\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Successful sequential therapy with rituximab and daratumumab for
refractory post-transplant immune thrombocytopenic purpura}



\author[1]{Katsutsugu Umeda}%
\author[1]{Yuki Shino}%
\author[1]{Yoshinori  Uchihara}%
\author[1]{Kazuki Mitani}%
\author[1]{Keiji Tasaka}%
\author[1]{Hideto Ogata}%
\author[1]{Hirokazu Kobushi}%
\author[1]{Satoshi Saida}%
\author[1]{Itaru Kato}%
\author[1]{Takeshi Yoshida}%
\author[1]{Atsushi Yokoyama}%
\author[1]{Hidefumi Hiramatsu}%
\author[1]{Junko Takita}%
\affil[1]{Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu Hattatsu Shoni Kagaku}%


\vspace{-1em}



  
  \date{May 20, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup








\sloppy


\textbf{LETTER TO THE EDITOR}

\textbf{Successful sequential therapy with rituximab and daratumumab for
refractory post-transplant immune thrombocytopenic purpura}

Yuki Shino\textsuperscript{1}, Katsutsugu Umeda\textsuperscript{1*},
Yoshinori Uchihara\textsuperscript{1}, Kazuki Mitani\textsuperscript{1},
Keiji Tasaka\textsuperscript{1}, Hideto Ogata\textsuperscript{1},
Hirokazu Kobushi\textsuperscript{1}, Satoshi Saida\textsuperscript{1},
Itaru Kato\textsuperscript{1}, Takeshi Yoshida\textsuperscript{1},
Atsushi Yokoyama\textsuperscript{1}, Hidefumi
Hiramatsu\textsuperscript{1}, Junko Takita\textsuperscript{1}

\textsuperscript{1}Department of Pediatrics, Graduate School of
Medicine, Kyoto University

*Correspondence to:

Katsutsugu Umeda, Department of Pediatrics, Graduate School of Medicine,
Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507,
Japan

Phone: +81-75-751-3290; Fax: +81-75-752-2361

E-mail address:\emph{umeume@kuhp.kyoto-u.ac.jp}

Main text word count: 581 words

Figures: 1

Tables: 0

Short running head: Rituximab and daratumumab for post-HCT ITP

\textbf{Keywords:} immune thrombocytopenic purpura, immune-mediated
cytopenia, rituximab, daratumumab, hematopoietic cell transplantation

\textbf{ABBREVIATIONS}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
BMT & Bone marrow transplantation\tabularnewline
\midrule
\endhead
GVHD & Graft-versus-host disease\tabularnewline
HCT & Hematopoietic cell transplantation\tabularnewline
HLA & Human leukocyte antigen\tabularnewline
ITP & Immune thrombocytopenic purpura\tabularnewline
IMC & Immune-mediated cytopenia\tabularnewline
IVIG & Intravenous immunoglobulin\tabularnewline
mAb & Monoclonal antibody\tabularnewline
RIC & Reduced-intensity conditioning\tabularnewline
TPO-RA & Thrombopoietin receptor agonist\tabularnewline
\bottomrule
\end{longtable}

To the Editor,

Immune-mediated cytopenias (IMCs), including immune thrombocytopenic
purpura (ITP), autoimmune hemolytic anemia, and autoimmune neutropenia,
have been newly highlighted as a significant complication after
allogeneic hematopoietic cell transplantation (HCT), with a cumulative
incidence of 2.1\% to 52.6\%.\textsuperscript{1,2} Major risk factors
for post-transplant IMC include younger recipient age at HCT,
non-malignant disease, cord blood transplantation, unrelated donor, and
a reduced-intensity conditioning (RIC)
regimen.\textsuperscript{1,2}Post-transplant IMCs are occasionally
resistant to conventional first-line therapy, i.e., corticosteroid
and/or intravenous immunoglobulin (IVIG) therapy in combination with
supportive therapy, such as granulocyte colony-stimulating factor,
thrombopoietin receptor agonist (TPO-RA), and transfusion. Rituximab, an
anti-CD20 monoclonal antibody (mAb), mycophenolate mofetil, bortezomib,
and daratumumab, an anti-CD38 mAb, have been used as second-line or
subsequent therapies for refractory or recurrent
cases.\textsuperscript{1--5}

A 17-year-old boy with adrenoleukodystrophy underwent allogeneic bone
marrow transplantation (BMT) from a human leukocyte antigen (HLA) 7/8
allele-matched unrelated donor using a RIC regimen consisting of
fludarabine (125 mg/m\textsuperscript{2}), melphalan (140
mg/m\textsuperscript{2}), rabbit anti-thymocyte globulin (5 mg/kg), and
total body irradiation of 4 Gy. Tacrolimus and short-term methotrexate
were administered as prophylaxis for graft-versus-host disease (GVHD).
Myeloid lineage cell engraftment and complete chimerism were achieved on
days 20 and 28, respectively. No significant GVHD was observed.

