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\begin{document}

\title{The difficulty to diagnose and treat a rare disease: response to
midostaurin in a case of aggressive systemic mastocytosis conditioning
bulky lymphadenopathy}



\author[1]{Mariarita Sciumé}%
\author[2]{Fabio Serpenti}%
\author[3]{Simona Muratori}%
\author[4]{Valerio Pravettoni}%
\author[5]{Fabio Massimo Ulivieri}%
\author[6]{Giorgio Alberto Croci}%
\author[7]{Andrea Esposito}%
\author[1]{Maria Cecilia Goldaniga}%
\author[1]{Giorgia Natascia Saporiti}%
\author[1]{Giulia Galassi}%
\author[1]{Luca Baldini}%
\author[1]{Francesco Onida}%
\author[8]{Federica Irene Grifoni}%
\affil[1]{Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy}%
\affil[2]{Università degli Studi di Milano, Milan, Italy}%
\affil[3]{Dermatology Unit, Department of Physiopathology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università di Milano}%
\affil[4]{U.O.C. General Medicine - Immunology and Allergology, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, Università di Milano}%
\affil[5]{Nuclear Medicine, Bone Metabolic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università di Milano}%
\affil[6]{Division of Pathology, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy}%
\affil[7]{Division of Radiology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy}%
\affil[8]{Hematology Unit, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, Università di Milano}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\selectlanguage{english}
\begin{abstract}
Systemic mastocytosis (SM) can be extremely heterogeneous and its
treatment should be highly individualized. We reported a description of
clinical management of an aggressive SM characterized at diagnosis by
multiple organ involvement. The patient underwent to different lines of
treatment, from standard chemotherapy to the novel tyrosine kinase
inhibitor midostaurin.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Systemic mastocytosis (SM) results from a clonal proliferation of
abnormal mast cells (MCs) in extra-cutaneous organs. It could be divided
into indolent SM (ISM), smoldering SM (SSM), SM with an associated
hematologic (non-MC lineage) neoplasm (SM-AHNMD), aggressive SM (ASM),
and mast cell leukemia (MCL). {[}1-3{]}

Clinical features of SM could be related to histamine release or to
uncontrolled growth and infiltration of clonal MCs in different organs.
{[}2-5{]} The latter clinical features are divided into B findings
(\textgreater{}30\% MC infiltration on BM biopsy and serum total
tryptase level \textgreater{}200 ng/mL, hepatomegaly with normal liver
function, palpable splenomegaly without hypersplenism, and/or
lymphadenopathy, signs of dysplasia or myeloproliferation in non-MC
lineage, but not diagnostic of an associated hematological neoplasm) or
C findings (organ dysfunction due to mast cell infiltration). {[}2-4{]}
Diagnosis of ISM is established with \textless{}2 B findings and no C
findings; when \emph{\textgreater{}} 2 B findings but no C findings are
present, the diagnosis is SSM, and when one or more C findings are
detected ASM can be diagnosed. {[}2-4{]}

The treatment of adult SM should be highly individualized; while the
backbone of therapy in ISM and SSM is symptom management, for aggressive
and leukemic forms cytoreductive treatment is indicated. {[}3,4{]}
Historically, cytoreductive agents include interferon-\selectlanguage{greek}α \selectlanguage{english}and cladribine.
{[}3,4,6,7{]} Allogeneic stem cell transplant could be considered in
SM-AHNMD when the associated hematologic neoplasm has an indication to
transplantation and in ASM patients with relapsed/refractory disease or
in those with acute MCL. {[}8{]}

With the advent of the tyrosine kinase inhibitors (TKIs) era, many
efforts have been made to find proper inhibitor of SM c-\emph{KIT}
--driver mutation. Midostaurin has been shown to induce major clinical
responses with improvement or disappearance of one or more C-findings, a
decrease in the MC burden, organomegaly and mediator-related symptoms.
{[}9{]}

Hereby, we report an extended description of a real-life management of
an ASM patient conditioning bulky lymphadenopathy who has undergone to
multiple lines of treatment.

All procedures were in accordance with the ethical standards of the
responsible committee on human experimentation (institutional and
national) and with the Helsinki Declaration of 1975, as revised in 2013.

\textbf{Case report}

In 30-year-old Caucasian man was referred to our Center for a ten-year
history of maculopapular rash, intractable itching, flushing and a
six-month history of diarrhea (3-4 bowel movements per day with loose
stools associated to a \textless{}10\% weight loss). The medical history
was otherwise unremarkable, except for a non-steroidal anti-inflammatory
drug-induced anaphylaxis.

