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.