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ACUTE MYELOID LEUKEMIA

Physician and patient perceptions on randomization of treatment intensity for unfit adults with acute myeloid leukemia and other high-grade myeloid neoplasm

Leukemia volume 36, pages 1386–1389 (2022)Cite this article

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Acute myeloid leukemia (AML) primarily affects older people, and thus many patients are felt to be medically less-than-fit (“unfit”) at the time of initial diagnosis (e.g., because of comorbid illnesses). How best to treat such individuals remains under debate, with ongoing uncertainty about the optimal treatment intensity. Results from three randomized trials conducted in the 1980s highlight this uncertainty and point to the delicate balance between efficacy and toxicity [1,2,3]. In a trial that included 45 patients aged ≥70 years, lower doses of daunorubicin, cytarabine, and 6-thioguanine were associated with fewer deaths within 60 days of treatment initiation, superior survival, and better quality of life (QOL) than full drug doses, while remission rates were similar [1]. A second trial, assigning 60 patients aged ≥65 years to either intensive induction chemotherapy or supportive care with hydroxyurea or low-dose cytarabine as necessary, found significantly higher complete remission (CR) rates and better survival for intensely treated patients, whereas the proportion of days spent in hospital was similar [2]. Yet another conclusion was be reached in a third trial, in which 87 patients aged ≥65 years were randomized between low-dose cytarabine or intensive chemotherapy: here, the more intensive therapy yielded more remissions, but survival was similar and the less intensive therapy required less supportive care and shorter hospital stays [3].

The uncertainty regarding optimal treatment intensity in unfit adults with newly diagnosed AML is ideally addressed via randomized treatment allocation. However, while these older studies suggest randomized assignment to lower- vs. higher-intensity chemotherapy is feasible, strong perceptions and pre-conceived preferences regarding treatment intensity may render randomization challenging or impractical. The latter is suggested by the experience in the NCRI/MRC AML 14 trial. This trial offered randomization between higher and lower intensity treatments in some patients but only 8 of the 1485 participants were randomized between the 2 approaches [4]. We therefore conducted a trial to evaluate the feasibility of randomization between different therapy intensities in unfit adults with newly diagnosed AML or other high-grade myeloid neoplasm. As intensive therapy, we used CLAG-M (cladribine, high-dose cytarabine, G-CSF, escalated-dose mitoxantrone), our institutional standard AML chemotherapy for fit adults [5]. Rather than selecting different classes of drugs in the two treatment arms– which may influence decision-making and therefore confound the question of treatment intensity – we used the same regimen at reduced dose (RD CLAG-M) as the less-intensive comparator.

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Acknowledgements

We dedicate this paper in honor of Dr. Elihu H. Estey who was instrumental in conceptualizing this study and enrolling subjects. Dr. Estey died after collapsing at home on October 8, 2021, prior to the final analysis of these data and manuscript completion.

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Author notes

  1. Pamela S. Becker

    Present address: University of California Irvine, Irvine, CA, United States

Authors and Affiliations

  1. Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA

    Anna B. Halpern, Genevieve Alcorn, Zahra Ali, Kelsey-Leigh A. Garcia, Mary-Elizabeth M. Percival, Siobán B. Keel, Ryan D. Cassaday, Pamela S. Becker, Elihu H. Estey & Roland B. Walter

  2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Anna B. Halpern, Mary-Elizabeth M. Percival, Ryan D. Cassaday, Pamela S. Becker, Elihu H. Estey & Roland B. Walter

  3. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Megan Othus

  4. Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA, USA

    Roland B. Walter

  5. Department of Epidemiology, University of Washington, Seattle, WA, USA

    Roland B. Walter

Authors
  1. Anna B. Halpern
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  2. Megan Othus
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  3. Genevieve Alcorn
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  4. Zahra Ali
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  5. Kelsey-Leigh A. Garcia
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  9. Pamela S. Becker
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  10. Elihu H. Estey
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  11. Roland B. Walter
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Contributions

ABH and RBW conceptualized the study, enrolled patients, collected data, analyzed data and wrote the manuscript. MO analyzed the data. GA, ZA, KG helped with patient enrollment and did data collection. MMP, SBK, RDC, PSB enrolled patients, contributed to data, and contributed to the manuscript. EHE conceptualized the study and enrolled patients.

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Correspondence to Anna B. Halpern.

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The authors declare no competing interests.

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Halpern, A.B., Othus, M., Alcorn, G. et al. Physician and patient perceptions on randomization of treatment intensity for unfit adults with acute myeloid leukemia and other high-grade myeloid neoplasm. Leukemia 36, 1386–1389 (2022). https://doi.org/10.1038/s41375-022-01524-1

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