Case presentation:
A nine-year-old male with Barth syndrome and history of heart transplantation for left ventricular non-compaction (LVNC) cardiomyopathy developed plasmacytoid PTLD seven years after transplant. He was initially diagnosed with LVNC at five months of age. He had an acute decompensation of heart failure requiring extra-corporeal membrane oxygenation (ECMO) and an orthotopic heart transplantation within one month of presentation. His induction therapy included anti-thymocyte globulin and prednisone.12 His post-operative course was complicated by cytomegalovirus (CMV) viremia (donor CMV +, patient CMV -). Patient and donor were both EBV Immunoglobin G (IgG) positive at the time of transplant and patient’s EBV polymerase chain reaction (PCR) remained negative. He was transitioned to mycophenolate and tacrolimus for maintenance immunosuppression and levels were titrated.14 He was compliant with immunosuppression and 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 syndrome characterized by dilated cardiomyopathy, skeletal myopathy, neutropenia, and short stature.15
At eight years of age, he presented with a lower gastrointestinal bleed, acute-onset anemia, somnolence, retinal hemorrhages, and increased serum viscosity. Serum protein electrophoresis showed two monoclonal bands (IgA Lambda and IgG Kappa) and an M spike. He was treated with plasmapheresis for hyperviscosity syndrome and his symptoms improved. Positron emission tomography-computed tomography (PET/CT) scan (Fig. 1A) showed diffuse cervical, mediastinal, axillary, abdominal, and inguinal lymphadenopathy. Axillary lymph node biopsy (Figs. 2A and 2B) demonstrated a nondestructive morphology with an increase in plasma cells expressing excess lambda light chain and IgA; these abnormal cells were CD20 negative and CD138 positive, suggesting a clonal process. 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 plasma cells. Combined, these studies were consistent with the diagnosis of early onset, nondestructive, plasmacytoid PTLD.
He was treated with reduction of immunosupression8 and a multiple myeloma-type regimen with dexamethasone and bortezomib. PET/CT scan after 2 cycles of therapy showed resolution of previous PET-avid lesions (Fig. 1B). Stem cell collection was performed after 3 cycles in preparation for potential future autologous stem cell transplant. He completed 5 cycles of therapy without complication. End of therapy PET/CT was significant for a new mediastinal mass and multiple intra-abdominal lymph nodes (Fig. 1C). Lymph node biopsy demonstrated a lymphoplasmacytic infiltrate, which was IgA and lambda positive. The cells showed plasmacytoid features, but in contrast to the initial biopsy at diagnosis, there was marked CD20 positivity (Figs 2C and 2D). EBER staining and serum EBV PCR remained negative. This recurrence was most suggestive of a marginal zone lymphoma (MZL) like PTLD.16 He was initiated on therapy with rituximab and bendamustine. Autologous stem cell transplant was discussed with the multidisciplinary team. Due to active disease, high risk in a transplant patient, and infectious risk associated with Barth syndrome, the team opted not to transplant. PET/CT scan at the end of cycle 2 demonstrated progression of disease in the mediastinal and abdominal regions (Fig. 1D).
While awaiting surgical biopsy, he presented with fever, poor oral intake, diarrhea and restlessness. Laboratory studies showed severe tumor lysis with 57% plasmablasts on peripheral blood by flow cytometry. Bone marrow biopsy showed 30-40% Kappa positive plasma cells, consistent with plasma cell leukemia (Figs. 2E and 2F). A new IGH/MAF gene fusion was identified on FISH analysis. He was treated with daratumumab, bortezomib, cyclophosphamide and dexamethasone, based on the LYRA study.17 Within one week, his peripheral flow cytometry showed no evidence of plasma cells. However, on day 12 of induction therapy, he was found to have a lower gastrointestinal tract bleed. CT scan demonstrated extensive abdominal and pelvic lymphadenopathy with interval worsening disease. Due to multiorgan dysfunction, chemotherapy was held. His clinical status rapidly deteriorated with uncontrollable abdominal disease over the course of 36 hours, and parents chose comfort care. He died the following day and parents declined an autopsy.