Gilteritinib as Posttransplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3
abstract
This abstract is available on the publisher's site.
Access this abstract nowPURPOSE
Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with acute myeloid leukemia (AML) harboring an internal tandem duplication mutation of FLT3 (FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit.
METHODS
Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS.
RESULTS
Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575).
CONCLUSION
Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.
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Additional Info
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Gilteritinib as Post-Transplant Maintenance for Acute Myeloid Leukemia With Internal Tandem Duplication Mutation of FLT3
J. Clin. Oncol 2024 Mar 12;[EPub Ahead of Print], MJ Levis, M Hamadani, B Logan, RJ Jones, AK Singh, M Litzow, JR Wingard, EB Papadopoulos, AE Perl, RJ Soiffer, C Ustun, M Ueda Oshima, GL Uy, EK Waller, S Vasu, M Solh, A Mishra, L Muffly, HJ Kim, JH Mikesch, Y Najima, M Onozawa, K Thomson, A Nagler, AH Wei, G Marcucci, NL Geller, N Hasabou, D Delgado, M Rosales, J Hill, SC Gill, R Nuthethi, D King, H Wittsack, A Mendizabal, SM Devine, MM Horowitz, YB ChenFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Levis and colleagues report on the randomized phase III study BMT-CTN 1506 (MORPHO) addressing the question as to whether gilteritinib, a FLT3 inhibitor, used as maintenance after allogeneic stem cell transplant in patients with FLT3 internal tandem duplication decreases the risk of relapse. The question is of high relevance, given that gilteritinib has been routinely used in this setting; however, data are lacking as the drug is now often used as part of induction.
In this study, 356 patients underwent a 1:1 randomization to placebo or gilteritinib at a dose of 120 mg orally daily. The primary endpoint was relapse-free survival (RFS), and secondary endpoints were overall survival (OS) and the assessment of the effect of minimal residual disease (MRD) status and treatment outcomes. Comparing the experimental and placebo arms, a similar proportion of patients received gilteritinib as part of induction therapy (61.8% vs 57.9%). The median follow-up was approximately 44 months. Adherence to the treatment was similar between the two arms, although grade 3 or higher treatment-emergent adverse events were more common with gilteritinib (82.0% vs 53.1%) and notable for myelosuppression, which is an expected toxicity.
A total of 98% of patients had marrow samples available to measure the MRD status. MRD was detected in 21.1% of patients before allogeneic transplant using a threshold of 10−4 but in up to 46.1% using the 10−6 threshold and in 51.1% at either time. MRD positivity was associated with decreased RFS and OS. Although the analysis of the total population did not reach statistical significance (HR, 0.679; 95% CI, 0.459–1.005), the analysis of patients who remained MRD-positive showed that gilteritinib was clearly beneficial (HR, 0.515; 95% CI, 0.316–0.838; P = .0065).
The authors properly state that these results should be considered practice-changing. The results of this study and those seen in trials in patients with acute lymphoblastic leukemia (ECOG ACRIN E1910) and multiple myeloma continue to show that attainment of an MRD-negative status should be the goal of modern therapies. Attaining MRD negativity will be an early indicator of better long-term outcomes and, as in this case, practice-guiding. Using legal terms, we are transitioning from a time when MRD was of interest to a time when it became clear that the preponderance of evidence showed its utility to now where it is becoming “beyond any reasonable doubt.” This author remains dumbfounded as to why this goal is still considered controversial by some.
In the book “The Emperor of All Maladies,” Siddhartha Mukherjee describes one of the first approaches to pursue MRD negativity in the 1950s. Among patients with choriocarcinoma treated at the NCI by Dr. Min Chiu Li and Dr. Roy Hertz, it was found that continuing treatment with methotrexate for those with remaining detectable serum hCG resulted in better survival. Li was first said to be obsessed with “treating a number” and considered a renegade; so, in July of 1956, he was fired. History proved that he was right.
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