\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{Severe tumor lysis syndrome during the induction therapy for the
treatment of blastic plasmacytoid dendritic cell neoplasm from
myelodysplastic/myeloproliferative neoplasms}



\author[1]{Ken Sagou}%
\author[1]{Makoto Ito}%
\author[1]{Yuma Kawamura}%
\author[1]{Shun Ukai}%
\author[1]{Miyo Goto}%
\author[1]{Nobuaki Fukushima}%
\author[1]{Kazutaka Ozeki}%
\author[1]{Ryuichi Fukuyama}%
\author[1]{Akio Kohno}%
\affil[1]{Konan Kosei Hospital}%


\vspace{-1em}



  
  \date{June 01, 2024}


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





\selectlanguage{english}
\begin{abstract}
Blastic plasmacytoid dendritic cell neoplasm is a rare disease with
difficulty in diagnosis, and clinical courses of patients with BPDCN
vary widely. We report a case of a 63-year-old man with BPDCN showing
severe tumor lysis syndrome (TLS). BPDCN with high tumor burden should
be carefully considered to prevent TLS.%
\end{abstract}%



\sloppy


\textbf{Key Clinical Message}

BPDCN shows clinically heterogeneous characteristics, and clinical
symptoms suggesting an aggressive clinical course with high tumor
burden, such as high white blood cell count or splenomegaly, should be
carefully considered to prevent TLS.

\textbf{Introduction}

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare
hematological malignancy with dismal prognosis. With difficulty in
diagnosis, BPDCN was used in the 2008 World Health Organization (WHO)
classification for the first time and became a distinct entity in 2016
WHO classification {[}1{]}. Recently, the presence of four out of five
characteristic markers of BPDCN, namely, CD4, CD56, CD123,~CD303, and
TCL1, has been shown to aid in the accurate diagnosis of BPDCN {[}2{]}.
Skin lesions commonly occur in a majority of patients with BPDCN, and
blasts of BPDCN are suggested to arise from pre-malignant hematopoietic
precursor clones {[}3{]}. Thus, patients with systemic lesions were
treated with conventional chemotherapies for acute lymphoblastic
leukemia, acute myeloid leukemia, or non-Hodgkin's lymphoma, sometimes
followed by autologous or allogeneic hematopoietic cell transplantation
as a consolidation therapy {[}4{]}. However, its clinical and biological
heterogeneous characteristics make its clinical management difficult
{[}5{]}. Herein, we describe the case of a patient who suddenly
developed leukemic form of BPDCN accompanied with CALReticulin
(\emph{CALR} ) mutation arising from myelodysplastic/myeloproliferative
neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
without cutaneous lesion, showing severe tumor lysis syndrome (TLS)
immediately after the induction therapy.

\textbf{Case Presentation}

A 63-year-old man previously diagnosed with MDS/MPN-RS-T 6 years before
the presentation was referred to our hospital for rapid progression of
leukocytosis and anemia. Physical examination and computed tomography
revealed splenomegaly and inguinal lymphadenopathy without skin
involvement (Fig. 1 A, B). He did not have fever and had a performance
status of 2 according to the Eastern Cooperative Oncology Group score.
Blood examination showed the following abnormalities: white blood cell
(WBC) count, 44.8 \selectlanguage{ngerman}× 10\textsuperscript{9}/L with 88\% blasts;
hemoglobin, 5.5 g/dL; platelet count, 17.0 × 10\textsuperscript{9}/L;
and serum lactate dehydrogenase (LDH), 300 IU/L. Genetic analyses of his
peripheral blood cells detected type 1 \emph{CALR} mutation without
Janus kinase 2 mutation. Severe hypercellular marrow occupied by
agranular blasts with small cytoplasm and fine chromatin were detected
in the bone marrow aspiration (Fig. 1 C, D), and bone marrow biopsy
showed severe myelofibrosis (MF-3) (Fig.1 E). Flow cytometry revealed
that blasts expressed CD4, CD7, CD56, and HLA-DR without other myeloid
and lymphoid markers. Similar blasts occupied the inguinal lymph node,
which suggested lymph node involvement. Based on these results, the
patient was suspected to have aggressive NK cell leukemia (ANKL), acute
leukemia with ambiguous lineage, or BPDCN.

