Successful Treatment of Isolated Bone Marrow Classic Hodgkin Lymphoma in a Patient With Cartilage Hair Hypoplasia

To the Editor: Cartilage hair hypoplasia (CHH) is a rare syndrome caused by mutations in the RMRP gene 1. Clinical presentation is variable but typically includes short stature, disproportionately short limbs, fine or blonde hair, variable immunodeficiency, and increased risk of malignancy 2, 3. Isolated bone marrow Hodgkin lymphoma (HL) is also exceedingly rare, particularly in pediatric patients 4, but has been described in immunocompromised individuals, primarily adults with HIV/AIDS 5, 6. To date, isolated bone marrow HL has not been described in patients with CHH. We present a 14-year-old male with CHH due to homozygous RMRP n.71 A>G mutations and known mild defects in T cell immunity (Figure 1A), but no history of recurrent infections, who was initially evaluated for 8 days of persistent fevers, abdominal pain, emesis, and fatigue. Notably, he did not have any clinically apparent lymphadenopathy on exam. Laboratory evaluation revealed new pancytopenia with hemoglobin of 5.6 g/dL, platelets of 26,000/mm3, and absolute neutrophil count of 1070/mm3. Peripheral blood smear did not show circulating blasts or other malignant cells. CT of neck, chest, abdomen, and pelvis showed only mildly prominent cervical and mediastinal lymph nodes. A broad differential diagnosis was considered including bone marrow failure, myelodysplastic syndrome/malignancy, and transient viral bone marrow suppression. Epstein–Barr virus (EBV) DNA PCR from whole blood returned positive with a high viral load of 255,036 copies/mL. Given his protracted clinical course, lack of prominent lymphadenopathy on exam and imaging, and known cancer predisposition in patients with CHH, a bone marrow aspirate and biopsy were performed. Pathologic evaluation of the bone marrow showed a markedly hypercellular lymphohistiocytic infiltrate with few large, atypical cells positive for CD30, CD15, BOB-1, EBER, and PAX5 (weak), and negative for CD20 and OCT-2, consistent with EBV-positive Hodgkin and Reed–Sternberg cells (Figure 1B). Importantly, these findings—in addition to positive IgG and negative IgM against EBV viral capsid antigen—were inconsistent with a diagnosis of infectious mononucleosis. Given the atypical presentation, a repeat bone marrow biopsy was performed and reaffirmed the presence of EBV-positive Hodgkin and Reed–Sternberg cells. Surprisingly, subsequent PET/CT did not demonstrate any areas of abnormal FDG uptake (Figure 1C). Together, these findings were diagnostic of stage IVB classic HL (cHL) and suggested EBV-induced malignant transformation of B cells in the bone marrow. In advanced stage cHL, the combination of adriamycin/doxorubicin, vinblastine, and dacarbazine (AVD) with nivolumab has demonstrated excellent progression-free survival 7. However, we surmised that nivolumab would be ineffective in our patient due to his impaired T cell immunity. He was thus started on induction therapy with 4-week cycles of brentuximab-vedotin (BV) and AVD (BV-AVD) administered on Days 1 and 15 of each cycle. His EBV infection was concurrently treated with ganciclovir/valganciclovir, and EBV DNA levels steadily declined (Figure 1D). Bone marrow evaluation after completing 2 cycles of BV-AVD showed no evidence of residual disease and negative EBER staining. When warranted, hematopoietic stem cell transplant (HSCT) can effectively treat immunodeficiency in patients with CHH 8. We also considered that HSCT may provide definitive therapy for our patient's isolated bone marrow cHL. We thus initiated bridging monotherapy with BV every 3 weeks while arranging for transplant. The patient's brother was identified as a 10/10 HLA match and was heterozygous for the pathogenic RMRP mutation, making him a suitable donor. Our patient received a myeloablative conditioning regimen of rabbit anti-thymocyte globulin, fludarabine, and busulfan (goal AUC ∼60 mg × h/L) prior to a matched sibling donor (MSD) allogeneic HSCT with successful neutrophil engraftment on Day +16. He is now more than 1-year post-transplant without evidence of disease and has full donor chimerism with excellent immune reconstitution. While patients with CHH are at increased risk for lymphoma, non-Hodgkin lymphoma, in particular diffuse large B cell lymphoma, is more common than HL 9, 10. Two cases were recently reported of EBV-associated cHL in siblings with CHH 11. However, our patient's presentation with isolated bone marrow cHL and treatment with HSCT once in remission is unique. Considering all cases, bone marrow involvement in cHL has an estimated incidence of 4%–10% 12. Isolated marrow disease is exceedingly rare with an estimated incidence of less than 1% 13. Whereas most cases of isolated bone marrow HL have been described in HIV-positive individuals 5, 6, our patient was HIV-negative. Despite this, our patient shared laboratory features with HIV-associated HL including impaired T cell immunity and EBV-positive status 14, 15. These shared characteristics suggest that impaired T cell immune surveillance is permissive to EBV-driven oncogenesis and may be a common pathogenic feature of isolated bone marrow HL. As such, leukemia and lymphoma should be actively investigated in patients with impaired T cell immunity in the context of subacute or chronic EBV infection, even when they do not have evidence of nodal disease. In summary, we demonstrate durable remission and immune reconstitution at >1-year in a patient with CHH and isolated bone marrow cHL treated with a truncated, 2-cycle course of BV-AVD followed by bridging BV and MSD HSCT. Patients with CHH and lymphoma who do not receive HSCT typically have dismal outcomes 10. HSCT should be considered in all patients with T-cell immunodeficiency-associated lymphoma and bone marrow involvement who have a suitable donor. No written consent has been obtained from the patient or their family, as no identifiable patient data included in this case report. The authors declare no conflicts of interest.