Introduction to a How I Treat series on acute myeloid leukemia

For decades, the only option for newly diagnosed acute myelogenous leukemia (AML) that provided a path to remission and long-term disease-free survival required initial treatment with intensive induction therapy. Anthracycline- and cytarabine-based regimens were the sole standard of care globally. Diagnosis and prognosis were based only on morphology and cytogenetics. Prolonged hospitalization with profound cytopenias, mucositis, and other complications was expected. Many community physicians did not feel that they could offer these patients optimal care locally, so patients were treated at specialty centers, often a distance from home. Given the potential morbidity and mortality of therapy, prognostic systems were devised based on age, comorbidities, cytogenetics, performance status, and standard laboratory parameters. Although fit patients up to age 80 years could potentially benefit from standard induction and consolidation therapy, elderly patients and those with comorbidities who were not candidates for such therapies were offered palliative therapy only because less-intensive agents have not been shown to provide a survival benefit. Recent advances have significantly changed the landscape. The incorporation of all-trans retinoic acid (ATRA) and, later, arsenic trioxide into the treatment of acute promyelocytic leukemia (APL) were breakthroughs, but for non-M3 AML, years passed before there were similar advances. However, now more sophisticated diagnostic prognostic techniques are available, incorporating disease mutations; hypomethylating agents, initially approved for use for patients with myelodysplastic syndrome, were found to have benefit as a single agent in patients with AML, and over the last 7 to 8 years, the development of new agents and regimens have significantly changed the landscape.

These new changes have provided us with many more opportunities. However, with opportunities also come challenges. This How I Treat series includes the following 4 articles that address treatment challenges in AML and provide insight into how best to use these agents, how to identify the right regimen for the right patients, and how to treat patients for whom these agents still may not offer favorable outcomes:

• Andrew H. Wei, Sun Loo, and Naval Daver, “How I treat patients with AML using azacitidine and venetoclax”

• Ghayas C. Issa, Eytan M. Stein, and Courtney D. DiNardo, “How I treat acute myeloid leukemia with differentiation therapy”

• Steven D. Green and Eunice S. Wang, “How I treat secondary acute myeloid leukemia”

• Gail J. Roboz and Jonathan Canaani, “How I use maintenance therapy in acute myeloid leukemia”

With the US Food and Drug Administration approval of hypomethylating agents and venetoclax in 2020, patients aged >75 years are now routinely treated with the ability to prolong survival. Moreover, many patients no longer require inpatient hospitalization and can therefore, remain near home. Venetoclax was an agent familiar to the oncology community because of its use in lymphoid malignancies, however the AML dosing, regimens, and complications were not. Real-world data rapidly demonstrated inferior outcomes and increased toxicity of these regimens compared with those used on trials. Each patient seems to require precise micromanagement of timing and dosing of the agents, and identification of those at highest risk for tumor lysis requires close monitoring and inpatient hospitalization. In addition, we now know that molecular profiles can inform expected outcomes. Expert guidance can provide us with the tools needed to optimize the use of these regimens.

ATRA, when first used to treat APL, was found to result in a previously undescribed, potentially life-threatening set of toxicities in some patients. Originally called retinoic acid syndrome, we have come to learn that this is a differentiation syndrome, seen not only with ATRA but with arsenic trioxide in APL and now with a cohort of newer agents in AML therapy. Its identification remains a challenge, because the symptoms of differentiation mimic those of the disease and treatment is not without consequences. Given the risk of morbidity and mortality associated with underdiagnosis, the How I Treat series on differentiation syndrome illustrates several scenarios to assist in both diagnosis and treatment.

Although novel agents have allowed us to provide life-prolonging therapy to older patients and patients with comorbidities, and targeted agents, alone or in combination with cytotoxic and lower-intensity regimens, are now being used not only for relapse but also in patients with newly diagnosed AML, patients with secondary AML continue to pose a challenge. Some of these patients have received hypomethylating agents for prior myeloid disorders or have mutations that are thought to be unlikely to benefit from the newer regimens. Often not included in clinical trials, expert guidance is welcome in both the analyses of value at diagnosis and treatment of these challenging cases.

Although most patients with AML will now achieve a remission, relapse and death from disease is still unfortunately a significant challenge. As such, allogeneic transplant remains the mainstay of therapy for those patients who do not have low-risk disease. For those patients who are not candidates for transplant or remain high-risk despite transplant, patients and physicians alike have always considered extending treatment, but until recently there were no agents available that offered a safety, toxicity, and efficacy profile that was of value. Hypomethylating agents have now been demonstrated to be of value as maintenance therapy in patients who do not proceed to transplant in first remission, however, many questions remain regarding the duration of maintenance, the role of maintenance after transplant, the use of targeted agents, and the approach to those for whom studies are not available.

By using illustrative patient examples, through narrative, tables, and figures, these How I Treat articles provide valuable insights and recommendations concerning the management of AML in an exciting evolving era with new diagnostic and therapeutic tools.