Disease Re-Characterization and Treatment Selection Framework at Relapse

Dr. Anand Patel from the University of Chicago and Dr. Cecilia Arana Yi from Mayo Clinic Phoenix introduce treatment considerations for relapsed/refractory (R/R) NPM1-mutated acute myeloid leukemia (AML). Dr. Arana Yi emphasizes comprehensive evaluation factors including relapse timing, prior therapy history, and current molecular profile assessment. Repeated molecular testing proves crucial, as the molecular landscape can change at relapse, potentially opening opportunities for targeted therapies. Patient fitness evaluation for intensive chemotherapy and transplant candidacy significantly influences overall treatment strategy.

European LeukemiaNet and National Comprehensive Cancer Network guidelines emphasize relapse reassessment including repeated molecular testing and transplant candidacy evaluation as factors extremely influencing treatment decisions. Dr. Patel discusses treatment selection considerations between intensive chemotherapy, lower-intensity therapy, or targeted approaches like menin inhibitors, with fitness, prior therapies, and individual patient factors guiding decision-making processes.

Major unmet needs in R/R NPM1-mutated AML include addressing continued relapse challenges despite historically excellent frontline responses and current venetoclax-based treatments. Responses after failing venetoclax-based chemotherapy remain limited and brief, creating urgent need for treatments overcoming venetoclax resistance. The increasing frontline use of venetoclax-based therapy has altered relapse patterns, with up to 50% of relapsed patients developing NPM1 wild-type disease and enrichment of RAS mutations, emphasizing that no acute leukemia remains favorable in the R/R setting regardless of initial molecular profile.