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\begin{document}

\title{A Single Institution Experience of Bortezomib for GVHD in a Pediatric
HSCT Population}



\author[1]{Devangi Shah}%
\author[1]{Jennifer Reichbach Douglas}%
\author[1]{Jumana Ashy}%
\author[2]{Greg Suhrheinrich}%
\author[1]{Asha Pillai}%
\author[1]{Julio Barredo}%
\author[1]{Edward Ziga}%
\author[1]{Warren Alperstein}%
\affil[1]{University of Miami Miller School of Medicine}%
\affil[2]{University of Florida Health Central Florida}%


\vspace{-1em}



  
  \date{May 23, 2024}


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\selectlanguage{english}
\begin{abstract}
Acute graft versus host disease (aGvHD) remains one of the most serious
complications, occurring in about 30-70\%, of allogeneic hematopoietic
stem cell transplantation (HSCT) recipients. While about 40-60\% of
these recipients will respond to steroids as first line, there is no
consensus on second line agents. The management of steroid-refractory
(SR) and steroid dependent (SD) GVHD after HSCT continues to be
challenging. In the absence of clinical trials, treatment in most cases
is based on individual physician or center experience. Herein, we
present our institutional experience with the use of bortezomib, a
first-generation reversible proteasome inhibitor, in SD aGvHD.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Corticosteroids remain first-line therapy for GVHD\textsuperscript{1}.
Although several salvage therapeutic options for SR and SD GVHD exist,
there is no consensus\textsuperscript{6}. Consequences of prolonged
steroid use is severe non-specific immunosuppression, potential loss of
graft-versus-tumor (GVT) effect in patients with malignancy, and
increased infection risk\textsuperscript{1}. Salvage therapy is often
selected based on adverse effect profile, patient's unique
characteristics, drug availability, or institutional
experience\textsuperscript{1}.

Bortezomib is a first-generation reversible proteasome inhibitor that
has shown efficacy in murine aGVHD models leading to clinical trials and
use in adult HSCT. Bortezomib inhibits nuclear factor-kappa B (NF-\selectlanguage{greek}κ\selectlanguage{english}B)
\textsuperscript{1}, resulting in inhibition of T- and B-cell activation
and pro-inflammatory cytokine transcription\textsuperscript{1,2}. It
increases T-cell apoptosis, decreases expression of activation markers
and receptors on T-cells, and decreases T-cell proliferation.
Additionally, bortezomib aids in treating GVHD by preventing activation
of DCs which mediate antigen presentation and cytokine transcription
that ultimately causes organ damage in GVHD\textsuperscript{1,2}.

Basic science studies demonstrated that bortezomib has the effect of
preserving GVT effect by allowing for persistence of T-regulatory cells
thus promoting recipient T-cell reconstitution.\textsuperscript{2}

Continuous administration of bortezomib after HSCT in pre-clinical
studies resulted in cutaneous aGVHD reduction, associated with decreased
IL-6 level\textsuperscript{14}. Bortezomib administration resulted in
the specific downregulation of CXCR3, a skin-homing chemokine receptor,
on donor CD8\textsuperscript{+} T~cells in a murine aGVHD
model.\textsuperscript{14}

Koreth \emph{et al} reported on 45 adult patients with mMUD donors who
received GVHD prophylaxis with bortezomib in addition to methotrexate
and tacrolimus\textsuperscript{2}. Grade 2-4 aGVHD was present in 22\%
and 29\% developed cGVHD, with a 2-year OS of 64\%\textsuperscript{2}.
Additionally, T-cell reconstitution was deemed favorable when compared
with matched patients who received standard GVHD prophylaxis without
bortezomib\textsuperscript{2}.

Miller \emph{et al} demonstrated patients with SD and SR cGVHD while on
bortezomib was able to wean from prednisone\textsuperscript{2}.
Pai\emph{et al} evaluated SR cGVHD patients treated with bortezomib,
documenting favorable responses including decreased sclerotic
non-healing skin lesions and reduced diarrhea\textsuperscript{2}.

