In the 64^th American Society of Hematology (ASH) Annual Meeting and Exposition 2022, Dr. Laura C. Michaelis from the Medical College of Wisconsin, United States (US), and Dr. Kristen O'Dwyer from the University of Rochester Medical Center, US, presented the current ASH recommendations for less intensive therapy and intensive therapy in older adults (i.e., ≥65 years) with acute myeloid leukemia (AML), and outlined the potential future direction.^1,2

AML treatment is difficult in elderly patients who cannot tolerate the standard treatment of intensive induction chemotherapy (IIC).¹ Dr. Michaelis stressed that before making any treatment guidelines decisions, it is important to clearly define key terms like ‘less intensive’, ‘older adults’, and even ‘AML’ since they could encompass a broader population than usually considered.¹ She also highlighted the significance of phase 3 trials on innovative drug regimens published since 2017, focusing on less intensive treatment for AML patients who are not candidates for IIC [e.g., venetoclax (VEN) combinations, gilteritinib (GIL), ivosidenib, etc.].¹

The VIALE-A was a phase 3 study that evaluated the safety and efficacy between azacitidine + venetoclax (AZA/VEN) and AZA with placebo.¹ Patient aged ≥75 years with untreated AML or other adults ineligible for IIC per the modified Ferrara criteria were randomized 2:1 to receive AZA/VEN (n=286) or placebo (n=145), with overall survival (OS) as the primary outcome.¹ Patients on AZA/VEN had a longer median OS (mOS) (14.7 months vs. 9.6 months; HR for death=0.66; 95% CI: 0.52-0.95; p<0.001) and a greater rate of complete remission/composite complete remission (CR/CRi)  than the placebo group (36.7%/66.4% vs. 17.9%/28.3%), after a median follow-up of 20.5 months with most responses occur relatively early.¹ A retrospective study comparing AZA/VEN with intensive cytotoxic induction therapy found that the overall response rates (ORR) were similar, though the mOS was longer in the intensive cytotoxic induction arm compared with the AZA/VEN arm (884 days vs. 483 days).¹ Dr. Michaelis highlighted that managing concomitant medications, adjusting doses for azoles, the timing of response assessment, and cytopenia management continue to be the challenges in administration.¹ She stressed the importance of checking protocol details in the supplementary data section of a paper when administering a novel regimen like AZA/VEN.¹

VIALE-C, another randomized, multinational, phase 3 trial, examined if adding VEN to low-dose cytarabine (LDC) would increase OS, compared to using LDC with a placebo.¹ The survival benefit was shown only with longer follow-up, but importantly, this study showed transfusion independence.¹ An improvement in the nucleophosmin (NPM1) subtype mutation in the secondary analysis was also observed.¹

Adults with untreated FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3^mut+) AML including internal tandem duplication (ITD) and mutation in the tyrosine kinase domain (TKD) that ineligible for IIC were randomized 2:1 to receive GIL + AZA (n=74) or AZA alone (n=49), and OS was evaluated in the Lacewing trial.¹ The trial was stopped for futility, as the comparator arm was no longer appropriate and there was no evidence of benefit to the interventional arm.¹ Of note, OS was not significantly different between the 2 groups, but the CRi rate was higher in the GIL/AZA arm compared with the AZA alone arm (58.1% vs. 26.5%), suggesting that there is not always a linkage between CR and OS in older patients.¹

With respect to the mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, ivosidenib was evaluated in the AGILE trial.¹ AGILE was a phase 1 trial that enrolled patients ineligible for IIC with untreated and newly diagnosed IDH1-mutated AML and randomized 1:1 to receive ivosidenib + AZA (n=72) or AZA with placebo (n=74).¹ The OS and event-free survival (EFS) were significantly longer in the ivosidenib + AZA group vs. the placebo group.¹

Following Dr. Michaelis’s presentation, Dr. O’Dwyer then shared her view on less intensive therapy.² Older patients have a 5-year survival rate of ≤10%, and long-term survival is dismal without hematopoietic stem cell transplantation (HSCT).² A CR rate of 60.3% has been observed with intensive chemotherapy in eligible older adults.² However, the debate about choosing between intensive and less intensive therapy continues.² Although Dr. O’Dwyer admitted that the majority of clinicians are using less intensive therapy for most older patients, she and her group reconsidered the candidates for both therapies by using the PICO (population, intervention, comparator and outcomes) method with the outcomes of mortality, stem cell transplantation, serious adverse events (SAEs), intensive care unit (ICU) admissions, hospitalizations, functional status, and quality of life (QoL).² Results showed that there were 88 fewer deaths in the intensive therapy group compared with the less intensive therapy group, pointing out that there was a very low quality evidence suggesting patients who received intensive antileukemic therapy were at lower risk of death than those who received less intensive therapy over time (HR=0.78; 95% CI: 0.69-0.89).²

Dr. O'Dwyer reviewed 4 studies published following the previous 2020 guidelines.² Among them, in the CPX-351 study, patients were randomized 1:1 to receive CPX-351 or standard therapy (7+3).² The mOS was longer with CPX-351, which was maintained at 5 years of follow-up. The survival benefit was especially notable in patients who reached HSCT, as mOS was not reached in the CPX-351 group.² The most common cause of death was progressive leukemia.² CAVEAT was a phase 1b dose-escalation study of VEN combined with modified intensive chemotherapy of cytarabine + idarubicin.² The ORR was high at 72% and even better in those who had de novo AML (97%).² In another phase 1b/2 study evaluating VEN with fludarabine, cytarabine, granulocyte colony stimulating factor (G-CSF), and idarubicin (FLAG-IDA), 8 patients over 60 years old achieved CR, with no survival difference between patients who were older or younger than 60.² Last but not least, a real-world study of 25,621 patients aged 60-79 years from the US National Cancer Data Base compared the use of multi-agent therapy (70%), which was assumed to be intensive therapy, with another single agent of less intensive therapy.² Results showed that the 1 year OS for patients on multi-agent therapy was higher in comparison to the monotherapy (43% vs. 28%).

In conclusion, more randomized trials testing targeted agent vs. intensive therapy, standardization of fitness, subgroup analysis based on disease characteristics, and consistent measurements of patient-reported outcome (PRO), QoL, and evaluation of patients’ values are needed in the future.