MRD can guide maintenance therapy in FLT3-ITD AML

Blood cancers

By Selina Wellbelove

27 Mar 2024

Measurable residual disease (MRD) can be used to guide prophylactic treatment after allogeneic haematopoietic stem cell transplantation (HSCT) in patients with FLT3-ITD positive acute myeloid leukaemia (AML) to achieve best outcomes, researchers report.

A new, personalised treatment paradigm involving frequent MRD testing pre- and post- HSCT could inform clinicians on which patients would most likely benefit from maintenance therapy with an FLT3 inhibitor, and thus also save those unlikely to benefit from suffering treatment-related toxicities, the data indicate.

International guidelines recommend use of post-HCT maintenance with FLT3 inhibitors to reduce the risk of relapse in AML patients, and some guidelines back off-label use of sorafenib in this clinical setting (link here), as long as patients demonstrate adequate engraftment and start therapy no longer than four months after transplant.

However, findings of a study assessing the FLT3 inhibitor gilteritinib, published in the Journal of Clinical Oncology (link here), suggest that only patients who exhibit detectable MRD peri-transplant stand to benefit from such an approach.

In the international Phase III MORPHO trial, 356 patients with FLT3-ITD AML in first remission were randomly assigned to receive either gilteritinib or placebo post-HSCT.

More than half of patients had FLT3-ITD AML MRD pre- or post-HCT detected by highly sensitive new assays using sequential polymerase chain reaction (PCR) and next-generation sequencing (NGS).

Overall, although relapse-free survival (RFS) was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR] 0.7 [95% CI, 0.459 to 1.005]; two-sided p=0.0518).

However, a significant RFS benefit from the drug was observed in patients with detectable peri-transplant MRD (HR 0.5 [95% CI, 0.316 to 0.838]; p=0.0065), and not in those without detectable MRD (HR 1.213 [95% CI, 0.616 to 2.387]; p=0.575).

“Participants in deep remissions did not benefit from maintenance gilteritinib and were therefore exposed unnecessarily to its potential toxicity,” the authors noted.

A linked editorial said that “while multiple retrospective and prospective studies have confirmed the importance of MRD for prognostication in AML, these data are the first to establish it as a predictive biomarker which should guide therapeutic decision making in fit adults with AML, a model now widely used in acute lymphoblastic leukaemia”.

“These important data establish gilteritinib as the standard of care in this patient population and convincingly demonstrate both the potential of tolerable pharmacological maintenance strategies to improve the outcome of patients allografted for AML and also the pivotal role of peritransplant MRD as a predictive factor in AML transplant decision making,” the authors wrote.

The results also “highlight that allo-HSCT should be viewed as a pivotal component of an integrated total therapy pathway in AML consisting of induction/consolidation chemotherapy, transplant, and post-transplant interventions,” they said.

According to the authors, the findings have also “validated the utility of FLT3-ITD mutations as useful markers of MRD with clear implications for intervention”.

“These findings are practice-changing, and further study of the data from this trial is likely to yield more insights into the biology and management of this disease,” they said.

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