On day 118, he was readmitted to our hospital with oral bleeding and
cutaneous purpura, and was diagnosed with ITP. The clinical course after
onset of ITP is shown in the Figure. Soon after re-admission, frequent
red blood cell and platelet transfusions were required to treat massive
gastric mucosal bleeding. Since various treatments, such as IVIG,
prednisolone, methylprednisolone, TPO-RAs (eltrombopag and romiplostim),
and four courses of 375 mg/m\textsuperscript{2}/week rituximab, failed
to improve thrombocytopenia, he received one course of 16 mg/kg
daratumumab on day 191, after the approval for use as an unapproved drug
from the Patient Safety Unit of Kyoto University Hospital. His platelet
counts soon exceeded 100\selectlanguage{ngerman}×10\textsuperscript{9}/L but suddenly decreased
7 months later while he was receiving romiplostim therapy. Since the
effect of the three courses of daratumumab was transient and serial flow
cytometric analyses demonstrated the reemergence of CD20+ B cells, which
had disappeared after rituximab therapy, just before the recurrence of
ITP, he received four courses of rituximab in combination with
prednisolone (1 mg/kg/day) and romiplostim. His platelet counts
gradually increased and reached more than 100×10\textsuperscript{9}/L 1
month after initiation of the second rituximab treatment, while he was
still undergoing therapy with prednisolone and romiplostim.

The pathophysiology of post-HCT IMCs is still poorly understood.
However, it has been speculated that immune dysregulation caused by
conditioning regimens, infections, GVHD, immunosuppressive agents,
reduced and dysfunctional regulatory T cells, and/or HLA mismatched
donor-derived naïve T cells trigger the development of post-HCT IMCs
mainly via auto-antibody production to hematopoietic
cells.\textsuperscript{1,2,6} High-throughput single-cell bioassay of
antibody-secreting cells of ITP patients has recently demonstrated the
existence and dissemination of autoreactive plasma cells in multiple
hematopoiesis organs, such as spleen, bone marrow, and lymph nodes,
which might reduce the efficacy of B cell depletion by
rituximab.\textsuperscript{5} In the present case, CD38-targeting
therapy using daratumumab quickly improved the first episode of
rituximab-refractory ITP, suggesting the presence of autoreactive plasma
cells. By contrast, additional rituximab therapy was effective in
counteracting the recurrence of daratumumab-refractory ITP, implying the
presence of remnant autoreactive B cells. Thus, sequential or
combination therapy with rituximab and daratumumab appears to be a
promising therapeutic option for refractory post-transplant IMCs, which
might be caused by multiple antibody-secreting cell populations.

\textbf{CONFLICTS OF INTEREST}

The authors declare no conflicts of interest associated with this
manuscript.



\textbf{REFERENCES}

\begin{enumerate}
\tightlist
\item
  Michniacki TF, Ebens CL, Choi SW. Immune-mediated cytopenias after
  hematopoietic cell transplantation: pathophysiology, clinical
  manifestations, diagnosis, and treatment strategies. \emph{Curr Oncol
  Rep} . 2019;21:87.
\item
  Gupta AO, Boelensbe JJ, Ebens CL, et al. Consensus opinion on
  immune-mediated cytopenias after hematopoietic cell transplant for
  inherited metabolic disorders. \emph{Bone Marrow Transplant} .
  2021;56:1238-1247.
\item
  Faraci M, Zecca M, Pillon M, et al. Autoimmune hematological diseases
  after allogeneic hematopoietic stem cell transplantation in children:
  an Italian multicenter experience. \emph{Biol Blood Marrow Transplant}
  . 2014;20:272-278.
\item
  Driouk L, Schmitt R, Peters A, et al. Daratumumab therapy for
  post-HSCT immune-mediated cytopenia: experiences from two pediatric
  cases and review of literature. \emph{Mol Cell Pediatr} . 2021;8:5.
\item
  Canales-Herrerias P, cricks E, Broketa M, et al. High-affinity
  autoreactive plasma cells disseminate through multiple organs in
  patients with immune thrombocytopenic purpura. \emph{J Clin Invest} .
  2022;132:e153580.
\item
  Kruizinga MD, van Tol MJD, Bekker V, et al. Risk factors, treatment,
  and immune dysregulation in autoimmune cytopenia after allogeneic
  hematopoietic stem cell transplantation in pediatric
  patients.\emph{Biol Blood Marrow Transplant} . 2018;24:772--778.
\end{enumerate}



\textbf{FIGURE LEGEND}

\textbf{FIGURE.} Clinical course of the present case after the first
episode of ITP (A) and after the recurrence of ITP (B). Abbreviations:
BMT, bone marrow transplantation; Hb, hemoglobin; IVIG, intravenous
immunoglobulin; mPSL, methylprednisolone; PC, platelet concentrate; Plt,
platelet; PSL, prednisolone; RCC, red cell concentrate.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/2023/2023}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

