Classical Hodgkin lymphoma (cHL) is a mature B-cell lymphoid neoplasm characterized by the presence of neoplastic Hodgkin and Reed–Sternberg (HRS) cells within a polymorphous inflammatory background composed of small T lymphocytes, histiocytes, eosinophils, and plasma cells [1]. As detailed in Robbins and Cotran Pathologic Basis of Disease, HRS cells are derived from germinal center B cells that retain clonal immunoglobulin gene rearrangements but exhibit loss of the typical B-cell transcriptional program [1]. These cells characteristically express CD30 and CD15, with variable CD20 expression, and demonstrate constitutive activation of NF-κB and JAK/STAT signaling pathways that promote immune evasion and survival [1]. Histologically, cHL is subdivided into nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted variants, with nodular sclerosis being the most common subtype among young adults [1]. From a clinical standpoint, Hodgkin lymphoma is regarded as one of the most curable hematologic malignancies in the era of combination chemotherapy [2]. According to Harrison’s Principles of Internal Medicine, five-year overall survival exceeds 90% in early-stage disease and approaches 70–80% in advanced-stage presentations with contemporary regimens [2]. Nevertheless, approximately 10–30% of patients with advanced-stage disease develop primary refractory disease or relapse after achieving remission [2]. Constitutional “B” symptoms—fever exceeding 38°C, drenching night sweats, and unintentional weight loss greater than 10% of body weight over six months—are present in nearly one-third of patients and correlate with systemic cytokine release [2]. At the global level, Hodgkin lymphoma accounts for a significant hematologic cancer burden. The World Health Organization Global Cancer Observatory 2024 reports more than 80,000 new cases annually worldwide, with a characteristic bimodal age distribution peaking between 15–35 years and again after 55 years of age [3]. Although survival has improved markedly in high-income countries, disparities remain due to differences in early detection, imaging availability, and access to standardized treatment protocols [3]. Current management strategies are stage-adapted and guided by response-based imaging. The National Comprehensive Cancer Network Guidelines 2024 emphasize the use of combination chemotherapy regimens with interim and end-of-treatment positron emission tomography (PET) assessment using the Deauville five-point scoring system [4]. Complete remission rates exceed 80% in most treated cohorts under these protocols [4]. For patients with relapsed or refractory disease, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) remains the recommended consolidative approach in eligible individuals [4]. Recent updates from the American Society of Clinical Oncology highlight the incorporation of antibody–drug conjugates and programmed death-1 (PD-1) pathway inhibitors into frontline and salvage regimens, reflecting the immune-evasive biology of HRS cells [5]. Amplification of chromosome 9p24.1 leading to PD-L1 overexpression provides the molecular rationale for checkpoint blockade in cHL [5]. Similarly, the European Society for Medical Oncology Clinical Practice Guidelines 2023 recommend risk-adapted integration of immunotherapeutic strategies to improve progression-free survival in high-risk and relapsed settings [6]. In India, the Indian Council of Medical Research National Cancer Registry Programme Report 2023 indicates that lymphomas constitute a substantial proportion of hematologic malignancies, with Hodgkin lymphoma presenting at a relatively younger median age compared with Western populations [7]. This demographic distribution underscores the long-term clinical implications of relapse, treatment-related toxicity, and immune-mediated complications in young survivors [7]. Although ASCT offers durable remission in a significant proportion of relapsed patients, post-transplant immune reconstitution may be complicated by persistent cytopenias, infectious susceptibility, and immune dysregulation. Thrombocytopenia persisting below 100,000/µL beyond the expected engraftment period requires evaluation for marrow suppression, disease relapse, drug toxicity, or immune-mediated platelet destruction. Recognition of refractory immune thrombocytopenia in lymphoma survivors warrants consideration of underlying immune regulatory abnormalities. The present case describes classical Hodgkin lymphoma complicated by refractory immune thrombocytopenia following autologous stem cell transplantation, with subsequent identification of a homozygous TNFRSF9 mutation consistent with immunodeficiency 109. Given the expanding understanding of immune regulatory pathways in lymphoma biology and survivorship, reporting such associations is essential to refine diagnostic algorithms and inform individualized patient management.

