Hemolytic anemia following alectinib reported to the U.S. Food and Drug Administration Adverse Event Reporting System
Authors: Graça M. Dores, Afrouz Nayernama, Connie Cheng, Charlotte Moureaud, S. Christopher Jones
Journal: American Journal of Hematology (2022)

Alectinib (Alecensa; Hoffman-La Roche/Genentech USA, Inc.), an oral tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK) and ret proto-oncogene kinase, is indicated for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) as detected by a Food and Drug Administration (FDA)-approved test.1 The drug was approved in the United States on December 11, 2015, and the accompanying U.S. Product Information (USPI) included the adverse reaction of anemia, without specific mention of acquired abnormal erythrocyte morphology or hemolytic anemia as was recently described.2, 3 We, therefore, investigated the finding of hemolytic anemia reported with alectinib to the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and in the literature to determine if regulatory action was required. We searched (June 4, 2021) for reports of alectinib submitted to FAERS, a passive surveillance system, between December 11, 2015, and June 3, 2021, with a Preferred Term included in the Standardized Medical Dictionary for Regulatory Activities Query of "hemolytic disorders." We also searched PubMed and Embase databases (June 25, 2021) for reports of hemolytic anemia and alectinib. We identified and manually reviewed 60 FAERS reports. From our literature search, we retrieved 38 publications. Five of these publications were also reported to FAERS and included the reports from Australia by Kuzich et al and Yuan et al.2, 3 The remaining 33 publications did not provide case-level information, nor did any study specifically assess alectinib-associated hemolytic anemia. We created a case series of reports meeting our prespecified case definition of hemolytic anemia. A category I case was defined as a report with a diagnosis of hemolytic anemia and a positive direct antiglobulin test or decreased haptoglobin, or at least two of the following: corrected reticulocyte count >2%, increased total and/or indirect bilirubin, increased lactate dehydrogenase not attributed to underlying malignancy, abnormal red blood cell morphology (e.g., schistocytes, spherocytes, bite cells), hemoglobinuria, increased plasma free hemoglobin. Reports of hemolytic anemia with alectinib that did not meet these criteria were considered category II cases with a lower level of diagnostic evidence. We applied the World Health Organization-Uppsala Monitoring Centre causality criteria to our cases, thereby requiring evidence of a temporal relationship of hemolytic anemia following exposure to alectinib. Reports that were duplicates, did not meet our case definition, or had an unlikely causal relationship were excluded. Descriptive statistics were calculated using SAS version 9.4 (Cary, NC, USA). We identified 31 cases of hemolytic anemia and assessed causality as probable in 10 (32%) cases and possible in 21 (68%) cases (Table 1). All probable cases met our category I case definition. Among the 20 cases that included information on time to onset, the median time from start of alectinib to first episode of hemolytic anemia was 56 days, with 75% of cases occurring within 90 days (inclusive) of drug exposure. Among cases reporting direct antiglobulin test (DAT) results, testing was uniformly negative. Most cases reported alectinib discontinuation, interruption, and/or dose reduction in response to hemolysis. Twelve cases described a positive dechallenge, and six cases noted a positive rechallenge. In two positive rechallenge cases, hemolytic anemia reoccurred after 20 and 84 days. Anemia is prevalent in cancer populations, particularly in those undergoing cancer-directed treatment, but drug-induced hemolytic anemia (DIHA) is rare, with an estimated incidence of one event per 1–2 million individuals.4 Anemia is a labeled adverse reaction for alectinib, reported in 62% of alectinib-treated patients with previously untreated ALK-positive metastatic NSCLC compared to 36% of crizotinib-treated patients.1 Based on the temporal association of hemolytic anemia and alectinib, resolution or improvement of hemolysis parameters with drug interruption (dechallenge), and recurrence of hemolytic anemia with drug reexposure (rechallenge), our case series suggests a plausible drug-event relationship. In their retrospective case series, Kuzich and colleagues identified 43 patients treated with alectinib at their institution during 2013–2019 and reported erythrocyte membrane abnormalities in 95% of 20 patients with peripheral blood smears available.2 They identified anemia in a majority of patients after start of alectinib and were able to confirm absence of abnormal red cell morphology prior to start of alectinib in a subset of these individuals. The authors had limited laboratory data on formal hemolysis assessments, but among four patients with DAT results, all reported a negative DAT, similar to the findings in our cases series. In retrospect, indirect support for hemolysis is also suggested by findings in the phase 3 ALEX trial that compared alectinib to crizotinib in previously untreated ALK-positive NSCLC, whereby a higher frequency of anemia (20% vs. 5%) and hyperbilirubinemia (15% vs. 1%) was reported in alectinib-treated than crizotinib-treated patients, respectively.5 Notably, both TKIs are associated with hepatotoxicity, but contrary to the bilirubin pattern observed, there was a lower occurrence of increased alanine transaminase (15% vs. 30%) and increased aspartate transaminase (14% vs. 25%) among individuals treated with alectinib compared to crizotinib, respectively,5 suggesting that hyperbilirubinemia might not be attributed solely to hepatotoxicity. DIHA is typically mediated by immunologic mechanisms and infrequently occurs through oxidative mechanisms.4, 6 Although DAT-negative results following alectinib exposure suggest a nonimmune mechanism, 5%–10% of autoimmune hemolytic anemias are DAT-negative due to low levels of immunoglobulin G (IgG) antibodies or complement, non-IgG antibodies, low-affinity antibodies removed from the red blood cell surface during washing procedures, assay sensitivity, or other factors.6 However, reduced eosin-5-maleimide staining described in alectinib-treated patients, an atypical finding in autoimmune hemolytic anemia, suggests that alectinib induces a nonimmune erythrocyte membranopathy.2 Additional investigation is needed to better understand the mechanism(s) underlying alectinib-related hemolysis, which may also provide insights into at-risk populations. Despite the limitations of passive surveillance systems, including variable report quality, underreporting, and duplicate reporting, we provide convincing evidence of an association of hemolytic anemia with alectinib exposure. To this end, the alectinib USPI was recently updated to include hemolytic anemia under Warnings and Precautions and recommendations for dose modifications.1 Although at-risk individuals and mechanisms of hemolysis with alectinib are undefined, heightened awareness of the potential for this adverse drug reaction will enable early diagnosis and facilitate appropriate management. The authors have no conflicts of interest to declare. Conception and design: all authors; collection and assembly of data: GMD, AN, CC, CM; data analysis and interpretation: all authors; manuscript writing and revision for important intellectual content: all authors; final approval of manuscript: all authors; financial support: none. The views expressed in this article are those of the authors and do not necessarily reflect those of the FDA. The FAERS database is publicly available.