Venetoclax with azacitidine for two younger Jehovahʼs Witness patients with high risk acute myeloid leukemia
Authors: Allison M. Bock, Daniel A. Pollyea
Journal: American Journal of Hematology (2020)

The standard of care for younger newly-diagnosed patients with acute myeloid leukemia (AML) is intensive induction chemotherapy (7 + 3). This regimen results in a high response rate but has considerable toxicity. Its myeloablative nature requires a temporary period of blood product transfusion dependence; the average induction requires 10.8 and 8.5 units of red blood cells and platelets, respectively.1 Jehovah's Witnesses (JW) are a Christian denomination with a religious objection to the receipt of blood products; when they develop AML, treatment options are limited. When 7 + 3 has been attempted, death from complications of cytopenias were common.2, 3 7 + 3 with reduced doses of chemotherapy, or substitutions of the chemotherapy backbone with less intensive therapies, have had limited success.3 Efforts to treat JW AML patients with alternative, off-label regimens often still result in life-threatening cytopenias,4 and practitioners are apprehensive to treat JW's with AML.2 Venetoclax is an oral BCL-2 inhibitor approved in the United States for older, newly diagnosed AML patients in combination with a hypomethylating agent or low-dose cytarabine.5 This regimen targets leukemia stem cells, and results in deep and durable responses.6 Although frequent, cytopenias result in few adverse clinical sequalae5. We describe two younger JW patients with newly diagnosed, high-risk AML who refused transfusion support, preventing them from receiving 7 + 3. Treatment with off-label venetoclax+azacitidine resulted in durable remissions without transfusion support. Case 1: A 33-year-old female patient with a history of systemic lupus erythematosus, Crohn's disease and thyroid carcinoma status post resection and radiation eight years previously presented with fatigue and pancytopenia. A bone marrow (BM) biopsy confirmed AML with 30% blasts (Table S1). Cytogenetic studies revealed an abnormal karyotype (46,XX,del(7)(q22q32)[5]/46,XX)[15] and next generation sequencing (NGS) showed a mutation in ASXL1 (c.1900_1922del23; p.e64FRfs*15) at a 7% allele frequency, making her adverse risk by the European Leukemia Network (ELN) criteria. Her initial white blood cell (WBC) count was 2.4 × 109/L with an absolute neutrophil count (ANC) of 0.5 × 109/L, hemoglobin 110 g/L and platelets 130 × 109/L. Her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was one. The patient informed the treatment team that as a JW she had a religious objection to the receipt of blood product transfusions; standard induction chemotherapy followed by an allogeneic stem cell transplant was withdrawn as a treatment option. Based on successful clinical trials of venetoclax with hypomethylating agents for newly-diagnosed, older AML patients unfit for induction chemotherapy, and in particular, its activity in patients with adverse disease biology5, venetoclax was prescribed and acquired off-label. The patient was admitted to the hospital and administered azacitidine at a 50% dose reduction (37.5 mg/m2) intravenously for five days to mitigate myelosuppression. On cycle one day 1, the patient was administered 100 mg of venetoclax; dose escalation to 200 mg on day 2 and 400 mg on day 3 occurred5. Tumor lysis syndrome (TLS) monitoring was performed as previously described5. On day 5 she was discharged; she continued self-administering 400 mg of venetoclax daily for 28 days of a 28-day treatment cycle. During cycle one the hemoglobin and platelets nadired at 90 g/L and 75 × 109/L, respectively, both on day nine (Figure 1). There were no bleeding complications. She remained above the threshold for routine transfusion support at our institution (hemoglobin <70 g/L and platelet count <10 × 109/L). Her course was complicated by a pulmonary embolism on day 8, treated with anticoagulation. On day 28, the patient had a post-cycle one BM biopsy which revealed a morphologic remission (1% blasts). Flow cytometry showed a small population (3%) with a phenotype consistent with the presenting AML. Cytogenetics showed ongoing low-level loss of 7q31 sequences (five of 200 cells by fluorescence in situ hybridization [FISH]). Blood counts had recovered; hemoglobin was 143 g/L, platelet count was 237 × 109/L and the WBC count was 2.2 × 109/L (Figure 1). The ANC was 0.9 × 109/L, and therefore the patient met criteria for a complete remission (CR) with incomplete recovery of blood counts (CRi). After a 12-day period off all therapy, the patient started a second treatment cycle, identical to the first except it was performed as an outpatient and venetoclax was resumed at 400 mg on day 1, without dose escalation. She completed two more identically-administered treatment cycles. The nadir hemoglobin and platelet count for each cycle is shown in Figure 1. After cycle four a repeat BM biopsy showed 2.5% blasts; flow cytometry showed no measurable residual disease (MRD) (estimated lower level of detection <0.02%). Cytogenetic testing showed a normal female karyotype; the deletion in 7q was no longer detectable by FISH. The patient met criteria for a CR. A post-cycle 10 BM biopsy showed a sustained CR. Serial cycles are planned until intolerance or disease progression; to date the patient has completed eleven cycles of therapy (520 days since