Overcoming Challenges in Relapsed or Refractory FLT3-Positive AML

Naval Daver, MD MD Anderson Cancer Center | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center | Uma Borate, MBBS The Ohio State University

Key Points

• Gilteritinib is the only FDA-approved FLT3-targeted therapy for patients with relapsed or refractory acute myeloid leukemia (AML).

• The combination ofgilteritinib plus a hypomethylating agent, venetoclax, or both, is the primary treatment paradigm for patients with relapsed or refractory disease.

• Pursuing a second transplant may be a viable strategy for patients with AML who are considered fit but have relapsed.

• Gilteritinib is well tolerated, but oncologists should use support prophylaxis for infections.

Standard of Care in FLT3-Mutated AML

The Oncology Brothers podcast invited Uma Borate, MBBS, of The Ohio State University, and Naval Daver, MD, of MD Anderson Cancer Center, to discuss relapsed or refractory FMS-like tyrosine kinase-3 (FLT3)-mutated acute myeloid leukemia (AML) and how to apply the standard of care therapies in two challenging cases.

In the relapsed or refractory AML setting, the only FDA-approved FLT3-targeted therapy is gilteritinib, based on data from the ADMIRAL trial. Depending on the patient and the goal of treatment, gilteritinib is typically given alone, combined with a hypomethylating agent (HMA), or combined with a HMA and venetoclax.

Notably, FLT3 testing must be done again at the time of relapse, as patients can lose baseline FLT3 mutations after receiving chemotherapy and a FLT3 inhibitor. Generally, a bone marrow biopsy should be used for polymerase chain reaction (PCR) and next-generation sequencing testing. However, peripheral blood can be substituted if a patient is very sick, Dr. Daver said.

The doctors considered appropriate treatments for each case in a community oncology setting, although Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, stated that clinical trial participation is preferred for relapsed or refractory FLT3-positive AML.

Treatment Options for Relapsed FLT3-Mutated AML After Transplant

First, the doctors considered the case of a fit 47-year-old woman with FLT3-internal tandem duplication (FLT3-ITD)–positive AML. The patient had received chemotherapy with midostaurin followed by allogeneic hematopoietic stem cell transplant, but relapsed after 14 months. At the time of relapse, PCR assay confirmed FLT3-ITD–positivity.

“If I could not get a trial and the patient is young, my goal is to consider—and this is another tricky area—a second transplant, which some centers do,” Dr. Daver said. In that scenario, he said he would probably use gilteritinib with either venetoclax or chemotherapy for induction, try to proceed with transplant, and then potentially start a maintenance regimen.

“It would not be unreasonable to try gilteritinib alone, but the response rate is a little lower than what we have seen with combos,” he continued. “If it’s a short-period treatment with the goal to bridge to transplant, I’m quite comfortable to do a venetoclax or HMA plus venetoclax combination to get a higher response rate.”

If a second transplant isn’t being pursued, Dr. Borate said gilteritinib monotherapy would be the most accessible option in the community setting. If venetoclax is also obtainable, she said she has found gilteritinib plus venetoclax to yield faster responses. However, this regimen can lead to more profound cytopenias. 

Treating a Frail Patient With Relapsed FLT3-TKD–Mutated AML

The second case the doctors discussed was an unfit 80-year-old man with FLT3-tyrosine kinase domain (FLT3-TKD)–positive disease. The patient had a partial response to upfront azacitidine plus venetoclax, but relapsed at nine months. FLT3-TKD–positivity was again reconfirmed via PCR testing.

Dr. Daver felt the upfront treatment selection was appropriate for a patient with FLT3-TKD–positive AML, but said he leans toward upfront gilteritinib, azacitidine, and venetoclax in the FLT3-ITD–mutated population based on the VICEROY trial findings.

For the choice of subsequent treatment, Dr. Daver suggested gilteritinib monotherapy may be an appropriate option, as intensified doublet or triplet regimens are more likely to lead to complications in a frail, older patient. Both Dr. Daver and Dr. Borate said that adding a single cycle of venetoclax when starting gilteritinib could be a reasonable approach to try to achieve more rapid disease control without too much additional toxicity and myelosuppression.

The doctors also discussed the choice of HMA between decitabine and azacitidine. For Dr. Daver, the choice has more recently been decitabine given its available oral formulation, which patients tend to prefer, although an oral formulation of azacitidine is being developed and the choice will need to be reevaluated when that is available.

This case also raised the question of supportive prophylaxis when treating patients with relapsed or refractory disease. Dr. Borate said she proceeds carefully given that patients are likely to be neutropenic for prolonged periods of time. Her practice implements antiviral, antibacterial, and antifungal prophylactics. She cautioned that venetoclax dosage needs to be adjusted based on the broad-spectrum azole used for antifungal prophylaxis.

Final Considerations for Community Oncologists

“I think there is a lot of excitement with the triplets, but in the community, one has to be very careful because the doses are quite modified,” Dr. Daver said. “If you are going to do it, I think it’s important to either look at the papers closely or coordinate with a clinical trial—or if the patient is able to, to go on one of the frontline trials, that will be even better because we can get more mature data.”

In closing, Dr. Borate said post-transplant FLT3-mutated AML on maintenance gilteritinib or quizartinib is one of the most favorable populations to care for, and community oncologists should primarily be familiar with either agent and potential drug-drug interactions.