Background: Historically, persons with hemophilia (PWH) have an increased incidence in cancers, primarily because of the high incidence of blood borne pathogens from contaminated blood and plasma-derived clotting factor products in the 1970s and 1980s (Zanon et al). Now, with low incidence of contaminated blood products and the rise of non-factor prophylaxis with emicizumab, a bispecific monoclonal antibody that mimics the function of factor VIII, the incidence of cancer in PWH is unknown. Treatment of PWH with cancer can be quite challenging due to careful management of the underlying bleeding disorder along with potential treatment related thrombocytopenia as well as other coagulopathies.

Case report: Here, we report a case of a 21-year-old Caucasian male with severe hemophilia A who developed classical Hodgkin lymphoma (HL) four years after starting prophylaxis with emicizumab. The patient was diagnosed with severe hemophilia A shortly after birth based on a positive family history and genetic testing showed an intron 22 inversion. His hemophilia related complications included gastrointestinal hemorrhage in childhood, port infection requiring replacement, and a left elbow target joint. He initially started prophylaxis with a standard half-life product three times per week, followed by an extended half-life product twice a week, and then finally changed to emicizumab prophylaxis in 2019. He was maintained on a 3mg/kg/dose regimen every two weeks.

In August 2023, he presented to the emergency department with three weeks of nausea and hematemesis followed by the development of a neck mass. A computerized tomography scan of his neck, chest, abdomen and pelvis demonstrated bulky supraclavicular, mediastinal, and abdominal lymphadenopathy with right-sided pulmonary nodules. Lymph node biopsy revealed classical HL and further staging determined stage IIIb with bulk disease and E lesions in the lung. He was treated with chemotherapy and radiation therapy as per Children's Oncology Group protocol AHOD1331. He completed five cycles of chemotherapy with brentuximab, doxorubicin, etoposide, prednisone, cyclophosphamide and vincristine. He received 21 Gy of radiation to bulk disease in the mediastinum. He completed treatment in January 2024 with no evidence of disease. The patient continued with emicizumab prophylaxis throughout chemotherapy and radiation treatment for HL and did not experience any significant bleeding events despite grade 2 thrombocytopenia. He also infused recombinant FVIII-Fc prior to procedures including lymph node biopsy, and insertion and removal of peripherally inserted central catheters without any bleeding complications or thrombotic events.

Discussion: To our knowledge, this is the first report of a patient undergoing treatment for HL while receiving prophylactic treatment with emicizumab. Despite published literature discussing the development of malignancies due to contaminated blood products in the hemophilia population, there is limited information on the association of newer medications with cancer in hemophilia patients. A study from the United Kingdom obtained data on 6,018 males with hemophilia A or B who were not infected with HIV and registered with the UKHCDO database during 1977 to 1998 to compare causes of death. Follow up was completed in all except for 3.2% of patients (Darby et al.). The standardized mortality ratio for HL compared to the general population was 4.95, which accounted for 4 deaths (Darby et al.). Aside from this, there is no significant data to support that hemophilia is a risk factor for the development of HL. Furthermore, there are no documented cases of emicizumab associated with HL. Importantly, our patient stayed on emicizumab prophylaxis throughout treatment with chemotherapy and radiation and did not experience any severe bleeds, despite having treatment-related thrombocytopenia. Additionally, our patient did not experience any thrombotic events while remaining on emicizumab prophylaxis with occasional use of recombinant FVIII-Fc, despite thrombotic risk factors including malignancy and a centrally placed catheter. As emicizumab is intended for long term maintenance therapy, it is critical to report any significant adverse events. This case further suggests that continued use of emicizumab during cancer-directed therapies is safe and effective for patients with hemophilia A.

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2025
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