FLT3 Inhibitors Offer Benefit in AML Post Transplant

The benefit of targeted therapies as maintenance after patients with acute myeloid leukemia (AML) whose tumor harbors a FLT3 mutation, and who underwent allogeneic hematopoietic cell transplantation (alloHCT), was explored by James M. Foran, MD, during a presentation at the National Comprehensive Cancer Network (NCCN) 2024 Annual Conference on April 5 to 7, 2024, in Orlando, Florida.¹ In general, mutations can occur in several genes in cytologically normal AML cells, including NPM1, FLT3, CEBPA, MLL, NRAS.

Foran, an oncologist at Mayo Clinic in Jacksonville, Florida, focused on the FLT3 mutation during his presentation, noting that “it is a common abnormality in AML, it is prognostically adverse, and it is targetable. These are good reasons to try to have an impact on the outcomes for patients.”

A German AML study group compared the mutational status of the NPM1, FLT3, CEBPA, MLL, and NRAS genes with the outcomes of 872 patients with cytogenetically normal AML.² Investigators found NPM1 mutations in 53% of patients and FLT3–internal tandem duplication (ITD) mutations in 31%. The overall complete remission rate was 77%. Complete remission was observed in patients with the genotype NPM1 without FLT3-ITD and CEBPA and who were aged less than 60 years.²

“This is an example of one of those rare, practice- changing reports on retrospective data,” Foran said. Of the 663 patients who received postremission therapy, 150 underwent hematopoietic stem cell transplantation from an HLA-matched related donor.

Looking at outcomes of patients who underwent an HLA-matched alloHCT at first remission, there was a significant reduction in the risk of death, as the recurrence-free survival (RFS) HR was 0.61, Foran said.² “That is a 39% reduction in the risk of death, and patients who had a donor-matched alloHCT had a significantly better survival rate,” Foran said.

An early trial³ (RATIFY; NCT00651261) evaluating midostaurin (Rydapt, Tauritmo) determined whether adding the agent to standard chemotherapy prolonged overall and event-free survival in patients with AML and a FLT3 mutation. A total of 717 patients were randomly assigned to receive midostaurin (n = 360) or placebo (n = 357). Investigators determined that 214 patients had FLT3-ITD high, 341 patients had FLT3-ITD low, and 162 patients had a point mutation in the tyrosine kinase domain.³

Overall survival was significantly longer in the midostaurin group than in the placebo group (HR, 0.78; 1-sided P = .009), as was event-free survival (HR, 0.78; 1-sided P = .002). The benefit of midostaurin was consistent across all FLT3 subtypes, and the rate of severe adverse events was similar among the groups.³

“This is one of the observations that led investigators to consider using FLT3 inhibitors after transplant as maintenance therapy to help prevent relapse,” Foran said.

Currently, the NCCN guidelines⁴ recommend that therapy not be initiated until a FLT3 mutation is detected, Foran said. “For patients who are fit for intensive therapy, it is recommended to give standard intensive therapy either with midostaurin or crizotinib [Xalkori],” Foran said. For patients with intermediate- risk AML, the guidelines recommend cytarabine; the combination of cytarabine, daunorubicin, and gemtuzumab ozogamicin; or alloHCT.

Relapse After Transplant

Relapse has replaced treatment-related mortality as the primary cause of treatment failure and occurs after 30% or more transplants for AML, noted Foran.⁵ “The prognosis of a patient who has recurrent AML after transplant is truly dismal,” Foran said. “The vast majority do not achieve a subsequent remission, and the 2-year overall survival is consistently less than 15%,” he continued.⁵

The use of FLT3 inhibitors before or after alloHCT was evaluated by Brunet et al.⁶ The trial included 206 patients who underwent HLA-identical sibling and matched unrelated HCT. Investigators reported that relapse incidence was significantly increased in patients who were FLT3-ITD positive (30% vs 16%; P = .006), and multivariable analysis indicated that FLT3-ITD was an independent risk factor (HR, 3.4; 95% CI, 1.46-7.94; P = .005). Multivariable analysis revealed an HR of 0.37 (95% CI, 0.19-0.73).

Another trial⁷ evaluated 1075 patients to determine whether DNA sequencing of patients with AML in first remission before alloHCT could identify those who were at increased risk of relapse and poorer overall survival compared with those without DNA variants. Higher rates of relapse at 3 years were reported for patients who were negative for NPM1/FLT3-ITD minimal residual disease vs those who were positive (68% vs 21%; HR, 4.32; 95% CI, 2.98-6.26; P < .001). Further, survival at 3 years also favored patients who were NMP1/FLT3-ITD positive (39% vs 63%; HR, 2.43; 95% CI, 1.713.45; P < .001).

“Having [minimal] residual disease at the time of transplant turns out to be very important, and that will play into the decision for FLT3 inhibitor maintenance,” Foran said.

Small, randomized trials such as SORMAIN (German Clinical Trials Register: DRKS00000591),⁸ which evaluated sorafenib (Nexavar), and RADIUS (NCT01883362; VISUAL SYNOPSIS),⁹ which evaluated midostaurin, have also been explored. Meta-analyses of these trials resulted in a recurrence-free survival HR of 0.48, and although adverse events occurred, the agents were generally well tolerated. Quizartinib (Vanflyta) is a feasible treatment option, but prospective data are limited.¹⁰

FLT3 mutations are common in AML, and the mutation represents a high-risk population. “There’s a clear benefit of targeted therapies in the first line and a benefit of targeted therapy after transplant,” Foran said.

REFERENCES:
1. Foran JM. Acute myeloid leukemia: role of FLT3 inhibitors after allogeneic hematopoietic cell transplantation. Presented at: National Comprehensive Cancer Network 2024 Annual Conference; April 5-7, 2024. Orlando, FL.
2. Schlenk RF, Döhner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909-1918. doi:10.1056/NEJMoa074306
3. 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
4. NCCN. Clinical Practice Guidelines in Oncology. Acute myeloid leukemia, version 2.2204. Accessed May 9, 2024. https://tinyurl.com/4m8ns7cy
5. Webster JA, Luznik L, Gojo I. Treatment of AML relapse after allo-HCT. Front Oncol. 2021;11:812207. doi:10.3389/fonc.2021.812207
6. Brunet S, Labopin M, Esteve J, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first
remission: a retrospective analysis. J Clin Oncol. 2012;30(7):735-741.
doi:10.1200/JCO.2011.36.9868
7. Dillon LW, Gui G, Page KM, et al. DNA sequencing to detect residual disease in adults with acute myeloid leukemia prior to hematopoietic cell transplant. JAMA. 2023;329(9):745-755. doi:10.1001/jama.2023.1363
8. Burchert A, Bug G, Fritz LV, et al. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3-internal tandem duplication mutation (SORMAIN). J Clin Oncol. 2020;38(26):2993-3002. doi:10.1200/JCO.19.03345
9. Maziarz RT, Levis M, Patnaik MM, et al. Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. Bone Marrow Transplant. 2021;56(5):1180-1189. doi:10.1038/s41409-020-01153-1
10. Sandmaier BM, Khaled S, Oran B, Gammon G, Trone D, Frankfurt O. Results of a phase 1 study of quizartinib as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic stem cell transplant. Am J Hematol. 2018;93(2):222-231.
doi:10.1002/ajh.24959