Complete blood count, common coagulation, liver and renal function tests
were in a normal range. A computed tomography (CT) scan showed diffuse
lymphadenopathy (up to ) and mild hepatosplenomegaly. The screening
serum tryptase level was 209 ng/ml (normal level \textless{}5 ng/ml).
Gastric, duodenal, distal ileal and colonic biopsies revealed a diffuse
mucosal mast cell infiltration, with abnormal expression of CD2 and
CD25, compatible with SM diagnosis. An abdominal lymph node biopsy also
confirmed the SM diagnosis and excluded a lymphoproliferative disease.
At bone marrow biopsy multifocal clusters of spindling mast cells CD25+
were equal to 70\% of total cellularity. Aspirate smears showed
\textless{}5\% of mast cells and a direct sequencing of the
\emph{KIT}gene was positive for the D816V mutation. A total skeleton
X-ray was negative for a bone lytic or sclerotic involvement, while
osteoporosis was diagnosed on the basis of reduced bone mineral density
at dual-energy X-ray absorptiometry scan for which calcium/vitamin D
supplements were started. Since the patient presented only B-findings,
diagnosis of SSM was made and he was not considered a candidate for a
cytoreductive treatment. The patient was instructed to avoid triggers of
MC degranulation and therapy with H1-H2 histamine receptor blockers;
sodium cromolyn was started with a symptomatic purpose for itching and
diarrhea obtaining a good control.

During the follow-up, patient's general conditions slowly worsened with
the appearance of a pathological weight loss (\textgreater{}10\%), a
more severe diarrhea and a progressive enlargement of abdominal lymph
nodes, liver and spleen. In April 2017 confluent abdominal
lymphoadenopathy had a maximum diameter of 6 cm, conditioning appearance
of ileal dislocation and ascites due to SM liver involvement
(histologically confirmed). Liver and spleen had a diameter of 24 and 17
cm, while bone marrow involvement remained unchanged as for biopsy and
morphology. Blood count was normal and serum tryptase level raised to
332 ng/ml. We concluded for aggressive evolution of SM. First line
cytoreductive therapy was started in April 2017 with subcutaneous
cladribine 0,14 mg/Kg per day for 5 days per cycle. A total of 5 cycles
every 6 weeks were administered. Therapy was overall well tolerated and
no grade 3/4 hematologic toxicities were observed. By the end of the
fifth cycle the disease had not yet reached a response with persistence
of symptoms, 60\% of MC involvement at bone marrow biopsy, and stable
lymphadenopathy and hepatosplenomegaly. Serum tryptase level was 173
ng/ml.

From December 2017 midostaurin was obtained through an expanded access
use and started at a dosage of 25 mg twice daily, gradually increased to
100 mg every 12 hours.

Rapidly after starting midostaurin, the patient experienced a
considerable improvement of general condition, clinical symptoms and
body weight. After 3 months of midostaurin therapy, a bone marrow biopsy
highlighted the reduction of MC infiltration to 30-40\%, lymphadenopathy
decreased to a diameter of 27 mm, hepatic and splenic diameter were 22
and 13 cm. Serum tryptase was 26 ng/ml. Unfortunately, the CT scan
allowed to incidentally diagnose a subclinical pulmonary embolism of a
segmental artery in the superior left lobe. Pulmonary embolism is
reported among adverse events during midostaurin treatment, therefore we
stopped the TKI treatment and start anticoagulant therapy. Midostaurin
was safely resumed one month later; evaluation at 6 month showed only
10\% of MC in the bone marrow biopsy and further reduction of
lymphadenopathy to a maximum diameter of 22 mm. \textbf{Figure 1}
and\textbf{2} respectively show the reduction of bone marrow MCs
infiltrate and organomegaly over time.

Today the patient is still on midostaurin 100 mg bid, completely
asymptomatic and with good tolerance to the therapy. A human leukocyte
antigen typing was performed, but allogeneic stem cell transplant isn't
currently taken consideration. At the last assessment (February 2020)
maximum diameter of abdominal lymphadenopathy and spleen were 1.5 and 13
cm, serum tryptase level was 27 ng/ml and bone marrow MCs have
stabilized on 10\% of the global cellularity. The response was
classified as partial according to Gotlib et al. {[}11{]}

For the clinical management of a SM patient the most relevant questions
are whether the patient has or develops advanced SM and what treatment
can be applied. Although the risk is relatively low, patients with ISM
may progress to ASM, SM-AHNMD or MCL. {[}1-5{]}

Here, we report the gradual evolution of a SSM case in ASM, conditioning
hepatomegaly with impairment of liver function and ascites, splenomegaly
and abdominal lymphoadenopathy with ileal dislocation.

According to the current guidelines, ISM therapy is generally focused on
symptom relief. {[}3,4{]} All patients should be advised to avoid any
potential triggers (food, drinks, drugs) that may provoke MCs
activation. High risk patients are advised to carry epinephrine
self-injector-pens. Treatment options include histamine H1/H2-blockers,
sodium cromolyn, leukotriene inhibitors, topical agents, aspirin,
ketotifen, omalizumab, corticosteroids and MC cytoreductive therapy only
in severe/refractory cases. {[}3,4{]} In our case, during the smoldering
phase, the patient received H1-H2 histamine receptor blockers and sodium
cromolyn for itching and diarrhea obtaining a good control.

