Revumenib for patients with acute leukemia: a new tool for differentiation therapy.

Treatment of acute leukemia is gradually moving away from a "one-size-fits-all" approach, as scientific and clinical advances expand the arsenal of available targeted therapies. One of the recent additions are the menin inhibitors; oral, selective, small molecules that disrupt the interaction between the chromatin adapter menin, and an epigenetic regulator, the Lysine Methyltransferase 2A (KMT2A) complex. Two susceptible leukemia subtypes have been identified: 1) Acute Myeloid Leukemia (AML) with a mutation in Nucleophosmin 1 (NPM1), and 2) any acute leukemia, myeloid or lymphoid, with a translocation resulting in the rearrangement of KMT2A. These leukemias share a distinct genetic expression, maintained by the KMT2A-menin interaction. Together they account for approximately 40% of patients with AML, and 10% of patients with Acute Lymphoblastic Leukemia (ALL). This review follows the journey of revumenib, as a representative of menin inhibitors, from bench to bedside. It will focus on the pathophysiology of leukemias sensitive to menin inhibition, delineation of how this understanding led to targeted drug development, and data from clinical trials. The important discovery of resistance mechanisms will also be explored, as well as future directions in using menin inhibitors for treating leukemia.

What Influences the Decision to Proceed to Transplant for Patients With AML in First Remission?

Although allogeneic hematopoietic cell transplantation (allo-HCT) remains the backbone of curative treatment for the majority of fit adults diagnosed with AML, there is indeed a subset of patients for whom long-term remission may be achieved without transplantation. Remarkable changes in our knowledge of AML biology in recent years has transformed the landscape of diagnosis, management, and treatment of AML. Specifically, markedly increased understanding of molecular characteristics of AML, the expanded application of minimal/measurable residual diseases testing, and an increased armamentarium of leukemia-directed therapeutic agents have created a new paradigm for the medical care of patients with AML. An attempt is herein made to decipher the decision to proceed to transplant for patients with AML in first complete remission on the basis of the current best available evidence. The focus is on factors affecting the biology and treatment of AML itself, rather than on variables related to allo-HCT, an area characterized by significant advancements that have reduced overall therapy-related complications. This review seeks to focus on areas of particular complexity, while simultaneously providing clarity on how our current knowledge and treatment strategies may, or may not, influence the decision to pursue allo-HCT in patients with AML.

Consolidation in AML: Abundant opinion and much unknown.

Consolidation therapy forms the backbone of post-remission therapy for AML and is uniformly accepted as an integral part of therapy designed to achieve long-term survival. The need for post-remission therapy was initially described over four decades ago and has since undergone many variations in terms of dosage, number of cycles and intensity of therapy. There is much empiricism in the current understanding of consolidation therapy and much that has not been rigorously studied. This review will consider the many aspects of consolidation therapy, focusing on the number of cycles, differences between young and older adults, first and subsequent remission as well as therapy prior to an allogeneic transplant. Emphasis will be given to differentiate strategies that are clearly evidence-based from those that have been incorporated into standard of care while bypassing the need for rigorous data-driven approaches. Finally, consideration will be given to the current ability to assess the minimal measureable residual disease and the impact that this may have on therapeutic paradigms, including superseding many of the time-honored prognostic features.