FLT3-Mutated AML: Transplanting with Precision in the Targeted Era.
Recent advancements in our understanding of the molecular underpinnings of acute myeloid leukemia (AML) disease biology have translated into breakthroughs in clinical management. In this review, we summarize the latest data incorporating precision approaches to treatment of FLT3-mutated AML with a focus on augmenting the curative role allogeneic hematopoietic cell transplantation (alloHCT) plays in the current treatment paradigm.
Incorporation of the next-generation FLT3 inhibitors quizartinib and gilteritinib into upfront therapy, whether in combination with intensive induction chemotherapy or less intensive hypomethylating agent/venetoclax combinations, have led to deeper and more durable remissions and resulted in greater transplant eligibility. AlloHCT candidacy has also expanded due to increased use of alternative donors, made possible with post-transplant cyclophosphamide-containing graft-versus-host disease prophylaxis regimens, and more tolerable reduced intensity conditioning. Additionally, risk stratification in the peri-transplant setting using ultra-sensitive FLT3-ITD measurable residual disease (MRD) assays has refined post-transplant maintenance approaches allowing escalation or de-escalation of therapy guided by each patient's risk of relapse. These advances have resulted in improved clinical outcomes for this historically high-risk disease. AlloHCT remains an integral component of the treatment of FLT3-mutated AML. Novel FLT3 inhibitors used in frontline combination regimens have led to more numerous and deeper remissions, and as post-transplant maintenance they have shown success in preventing the early relapse characteristic of this disease. MRD has emerged as an integral component of FLT3-ITD AML risk stratification and surveillance and is likely to further revolutionize our current treatment approaches.
Incorporation of the next-generation FLT3 inhibitors quizartinib and gilteritinib into upfront therapy, whether in combination with intensive induction chemotherapy or less intensive hypomethylating agent/venetoclax combinations, have led to deeper and more durable remissions and resulted in greater transplant eligibility. AlloHCT candidacy has also expanded due to increased use of alternative donors, made possible with post-transplant cyclophosphamide-containing graft-versus-host disease prophylaxis regimens, and more tolerable reduced intensity conditioning. Additionally, risk stratification in the peri-transplant setting using ultra-sensitive FLT3-ITD measurable residual disease (MRD) assays has refined post-transplant maintenance approaches allowing escalation or de-escalation of therapy guided by each patient's risk of relapse. These advances have resulted in improved clinical outcomes for this historically high-risk disease. AlloHCT remains an integral component of the treatment of FLT3-mutated AML. Novel FLT3 inhibitors used in frontline combination regimens have led to more numerous and deeper remissions, and as post-transplant maintenance they have shown success in preventing the early relapse characteristic of this disease. MRD has emerged as an integral component of FLT3-ITD AML risk stratification and surveillance and is likely to further revolutionize our current treatment approaches.