Gilteritinib and CX-01 in the Treatment of Patients with Acute Myeloid Leukemia

October 2019 Vol 10, No 10

Gilteritinib, a recently approved FLT3 inhibitor, prolonged survival in patients with relapsed or refractory acute myeloid leukemia (AML) and an FLT3 mutation in the phase 3 ADMIRAL clinical trial. A new analysis presented at ASCO 2019 was focused on the impact of baseline comutations and FLT3-ITD allelic burden on the overall response and on overall survival (OS) in patients with relapsed or refractory AML who received treatment with gilteritinib.

Gilteritinib received an initial approval from the FDA in November 2018. In May 2019, based on results from the ADMIRAL study, the FDA approved additional survival data for the prescribing information of gilteritinib in the treatment of relapsed or refractory AML and with FLT3-ITD mutation, as detected by an FDA-approved test.

The analysis showed that patients with AML and comutations of FLT3 and NPM1 had the best response to gilteritinib, whereas NPM1-positive disease is associated with poor response to chemotherapy.

“The group of FLT3-positive patients treated with gilteritinib who were NPM1-positive really did well. I wonder if we used this drug upfront in NPM1-positive patients if that would improve outcomes. The same group of patients treated with chemotherapy did very poorly,” said lead investigator Mark J. Levis, MD, PhD, Program Leader, Hematologic Malignancies and Bone Marrow Transplant Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University.

This analysis failed to identify a molecular subtype that responds better to gilteritinib and showed that high allelic FLT3-ITD ratio still portends worse outcomes.

“Previous studies have found that FLT3-ITD is associated with poor survival and high risk of relapse, and that a high allelic ratio negatively impacts survival and achievement of remission with intensive chemotherapy,” Dr Levis told listeners.

In the ADMIRAL study, gilteritinib was compared with salvage chemotherapy in patients with FLT3-positive AML. Of these patients, 90% had FLT3-ITD mutations. Gilteritinib achieved superior OS and response rates, including complete responses. Grade 3/4 adverse events were also less frequent in the gilteritinib arm.

For the analysis of comutations, baseline blood or bone marrow–derived DNA samples from 361 patients with FLT3-positive disease were analyzed by next-generation sequencing. The 4 common comutations identified in at least 10% of patients were NPM1 (47.9%), DNMT3A (31.9%), DNMT3A/NPM1 (23.8%), and WT1 (18%).

The response rate with gilteritinib in the overall study population was 34% compared with 15.3% with standard chemotherapy. In each of the subsets of common comutations, gilteritinib treatment was superior to salvage chemotherapy. The survival analysis showed that patients with NPM1-positive AML who received salvage chemotherapy had worse survival than those who received gilteritinib (median OS, 8.3 vs 5.1 months, respectively; P <.0001).

CX-01 for Newly Diagnosed AML

Despite the availability of novel agents, including gilteritinib and midostaurin, elderly patients with newly diagnosed AML often have poor outcomes. A randomized phase 2 dose-finding clinical trial with the investigative agent CX-01 in elderly patients (age >59 years) with newly diagnosed AML showed encouraging outcomes in combination with standard therapy (idarubicin plus cytarabine, 7+3 schedule).

The study was presented at ASCO 2019 by lead investigator Tibor Kovacsovics, MD, Medical Director, Inpatient Service, Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City.

CX-01 is a low anticoagulant derivative of heparin that retains heparin’s ability to alter several properties, including the activity of the CXCL12/CLCL4 axis, explained Dr Kovacsovics.

“CX-01 is well tolerated when combined with conventional chemotherapy for treatment of AML in elderly fit patients. Adverse events are consistent with what is expected for aggressive AML therapy in this group of patients,” said Dr Kovacsovics. “At a high dose [0.25 mg/kg per hour], CX-01 improves complete response, event-free survival, and OS when given with standard chemotherapy. The benefits of high-dose CX-01 appear to be irrespective of molecular profile,” he noted.

A previous pilot study showed a complete remission rate of 92% for the combination of CX-01 plus standard therapy. The study Dr Kovacsovics presented at ASCO was a randomized dose-finding clinical trial that compared 2 doses of CX-01 plus chemotherapy versus controls who received chemotherapy alone in 76 fit elderly patients (median age, 68 years) with AML.

The control group received standard induction therapy with idarubicin plus cytarabine using a 7+3 schedule; group 2 received low-dose CX-01 (0.125 mg/kg per hour) plus induction therapy; and group 3 received high-dose CX-01 (0.25 mg/kg per hour) plus induction therapy.

Overall, 9% of patients had favorable-risk disease, 36% had intermediate-risk disease, and 55% had high-risk disease. More unfavorable-risk patients were in the low-dose group.

A total of 66 patients were evaluable for response. The complete and incomplete response rate was highest in the high-dose CX-01 group (89%) compared with the control group (58%) and the low-dose group (50%).

Event-free survival was superior with high-dose CX-01 compared with low-dose CX-01 (median event-free survival, 23.4 months vs 6.5 months). The benefit of high-dose CX-01 extended to OS compared with the control group and low-dose group (median OS not reached vs 11.2 months vs 12 months, respectively).

CX-01 was well tolerated. Adverse events, including serious adverse events, were similar across all treatment arms. Febrile neutropenia (7 cases) and respiratory failure (3 cases) were the most common serious adverse events.

Expert Commentary

Leslie R. Ellis, MD, MSHPEd, FACP, Associate Professor of Medicine, Wake Forest Baptist Health, Winston-Salem, NC, discussed the results, noting that although gilteritinib improves survival in patients with high allelic burden, better options are still needed for these patients.

“There was improvement on gilteritinib, regardless of allelic ratio, but survival is still in the order of months, and we need more definitive options,” Dr Ellis stated.

Remaining questions for patients with FLT3-ITD allelic burden include whether gilteritinib could be combined with standard induction therapy in the frontline setting, Dr Ellis said.

Regarding CX-01, Dr Ellis said, “Higher-dose CX-01 in combination with the 7+3 regimen appears to be associated with improved complete response and OS compared with standard treatment regimen for elderly fit patients. We await data on side effects and adverse events.”

“Since patients with unfavorable disease characteristics had the highest dropout rate, we would like to see this cohort expanded,” Dr Ellis added.

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Last modified: August 10, 2023

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