Early Development of Ubiquitous Acanthocytosis and Extravascular Hemolysis in Lung Cancer Patients Receiving Alectinib

Abstract

Alectinib is a standard initial treatment for patients with advanced anaplastic lymphoma kinase (ALK) rearranged non-small-cell lung cancer (NSCLC). The current study analyzed a prospective cohort of 24 consecutive alectinib-treated patients and controls in order to comprehensively characterize longitudinal erythrocyte changes under treatment with ALK inhibitors. Upon starting alectinib, all examined patients developed reticulocytosis and abnormal erythrocyte morphology with anisocytosis and a predominance of acanthocytes (64% of red blood cells on average, range 36–100%) in the peripheral blood smear within approximately 2 weeks. Changes were accompanied by a gradual reduction in Eosin-5-maleimide (EMA) binding, which became pathologic (<80% of cells) within 1–2 months in all cases, mimicking an abortive form of hereditary spherocytosis. The latter could be ruled out in 3/3 of analyzed cases by normal sequencing results for the ANK1, EPB42, SLC4A1, SPTA1, or SBTB genes. The direct Coombs test was also negative in 11/11 tested cases. Besides, anemia, increased LDH, and increased bilirubin were noted in a fraction of patients only, ranging between 42 and 68%. Furthermore, haptoglobin decreases were infrequent, occurring in approximately 1/3 of cases only, and mild, with an average value of 0.93 g/L within the normal range of 0.3–2 g/dL, suggesting that hemolysis occurred predominantly in the extravascular compartment, likely due to splenic trapping of the deformed erythrocytes. These changes showed no association with progression-free survival under alectinib or molecular features, i.e., ALK fusion variant or TP53 status of the disease, and resolved upon a switch to an alternative ALK inhibitor. Thus, alectinib induces mild, reversible erythrocyte changes in practically all treated patients, whose most sensitive signs are aberrant red cell morphology in the peripheral smear, a pathologic EMA test, and reactive reticulocytosis. Frank hemolytic anemia is rare, but mild subclinical hemolysis is very frequent and poses differential-diagnostic problems. Alectinib can be continued under the regular control of hemolysis parameters, but the risk of long-term complications, such as cholelithiasis due to increased serum bilirubin in most patients, remains unclear at present.

Lorlatinib and compound mutations in ALK+ large-cell neuroendocrine lung carcinoma: a case report

“…Upon multifocal progression in the left lung, chest wall, left breast, and left parotid gland 2 mo later, therapy was empirically switched to alectinib, which resulted in durable tumor shrinkage of >30%, corresponding to a partial response (PR) by RECIST v1.1. The treatment was generally well-tolerated without significant hemolysis, and a transient reduction of hemoglobin from 13.3 g/dL at baseline to 12.4 g/dL 1 wk later, gradually recovered within the next few weeks ( Kunz et al 2022 ). A second oligoprogression in the left breast 10 mo later was treated by surgical excision of the growing lesion, whose molecular workup revealed an ALK :p.V1180L mutation.…”

Alectinib-Induced Severe Hemolytic Anemia in a Patient with ALK-Positive Non-Small Cell Lung Cancer: A Case Report

“…Alectinib is considered to invariably induce subclinical hemolysis in all patients with morphological changes such as acanthocytes or spherocytes of erythrocytes. 9 , 10 The US package insert of alectinib mentions potential for hemolytic anemia. Nevertheless, hemolytic anemia is underreported because many physicians are unaware of its existence.…”

“…In a similar vein to previous reports of alectinib-induced hemolytic anemia, the results of DAT were consistently negative. 8 , 9 , 12 , 13 The DAT demonstrates the presence of antibodies or complement on the surface of red blood cells. 16 The negative result for DAT suggested that the hemolysis observed was occurring via a nonimmune mechanism.…”

“…There have been no reports to date examining the mechanism of hemolytic anemia due to alectinib, although differences in EML4-ALK variants status do not appear to have any effect on the hemolytic response. 9 Most DIHA events are due to drug-induced immune hemolytic anemia (DIIHA), caused by an immune mechanism against red blood cells with positivity for DAT seen. 1 Hemolysis due to alectinib differs from DIIHA in that there are morphological changes in the erythrocytes and the DAT is negative.…”

Expert consensus of management of adverse drug reactions with anaplastic lymphoma kinase tyrosine kinase inhibitors

“…Recent studies reveal that alectinib may include ubiquitous acanthocytosis and subclinical hemolysis though most patients do not suffer significant hemolytic anemia. 45 , 46 Abnormal erythrocyte morphology, increased reticulocytes, and decreased eosin-5-maleimide binding are helpful for the diagnosis of alectinib-induced hemolysis. 46 Withhold alectinib and initiate appropriate laboratory testing if hemolytic anemia is suspected.…”