Conference Update

New approaches for geriatric acute myeloid leukemia

Hematology
2 months ago, OP Editor

Acute myeloid leukemia (AML) therapy planning usually requires stratification of patients based on their age and performance status. Only young and fit patients would be eligible for intensive chemotherapy, limiting older unfit patients to lower intensity treatment which would usually result in lower long-term survival rate.1 In her update on the treatment options for older AML patients in the 25th European Hematology Association Annual Congress (EHA25), Dr. Courtney D. DiNardo, clinical researcher at MD Anderson Cancer Center, The University of Texas Houston, United States, stated, “There are now more than just two dichotomous treatment options for our older AML patients.”

Although the typical regimen of low-dose cytarabine and hypomethylating agents (HMA) showed improvement in the survival outcomes among AML patients, long-term responses remain uncommon and varied across AML subgroups. For instance, durable remission was observed in AML with NPM1 and IDH2 mutations, while relapse was seen in patients with complex cytogenetics and mutations of TP53 and signalling.2 To better manage AML, patients should be stratified by AML subtypes instead of dichromatically by age and performance status.

For induction and consolidation, targeted therapeutic approaches could enhance remission and survival outcomes of some subgroups. IDH mutations, which encompass 20% of the AML cases that could be acquired at progression, are mostly carried by older patients. Ivosidenib and enasidenib are two IDH inhibitors studied in newly diagnosed IDH-mutated AML patients in which both showed increase in the overall response rate and complete remission rate when used in combination with azacitidine. Oral enasidenib medication might enable outpatient therapy of AML with IDH mutations in the future.3

FLT3 mutations, which occur in 25-33% of AML patients and more frequently in younger patients, are usually associated with a poorer prognosis. A panel of FLT3 inhibitors is available for treating newly diagnosed older patients with FLT3-mutated AML in combination with lower intensity therapy. These combinations delivered modest complete remission rate and increase in overall survival rate.3

TP53 mutations, a difficult-to-treat subgroup with poor prognostic outcomes, are prevalent in up to 20% of AML and myelodysplastic syndrome (MDS) patients. APR-246 is the first-of-the-class apoptosis inducing agent which reactivates mutant p53 protein to induce leukemia cell apoptosis. The combination of APR-246 and azacitidine resulted in a promising 87% overall response rate, which prompted the doublet and triplet trials with azacitidine and venetoclax for studying safety and efficacy. CD47 monoclonal antibody magrolimab plus azacitidine demonstrated 75% overall response rate and 91% 6-month overall survival rates among TP53-mutated AML patients.3

For the treatment of FLT3 and IDH-mutated AML, Dr. DiNardo stated, “azacitidine with a targeted therapy appears to be effective, azacitidine with venetoclax also appears to be effective. The future may be the incorporation or the appropriate sequencing of these triplet combinations.” Additionally, the recent development of glasdegib, a hedgehog inhibitor used with low-dose cytarabine, could be a potential option for AML patients when used with azacitidine.

For maintenance, intensive induction therapy prior to stem cell transplant (SCT) was commonplace, yet recent studies demonstrated that venetoclax-based regimens might be capable of replacing the intensive approaches among older patients. An oral formula of azacitidine, CC-486, was also studied as the maintenance medication.3 Dr. DiNardo said, “[Dose] interruptions, and less commonly reductions, were required in many patients for optimal therapy. Again, this highlights the importance of ongoing assessment and appropriate dose modification for the optimal care of our AML patients.”

  1. Lazenby M, et al. The prognostic relevance of FLT3 and NPM1 mutations on older patients treated intensively or non-intensively: a study of 1312 patients in the UK NCRI AML16 trial. Leukemia. 2014 Oct;28(10):1953-9.
  2. DiNardo CD, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020 Mar 12;135(11):791-803.
  3. DiNardo CD. New frontiers in AML: treatment of the older patient. EHA25, oral presentation.

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