Neutropenia with Thrombocytopenia after Alemtuzumab? − Case Report
Early neutropenia with thrombocytopenia is not a common side effect of alemtuzumab. However, the patient in the following case report by Italian colleagues was affected. What was the outcome?
How does alemtuzumab affect lymphocytes?
Alemtuzumab is a humanized monoclonal antibody that binds to CD52, a surface antigen present in high levels on T (CD3+) and B (CD19+) lymphocytes and in lower levels on NK cells, monocytes, and macrophages. CD52 is detected very little or not at all on neutrophils, plasma cells, or bone marrow stem cells.
Alemtuzumab works through antibody-dependent cellular cytolysis and complement-mediated lysis after binding to the cell surface of T and B lymphocytes. The lowest lymphocyte counts were observed one month after the first treatment cycle. Over time, lymphocytes repopulate with B cell recovery usually completed within 6 months. CD3+ and CD4+ lymphocytes increase toward normal more slowly but generally do not return to baseline within 12 months post-treatment. Neutrophils, monocytes, eosinophils, basophils, and NK cells are only transiently affected by alemtuzumab.
Case description
A 38-year-old woman came for a neurological examination in July 2006 due to right-sided hemiparesis. MRI revealed multiple T2 lesions of the brain and spinal cord, leading to a diagnosis of relapsing-remitting multiple sclerosis (RRMS). As the first disease-modifying drug (DMD), interferon beta-1a was initiated. Due to disease progression both clinically and radiologically, a switch to natalizumab was performed in March 2014 and subsequently to glatiramer acetate in July 2016 due to high JC virus antibody titers. Unfortunately, the desired effect was not achieved, and considering two severe relapses and an increase in T2 lesions on MRI, therapy with alemtuzumab was started in May 2017.
Initial blood tests showed no remarkable findings. However, on the 24th day after the first cycle of alemtuzumab, the patient developed severe leukopenia (WBC 0.93 × 103/μl) with neutropenia (0.83 × 103/μl) and lymphopenia (0.04 × 103/μl). There was also a decrease in platelet count (PTL: 140 × 103/ml). Fortunately, the patient showed no signs of infection, fever, or purpura.
Prophylactically, ampicillin was initiated, and the patient was monitored. After 2 weeks, the counts of leukocytes, neutrophils, and platelets spontaneously returned to normal without the need for growth factors. Lymphopenia persisted.
Discussion
Thrombocytopenia after alemtuzumab treatment is not uncommon, but it is usually of autoimmune etiology and appears as a late effect. However, cases of thrombocytopenia have been reported early in treatment, typically resolving within a few weeks. Careful monitoring is essential. As platelets do not express CD52, the cause is likely a cytokine release syndrome, alemtuzumab sensitization leading to the formation of specific antibodies binding to epitopes on platelet surfaces, or complement-mediated platelet lysis.
On the other hand, neutropenia is not commonly seen as a side effect of alemtuzumab in RRMS patients. It is often observed in patients with chronic lymphocytic leukemia, typically 4–8 weeks after application, generally being mild. The etiology remains unclear. Although neutrophils express very small amounts of CD52, it could partly be a factor. Another potential cause is a complement reaction mediated by the release of tumor necrosis factor-alpha, interleukin-6, -8, and interferon-gamma. Myelotoxicity is also discussed, and in some cases, neutropenia may have an autoimmune basis or be an expression of an immune reconstitution process. Lastly, neutropenia may be a side effect of antivirals administered concurrently with alemtuzumab.
Conclusion and recommendations
This case report describes a very rare occurrence of neutropenia with thrombocytopenia following alemtuzumab administration in an MS patient. Although the subsequent course fortunately proceeded without complications and the need for specific therapy, it underscores the importance of careful monitoring of patients after this DMD administration.
Clinical examinations and laboratory tests should be performed at regular intervals for at least 48 months after the last treatment cycle. A complete blood count with differential, serum aminotransferases, and serum creatinine levels need to be determined before starting treatment and then monthly. A microscopic urine analysis should be done before starting treatment and then at monthly intervals. Thyroid function tests, i.e., determination of thyroid-stimulating hormone levels, should be done before starting treatment and then every 3 months. Platelet counts should be determined immediately after infusion on the 3rd and 5th day of the first infusion cycle and then immediately after infusion on the 3rd day of each subsequent cycle. Clinically significant thrombocytopenia should be monitored until resolved. If necessary, referral to a hematologist should be considered to ensure appropriate care.
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Sources:
1. Maniscalco G. T., Cerillo I., Servillo G. et al. Early neutropenia with thrombocytopenia following alemtuzumab treatment for multiple sclerosis: case report and review of literature. Clin Neurol Neurosurg 2018; 175: 134−136, doi: 10.1016/j.clineuro.2018.11.002.
2. SPC Lemtrada. Available at: https://ec.europa.eu/health/documents/community-register/2018/20180702141301/anx_141301_cs.pdf
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