Introduction to a Blood Spotlight series on acute myeloid leukemia Free

In the 1990s, the most common indication for allogeneic transplant was chronic myelogenous leukemia (CML) in early chronic phase. Offered to all young, healthy patients, it was the only treatment likely to result in long-term disease-free survival. With the understanding that BCR-ABL was not only diagnostic but causative, and the availability and success of ABL tyrosine kinase inhibitors, the prognosis and treatment of CML have changed dramatically. For decades, for patients with acute myelogenous leukemia (AML), prognostication was based on age and karyotype alone, and those factors have similarly determined the risk/benefit ratio at which patients should proceed to allogeneic transplant in first remission.^1,2 With the elucidation of recurrent mutations in AML that were prognostic in determining both likelihood of remission induction and its durability, risk assessment is evolving, as is the search for risk adapted and targeted therapies.^3-9 The RATIFY trial demonstrated the benefit of adding a targeted agent to standard cytotoxic chemotherapy for patients with FLT3-mutated disease.^10,NPM1 mutations were found to have a favorable prognosis in AML, particularly in those who achieved a measurable (or minimal) residual disease (MRD)–negative remission after 2 cycles of therapy.¹¹ The use of increasingly sophisticated MRD assessments is now allowing further refinement of treatment decisions.¹² However, although progress is being made, at the same time there is increasing awareness of knowledge gaps and unmet needs.

This Blood Spotlight series comprises articles that focus on particular patient subgroups. The series includes the following articles.

• David A. Sallman and Maximilian Stahl, “TP53-mutated acute myeloid leukemia: how can we improve outcomes?”

• Alexander E. Perl, “Approaching a therapeutic inflection point for FLT3-mutated AML”

• Sameem Abedin, Geoffrey L. Uy, and Laura C. Michaelis, “The fit older adult with acute myeloid leukemia: clinical challenges to providing evidence-based frontline treatment”

• Roland B. Walter, Victoria Potter, and Charles Craddock, “Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in adults over 70 years old”

Sallman and Stahl’s Spotlight helps us to understand the intricacies of p53-mutated myeloid malignancies. While overall portending for a poorer outcome, not all p53-mutated diseases invite the same approach. The authors explain how blast percentage loses significance in patients with p53 mutations and >10% blasts, a group for whom our standard and recent investigational therapies have been unsuccessful and for whom novel interventions are needed.

In the Spotlight on FLT3-mutated AML, Perl describes the recent evolution in therapy for FLT3-mutated disease. Originally, if FLT3-ITD-mutated, the disease was considered universally of poor prognosis and in need of allogeneic transplant. With knowledge of comutations and MRD assessments, a variety of treatment choices may be considered and the entity no longer definitively qualifies for “high risk” categorization with current therapies and those under investigation.

Abedin, Uy, and Michaelis, in their Spotlight on therapy for the fit older patient with AML, highlight the fact that although AML is a disease of the older adult, many of the trials which have advanced therapy for fit patients have been conducted with younger patients. Hypomethylating agents with or without venetoclax have been shown to improve survival in the unfit patient but for the fit patient, no lower-intensity therapy has yet been definitively shown, in a randomized phase 3 trial, to improve survival compared to anthracycline and cytarabine based induction. The authors emphasize that we need to make an effort to design and enroll patients in clinical trials that will allow us to improve the outcomes in this population.

In the Spotlight by Walter, Potter, and Craddock, we are reminded that allogeneic transplant is of benefit to many older patients in remission today, even those over the age of 70 years. The value of this approach, however, depends on an appropriate selection of patients, response to initial therapy (both in terms of efficacy and toxicity, a factor that may impact choice of initial therapy), choice of transplant regimen, and incorporation of posttransplant leukemia–directed care. For that reason, we need to consider transplant early on in care, and additional studies are needed to improve the likelihood of success.

This Blood Spotlight series highlights the fact that much progress has been made in AML, in diagnostics, prognostics and therapeutics, yet there remain significant areas of unmet need.