Herrera \emph{et al} evaluated a combination of bortezomib and
prednisone treatment of cGVHD \textsuperscript{2}. A positive response
reported in 80\%, with 10\% a complete response (CR) and the remainder
had a partial response (PR). Best results were seen in the skin and
gastrointestinal tract\textsuperscript{2}.

Further studies of bortezomib are needed in children and young adults to
delineate its potential benefits and toxicities in this age group in
terms of GVHD prophylaxis and treatment. Over a period of five years,
five pediatric BMT patients at Sylvester Comprehensive Cancer Center at
the University of Miami and Holtz Children's Hospital were treated with
bortezomib as part of their treatment for SR and SD GVHD post-HSCT. We
review these to provide proof of principle for potential future trials
of this agent for SR and SD GVHD in pediatric HSCT.

\textbf{CASE EXAMPLES}

\textbf{Case 1:}

A 7-year-old male patient with high-risk AML developed initial
gastrointestinal and ocular GVHD 23 days post-allogenic HSCT. He was
initially on prednisone and sirolimus; first attempts included weaning
him from prednisone with extracorporeal photopheresis (ECP), but he
continued to have multiple skin GVHD flares with worsening
manifestations to grade 4 aGVHD. Bortezomib was initiated due to
continued steroid dependence (Table 1). Due to development of
pancytopenia, dose reduction was required temporally, before increasing
again. His skin lesions steadily improved, permitting bortezomib dose
taper to discontinuation and discontinuation of prednisone with
subsequently stopped all immune suppression.

\textbf{Case 2:}

A 4-year-old male patient with X-linked lymphoproliferative disorder and
associated EBV-positive DLBCL presented with aGVHD of the skin on day
+78 after haploidentical maternal HSCT. GVHD prophylaxis was with
sirolimus. Steroids were initiated once GVHD developed. Unable to wean
off steroids, bortezomib was initiated (Table 1), during which
prednisone was weaned and eventually discontinued. Subsequently, all
other immune suppression was discontinued. Later, he subsequently
developed intervening liver GVHD at day +341 and restarted bortezomib,
requiring a 50\% dose reduction due to neutropenia. Upon neutrophil
count recovery, the bortezomib dose was increased but, liver function
did not improve. After five doses bortezomib was discontinued and
pentostatin initiated. The patient was then successfully weaned from
prednisone. Bortezomib showed promise in treatment of skin GVHD but had
no effect on his liver GVHD.

\textbf{Case 3:}

A 1-year-old female with Radioulnar Synostosis and Amegakaryocytic
Thrombocytopenia presented with SD aGVHD of the skin around day +177.
The patient was started on prednisone and sirolimus. Attempts to wean
from prednisone led to multiple skin GVHD flares. Rituximab was given
without success. She was deemed underweight for ECP catheter placement,
so bortezomib was initiated and increased as tolerated for total of 24
weekly doses (Table 1). There was initial PR to bortezomib, allowing
wean of steroids; however, she was unable to completely discontinue
prednisone. All bortezomib doses were well tolerated, with the only
complications including delayed dose due to rhinovirus infection, and a
temporary dose reduction due to pancytopenia. The patient ultimately
continued to have skin flare-ups after the initial response, and
bortezomib was discontinued.

\textbf{Case 4:}

A 19-year-old male with Ewing Sarcoma followed by treatment related MDS
developed lung GVHD on day +451 after a MUD HSCT. GVHD therapy included
sirolimus, prednisone, bortezomib, solumedrol, rituximab, and ECP. He
responded well to bortezomib, allowing wean from prednisone (Table 1).
He subsequently developed pancytopenia requiring bortezomib dose
reduction and eventual discontinuation. The pancytopenia improved after
discontinuation of bortezomib and he was able to remain steroid-free. He
later developed a GVHD flare and was restarted on bortezomib along with
prednisone, while remaining on sirolimus. Bortezomib was again
discontinued due to pancytopenia and development of peripheral
neuropathy. ECP was initiated with demonstrable initial respiratory
response, but he subsequently experienced acute respiratory failure and
succumbed to multi-organ failure.