Patient Information A 25-year-old woman presented in June 2021 with a 20-day history of intermittent low-grade fever with evening rise, unintentional weight loss, and anorexia. She denied cough, hemoptysis, photosensitivity, or inflammatory joint symptoms. There was no significant past medical history or family history of autoimmune or hematologic disorders. Clinical Findings and Initial Evaluation Initial laboratory investigations revealed hemoglobin 7 g/dL, total leukocyte count 5,030/µL, and platelet count 75,000/µL. Peripheral blood smear demonstrated normocytic normochromic anemia with thrombocytopenia. Ultrasonography of the neck showed necrotic, matted lymph nodes in the left level IV cervical region with loss of fatty hilum. Fine-needle aspiration cytology suggested granulomatous inflammation; acid-fast bacilli staining was negative. Antinuclear antibody (ANA) testing was positive at a titer of 1:320, while anti-double-stranded DNA antibodies and direct Coombs test were negative. In view of granulomatous lymphadenitis and constitutional symptoms, she was empirically initiated on antitubercular therapy. Subsequently, she developed left hip pain with restricted extension. Magnetic resonance imaging of the hip revealed intramuscular edema involving the obturator externus and pectineus muscles. She received muscle relaxants and corticosteroids with symptomatic improvement. Based on alopecia, Raynaud’s phenomenon, cytopenias, and positive ANA, a provisional diagnosis of mixed connective tissue disease was considered. Disease Progression and Diagnostic Clarification In July 2021, she was re-admitted with high-grade fever, left iliac fossa pain, fatigue, and dizziness. Laboratory parameters showed severe anemia (hemoglobin 4.4 g/dL), leukocyte count 6,260/µL, and platelet count 30,000/µL. Blood and urine cultures were sterile. Computed tomography of the chest and abdomen was unremarkable. Bone marrow examination revealed hypercellular marrow with erythroid hyperplasia without evidence of malignancy. She received pulse methylprednisolone (500 mg intravenously daily for five days), following which hemoglobin improved to 8 g/dL and platelet count to 77,000/µL. Isoniazid was discontinued due to intolerance. Given persistent symptoms, fluorodeoxyglucose positron emission tomography–computed tomography (FDG PET-CT) performed in September 2021 demonstrated metabolically active lymphadenopathy with skeletal involvement (Deauville score 4). Excisional biopsy of a left cervical lymph node confirmed classical Hodgkin lymphoma, mixed cellularity subtype. Oncologic Management She received three cycles of ABV chemotherapy; dacarbazine was discontinued due to intolerance. Interim PET-CT demonstrated complete metabolic response (Deauville score 1), and four additional cycles of ABV were administered. End-of-treatment PET-CT confirmed complete metabolic remission (Deauville score 1). In June 2022, six months after completing therapy, PET-CT revealed metabolically active internal and external iliac lymph nodes consistent with relapse. She received one cycle of ABV at a peripheral center and was subsequently referred to a tertiary care institution. Three cycles of GDP chemotherapy were administered between January and March 2023. PET-CT in April 2023 demonstrated mixed response with persistent iliac and inguinal lymphadenopathy. Salvage therapy with four cycles of ICE was given from May to August 2023, resulting in significant radiologic regression. Autologous Stem Cell Transplantation In October 2023, she underwent autologous stem cell transplantation (ASCT). Pre-transplant complete blood counts showed hemoglobin 10.5 g/dL, white blood cell count 19,200/µL, and platelet count 124,000/µL. Stem cell mobilization with granulocyte colony-stimulating factor yielded a CD34+ cell dose of 4.1 × 10⁶ cells/kg. She received BEAM conditioning followed by autologous stem cell infusion. The post-transplant course was complicated by engraftment syndrome and Staphylococcus aureus bacteremia on day +8, which was managed with intravenous antibiotics. She was discharged on day +18 with hemoglobin 10.3 g/dL, leukocyte count 26,000/µL, and platelet count 30,000/µL. One-month post-transplant PET-CT demonstrated complete metabolic remission (Deauville score 1). She subsequently received consolidative radiotherapy (36 Gy in 18 fractions). Follow-up PET-CT scans in June 2024 and February 2025 showed no evidence of metabolically active disease. Post-Transplant Immune Complication Despite sustained remission, she exhibited persistent thrombocytopenia