FLT3 Mutated AML: Are Triplets Better Than Doublets?

Eunice Wang, MD

FLT3 mutations were the first molecular abnormality to be successfully targeted therapeutically for acute myeloid leukemia (AML). Despite this, defining the optimal regimen, particularly for older patients unable to receive intensive chemotherapy backbones, is still a work in progress.

FLT3 mutations are among the most frequently identified in AML, occurring in 25% to 37% of newly diagnosed cases and often associated with chemotherapy resistance and shorter overall survival. The multikinase inhibitor midostaurin (Rydapt) was repurposed as a FLT3 kinase inhibitor and successfully combined with intensive chemotherapy for the treatment of younger patients with FLT3-mutant disease.¹ Second-generation FLT3 tyrosine kinase inhibitors (TKIs) —gilteritinib (Xospata), quizartinib, and crenolanib—were clinically developed with much higher sensitivity and specificity for mutant FLT3 kinase than midostaurin. However, the outcomes of FLT3 TKI monotherapy remain suboptimal, with response rates of 20% to 30% and overall survival measured in several months.² Rapid disease recurrence appears to be driven by 2 factors: the eventual emergence of therapy-resistant FLT3-mutant clones with other co-mutation and/or FLT3 wild-type disease. To overcome this, combination therapy including second-generation FLT3 inhibitors likely is needed, but balancing clinical efficacy with potential adverse effects of multidrug therapy remains a key issue.

In my presentation “FLT3-Mutated AML: Triplets or Doublets” during the Acute Myeloid Leukemia session at 2:31 pm on September 28, 2022, I will discuss the latest developments in FLT3 inhibitor therapy, specifically 3- vs 2-drug FLT3 inhibitor regimens.

Doublet therapy with a targeted agent added to a hypomethylating agent (HMA)—azacitidine (Vidaza) vs decitabine (Dacogen)—was developed to treat older and/or unfit patients with newly diagnosed AML. In the phase 3 VIALE-A trial (NCT02993523), a subset of older adults with newly diagnosed AML and with FLT3-mutant disease at diagnosis were randomly assigned to receive venetoclax (Venclexta) plus azacitidine vs azacitidine alone as standard upfront therapy. Although this trial established venetoclax plus azacitidine as the new standard-of-care chemotherapy regimen for the overall population of older patients, subsequent subgroup analyses revealed that patients with FLT3-ITD mutations had similar overall survival as those receiving azacitidine alone. Although this trial was not powered to look at specific patient populations, these data did suggest that additional agents may need to be added to substantially improve outcomes for patients with this mutational subset. Previous trials have interrogated the efficacy and tolerability of first generation FLT3 inhibitors, specifically sorafenib (Nexavar) plus azacitidine or midostaurin plus azacitidine.^3,4 Although these combinations were demonstrating clear responses and tolerability in these patients, overall survival remained less than 1 year.

The phase 3 LACEWING trial (NCT02752035) randomly assigned older unfit patients to upfront therapy with either gilteritinib plus azacitidine or azacitidine alone. Results of this trial showed that gilteritinib plus azacitidine significantly improved overall response rates, but not overall survival, compared with azacitidine alone. Of note, however, many patients in the azacitidine alone arm received subsequent FLT3 TKI therapy, suggesting the potential benefit of sequential azacitidine followed by gilteritinib therapy.⁵ Daver and colleagues recently presented data from a phase 1b trial (NCT03625505) demonstrating high response rates (the majority without complete count recovery) following concomitant administration of gilteritinib and venetoclax in patients with relapsed/refractory FLT3-mutant disease even following prior FLT3 TKI therapy in some cases.⁶

These somewhat underwhelming outcomes of concomitant FLT3 TKI and HMA therapies in older patients with FLT3-mutantAML and the promising results of the combination of gilteritinib and venetoclax have logically led to the development of triplet approaches combining FLT3 TKI plus HMA plus venetoclax. Encouraging evidence of tolerability and responses have been shown in multiple clinical trials in the relapsed/refractory and upfront AML settings.⁷ To date, the results of triplet therapy in patients with FLT3-mutant AML have been highly encouraging. In early retrospective analysis, the therapy resulted in improved outcomes as compared with doublet therapy at a single academic setting.⁸ The overwhelming majority of patients (90%-100%) achieved overall responses, the majority of which were negative for measurable residual disease without FLT3 mutations. These results, however, must be viewed cautiously. Limitations of these data include short follow-up (only a matter of months) and inclusion of small patient cohorts treated with a variety of FLT3 TKI, HMA (such as decitabine 5 and 10 days, azacitidine for 7 days), and venetoclax doses. These factors make it difficult to know what the true outcomes would be in current practice.

