New perspectives on the management of unfit patients with acute myeloid leukemiaNew perspectives on the management of unfit patients with acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive disease that predominantly affects older individuals.1 While hematopoietic stem-cell transplantation (HSCT) after induction chemotherapy is potentially curative, this option is not feasible for many older AML patients due to advanced age, coexisting conditions or a high incidence of unfavorable genomic features.1,2 However, as intensive induction chemotherapy still remains the best curative approach, The National Comprehensive Cancer Network (NCCN) has previously updated their guidelines to recommend driving therapy choice based on patients’ fitness instead of age. In addition, actionable genetics that were previously used for the evaluation of disease persistence are now used for risk stratification, and Dr. Alexander Perl, Associate Professor of Medicine at the Hospital of the University of Pennsylvania, United States, highlighted that AML karyotypes should now be tested at diagnosis with therapy initiation delayed in stable patients until their cytogenetic risks are determined.

Following this update, Dr. Perl noted that many major AML treatment concepts remain unchanged in the 2021 updated NCCN guidelines. Intensive post-remission chemotherapy and HSCT remain the recommended choice for fit patients due to its high curative rate. However, unfit patients who are ineligible for intensive chemotherapy can now consider oral azacitidine, a treatment option that was shown in the phase 3 QUAZAR AML-001 study to be associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy.1

Of note, as most AML stem cells express aberrantly high levels of B-cell lymphoma 2 (BCL2) and are dependent on BCL2 for survival, the selective small-molecule BCL2 inhibitor, venetoclax, can synergize with azacitidine to further improve survival and remission among AML patients.2 In the recently published phase 3 VIALE-A study, patients who were considered ineligible for standard induction therapy, i.e., either ≥75-years-old or had at least one coexisting condition precluding intensive chemotherapy, were included.2 After a median follow-up of 20.5 months, patients receiving the combination of azacitidine plus venetoclax achieved a significantly longer overall survival (OS) of 14.7 months with a survival plateau after 2 years when compared to 9.6 months in the azacitidine plus placebo group (HR=0.66; 95% CI: 0.52-0.85; p<0.001).2 The incidences of complete remission (CR) and composite CR were also significantly higher with azacitidine plus venetoclax (both p<0.001).2 Notably, older patients ≥75-years-old received a greater survival benefit with the combination therapy (HR=0.54).2 Also, patients with poor genetic risk factors including IDH1, IDH2 and IDH1/2 mutations had significantly improved OS with azacitidine plus venetoclax (HR=0.28, 0.34 and 0.34, respectively).2 In fact, those with IDH1/2 mutations achieved a greater CR and CR with partial hematologic recovery (72% vs. 60%) as well as doubled median OS (24.5 vs. 12.3 months) than patients without IDH1/2 mutations.3

Based on the results of the VIALE-A study, Dr. Perl recommended the following treatment strategy for AML patients who are unfit for intensive induction chemotherapy:

  1. Start venetoclax and azacitidine together after cytoreduction to a white blood cell count below 25,000 units/μL using hydroxyurea
  2. Monitor for tumor lysis syndrome during three days of venetoclax ramp-up
  3. Decrease venetoclax dose for concurrent moderate to strong CYP3A4 inhibitors
  4. Check response at the conclusion of cycle 1 therapy of venetoclax and azacytidine, and delay the initiation of cycle 2 treatment if morphologic leukemia-free state is observed
  5. Treatment-emergent cytopenia in responding patients may warrant dosing adjustment of venetoclax in subsequent cycles, e.g., prescribe venetoclax on days 1-21 or 1-14 only
  6. Bone marrow biopsy can be performed every 3 to 6 months to confirm ongoing response

In addition to venetoclax, ivosidenib was also studied in combination with azacitidine for unfit AML patients in a phase 1b study.4 With a high overall response rate of 78.3% and CR rate of 60.9%, the combination of ivosidenib plus azacitidine showed promising benefit for unfit AML patients.4 Dr. Perl highlighted, “Oral azacitidine is a new option for AML patients in remission who have completed all planned intensive post-remission therapy and are transplant ineligible.”

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