Acute Coagulopathy As an Underappreciated Toxicity of Azacitidine/Venetoclax Induction in AML

Introduction: Hypomethylating agents (HMA) with the oral Bcl-2 inhibitor venetoclax (Ven) is the current standard of care for older and unfit patients (pts) with newly diagnosed acute myeloid leukemia (AML). Initiation of HMA/Ven can precipitate rapid cytolysis of leukemic cells, predisposing to tumor lysis syndrome (TLS); therefore, it is a common practice to initiate Ven at a lower dose and ramp up dosing over several days. To our knowledge, however, acute coagulopathy and disseminated intravascular coagulation (DIC) have not been described in the literature as a toxicity of HMA/Ven initiation. We describe four cases of pts with newly diagnosed AML, both de novo (n=3) and secondary AML (sAML; n=1) following myelodysplastic syndrome (MDS), who received Ven with azacitidine as induction therapy and experienced acute coagulopathy.

Case Series: All four pts were of advanced age (ages 70, 74, 74, and 79 years). All three de novo cases presented with high bone marrow (BM) blast burden (mean 77%; range, 62-87%), peripheral blood leukocytosis (mean WBC 49 x 10⁹/L; range, 31-62 x 10⁹/L) and high circulating blasts (mean 47%; range, 46-63%). In contrast, the sAML pt had pancytopenia with 20% BM blasts and no circulating blasts. None of the pts exhibited monocytic morphology. Two of the three de novo pts displayed Auer Rods. All four pts carried mutations in either TET2 (n=2; variant allele frequency (VAF) 46% in a de novo pt and 4% in a sAML pt) or IDH1/2 (n=2; VAF 48% and 47%, both in de novo pts). No other shared mutations were identified.

At the time of HMA/Ven initiation two pts were receiving antifungal prophylaxis with the CYP3A4 inhibitor posaconazole and received full-dose Ven (100 mg) on day 1 without ramp up; the other two were receiving micafungin with ramp up Ven dosing. All three pts with de novo AML received hydroxyurea and had WBC <25 x 10⁹/L at the time of HMA/Ven initiation. Three of four pts met criteria for laboratory TLS with hyperkalemia, hyperphosphatemia, and/or hyperuricemia occurring 1-2 days after the start of therapy. All four pts developed DIC 1-3 days after beginning treatment. Four pts exhibited a mean fibrinogen decrease of 103 g/L (range, 52-150), and all three de novo pts experienced an increase in the international normalized ratio (mean increase, 0.77; range, 0.3-1.2). Three of four pts required transfusion of cryoprecipitate and/or fresh frozen plasma. Ven was held in two pts until resolution of DIC and TLS. In each case, DIC and TLS resolved with management after 2-4 days. Hemorrhagic and renal complications were not seen. All three de novo pts had BM blast reduction, with two obtaining complete and one obtaining partial response with refractory disease following a second cycle. The sAML pt experienced hematologic improvement.

Discussion: In this retrospective case cohort, we demonstrate that acute coagulopathy is a previously unappreciated complication of HMA/Ven induction in AML. As HMA/Ven is the standard of care for older/unfit adults, with expanding usage in high-risk MDS, it is of importance to recognize this toxicity. The mechanism of HMA/Ven-induced coagulopathy requires further study; however, we theorize that lysis of leukemic cells releases procoagulant and/or inflammatory factors into the circulation, a pathophysiology associated with therapy-induced DIC in various hematologic malignancies and advanced solid tumors such as small cell lung cancer. Although acute coagulopathy may be related to tumor lysis, and that proliferative disease with high BM blast burden is recognized as a risk factor for TLS, our case series includes a pt with oligoblastic sAML. It remains unclear if mutational profile shares any association with DIC risk; however, we note that all four pts harbored mutations in the demethylation-associated genes TET2 or IDH1/2. This raises the possibility that TET2/IDH-mutant disease may have increased therapeutic sensitivity. Arguing against such a notion is the observation that acute coagulopathy was not uniformly associated with a favorable response, suggesting the possibility of an off-target toxicity. Our findings suggest that further investigation may be beneficial to determine the real-world incidence of this rare complication and the potential need for additional monitoring guidelines/preventative measures during HMA/Ven induction. Ramp up dosing and close monitoring of TLS/DIC markers should be considered in AML pts receiving HMA/Ven induction.

Iyer:MorphoSys: Membership on an entity's Board of Directors or advisory committees. Viny:Arima Genomics: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Jurcic:BMS/Celgene: Research Funding; Rigel Pharmaceuticals: Consultancy; Forma Therapeutics: Research Funding; Sumitomo Pharma: Research Funding; Pfizer: Research Funding; Blueprint Medicines: Research Funding; Gallop Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Syros Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.