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Ferrata Storti Foundation
Haematologica 2021 Volume 106(10):2544-2554
Dose intensity for induction in acute myeloid leukemia: what, when, and for whom?
Shannon R. McCurdy and Selina M. Luger
Division of Hematology-Oncology/Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
ABSTRACT
Intensive chemotherapy has been the backbone of the treatment of acute myeloid leukemia (AML) for decades. However, an increase in novel targeted agents, which has been brought about in part by a deeper understanding of the genetic makeup of AML, has led to remis- sion-inducing regimens that do not require traditional cytotoxic agents. Combinations of a hypomethylating agent (HMA) and venetoclax have doubled the chance of remission for patients considered unfit for induc- tion chemotherapy who would have traditionally been offered single- agent HMA. In fact, this regimen may rival the complete remission rate achieved with induction chemotherapy for certain populations such as the very elderly and those with secondary AML, but equivalency has yet to be established. Further advances include the addition of gemtuzumab ozogamicin and FLT3 inhibitors to induction chemotherapy, which improves survival for patients with core-binding factor and FLT3-mutated AML, respectively. Still, much work is needed to improve the outcomes of the highest-risk subgroups: frail patients and those with high-risk cyto- genetics and/or TP53 mutations. Promisingly, the landscape of AML ther- apy is shifting dramatically and no longer is intensity, when feasible, always the best answer for AML.
Introduction
The initial data for the most widely utilized intensive induction chemotherapy regimen for acute myeloid leukemia (AML), a combination of cytarabine and an anthracycline (“7+3”), were published in 1973.1 In the subsequent four decades the question of increasing or decreasing the intensity of induction had been asked mul- tiple times. Various institutions adopted modified cytarabine and anthracycline plat- forms that included the addition of a third agent such as etoposide and/or employ- ing time sequential therapy.2 However, no modifications, other than variations in dose intensities of anthracycline, have been widely adopted. Hypomethylating agents (HMA) and low or intermediate doses of cytarabine have been utilized for patients over 70-75 years old or those considered unfit for intensive therapy due to comorbidity or poor performance status (PS), but intensive induction was the only AML-directed therapy with a known survival benefit. After years of stagnation in new agents, beginning in 2017 the world of AML therapy was uplifted by the approval of new therapies. However, until recently none has provided a true alter- native to induction for those individuals who are otherwise induction candidates, and upfront therapy for those who were unfit was still limited. Given the survival benefit seen with venetoclax combination therapies when compared with HMA alone,3 the question of intensity has risen again, but with no clear answers regarding whether fit patients would benefit from this intermediate intensity option. Here we will review the literature and provide our position on when to consider dose inten- sity in the era of novel, less intensive induction strategies.
To treat or not to treat?
While induction therapy is still considered the standard of care for younger patients with favorable- or intermediate-risk disease, not all patients are deemed
Correspondence:
SELINA M. LUGER
selina.luger@pennmedicine.upenn.edu
Received: February 11, 2021. Accepted: June 11, 2021. Pre-published: July 29, 2021.
https://doi.org/10.3324/haematol.2020.269134 ©2021 Ferrata Storti Foundation
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