML Study Group (AMLSG) conducted the of midostaurin with intensive chemotherapy and as maintenance after ASCT and expanded enrollment to include patients as old as 70. The investigators enrolled 440 patients (128 ages 61-70) with newly diagnosed FLT3-ITD-positive AML. For a comparator, the researchers used data from five previous AMLSG trials, comprising a total of 415 patients. The trial's primary objectives were EFS and OS in the overall population and in the age-defined subgroups of 18-60 and 61-70.

As compared with the historical control group, the patient population in AMLSG 16-10 was older (54 vs 50.5), had more patients with ECOG Performance Status 0 (38% vs 22%), had fewer patients with de novo AML (89% vs 96%), and more patients with intermediate-II cytogenetics (25% vs 17%).

The 74.9% CR rate (including incomplete hematologic recovery) in AMLSG 16-10 exceeded the control group's 64.6% rate. Among patients who achieved CR, twice as many underwent transplantation in AMLSG 16-10 (45.2% vs 22.6%). Additionally, 72.9% of patients in AMLSG 16-10 underwent transplantation at some point during the course of their disease as compared with 57.1% of the control group.

As compared with treatment in the control group, the addition of midostaurin was associated with a 45% reduction in the EFS hazard ratio and a 47% reduction in the survival hazard (P<0.001 vs control for both comparisons). The HR reduction with midostaurin was 41% in younger patients and 58% in the older subgroup. OS hazards were similarly reduced in younger and older patients.

Döhner said the results remained unchanged after adjustment for the higher rate of ASCT in the midostaurin-treated patients.

Analysis of grade ≥3 adverse events (AEs) by age group showed that only metabolic and nutrition disorders (38% vs 23%, P=0.003) and vascular AEs (21% vs 13%, P=0.04) occurred significantly more often in older patients.

During the discussion that followed his presentation, Döhner noted that AMLSG 16-10 was not a randomized trial, so the results do not speak directly to the potential contributions of maintenance therapy.

The results are not surprising but are nonetheless encouraging, given the favorable outcome of the RATIFY trial, said Peter Abdelmessieh, DO, of Fox Chase Cancer Center in Philadelphia.

"It's a practice that most transplant centers have adopted for FLT3-positive patients with AML," Abdelmessieh told ֱ via email. "There have been a few retrospective studies showing the benefit of continued FLT3 inhibition with midostaurin and with sorafenib (Nexavar) prior to this study, which is why it has been adopted in clinical practice."

The major limitation of the AMLSG 16-10 trial is the lack of randomization and blinding, unlike the phase III RATIFY trial, he added.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ֱ in 2007.

Disclosures

The trial was sponsored by the University of Ulm in collaboration with Novartis.

Döhner disclosed relationships with Amgen, Celgene, AstraZeneca, Astex, Amgen, Agios, AbbVie, GEMoaB, Bristol Myers Squibb, Berlin-Chemie, Helsinn, Janssen, Jazz, Novartis, Oxford Biomedicals, Roche, Gilead, and Pfizer.

Primary Source

American Society of Hematology

Döhner H, et al "Midostaurin plus intensive chemotherapy for younger and older patients with acute myeloid leukemia and FLT3 internal tandem duplications" ASH 2021; Abstract 692.