\textbf{Case 5:}

A 14-year-old female with MDS underwent a haploidentical HSCT
complicated by SD aGVHD of the liver. This was preceded by grade 1
steroid-responsive aGVHD of the gut, B-K viremia and viruria, HHV-6
viremia, CMV viremia and hypertension. Throughout her HSCT course, she
had aGVHD flares of skin and gut due to non-compliance with her
immunosuppression. Each flare was steroid responsive. Shortly after day
+300, she developed worsening transaminitis and skin GVHD that was SD.
Bortezomib was started with successful steroid wean initiated within one
week of her initial bortezomib dose (Table 1). Over the subsequent three
months, while receiving weekly bortezomib, she was successfully weaned
from steroids.

\textbf{Conclusion}

Our single institutional case series experience with bortezomib for SR
and SD GVHD after pediatric HSCT, serves as proof of principle for
tolerability, potential efficacy and development of future clinical
trials. Among dose-limiting toxicities, pancytopenia was observed in
almost all patients to varying degrees. No patients experienced
infections or prolonged complications, and all had resolution of
pancytopenia following dose reduction of bortezomib. Most patients
tolerated bortezomib well, without serious adverse events. One patient
experience peripheral neuropathy.

Though limited by sample size and single-center non-controlled anecdotal
experience, we believe that this series is supportive of the possibility
that bortezomib's use in pediatric patients could be effective as
second-line, steroid-weaning therapy in SD or SR GVHD. Bortezomib
appears to be more effective in skin GVHD, and some response with liver
GVHD. Our goal in the future is to create a clinical trial to evaluate
the tolerability and efficacy of bortezomib in SR and SD GVHD and to
standardize a dosing regimen for pediatric patients.

\emph{References}

1. Hill, L., Alousi, A., Kebriaei, P., Mehta, R., Rezvani, K., Shpall,
E. New and emerging therapies for acute and chronic graft versus host
disease. Therapeutic Advances in Hematology. 2018; 9:21-46.

2. Al-Homsi, A. S., et al. Bortezomib for the prevention and treatment
of graft-versus-host-disease after allogenic hematopoietic stem cell
transplantation. Experimental Hematology. 2016; 44: 771-777.

3. Kuroda, J., et al. Bortezomib for post-allogenic hematopoietic stem
transplantation relapse and GVHD in multiple myeloma: a single institute
experience. International Journal of Hematology. 2010; 92: 669-672.

4. Kumar, S., Mohammadpour, H., Cao, X. Targeting Cytokines in GVHD
Therapy. Journal of Immunology research and therapy. 2017. 2: 90-99.

5. Toubai, T., Sun, Y., Reddy, P. GVHD Pathophysiology: is acute
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6. Ram, R. and Storb, R. Pharmacologic Prophylaxis Regimens for Acute
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7. Vodanovic-Jankovic, S., Hari P., Jacobs, P., Komorowski, R.,
Drobyski, W. R. NF-\selectlanguage{greek}κ\selectlanguage{english}B as a target for the prevention of
graft-versus-host disease: comparative efficacy of bortezomib and
PS-1145 2006.

8. Sun, Kai, E.C, Danice, Anyer, Miriam R, et al. Differential Effects
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9. Malard F, Labopin M, Yakoub-Agha I, et al. Rituximab-based first-line
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13. Koreth, J., Stevenson, K.E., Kim, H.T. et al. Bortezomib,
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\textbf{Hosted file}

\verb`Bortez paper Table 1- final submission.docx`  available at \url{https://authorea.com/users/735929/articles/711937-a-single-institution-experience-of-bortezomib-for-gvhd-in-a-pediatric-hsct-population}

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