Due to rapidly increasing WBC count of 106 × 10\textsuperscript{9}/L and
worsening malaise, the dose-reduced SMILE regimen without methotrexate
which contained etoposide 70mg/m\textsuperscript{2} day1--3, ifosfamide
1050mg/m\textsuperscript{2} day1--3, dexamethasone 30mg/body day1--3,
and L-asparaginase 4000U/m\textsuperscript{2} day7, 9, 11, 13, 15, 17,
19 was immediately initiated without accurate diagnosis {[}6{]}. More
than 3 L/day of intravenous hydration and 60 mg/day of febuxostat were
administered as prophylaxis for tumor lysis syndrome (TLS). Then,
immunohistochemistry demonstrated that blasts were positive for CD123,
TCL-1, and CD303, and thus, he was diagnosed with BPDCN (Fig. 2). In
addition, blasts were positive for cMyc and Bcl-2 and negative for TdT,
with relatively low Ki67 index (Fig. 2). Cytogenetic analysis revealed
normal karyotype of blasts. The urine volume after initiating the
chemotherapy was 3,000 mL/day, and his condition improved that he could
eat a meal the next day. However, his urine volume suddenly decreased,
and his condition worsened again on the third day. WBC count immediately
decreased; uric acid, potassium, and phosphorus concentrations
increased; calcium concentration decreased with rapid increase in serum
creatinine concentration, suggesting a clinical TLS (Table 1). Despite
the intensive treatment such as aggressive hydration with noradrenaline
administration to restore circulation and bicarbonate to correct
metabolic acidosis, he finally died of circulatory failure. Autopsy
revealed massive ascites and alveolar hemorrhage, whereas majority of
malignant cells were not found.

\textbf{Discussion}

In this case report, the patient was diagnosed with BPDCN arising from
MDS/MPN-RS-T that progressed into clinical TLS immediately after the
initiation of chemotherapy. Majority of patients with MDS/MPN-RS-T have
a \emph{SF3B1} mutation {[}7{]}. Although \emph{SF3B1} mutations were
not examined in this case, morphologically apparent dysplasia and the
presence of ringed sideroblasts strongly supported the diagnosis of
MDS/MPN-RS-T. On the other hand, while there is one case report about a
patient with MDS/MPN-RS-T that was positive for both \emph{CALR}
and\emph{SF3B1} gene mutations {[}8{]}, BPDCN with \emph{CALR} mutation
has not yet been reported to the best of our knowledge. Therefore, in
this case, MDS/MPN-RS-T might already have been accompanied with
\emph{CALR}mutation.

TdT negativity was reportedly associated with inferior survival in BPDCN
{[}9{]}; however, whether the aggressive clinical course observed in
this case was typical for TdT-negative BPDCN remains unknown.
Conversely, majority of patients with BPDCN expressing cMyc were
reportedly accompanied by 8q24 rearrangement, immunoblastoid morphology,
and skin lesions {[}10{]}. Although 8q24 rearrangement was not examined
in this case, the patient had no skin lesions and his blasts showed
classic cytomorphology, which suggested that his clinical features were
not typical for MYC-positive BPDCN.

Previous studies showed that BPDCN with leukemic presentation without
skin manifestation rarely occurs and tends to present with cytopenia
rather than leukocytosis {[}11{]}. However, although the patient had
leukemia at diagnosis, it was not accompanied with skin lesions and
showed very high WBC count, suggesting it to be a very rare case.
Moreover, rapid increase in WBC counts and massive splenomegaly
indicated a very high tumor burden and rapid tumor growth. The SMILE
regimen was selected because it was effective for ANKL {[}12{]} and the
etoposide contained in SMILE regimen was also effective for BPDCN
{[}13{]}. Although occurrence of TLS was cautiously considered in spite
of low Ki67 index and enough hydration and febuxostat were provided to
the patient for the prevention of TLS, he developed fatal TLS. More
rigorous management including the early use of rasburicase and induction
of hemodialysis is required.

Although the risk prediction of TLS in BPDCN is difficult because of the
rarity and heterogeneity of this disease, the evaluation of peripheral
blood WBC counts and serum LDH concentration may be useful for risk
classification of TLS in BPDCN as in acute leukemia {[}14{]}.

In conclusion, BPDCN shows clinically heterogeneous characteristics, and
patients with clinical symptoms suggesting an aggressive clinical course
with high tumor burden, including high WBC count or splenomegaly, should
be carefully considered to prevent TLS.

\textbf{Financial disclosure statement:} The authors have nothing to
disclose.

\textbf{Conflict of Interest:} There are no conflicts of interest to
report.

\textbf{Author Contribution:} KS selected the patient and designed the
manuscript. KS, MI, NF, and AK wrote the manuscript. RF performed the
immunohistochemistry. All the authors reviewed the paper and agreed with
the final version.



\textbf{References}

1. Arber DA, Orazi A, Hasserjian R, \emph{et al.} The 2016 revision to
the World Health Organization classification of myeloid neoplasms and
acute leukemia. \emph{Blood} 2016; \textbf{127} : 2391--405.

2. Julia F, Dalle S, Duru G, \emph{et al.} Blastic plasmacytoid
dendritic cell neoplasms: Clinico-immunohistochemical correlations in a
series of 91 patients. \emph{Am J Surg Pathol} 2014; \textbf{38} :
673--80.

3. Venugopal S, Zhou S, El Jamal SM, Lane AA, Mascarenhas J. Blastic
Plasmacytoid Dendritic Cell Neoplasm--Current Insights. \emph{Clin
Lymphoma, Myeloma Leuk} 2019; \textbf{19} : 545--54.

4. Pagano L, Valentini CG, Grammatico S, Pulsoni A. Blastic plasmacytoid
dendritic cell neoplasm: Diagnostic criteria and therapeutical
approaches. \emph{Br J Haematol} 2016; \textbf{174} : 188--202.