One concern with triplet therapy is the incidence of prolonged myelosuppression leading to increased infectious and bleeding complications. In some patients, the duration of time until ANC level and platelet recovery with triplet therapy in cycle 1 was 50 to 60 days. Given this observation, it remains unclear how to treat these patients in subsequent cycles. Clearly all 3 agents cannot feasibly be continued indefinitely in older patients, and the current approach to triplet combinatorial regimens is to reduce the duration of venetoclax and FLT3 TKI therapy specifically to mitigate prolonged myelosuppression. Currently the investigators have recommended administration of venetoclax for 14 days and gilteritinib (dose reduced to 80 mg daily) for 28 days during cycle 1 of triplet therapy (venetoclax plus gilteritinib plus azacitidine).⁸ However, additional data on the feasibility and efficacy of this recommendation remain to be presented.

Despite the promising response rates, this 3-drug triplet approach is best administered in the context of appropriate clinical trials. Active studies are examining the appropriate dose and duration of drugs in this combination in patients with newly diagnosed FLT3-mutant AML not suitable for intensive chemotherapy. It remains to be seen if there are significant differences in toxicities and efficacy with different FLT3 TKIs (midostaurin, gilteritinib, quizartinib) or hypomethylating agents (azacitidine, decitabine). It is also uncertain what minimal dose and duration of therapy of each drug is required for optimal efficacy. Although dose reduction or truncation of treatment would likely mitigate myelosuppression, it is important not to compromise the clinical efficacy by reducing effective drug levels to the point that recurrence occurs. To date, the validation and fine-tuning of specific triplet regimens in ongoing clinical trials are eagerly awaited before such regimens can be adopted for mainstream therapy.

Future approaches include consideration of triplet induction approaches during cycle 1 to rapidly cytoreduce newly diagnosed disease followed by subsequent doublet (FLT3 inhibitor plus azacitidine vs FLT3 inhibitor plus venetoclax vs venetoclax plus azacitidine) or even single-agent therapy in responding patients. Alternatively, some patients may tolerate sequential doublet therapy (ie, venetoclax plus azacitidine followed by FLT3 inhibitor plus azacitidine) better in terms of toxicities with durable prolonged responses. In addition, the outstanding response rates achieved with triplet therapy in the older AML population has led to questions of whether approach is equivalent to and/or superior to what is achieved with midostaurin and intensive chemotherapy in younger patients with newly diagnosed FLT3-mutant AML.¹ If so, then these FLT3 TKI combination regimens hold promise to not only improve outcomes for older individuals with this disease but also potentially for all patients with FLT3-mutant AML, regardless of age or fitness.

_REFERENCES:

_{1. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi:10.1056/NEJMoa1614359}

_{2. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-Mutated AML. N Engl J Med. 2019;381(18):1728-1740. doi:10.1056/NEJMoa1902688}

_{3. Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121(23):4655-4662. doi:10.1182/blood-2013-01-480228}

_{4. Cooper BW, Kindwall-Keller TL, Craig MD, et al. A phase I study of midostaurin and azacitidine in relapsed and elderly AML patients. Clin Lymphoma Myeloma Leuk. 2015;15(7):428-432 e422. doi:10.1016/j.clml.2015.02.017}

_{5. Wang ES, Montesinos P, Minden MD, et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. Published online August 2, 2022. doi:10.1182/blood.2021014586.}

_{6. Daver N, Perl AE, Maly J, et al. Venetoclax plus gilteritinib for FLT3-mutated relapsed/refractory acute myeloid leukemia. Published online July 18, 2022. J Clin Oncol. doi:10.1200/JCO.22.00602.}

_{7. Short NJ, DiNardo DC, Daver N, et al. A triplet combination of azacitidine, venetoclax, and gilteritinib for patients with FLT3-mutated acute myeloid leukemia: results from a phase I/II study. Blood. 2021;138(suppl 1):696. doi:10.1182/blood-2021-153571}

_{8. Yilmaz M, Kantarjian H, Short NJ, et al. Hypomethylating agent (HMA) therapy and venetoclax (VEN) with FLT3 inhibitor “triplet” therapy is highly active in older/unfit patients with FLT3 mutated AML. Blood. 2021;138(suppl 1):798. doi:10.1182/blood-2021-154143}