Joshua Zeidner, MD

Joshua Zeidner, MD, Associate Professor of Medicine, Chief of Leukemia Research, and Associate Chief of Hematology Research at the University of North Carolina Lineberger Comprehensive Cancer Center, emphasized the high risk of relapse, even after allogeneic stem cell transplantation, for patients with FLT3-ITD mutations.

According to Dr. Zeidner, FLT3 inhibitors have been shown to improve relapse-free survival after allogeneic stem cell transplantation, though it is “unclear which FLT3 inhibitor is optimal” and whether FLT3 inhibitors improve outcomes after allogeneic bone marrow transplantation (BMT) in the current era whereby most patients receive FLT3 inhibitors during their front-line therapy.

“Sorafenib (and midostaurin) are other commonly used FLT3 inhibitors in the maintenance setting after allogeneic stem cell transplant to delay or prevent relapse,” Dr. Zeidner told The ASCO Post. “Sorafenib, in particular, led to significantly improved relapse-free survival compared with placebo as a maintenance therapy after allogeneic stem cell transplant in the SORMAIN trial, though this study was done at a time when FLT3 inhibitors were not standardly used in the front-line setting.”¹

Although the MORPHO trial did not meet the primary endpoint of relapse-free survival, Dr. Zeidner noted the nonsignificant improvement in relapse-free survival in those treated with gilteritinib compared with placebo, with a P value that was “just over .05.”

“Although not statistically significant, this may still be clinically significant,” Dr. Zeidner explained. “Further, in subsets of patients, it appears that in those with MRD-positive disease (either before allogeneic bone marrow transplantation or before randomization) by a highly sensitive FLT3 next-generation sequencing–polymerase chain reaction, gilteritinib significantly improved relapse-free survival over placebo.”

Thoughts on MRD Testing

Dr. Zeidner also highlighted the apparent lack of benefit for patients without MRD (measurable residual disease). “We know that MRD-positive patients have worse outcomes (before and after allogeneic bone marrow transplantation) compared with those who achieve MRD-negative remissions, so it is not surprising that gilteritinib appears to be most impactful in those with MRD-positive disease,” Dr. Zeidner said. “However, a highly sensitive polymerase chain reaction MRD test was investigated in this trial, and it is not commonly used in clinical practice. If you are using results from this study to determine whether to prescribe gilteritinib as a maintenance therapy post–allogeneic stem cell transplant, you have to use this same assay to measure FLT3-ITD MRD. Otherwise, you are comparing apples to oranges with other MRD assessments. It is unclear how to extrapolate these results to more conventional MRD methodologies, such as flow cytometry or less sensitive polymerase chain reaction tests.”

“Overall, these data substantiate that FLT3 inhibitors remain an important treatment for patients with FLT3-ITD mutations after allogeneic BMT but are most effective in patients with MRD-positive disease,” Dr. Zeidner continued. “We need a uniform way of measuring FLT3 MRD after allogeneic BMT to better select the patient populations who benefit the most from gilteritinib and/or other FLT3 inhibitors, since our conventional MRD testing may miss a proportion of patients who are likely to benefit from maintenance therapy.” 

DISCLOSURE: Dr. Zeidner has received honoraria and/or consultant fees from AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Foghorn, Gilead, Immunogen, Novartis, Sellas, Servier, and Sumitomo Dainippon.

REFERENCE

1. 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 38:2993-3002, 2020.