ranging from 40,000–75,000/µL. In June 2025, an acute decline in platelet count was noted. She was treated with pulse corticosteroids followed by low-dose oral steroids and thrombopoietin receptor agonist therapy with romiplostim at 5 µg/kg weekly starting July 2025. Bone marrow examination showed trilineage hematopoiesis with adequate megakaryocytes and increased iron stores, without evidence of lymphoma relapse. PET-CT in August 2025 confirmed continued remission. Genetic Evaluation and Long-Term Outcome Given persistent immune thrombocytopenia in the absence of relapse or marrow failure, next-generation sequencing was performed in September 2025. This revealed a homozygous pathogenic mutation in TNFRSF9 involving introns 2 and 7, consistent with immunodeficiency 109 with lymphoproliferation, inherited in an autosomal recessive pattern. Romiplostim was transitioned to eltrombopag 50 mg daily, and she continues on low-dose corticosteroids. At last follow-up, complete blood counts demonstrated hemoglobin 13.3 g/dL, leukocyte count 7,100/µL, and platelet count 136,000/µL. There was no clinical, biochemical, or radiologic evidence of lymphoma recurrence

The present case illustrates an unusual clinical intersection between classical Hodgkin lymphoma (cHL), post–autologous stem cell transplantation (ASCT) immune dysregulation, and an underlying monogenic immune defect involving TNFRSF9. While cHL is traditionally associated with long-term survival rates exceeding 80–90% in early-stage disease and approximately 70–80% in advanced-stage disease, relapse occurs in nearly 10–30% of patients despite appropriate therapy. Our patient followed this expected relapse trajectory but demonstrated an atypical post-remission immune phenotype characterized by persistent thrombocytopenia despite sustained complete metabolic response. Shen et al. [8] reported CD137 deficiency due to biallelic TNFRSF9 mutations in a patient presenting with severe Epstein–Barr virus–associated lymphoproliferative disease. Their patient developed progressive EBV-driven lymphoproliferation with impaired T-cell activation and reduced cytotoxic function. Notably, their report described significant immune dysfunction manifesting early in life with severe viral susceptibility. In contrast, our patient did not demonstrate recurrent viral infections but developed lymphoma in early adulthood, followed by post-transplant immune thrombocytopenia. Shen et al. documented defective CD8+ T-cell responses and impaired interferon-γ production in functional assays [8], whereas our case clinically manifested as immune-mediated platelet destruction despite preserved marrow megakaryopoiesis. This suggests phenotypic variability within TNFRSF9-associated immunodeficiency, where impaired costimulatory signaling may predispose either to viral-driven lymphoproliferation or dysregulated autoimmunity. Ansell [9] emphasized that approximately 10–30% of advanced-stage cHL patients experience relapse, and that ASCT achieves durable remission in nearly 50–60% of relapsed cases at five years. Our patient relapsed six months after frontline therapy, consistent with high-risk relapse patterns described by Ansell [9]. Following salvage chemotherapy and ASCT, she achieved complete metabolic remission, aligning with expected response rates. However, persistent thrombocytopenia (40,000–75,000/µL) beyond the expected engraftment period diverges from typical post-ASCT recovery, where platelet counts generally exceed 100,000/µL within weeks to months in uncomplicated cases. Alibrahim et al. [10] described immune deficiency/dysregulation–associated EBV-positive cHL as a distinct clinicopathologic entity. They reported that immune-compromised patients often present with advanced-stage disease and systemic symptoms. In their review, EBV positivity in immune-dysregulated settings was associated with altered tumor microenvironment composition and distinct immune checkpoint expression profiles [10]. While our patient’s EBV status was not the defining feature, both scenarios share an underlying immune-compromised milieu. A key distinction lies in prognosis; Alibrahim et al. noted variable outcomes depending on immune status, whereas our patient achieved sustained oncologic remission despite genetic immune dysregulation. Post-transplant immune cytopenias remain uncommon but clinically significant. Fukui et al. [11] reported severe autoimmune pancytopenia following ASCT for Hodgkin lymphoma. Their patient developed multi-lineage cytopenia with marrow findings suggestive of immune-mediated