When an aggressive phase was diagnosed, considering the burden of the
disease and the absence of comorbidities, we decided to offer a
cytoreductive treatment with cladribine. MC reducing therapy is
indicated in advanced SM to prevent further organ damage, extend
survival, often at the expense of significant side effects. {[}6,7{]}
Cladribine was one of the first agent used for symptom relief and rapid
MC debulking, with a demonstrated therapeutic activity in all SM
subtypes and an overall response rate (ORR) of 50-60\%. {[}6,7{]}
Myelosuppression and lymphopenia are the most frequent adverse events.
{[}6,7{]} In our case cladribine was well tolerated without grade 3/4
toxicities. With the advent of \emph{KIT} -targeted TKIs, the use of
cytoreductive therapy has declined. {[}3,4{]} The multikinase inhibitor
midostaurin is currently approved for patients with advanced SM. In this
population it demonstrated a 60\% ORR and a good tolerability with few
reported adverse events apart from hematological toxicity, nausea, vomit
and diarrhea. {[}8{]}

Our patient received midostaurin after failure of first-line therapy
with cladribine. Midostaurin lead to a significant improvement of
organomegaly, liver function and body weight; moreover a substantial
reduction in MC burden and mediator-related symptoms were observed,
translating into a significant amelioration of patient's life quality.
This treatment is still ongoing, with almost 2 years of therapy,
allowing to obtain and keep a partial response.

In conclusion, mastocytosis is a rare disease with a complex biology and
an unpredictable clinical course. The diagnosis and management of MC
neoplasms is an emerging challenge and requires vast knowledge, a
multidisciplinary diagnostic approach and personalized treatment
strategy.

\textbf{Disclosure Statement} : FIG received compensation by Novartis as
expert testimony and as a member of advisory board. The remaining
authors declare no conflict of interest.

\textbf{Author Contribution} : MS, FS, MCG, GNS, GG, LB, FO and FIG
provided the patient data regarding the hematological disease; MS, FS
and FIG wrote the manuscript; SM, VP and FMU provided patient data for
what concerns dermatological, allergological and rheumatological
aspects; GAC performed the histological examinations of bone marrow,
provided iconographic materials, interpreted these data and integrated
them in the manuscript; ACM revised patient peripheral blood smears; AE
provided radiological iconographic material. All authors critically read
and approved the final manuscript.

\textbf{References}

Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World
Health Organization classification of myeloid neoplasms and acute
leukemia. Blood 2016;127(20):2391-2405.

2 Horny HP, Metcalfe DD, Akin C, et al. Mastocytosis. In: Swerdlow SH et
al., eds. WHO Classification of Tumors of Hematopoietic and Lymphoid
Tissues. Lyon, France: International Agency for Research and Cancer
(IARC); 2017:62-69.

3 Pardanani A. Systemic mastocytosis in adults: 2019 update on
diagnosis, risk stratification and management. Am J Hematol
2019;94(3):363-377.

4 Scherber RM, Borate U. How we diagnose and treat systemic mastocytosis
in adults. Br J Haematol 2018;180(1):11-23.

5 Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342
consecutive adults: survival studies and prognostic factors. Blood 2009;
113:5727-5736.

6 Lim KH, Pardanani A, Butterfield JH, Li CY, Tefferi A. Cytoreductive
therapy in 108 adults with systemic mastocytosis: outcome analysis and
response prediction during treatment with interferon-alpha, hydroxyurea,
imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol
2009;84:790-794.

7 Barete S, Lortholary O, Damaj G, et al. Long-term efficacy and safety
of cladribine (2-CdA) in adult patients with mastocytosis. Blood
2015;126:1009-1016.

8 Ustun C, Gotlib J, Popat U, et al. Consensus opinion on allogeneic
hematopoietic cell transplantation in advanced systemic mastocytosis.
Biol Blood Marrow Transplant 2016;22:1348-1356.

9 Chandesris MO, Damaj G, Canioni D, et al. Midostaurin in advanced
systemic mastocytosis. N Engl J Med 2016;374(26):2605-2607.

10 Escribano L, Alvarez-Twose I, S\selectlanguage{ngerman}ánchez-Muñoz L, et al. Prognosis in
adult indolent systemic mastocytosis: A long-term study of the Spanish
Network on Mastocytosis in a series of 145 patients. J Allergy Clin
Immunol 2009; 124, 514--521.

11 Gotlib J,~Pardanani A,~Akin C, et al. International Working
Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) \&
European Competence Network on Mastocytosis (ECNM) consensus response
criteria in advanced systemic mastocytosis. Blood 2013;
121(13):2393-401.\selectlanguage{english}
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