Anemia is a commonly encountered problem in cancer patients receiving chemotherapy, with or without radiation [1] [2] . However, Drug-Induced Hemolytic Anemia (DIHA) is relatively rare, with an estimated incidence of approximately one case per 1 - 2 million individuals [3] - [5] . DIHA is usually mild, but is occasionally associated with acute severe hemolytic anemia and death [4] . Therefore, the possibility of DIHA should always be considered when using the offending drugs. Recently, several drugs against various molecular targets have been developed, resulting in a remarkable improvement in the prognosis of lung cancer. Alectinib is a selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used as standard therapy for non-small cell lung cancer harboring an ALK fusion gene [6] [7] . Anemia due to alectinib has been reported to account for 6% - 26.3% of adverse events [8] . To the best of our knowledge, alectinib-induced hemolytic anemia has never been described in the literature in Korea, but there are potentially many other similar cases that have not been reported.

Here, we report a case of a 78-year-old female with ALK-positive adenocarcinoma of the lung who developed grade 4 anemia due to alectinib-induced hemolytic anemia.

A 78-year-old Asian female, a non-smoker, presented with chest Computed Tomography (CT) abnormalities and no symptoms at our hospital in August 2019. The chest CT revealed a 2.8 cm tumor in the right lower lobe of the lung and diffusely scattered nodules in the right pleura and fissural area ( Figure 1 ). After a comprehensive examination, the patient was diagnosed with lung adenocarcinoma, specifically clinical T1cN2M1a stage IVA with ALK-rearrangement positivity. Accordingly, alectinib (600 mg) was administered orally twice daily as first-line treatment in September 2019, which induced a partial response and was subsequently continued.

However, laboratory findings showed progressive anemia. The initial hemoglobin level was 11.6 g/dL before starting alectinib therapy. Two months after the initiation of alectinib, the hemoglobin level had decreased to 8.2 g/dL. The patient was referred to the hematology department in July 2020 and diagnosed with macrocytic, hyperchromic anemia related to chronic disease combined with anemia from chemotherapy. About three years after starting treatment, the hemoglobin level gradually decreased to 6.7 g/dL. The patient was referred to the hematology department again in April 2022. Laboratory findings showed elevated levels of total bilirubin (1.83 mg/dL), low levels of reticulocytes (5.01%), and haptoglobin (< 8 mg/dL) ( Table 1 ). Folic acid and vitamin B12 levels were normal. Spherocytes appeared on a peripheral blood smear ( Figure 2 ), and the results of the Direct Antiglobulin Test (DAT) were negative. There was no evidence of active bleeding as determined by upper and lower gastrointestinal endoscopy. We also confirmed no recurrence of lung cancer and no splenomegaly by contrast-enhanced CT.

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WBC: white blood cells, RBC: red blood cells, Hb: hemoglobin, Hct: hematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, Plt: platelets, Ret: reticulocyte, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: asparatate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, Cr: creatinine, Na: sodium, K: potassium, Cl: chlorine, TP: total protein, Alb: albumin, Fe: serum iron, UIBC: unsaturated iron binding capacity, CRP: C-reactive protein.

Based on the clinical course during the period of alectinib administration, the patient was diagnosed with alectinib-induced hemolytic anemia. We instructed the patient to discontinue alectinib in May 2022. The patient required a blood transfusion once, but there was no further progression of anemia. Two months after discontinuing alectinib, the hemoglobin level increased to 9.8 g/dL. Other laboratory findings also indicated the resolution of hemolytic anemia. The total bilirubin level was 0.61 mg/dL, the reticulocyte count was 1.23%, and the haptoglobin level was 38 mg/dL. The total bilirubin level and hemoglobin level are shown in ( Figure 3 ).

Treatment was switched to brigatinib in July 2022. The patient has been taking brigatinib for over a year without any evidence of cancer recurrence. The patient’s hemoglobin level has consistently remained above 10.0 g/dL.

To the best of our knowledge, this is the first reported case of hemolytic anemia caused by alectinib in Korea. In this case, alectinib-induced hemolytic anemia gradually progressed to grade 4 over two years after starting treatment with alectinib, and improved after discontinuation of the drug.

DIHA is typically mediated by immunologic mechanisms and infrequently occurs through non-immunologic mechanisms [5] [9] . Immune-mediated mechanisms are classified into three types: hapten-drug adsorption, immune-complex formation, and the production of true autoantibodies. In hapten-drug adsorption, hemolytic anemia usually occurs due to IgG class antibodies against drug epitopes. This leads to the elimination of red blood cells (RBCs) coated with the drug and anti-drug antibodies in the spleen. On the other hand, immune-complex mechanisms involve either complement-related direct cell destruction following the binding of the drug-RBC antibody complex or the development of autoantibodies. In all immune-mediated cases, antibodies are found, and DAT is usually positive. Non-immunologic mechanisms involve the deposition of proteins on RBCs, which accelerates cytoplasmic clearance [4] [10] .

In line with previous studies, the results of the DAT were negative in this case [11] - [14] . The DAT detects the presence of antibodies or complement on the surface of RBCs. The negative DAT result suggests that the hemolysis was occurring via a nonimmune mechanism. Alectinib has been found to induce subclinical hemolysis in some patients, accompanied by morphological changes in erythrocytes, such as acanthocytes or spherocytes [12] [15] . We also observed the presence of spherocytes on a peripheral blood smear, suggesting that alectinib-induced hemolytic anemia is possibly related to RBC oxidative stress. Further investigation is needed to better understand the mechanism underlying Alectinib-related hemolysis.

In a previous study, the median time from the start of alectinib to the first episode of hemolytic anemia was 56 days, with 75% of cases occurring within 90 days of drug exposure [16] . In this case, although DIHA was diagnosed approximately three years after starting alectinib treatment, total bilirubin levels were already elevated above baseline two months after alectinib administration. We did not initially recognize DIHA, because anemia is prevalent in cancer patients, especially those undergoing cancer-directed treatment. Additionally, tests such as peripheral blood smear, haptoglobin, and DAT were not performed at that time. As the anemia progressed, further hematological tests were conducted, and the patient was ultimately diagnosed with DIHA.

In conclusion, we report a case of grade 4 hemolytic anemia induced by alectinib in a patient with ALK-positive lung adenocarcinoma. Most cases of DIHA are reversible upon discontinuation of alectinib. Therefore, regular hematologic monitoring is recommended during alectinib treatment. DIHA should be considered in patients with progressive anemia.

DIHA: drug-induced hemolytic anemia; ALK: anaplastic lymphoma kinase; CT: computed tomography; DAT: direct antiglobulin test; RBCs: red blood cells.