destruction. In contrast, our patient demonstrated isolated thrombocytopenia with preserved erythroid and myeloid lineages and adequate megakaryocytes, indicating peripheral immune-mediated platelet destruction rather than marrow failure. The difference between pancytopenia in Fukui et al. [11] and isolated thrombocytopenia in our case suggests variability in the spectrum of post-ASCT immune dysregulation. Mukae et al. [12] evaluated classical Hodgkin lymphoma associated with immune deficiency and dysregulation and reported that overall survival may be comparable to sporadic cases, although distinct predictive markers were identified. Importantly, they did not observe universally inferior survival in immune-associated cHL [12]. Our patient’s sustained remission following salvage therapy and ASCT is consistent with this observation. However, Mukae et al. also emphasized immunologic heterogeneity, which aligns with our patient’s delayed immune complication rather than aggressive lymphoma behavior. From a regional perspective, Vinodhini et al. [13] reported real-world lymphoma outcomes in an Indian tertiary center, highlighting variability in relapse rates and transplant responses. While their cohort primarily involved non-Hodgkin lymphoma, transplant-related complications and relapse patterns were influenced by real-world clinical heterogeneity [13]. Unlike population-level analyses, our case underscores the importance of individualized evaluation when atypical immune complications arise, particularly in young patients with sustained remission but persistent cytopenia. Numerically, our patient maintained platelet counts between 40,000–75,000/µL for nearly two years post-ASCT before improving to 136,000/µL with thrombopoietin receptor agonist therapy. This prolonged thrombocytopenic phase contrasts with expected platelet recovery beyond 100,000/µL in standard engraftment scenarios. Furthermore, her CD34+ stem cell dose of 4.1 × 10⁶ cells/kg was within the adequate engraftment range, reducing the likelihood that delayed platelet recovery was due to insufficient stem cell infusion. Collectively, this case demonstrates that TNFRSF9-associated immune dysregulation may not necessarily worsen lymphoma-specific survival but may predispose to post-transplant immune-mediated complications. The numerical contrasts—relapse rates of 10–30%, ASCT remission durability of approximately 50–60%, and persistent platelet counts below 75,000/µL in our patient—highlight the deviation from expected hematologic recovery despite oncologic success.

This case underscores the intricate interface between classical Hodgkin lymphoma, post–autologous stem cell transplantation immune reconstitution, and previously unrecognized monogenic immune dysregulation. Although classical Hodgkin lymphoma carries favorable survival outcomes with contemporary multimodal therapy, persistent cytopenias in the setting of sustained metabolic remission warrant systematic evaluation beyond routine oncologic surveillance. In this patient, durable complete metabolic response following salvage chemotherapy, autologous transplantation, and consolidative radiotherapy contrasted with prolonged thrombocytopenia that was not attributable to marrow failure, relapse, or treatment toxicity. Bone marrow examination demonstrated preserved trilineage hematopoiesis with adequate megakaryocytic representation, supporting peripheral immune-mediated platelet destruction. Identification of a homozygous pathogenic TNFRSF9 mutation reclassified the clinical scenario from secondary immune thrombocytopenia to an underlying autosomal recessive immunodeficiency with lymphoproliferative predisposition. TNFRSF9 encodes CD137, a costimulatory receptor essential for effective T-cell activation and cytotoxic function. Deficiency in this pathway may impair immune surveillance and disrupt immune homeostasis, potentially predisposing to lymphoid malignancy and post-transplant immune dysregulation. This case expands the clinical spectrum of TNFRSF9-associated disease by demonstrating that lymphoma may precede overt immunodeficiency manifestations and that immune stress following transplantation may unmask latent genetic defects. Recognition of inherited immune regulatory abnormalities should be considered in young patients with unexplained, refractory immune cytopenias after definitive oncologic therapy. Early genetic evaluation may refine diagnosis, guide long-term surveillance, and inform individualized immunomodulatory management strategies.

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