Inclusion Matters: Effective AML Treatment with HMA/Venetoclax for Older Jehovah's Witnesses

Introduction: Standard acute myeloid leukemia (AML) treatment often requires blood transfusions, posing a challenge for Jehovah's Witnesses (JW) who refuse blood products. Hematologists have often been reluctant to treat such patients. Venetoclax (Ven) with hypomethylating agents, such as azacitidine (Aza), offers a promising alternative. This study reports on 4 consecutive, older JW patients with AML treated with this regimen at our institution.

Case 1: A 66-year-old woman with a white blood cell count (WBC) of 122 × 10⁹/L, hemoglobin (Hb) level of 7.8 g/dL, and platelet count (Plt) of 130 × 10⁹/L was diagnosed with AML (68% blasts). Cytogenetics were normal; Next-Generation Sequencing (NGS) showed DNMT3A, FLT3-ITD, and NPM1 mutations. Initial treatment included Aza (7 days) and Ven (21 days; 400 mg) with brief hydroxyurea. Hb and Plt nadired at 5.6 and 207, respectively. After cycle 1, bone marrow biopsy revealed 50% blasts. Ven was reduced to 14 days from cycle 2, and gilteritinib (80 mg) was started. Hb and Plt nadired at 5.5 and 154, respectively. She was hospitalized briefly for febrile neutropenia. Repeat bone marrow biopsy showed 10% blasts. Hb improved to 12.2. Bone marrow biopsies after cycles 4 and 8 showed complete morphologic remission with normal cytogenetics and DNMT3A on NGS. Cycles 2-8 were delayed by a median of 2 weeks (range 0-3) due to neutropenia, leading to discontinuation of Ven after cycle 9. She is 426 days post-diagnosis.

Case 2: A 62-year-old woman with diabetes, hypertension, and coronary artery disease presented with WBC 5.8, Hb 8.2 and Plt 174. Bone marrow biopsy showed AML (26% blasts). Cytogenetics were normal, and NGS revealed FLT3-ITD, NPM1, TET2, and TET3 mutations. Initial treatment included Aza (7 days) and Ven (200 mg; 4 weeks) with fluconazole. Nadir counts were Hb 9.4 and Plt 108. Bone marrow biopsy after cycle 1 showed complete remission with persistent FLT3-ITD and NPM1. From cycle 2, fluconazole was discontinued, and Ven increased to 400 mg for 3 weeks. Unfortunately, after cycle 4, cytopenia worsened (WBC 1.3, Plt 37, and Hb 8.2), and bone marrow biopsy revealed relapsed AML (42% blasts). NGS showed monoallelic CEBPA, TET2, FLT3-ITD, and NPM1. Treatment was switched to gilteritinib (80 mg). Counts improved to WBC 3.6, Hb 11.6, and Plt 133. Bone marrow biopsy 2 months later showed morphologic remission. However, 6 months after gilteritinib, WBC increased to 24.7, Plt 33, and Hb 8.9. Bone marrow biopsy confirmed relapsed disease (92% blasts) with NPM1 and TET2 on NGS. Hospice referral was made, and gilteritinib was stopped. She was 392 days post-diagnosis.

Case 3: A 78-year-old woman with history of radiation therapy for stage I breast cancer completed 5 years ago presented with WBC 2.2, Hb 8.7, and Plt 95. Bone marrow biopsy confirmed therapy-related AML (26% blasts). Cytogenetics showed del(5q) and del(12p). NGS revealed DNMT3A, ASXL1, EZH2, PTPN11, and RUNX1 mutations. She was treated with Aza (7 days) and Ven (400 mg; 14 days). Nadir Hb was 5.7, and Plt 10. Post-cycle 1 bone marrow biopsy showed complete remission with normal cytogenetics and no molecular abnormalities on NGS. Hb improved to 13 after 2 cycles. Worsening pancytopenia after cycle 8 prompted a bone marrow biopsy, revealing relapsed AML (30% blasts) and complex cytogenetics. NGS was positive for two DNMT3A variants. Comfort measures were pursued. She relapsed 301 days post-diagnosis.

Case 4: A 73-year-old woman with WBC 51.6, Hb 7.9, and Plt 86 was diagnosed with AML (80% blasts). FLT3 mutation was negative. She was treated with Aza (5 days) and Ven (14 days; 100 mg) with posaconazole during cycle 1. Counts improved with nadir Hb 8 and Plt 279. Cycle 2 started with Aza (7 days) and Ven (14 days; 400 mg) without fungal prophylaxis. A follow-up bone marrow biopsy is pending. She is 55 days post-diagnosis.

All patients received darbepoetin until hemoglobin improvement, and some were given intravenous iron. All therapy cycles, except one, were administered outpatient. All patients achieved complete hematological recovery, with no bleeding or ischemic cardiac events.

Conclusion: Ven and Aza provided durable remissions in older JW patients with AML, offering a safe alternative for those refusing blood transfusions. The regimen showed minimal cytopenia-related complications, even in patients with proliferative disease. Refusal of blood transfusions should not preclude initial treatment in most patients with AML.

Yang:Pfizer: Research Funding; Puretech: Research Funding; Novartis: Consultancy, Research Funding.