Individualizing Treatment for Patients With AML Unfit for Intensive Chemo

Management of newly diagnosed acute myeloid leukemia (AML) in patients deemed unfit for intensive chemotherapy is undergoing rapid transformation toward highly individualized regimens. The combination of venetoclax with a hypomethylating agent (HMA), is the new standard of care in first-line therapy, although the treatment responses and survival outcomes among this population is highly variable and requires further refinements in therapy selection, according to a review published Blood Cancer.¹

AML is typically diagnosed in older adults, with the median age at diagnosis being 69 years old.² However, traditionally, intensive chemotherapy was the standard of care that induced the most meaningful rates of response in AML, and most older patients are not considered suitable candidates for this approach given rates of toxicity and treatment-related mortality.³ In 2018, the FDA granted accelerated approval for venetoclax plus HMA to treat patients with newly diagnosed AML who were ineligible for intensive chemotherapy.⁴

“With the increase in treatment options, management of AML relies on a shared decision-making process, which not only considers disease features but importantly patient fitness, quality of life metrics and preference,” the authors explained.

How to Can Determining Fitness Influence Treatment Selection?

Patient fitness should not be determined by chronological age; however, there is a lack of validated fitness screening criteria, they noted. Instead, scores rely on comorbidities, disease characteristics, or consensus from expert panels. The HCT Frailty Scale assesses patients before undergoing bone marrow transplant.

Research has shown that patients who were determined to be unfit have higher 28-day mortality rates and reduced overall survival rates compared with patients who were considered to be fit. One recent study used an integrated geriatric assessment to guide treatment selection.⁵ Patients who were considered fit based on a geriatric assessment received more intensive therapy with unfit patients who received lower-intensity therapy, such as venetoclax plus HMA.

What Role Do Genetic Risk Factors Play in Treatment Selection?

The ELN-2022 genetic risk model is usually used for prognostication in AML by identifying certain risk factors that put patients into a favorable, intermediate, or adverse risk category. ELN-2024 was proposed to guide which patients should receive less-intensive therapies.

“In general, genetic predictors for survival and response tend to overlap,” the authors wrote, with “distinct molecular predictors of treatment response” to venetoclax plus HMA.

Analyses showed that patients with high-risk mutations—like TP53, FLT3-ITD, KRAS, or NRAS—fared worse, while those without these alterations achieved the highest remission rates. Additional studies identified that favorable mutations (NPM1, IDH2, DDX41) strongly improve responses, but long-term survival is most dependent on achieving remission and measurable residual disease negativity, regardless of genetic risk. Importantly, patients who achieved remission and proceeded to transplant had markedly better survival compared with those who did not.

Personalizing Treatment Strategies

Taking into consideration both disease-related factors and patient characteristics is strongly advised to manage newly diagnosed AML. Although investigational therapies should be given preference for patients who are unfit for intensive therapies, venetoclax plus HMA is preferred as a first-line treatment for most patients if investigational therapies are not feasible.

Some exceptions to this are patients with an IDH1 mutation, who should be treated with azacitidine plus ivosidenib and patients with a TP53 mutation for whom HMA monotherapy may be considered since adding venetoclax offers no improvements in remission or survival for this group of patients.

Following treatment, allogeneic stem cell transplantation (ASCT) plays a role in securing long-term survival, the authors noted. Studies have shown that patients who receive venetoclax plus HMA have improved fitness to become eligible for transplant. One Mayo Clinic cohort showed a 3-year survival rate of 62% for patients who bridged to transplant after achieving remission on the combination therapy.⁵

“Given that Ven-HMA therapy is not curative in the vast majority of patients, an individualized approach to treatment selection is recommended and ASCT in remission should be strongly considered,” the authors concluded. “We recommend comprehensive NGS testing, or at minimum testing for actionable mutations, with consideration of rapid turnaround times to facilitate timely selection of appropriate therapies.”

References

1. Gangat N, Dinardo CD. Newly diagnosed acute myeloid leukemia in unfit patients: 2026 treatment algorithms. Blood Cancer J. 2025;15(1):139. doi:10.1038/s41408-025-01346-1

2. Key statistics for acute myeloid leukemia (AML). American Cancer Society. Revised March 4, 2025. Accessed September 24, 2025. https://www.cancer.org/cancer/types/acute-myeloid-leukemia/about/key-statistics.html

3. Short NJ, Kantarjian H. When less is more: reevaluating the role of intensive chemotherapy for older adults with acute myeloid leukemia in the modern era. J Clin Oncol. 2021;39(28):3104-3108. doi:10.1200/JCO.21.00960

4. FDA approves venetoclax in combination for AML in adults. News release. FDA. December 14, 2018. Accessed September 25, 2025. https://www.fda.gov/drugs/fda-approves-venetoclax-combination-aml-adults

5. Bhatt VR, Wichman CS, Koll TT, et al. A phase II trial of geriatric assessment-guided selection of treatment intensity in older adults with AML. Am J Hematol. 2025;100(7):1163-1172. doi:10.1002/ajh.27694

5. Johnson I, Elbeih A, Ghosoun N, McCullough K, Al-Kali A, Alkhateeb HB, et al. Predictors of post-transplant survival in patients with newly diagnosed acute myeloid leukemia receiving frontline venetoclax and hypomethylating agents. J Clin Oncol. 2025;43(suppl 16):e18523-e. doi:10.1200/JCO.2025.43.16_suppl.e18523