diagnosis). Case 2: A 48-year-old male with past medical history of hypertension was noted to have leukopenia and anemia on routine laboratory monitoring. Bone marrow biopsy revealed AML with 20% blasts (Table S1). Cytogenetic studies revealed the adverse risk karyotype 46,XY,t(3;3)(q21;q26)[11]/46,XY[9], and NGS showed a mutation in SF3B1(c.2098A>G p.K700E) at a 7% allele frequency. He had an initial WBC count of 3.1 × 109/L with an ANC of 1.5 × 109/L, hemoglobin of 127 g/L and platelets of 177 × 109/L. His ECOG PS was one. He communicated his refusal to accept blood products due to his JW faith; treatment options were discussed and the same regimen as in case 1 was prescribed. During cycle one, the hemoglobin nadired at 108 g/L and the platelets nadired at 132 × 109/L, on days 4 and 5, respectively (Figure 1). There were no bleeding complications. He remained above the threshold for transfusion support. On day 28, the patient had a post-cycle one BM biopsy which revealed 3% blasts, and a phenotype by flow cytometery consistent with his presenting AML. FISH showed low-level evidence of the t(3;3) (4.5 out of 200 cells). Droplet digital PCR (ddPCR) with a lower level of detection of 0.05% showed persistence of the SF3B1 mutation (1.25%). The cytopenias had improved; hemoglobin was 132 g/L, platelet count was 167 × 109/L and the WBC count was 2.0 × 109/L with an ANC of 1.3 × 109/L (Figure 1), meeting criteria for a CR. During subsequent cycles, nadir blood counts remained above the thresholds for transfusions (Figure 1). BM biopsy after cycle four showed MRD: FISH was positive for the t(3;3) in 2.5/200 cells, multi-parameter flow cytometry showed a residual population (0.3%), and ddPCR for the SF3B1 was 0.26%. He had an ongoing CR with recovery of blood counts (hemoglobin 143 g/L, platelets 141 × 109/L and ANC 1.5 × 109/L). As in case 1, serial cycles of treatment are planned until intolerance or disease progression; to date he has completed seven cycles of therapy (375 days since diagnosis). We report two cases of young AML patients with adverse-risk disease who were suitable candidates for intensive induction chemotherapy, but could not receive this treatment due to refusal to accept blood product transfusions. Both have achieved durable remissions with a low-intensity therapy that is approved for use in older, unfit patients. In contrast to the month-long hospital stay that would be expected for 7 + 3, these patients were hospitalized for five days during cycle one for TLS monitoring, with the rest of their therapy administered as an outpatient. With the azacitidine dose reductions described, they did not approach our institution's thresholds for transfusion support, and have had no adverse complications related to cytopenias. Many JWs have a religious belief that the Bible prohibits the ingestion of blood; therefore, the acceptance of a blood transfusion under any circumstances can represent a religious violation with significant practical and spiritual consequences. Finding effective therapies for JW patients when they develop blood cancers can be challenging. In addition, conflict from these challenges can compromise the therapeutic relationship between doctor and patient. The standard of care for newly diagnosed AML patients for decades has been 7 + 3. Recently, there have been a multitude of promising new therapies for AML. Frequently, drug development is focused on AML patients deemed unfit for 7 + 3 due to older age or comorbidities, a group that has long had poor outcomes; venetoclax-based regimens in particular are highly effective in this population.5 Historically, all patients deemed "fit" for 7 + 3 have been recommended to receive this treatment. However, some patients, such as those presented in this report, may be suitable to receive 7 + 3, but have other obstacles preventing its administration. Adverse risk disease features historicallydefined in the context of 7 + 3 may not predict poor outcomes in the setting of venetoclax-based regimens.5 The patients described in this report were "fit" for 7 + 3 with respect to age and comorbidities, but had adverse biological disease features that made their disease unlikely to respond to 7 + 3. We suggest that patients with such disease characteristics may be better candidates for other therapies, regardless of "fitness" for 7 + 3. An ongoing study is assessing the feasibility of using venetoclax with azacitidine to treat newly diagnosed younger, induction eligible patients with adverse risk disease (NCT03573024). In summary, venetoclax-based regimens allowed for durable remissions in two JW patients with adverse risk disease features, who historically have had limited treatment options. This therapy may extend therapeutic options to patients unwilling to accept blood product transfusions, and perhaps other younger patients with adverse risk biology who may be expected have poor outcomes with 7 + 3, regardless of their "fitness" to receive this treatment. D.A.P has served as a consultant for Abbvie, Pfizer, Gilead, Astellas, Daichii Sankyo, Celgene, Agios, Janssen, Forty-Seven, Takeda, Amgen, Genentech, Novartis, Karyopharm, has received research funding from Abbvie and Pfizer and serves on a Data and Safety Monitoring Committee for Glycomimetics. Table S1. Baseline clinical characteristics of the two patients with detailed treatment information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.