Severe Warm Autoimmune Hemolytic Anemia as the Initial Manifestation of EBV-Positive Lymphocyte-Rich Classic Hodgkin Lymphoma in a Young Adult

Autoimmune hemolytic anemia (AIHA) is a recognized paraneoplastic complication of lymphoid malignancies, most frequently seen with chronic lymphocytic leukemia and non-Hodgkin lymphoma. Its occurrence as the initial manifestation of classic Hodgkin lymphoma (cHL) is exceedingly rare. Lymphocyte-rich classic Hodgkin lymphoma (LRCHL) comprises approximately 5% of cHL and typically presents as localized, low-risk disease in older adults. We report a young man with EBV-positive, stage IV LRCHL presenting with life-threatening warm AIHA, highlighting the diagnostic complexity and therapeutic dilemma surrounding nivolumab use in this setting.

A previously healthy 28-year-old man presented with two weeks of progressive fatigue, dyspnea on minimal exertion, and headache. Initial hemoglobin was 3.5 g/dL with reticulocytosis (19.3%), elevated indirect bilirubin, and a positive direct antiglobulin test for IgG, confirming warm AIHA. AIHA was managed with prednisone 1-2 mg/kg with taper, transfusion support, and folic acid; rituximab was held given response to steroids alone. Transfusion was complicated by a positive alloantibody screen, with workup excluding significant alloantibodies except anti-D; RhD-positive typing confirmed this as an autoantibody mimic, permitting D-negative transfusion. Staging PET/CT demonstrated hypermetabolic supra- and infra-diaphragmatic lymphadenopathy with splenic and multifocal osseous involvement (Deauville score 5). Bone marrow biopsy showed a focal lympho-histiocytic aggregate with scattered CD30-positive cells suspicious for involvement, though flow cytometry was non-diagnostic, a discordance attributed to focal, unilateral sampling; the patient was staged as marrow-positive stage IV disease. Excisional cervical lymph node biopsy confirmed EBV-positive, lymphocyte-rich classic Hodgkin lymphoma (CD30+, PAX5-dim, MUM1+, CD79a-dim, OCT2-dim, EBER-ISH+; negative CD15, CD45, ALK1). Hospitalization was complicated by transaminitis (peak ALT 306 U/L); autoimmune and infectious hepatitis were excluded, and transaminitis resolved after discontinuing prophylactic trimethoprim-sulfamethoxazole, implicating a medication-related etiology.

The patient initiated frontline AVD (doxorubicin, vinblastine, dacarbazine); nivolumab was withheld, despite the biologic rationale for PD-1 blockade in EBV-driven disease, given AIHA exacerbation risk. He tolerated AVD with no recurrent hemolysis, and his transaminitis resolved. Interim PET/CT after two cycles showed complete metabolic response (CMR; Deauville score 1) despite omission of nivolumab. Given this response, a shared decision-making discussion reviewed three options: continuing AVD alone, adding nivolumab with accepted AIHA risk, or adding brentuximab vedotin (BV) per the ECHELON-1 regimen, an NCCN Category 1 alternative to ABVD with superior progression-free survival. The patient elected to add BV to enhance cure probability while avoiding nivolumab, tolerating the transition well with growth factor support, and remained in CMR with normal hemoglobin. 

This case illustrates an atypical, high-risk presentation of EBV-positive LRCHL, a subtype classically indolent and localized in older patients, presenting instead with stage IV disease and life-threatening AIHA in a young adult. Recognition of lymphoma-associated autoimmune cytopenias is essential for timely diagnosis, particularly when treatment options are constrained by autoimmune comorbidity. This report demonstrates that a nivolumab-sparing regimen can achieve complete metabolic response despite immune-mediated comorbidity, and that brentuximab vedotin, per ECHELON-1 data, offers a viable, evidence-based alternative to nivolumab for treatment intensification when PD-1 blockade carries unacceptable autoimmune risk. This case underscores the necessity of personalized, risk-adapted therapy selection in advanced classic Hodgkin lymphoma.