Updating the American Society of Hematology guidelines for treating older adults with acute myeloid leukemia

TO THE EDITOR:

The American Society of Hematology (ASH) 2020 guidelines for treating newly diagnosed acute myeloid leukemia (AML) in older adults answered 6 critical treatment questions concerning choices in induction treatment approach, postremission therapy, and palliative care. A guiding principle of the recommendations was to consider conversations that occur between a provider and a patient in making treatment decisions throughout the patient’s disease course.

The multidisciplinary guideline panel included patients and specialists in myeloid leukemia, geriatric oncology, patient-reported outcomes and decision-making, frailty, epidemiology, and methodology. The McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process by including performing systematic evidence reviews (up to 24 May 2019). The panel prioritized clinical questions and outcomes based on their importance to patients. The panel then used the GRADE approach, including GRADE’s evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment.¹ 

The final 6 recommendations addressed the evidence regarding the care of older adults with AML supporting whether (1) a newly diagnosed patient should receive antileukemic therapy or best supportive care alone, (2) a newly diagnosed intensive chemotherapy candidate should receive intensive or less-intensive therapy, (3) patients who achieve a remission after intensive therapy and who are not candidates for allogeneic hematopoietic cell transplantation should receive postremission therapy, (4) newly diagnosed older adults considered eligible for receiving antileukemic therapy but not for intensive antileukemic therapy should be administered a hypomethylating agent or low-dose cytarabine monotherapy (4a) alone or (4b) in combination with other agents, (5) patients who achieve a response after receiving less-intensive therapy should continue therapy indefinitely until progression or unacceptable toxicity or should stop therapy, and (6) those who are no longer receiving antileukemic therapy (including those receiving end-of-life care or hospice care) should receive red blood cell or platelet transfusions or not have transfusions available.

During the two-year period since the publication of the guidelines,² changes in standard AML treatment necessitate their revision. On the basis of presentations that occurred at major international meetings contemporaneous with guideline development, the panel recognized that the guidelines for treating AML in older adults would be out of date soon after hitting the newsstands. In the same month as the guideline publication, the practice-changing randomized trial of azacitidine + venetoclax vs azacitidine monotherapy in older adults with AML was published, showing a significant survival advantage for the combination, at a median of 14.7 months vs 9.6 months for patients receiving monotherapy (P < .001).³ Although the guidelines mentioned the available data, the study could not be formally included in the systematic evidence review. The results of this study would be anticipated (after formal systematic review and consensus guideline approaches were undertaken) to change recommendation 4 to favor combination therapies (for older adults with AML considered eligible for antileukemic therapy, such as hypomethylating agents (azacitidine and decitabine) or low-dose cytarabine, but not for intensive antileukemic therapy), the ASH guideline panel suggests the modification or elimination of recommendation 4a because monotherapy is no longer considered the best approach for candidates who will receive nonintensive chemotherapy. Changing recommendation 2 to not favor intensive over nonintensive therapy (for older adults with newly diagnosed AML considered eligible for intensive antileukemic therapy, the ASH guideline panel suggests intensive antileukemic therapy instead of less-intensive antileukemic therapy) is supported by a retrospective study recently published in Blood Advances comparing azacitidine + venetoclax with intensive chemotherapy,⁴ but remains controversial becuase of nuances related to age, comorbidity of the disease, and the biological subtype of AML.

In addition, a recently published randomized trial of azacitidine + ivosidenib vs azacitidine monotherapy in older adults with IDH1 mutant AML showed a survival advantage for the combination over monotherapy, with a median survival of 24 months for the combination vs 7.9 months for monotherapy (P = .001).⁵ The results also support a change in recommendation 4 in favor of combination therapies for patients whose leukemia is associated with the IDH1 mutation. Patients having AML with other mutations may also merit separate combination or specific targeted therapies in the near future.

The purpose of the 2020 guidelines was to provide evidence-based recommendations on treating older adults with newly diagnosed AML. The panel deliberately chose the most important, and occasionally controversial, questions that significantly inform the conversations regarding treatment that occur between the provider and the patient, even when high-quality evidence was not uniformly available for each topic. Because new evidence that changes the standards of care for older adults with AML has become available, we have recommended updating the guidelines to reflect new management approaches that are both useful and relevant to clinical practice.

Contribution: R.M.S., J.K.A., and M.A.S. wrote and reviewed the manuscript.

Conflict-of-interest disclosure: R.M.S. is a member of a data safety monitoring boards for Takeda and Aptevo and has been a consultant or advisor for AbbVie, Amgen, Bristol Myers Squibb (BMS), CTI Biopharma, Curis, GSK, Hemavant, Ligand, Lava, Rigel, and Redona. J.K.A. serves on the data monitoring committee for GlycoMimetics and is a consult or adviser for AbbVie, Astellas Pharma, BioSight, bluebird bio, Curio, Gilead, Kura Oncology, Kymera Therapeutics, Stemline Therapeutics, and Syros. M.A.S. serves on an advisory board for BMS, Novartis, and Kurome Therapeutics.

Correspondence: Richard M. Stone, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, D-2053, Boston, MA 02215; email: richard_stone@dfci.harvard.edu.