5. Martín-Martín L, López A, Vidriales B, \emph{et al.} Classification
and clinical behavior of blastic plasmacytoid dendritic cell neoplasms
according to their maturation-associated immunophenotypic
profile.\emph{Oncotarget} 2015; \textbf{6} : 19204--16.

6. Yamaguchi M, Kwong YL, Kim WS, \emph{et al.} Phase II study of SMILE
chemotherapy for newly diagnosed stage IV, relapsed, or refractory
extranodal Natural Killer (NK)/T-cell lymphoma, nasal type: The NK-cell
tumor study group study. \emph{J Clin Oncol} 2011; \textbf{29} :
4410--6.

7. Klampfl T, Gisslinger H, Harutyunyan AS, \emph{et al.} Somatic
Mutations of Calreticulin in Myeloproliferative Neoplasms. \emph{N Engl
J Med} 2013; \textbf{25} : 2379--90.

8. Nakao K, Oka S, Utsumi T, \emph{et al.} {[}Concurrent CALR and SF3B1
gene mutations in a patient with myelodysplastic/myeloproliferative
neoplasm with ring sideroblasts and thrombocytosis{]}. \emph{Rinsho
Ketsueki} 2019; \textbf{60} : 915--9.

9. Taylor J, Haddadin M, Upadhyay VA, \emph{et al.} Multicenter Analysis
of Outcomes in Blastic Plasmacytoid Dendritic Cell Neoplasm Offers a
Pre-Targeted Therapy Benchmark. \emph{Blood} 2019; \textbf{134} :
678--87.

10. Sakamoto K, Katayama R, Asaka R, \emph{et al.} Recurrent 8q24
rearrangement in blastic plasmacytoid dendritic cell neoplasm:
association with immunoblastoid cytomorphology, MYC expression, and drug
response. \emph{Leukemia} 2018; \textbf{32} : 2590--603.

11. Pagano L, Valentini CG, Pulsoni A, \emph{et al.} Blastic
plasmacytoid dendritic cell neoplasm with leukemic presentation: An
italian multicenter study. \emph{Haematologica} 2013; \textbf{98} :
239--46.

12. Suzuki R. NK/T-cell lymphomas: Pathobiology, prognosis and treatment
paradigm. \emph{Curr Oncol Rep} 2012; \textbf{14} : 395--402.

13. Sugimoto KJ, Shimada A, Yamaguchi N, \emph{et al.} Sustained
complete remission of a limited-stage blastic plasmacytoid dendritic
cell neoplasm followed by a simultaneous combination of low-dose DeVIC
therapy and radiation therapy: A case report and review of the
literature. \emph{Int J Clin Exp Pathol} 2013; \textbf{6} : 2603--8.

14. Cairo MS, Coiffier B, Reiter A, Younes A. Recommendations for the
evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in
adults and children with malignant diseases: An expert TLS panel
consensus. \emph{Br J Haematol} 2010; \textbf{149} : 578--86.

\textbf{Table .} Blood tests before and after the induction therapy.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& & Before treatment & Day 2 & Day 3\tabularnewline
\midrule
\endhead
BUN & mg/dL & 34.2 & 87.9 & 123.5\tabularnewline
Creatinine & mg/dL & 1.3 & 1.6 & 2.7\tabularnewline
UA & mg/dL & 6.0 & 5.5 & 8.5\tabularnewline
P & mg/dL & 3.0 & 17 & 22.4\tabularnewline
Na & mmol/l & 137 & 134 & 137\tabularnewline
K & mmol/l & 4.7 & 7.2 & 6.9\tabularnewline
Ca & mg/dL & 7.6 & 6 & 6.5\tabularnewline
LDH & U/L & 395 & 828 & 784\tabularnewline
WBC & 10\textsuperscript{9}/L & 106 & 55.7 & 2.4\tabularnewline
Blast & \% & 96 & 85 & 76\tabularnewline
RBC & 10\textsuperscript{12}/L & 1.2 & 1.4 & 1.1\tabularnewline
Hb & g/dL & 3.7 & 4.4 & 3.3\tabularnewline
Platelet & \selectlanguage{ngerman}×10\textsuperscript{9}/L & 17.0 & 15.0 & 10.0\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: BUN, blood urea nitrogen; UA, uric acid; LDH, lactate
dehydrogenase; WBC, white blood cell; RBC, red blood cell; Hb,
hemoglobin.

\textbf{Figure 1.} Computed tomography revealed splenomegaly (A) and
inguinal lymphadenopathy (B). Severe hypercellular marrow was occupied
by blasts (C), presenting agranular small cytoplasm and fine chromatin
(D). Bone marrow showed severe fibrosis (MF-3) (E) (magnification of all
images \selectlanguage{ngerman}×400).

\textbf{Figure 2.} Blasts were positive for CD4, CD56, CD123, CD303,
TCL-1, cMyc, and Bcl-2 and negative for TdT, myeloperoxidase, CD3, and
CD8. Positive rate of Ki67 was approximately 30\% (magnification of all
images ×400).

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

