Alectinib induces marked red cell spheroacanthocytosis in a near-ubiquitous fashion and is associated with reduced eosin-5-maleimide binding

Kuzich, James A.; Heynemann, Sarah; Geoghegan, Niall; Evelyn, Cindy; O'Mahoney, Susan; Wilson, Susan J.; Campbell, Janine; Rogers, Kelly L.; Solomon, Benjamin; Westerman, David; Pasricha, Sant‐Rayn

doi:10.1016/j.pathol.2020.10.023

Cited by 11 publications

(16 citation statements)

References 11 publications

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“…Other authors have recently reported cases of ALK+ NSCLC under alectinib with similar findings [ 25 , 26 ]. The specific strengths of the current study are the relatively large number of patients, including a control group of patients under other ALK TKIs; the wide array of examined hematologic parameters, including longitudinal tracking; the precise quantification of various morphologically abnormal erythrocyte subpopulations; the genetic testing using NGS to rule out spherocytosis; and consideration of patient outcomes as well as the molecular features of the disease.…”

Section: Discussionsupporting

confidence: 80%

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

Kunz

Wiedemann

Grosch

et al. 2022

Cancers

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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.

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Section: Discussionsupporting

confidence: 80%

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

Kunz

Wiedemann

Grosch

et al. 2022

Cancers

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“…The mechanisms responsible for acanthocytosis, spherocytosis and other alectinib‐induced red cell morphological changes are unknown. A recent study has shown that use of alectinib is associated with reduced eosin‐5‐maleimide binding, suggesting that the drug could affect erythrocyte cytoskeleton 4 . Moreover, we hypothesize that patients with haemoglobinopathies may be more susceptible to alectinib‐induced haemolysis and show a more significant red cell fragmentation due to the pre‐existing impaired red cell survival.…”

Section: Figurementioning

confidence: 81%

“…In the ALEX study on alectinib, anaemia was reported in 26.3% of patients receiving the drug, and 5.9% of the patients showed grade 3 or worse anaemia 1 . Although the association between alectinib and anaemia was known, there were only a limited number of reports on its association with red cell morphological changes 2‐4 …”

Section: Figurementioning

confidence: 99%

Alectinib‐induced red cell morphological changes in a patient with underlying α‐thalassaemia trait

Chik

Wong

2021

Int J Lab Hematology

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“…A recent publication reported similar cytological abnormalities and an abnormal EMA test in six alectinib‐treated patients 1 . This effect of alectinib on the red blood cell membrane appears to be rarely associated with significant anaemia 1 . Nevertheless, it is important to be aware of the potential for haemolysis in these patients.…”

mentioning

confidence: 82%

Acanthocytosis in an alectinib‐treated patient

et al. 2022

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An 85-year-old woman who was being treated for an ALKpositive bronchial adenocarcinoma with alectinib, an ALK (anaplastic lymphoma kinase) inhibitor, was hospitalised with a pulmonary embolus. She was found to have a haemoglobin concentration of 135 g/l, a reticulocyte count at 65.4 × 10 9 /l, a conjugated bilirubin of 8.9 µmol/l, unconjugated bilirubin of 15.3 µmol/L and undectectable haptoglobin (<0.10 g/l). Other liver function tests were normal. Her blood film showed acanthocytes, spheroacanthocytes and spherocytes (left image, ×100 objective). An eosin-5-maleimide (EMA) flow cytometry test showed a 60% decrease in fluorescence intensity compared to a control subject (centre and right images), this being even more decreased than in hereditary spherocytosis (HS), which is typically around 20% decreased. The dispersion of the fluorescence peak was greater than in HS and control subjects; the peak was broad (CV 30%), whereas it is narrow both in HS and in controls (CV approximately 10%).A recent publication reported similar cytological abnormalities and an abnormal EMA test in six alectinib-treated patients. 1 This effect of alectinib on the red blood cell membrane appears to be rarely associated with significant anaemia. 1 Nevertheless, it is important to be aware of the potential for haemolysis in these patients. More in-depth studies are needed to determine whether there are long-term clinical implications.

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Alectinib induces marked red cell spheroacanthocytosis in a near-ubiquitous fashion and is associated with reduced eosin-5-maleimide binding

Cited by 11 publications

References 11 publications

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

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

Alectinib‐induced red cell morphological changes in a patient with underlying α‐thalassaemia trait

Acanthocytosis in an alectinib‐treated patient

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