A 9‐year‐old male with Barth syndrome and cardiac transplant presenting with hyperviscosity syndrome caused by EBV‐negative plasmacytoid posttransplant lymphoproliferative disorder

Abstract

To the Editor: Posttransplant lymphoproliferative disorder (PTLD) is a disorder characterized by lymphoid or plasmacytoid proliferation secondary to extrinsic immunosuppression in solid organ or hematopoietic transplant recipients.1 We report a case of Epstein–Barr virus (EBV)negative, plasmacytoid PTLD in a pediatric heart transplant recipient. A 9-year-old male with Barth syndrome developed plasmacytoid PTLD 7 years after orthotopic heart transplant. He was diagnosed with left ventricular noncompaction cardiomyopathy when he was 5 months old. He had an acute decompensation of heart failure 1 month later, requiring an orthotopic heart transplantation. His induction therapy included anti-thymocyte globulin and prednisone.2 He was transitioned to mycophenolate and tacrolimus for maintenance immune suppression. Patient’s serum EBV polymerase chain reaction (PCR) remained negative despite positive EBV IgG of both donor and recipient. Surveillance biopsies demonstrated no cellular or antibody-mediated rejection. He was later diagnosed with Barth syndrome caused by a hemizygous TAZ mutation, a rare X-linked genetic syndromecharacterizedbydilated cardiomyopathy, skeletalmyopathy, neutropenia, and short stature.3 At 8 years of age, he presented with an acute-onset lower gastrointestinal hemorrhage and somnolence secondary to hyperviscosity syndrome. Serum protein electrophoresis was positive for a M-spike, including IgA Lambda and IgG Kappa. He was treated with plasmapheresis for hyperviscosity syndrome. Positron emission tomographycomputed tomography (PET/CT) scan (Figure S1A) showeddiffuse lymphadenopathy.Axillary lymphnodebiopsy (Figure1A,B) demonstrated a nondestructive morphology with an increase in plasma cells expressing excess lambda light chain and IgA, which were CD20 negative and CD138 positive. Cytogenetic fluorescence in situ hybridization (FISH) showed loss of TP53. Serum EBV PCR and EBV-encoded RNA (EBER) staining on lymph node pathology were negative. Bone marrow biopsy demonstrated a hypocellular marrow with trilineage hematopoiesis and 5%–10% CD138 positive cells. When combined, these studies were consistentwith the diagnosis of early onset, nondestructive, plasmacytoid PTLD.4 He was treated with reduction of immunosuppression and a multiple myeloma-type regimen with dexamethasone and bortezomib.5 PET/CT after two cycles of therapy showed complete resolution of previous PET-avid lesions (Figure S1B). Hematopoietic stem cells were collected in preparation for potential autologous stem cell transplant (SCT). He completed five cycles of therapy without complication. End of therapy PET/CTwas significant for a newmediastinal mass andmultiple intraabdominal lymph nodes (Figure S1C). Intraabdominal lymph node biopsy demonstrated lymphoplasmacytic infiltration, which was IgA and lambda positive. There was marked CD20 positivity, contrary to first biopsy (Figure 1C, D). EBER staining and serum EBV PCR remained negative. This recurrence was most suggestive of a marginal zone lymphoma (MZL)-like PTLD. EBV-negative MZL was recently reported as an unusual form of PTLD.6 Our patient was treated with bendamustine and rituximab as a targeted anti-CD20 therapy, according to the BRISMA/IELSG36 study.7 Autologous stem cell transplant was deferred, due to active disease, high risk in a heart transplant patient, and infectious risk associated with Barth syndrome. After two cycles of therapy, PET/CT demonstrated progression of disease (Figure S1D). While awaiting another surgical biopsy due to progressive disease, he presentedwith fever, severe tumor lysis, andplasmablasts in peripheral blood. Bone marrow biopsy showed 30%–40% Kappa positive plasmablasts, consistentwithplasmacell leukemia (Figure1E, F). Anew t (14;16) anomaly was identified on FISH analysis, which is a high-risk cytogenetic feature in myeloma patients.8 Plasma cell leukemia is the most aggressive form of plasma cell dyscrasias with very poor prognosis. Daratumumab (anti-CD 38 antibody)-based regimens have shown superior outcome and tolerable safety profile in adults with relapsed multiple myeloma.9,10 The LYRA study showed a 44% partial response rate after four cycles with 87% 1 year progression-free survival, and it was well tolerated. Other relapsedmyeloma therapies, such as DPACE (dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide), are extremely myelosuppressive and toxic.11 Given the dismal diagnosis and potentially significant toxicities, his family and our team preferred the LYRA regimen (daratumumab, bortezomib, cyclophosphamide, and dexamethasone) as a more tolerable therapy. Within 1 week of induction therapy, the patient’s peripheral flow cytometry showed no evidence of plasmablasts. However, he was found to have a new lower gastrointestinal bleeding and worsening intraabdominal lymphadenopathy during induction. His clinical status rapidly deteriorated, so chemotherapy was held, and his parents chose comfort care.