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\begin{document}

\title{A Nine-Year-Old Male with Barth Syndrome and Cardiac Transplant
Presenting with Hyperviscosity Syndrome caused by EBV-Negative
Plasmacytoid PTLD}



\author[1]{Yixian Li}%
\author[1]{Adit Tal}%
\author[1]{Rachel Offenbacher}%
\author[1]{Nicolas Corral}%
\author[1]{Neha Bansal}%
\author[2]{Juan Ding}%
\author[1]{Lisa Gennarini}%
\author[1]{Leanne Ostrodka}%
\affil[1]{Children's Hospital at Montefiore}%
\affil[2]{Montefiore Medical Center}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Posttransplant lymphoproliferative disorder is a rare but well-known
complication in solid organ or hematopoietic transplant recipients
secondary to immunosuppression. It can range from a cellular hyperplasia
to a classic lymphoma. We describe a case of a nine-year-old male with
Barth syndrome and a history of cardiac transplantation who developed
plasmacytoid EBV-negative PTLD, an extremely rare entity in the
pediatric population, and the evolvement of his PTLD to a more
aggressive plasma cell neoplasm.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Posttransplant lymphoproliferative disorder (PTLD) is a spectrum of
disorder characterized by lymphoid or plasmacytoid proliferation
secondary to extrinsic immunosuppression in solid organ or hematopoietic
transplant recipients. PTLD ranges from lymphoid or plasmacytoid
hyperplasia, polymorphic, monomorphic to classical
lymphoma.\textsuperscript{1} While Epstein-Barr Virus (EBV) is the key
driver of abnormal lymphocytic proliferation in the majority of PTLDs,
EBV-negative PTLD is a distinct entity.\textsuperscript{2} The incidence
of PTLD in the pediatric population is closely associated with the type
of transplanted organ, with the highest incidence in lung, small bowel
and heart transplant recipients. \textsuperscript{3--6}

Plasmacytoid PTLD is a rare subtype of PTLD in the pediatric population.
There are few pediatric cases reported in the literature, with
heterogenicities of the types of transplant, clinical manifestations,
and treatment regimens.\textsuperscript{7--13} We report a case of
EBV-negative, plasmacytoid PTLD in a pediatric heart transplant
recipient and describe his clinical presentation, response to
chemotherapy, and evolution of disease.

\textbf{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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 immunosupression\textsuperscript{8} 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.\textsuperscript{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.\textsuperscript{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.

\textbf{Discussion:}

Plasmacytoid PTLD is a rare entity in pediatric solid organ transplant
patients.\textsuperscript{2} The first case was described in a teenager
with a kidney transplant who presented with EBV-associated
post-transplant multiple myeloma.\textsuperscript{13} The largest case
series reported by Perry \emph{et al} . included five cases in patients
after liver and small bowel combined transplant, and these patients
responded very well to high dose
dexamethasone.\textsuperscript{7}Several subsequent cases were treated
successfully with bortezomib, dexamethasone, with or without
lenalidomide and autologous stem cell transplant. Most patients remain
in remission.\textsuperscript{8--10,12}

Our patient initially responded well to bortezomib and dexamethasone but
relapsed with a different presentation of EBV-negative MZL. EBV-negative
MZL was recently reported by Galera \emph{et al} as an unusual form of
PTLD.\textsuperscript{16} Here, the authors presented this as an
indolent disease process that could be managed conservatively. Our
patient was treated with bendamustine and rituximab as a targeted CD20
therapy, according to the BRISMA/IELSG36 study.\textsuperscript{18}

He relapsed on therapy with plasma cell leukemia with a new t (14;16)
(q32;q23) anomaly. This translocation leads to the IgH/MAF fusion gene,
a high-risk cytogenetic abnormality occurring in 5\% of myeloma
patients.\textsuperscript{19} Plasma cell leukemia is the most
aggressive form of plasma cell dyscrasias with very poor prognosis.
Treatment is based on myeloma-type regimens. Recently, novel agents have
advanced the treatment efficacy of multiple myeloma in adult
patients.\textsuperscript{17,20} The LYRA study showed a 44\% partial
response rate after 4 cycles with 87\% one year progression-free
survival.\textsuperscript{17} Although the peripheral leukemic cells
responded to this regimen, he passed away from gastrointestinal
hemorrhage secondary to progressive intraabdominal disease. We
hypothesize that his intraabdominal pathology may be distinct from his
plasma cell leukemia, as he rapidly progressed on a plasma cell targeted
regimen.

Our case highlights the heterogenicity of EBV-negative PTLD in pediatric
transplant patients, and the evolution of plasma cell neoplasms. The
rapid progress of three different forms of PTLD within less than one
year is a distinct feature. The literature of pediatric plasmacytoid
PTLD is isolated to a few case reports, thus, there is no standard of
care. Our case shows that patients with aggressive plasma cell PTLD may
respond to a combination of targeted and standard chemotherapy. Further
research is needed to understand the pathophysiology of these distinct
disease entities.

\textbf{Conflict of interest statement:}

The authors state no conflict of financial interests to this manuscript
or project.

\textbf{Acknowledgement:}

We thank the patient and his family for their trust as their caregivers.
We appreciate Dr. Renee Moadel and Dr. Yang Shi for their contribution
to provide PET scan images and pathology slides.

\textbf{References:}

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5. Mynarek M, Schober T, Behrends U, Maecker-Kolhoff B. Posttransplant
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6. West SC, Friedland-Little JM, Schowengerdt KO, et al.
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\textbf{Figure Legend:}

\textbf{Figure 1:}

Figure 1A: PET/CT scan at initial diagnosis showed multiple
fluorodeoxyglucose (FDG)-avid lymph nodes above and below diaphragm,
including cervical, mediastinal, axillary, abdominal, and inguinal nodal
stations.

Figure 1B: PET/CT scan after 2 cycles of therapy showed resolution of
previous FDG-avid lymph nodes seen in Fig. 1A.

Figure 1C: PET/CT scan after 5 cycles of chemotherapy (completion of
therapy) showed new anterior mediastinal mass, new intraabdominal
FDG-avid lesion and increased activities of bilateral axillary lymph
nodes. This scan was concerning for progression of disease.

Figure 1D: PET/CT scan after 2 cycles of rituximab and bendamustine
showed new and worsening lymphadenopathy above and below the diaphragm,
concerning for interval progression of PTLD.

\textbf{Figure 2:}

\begin{itemize}
\tightlist
\item
  Figure 2A and 2B: Lymph node biopsy showed sheets of interfollicular
  lambda predominant plasmacytoid cells that express IgA.
\item
  Figure 2C and 2D: Retroperitoneal lymph node biopsy showed an atypical
  small B cell proliferation highlighted by CD20; the final diagnosis
  was consistent with marginal zone lymphoma with plasmacytoid
  differentiation.
\item
  Figure 2E and 2F: Bone marrow biopsy showed Normocellular~marrow
  (80\%) with 30-40\% atypical kappa predominant plasma cells with
  nuclear MUM1 expression, compatible with atypical plasma cells.
\end{itemize}\selectlanguage{english}
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