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\begin{document}

\title{High-dose continuous infusion ifosfamide in the treatment of bone marrow
infiltration with severe thrombocytopenia in a patient with Ewing
sarcoma: a case report}



\author[1]{Fabio Murtas}%
\author[1]{Benedetta Chiusole}%
\author[1]{Ilaria Tortorelli}%
\author[1]{Silvia Finotto}%
\author[1]{Marta Burei}%
\author[1]{Marina Coppola}%
\author[1]{Antonella Galiano}%
\author[1]{Maital Bolshinsky}%
\author[2]{Elena Bellan}%
\author[2]{Marta Sbaraglia}%
\author[2]{Angelo Paolo Dei Tos}%
\author[1]{Antonella  Brunello}%
\affil[1]{Istituto Oncologico Veneto IRCCS}%
\affil[2]{Azienda Ospedale Universita Padova}%


\vspace{-1em}



  
  \date{May 29, 2024}


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\selectlanguage{english}
\begin{abstract}
Ewing sarcoma is a rare primary mesenchymal tumor of the bone that
requires an intensive multimodal therapeutic approach. Multidrug
chemotherapy regimens are also the backbone for relapsing/recurring
Ewing sarcoma treatment, yet when relapse occurs as bone marrow
infiltration, combination chemotherapy might be difficult to be
administered and prognosis is poor. This report describes the case of a
22-year-old patient with Ewing sarcoma who developed severe pancytopenia
due to bone marrow infiltration, who was treated with high-dose
continuous infusion ifosfamide, obtaining both clinical, radiological
and hematological response lasting for about 7 months.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Ewing sarcoma is the third most common bone sarcoma and the second most
common malignant bone tumor in children and young adults, with an
incidence of 0.1/100 000/year and a median age at diagnosis of 15 years.
Most cases arise in the extremities, but axial skeleton and soft tissue
origin are possible. {[}1{]} Histological diagnosis is supported by the
detection of specific gene translocations, generally resulting in
EWSR1-FLI1 fusion (EWS-RNA binding protein 1 - Friend leukemia
integration 1 transcription factor) or, more rarely, in other ETS genes
(Erythroblast Transformation-Specific) such as EWSR1-ERG fusion (ETS
Related Gene). {[}2{]} With the introduction of multiagent perioperative
chemotherapy, including vincristine, doxorubicin, cyclophosphamide,
ifosfamide and etoposide, 5-year OS increased to 65-70\% in localized
disease. {[}1{]} About 25\% of patients present at diagnosis with
advanced disease at diagnosis: most frequently involved sites are lung,
bone and bone marrow. For this reason, an accurate skeletal staging with
positron emission tomography (PET-CT) is mandatory and, in doubt cases,
it must be completed with bone marrow biopsy and aspirate. {[}3{]}
Five-year overall survival in patients with metastatic disease ranges
from 20 to 40\% according to metastases site, with bone localizations
conferring a poorer prognosis. {[}4{]}

Moreover, Ewing sarcoma recurrence with bone marrow involvement has been
associated with very poor survival and unavoidable fatal outcome, in
contrast to patients with multiple bone metastases but no marrow
involvement {[}5{]}. High-dose ifosfamide has been recently demonstrated
to be highly effective on recurrent disease, with other active regimens
being cyclophosphamide and topotecan, temozolomide and irinotecan, and
gemcitabine and docetaxel. {[}6{]} Here we present the case of a young
male patient affected by extremity Ewing sarcoma recurring with bone
marrow infiltration causing severe pancytopenia 15 months after the end
of adjuvant chemotherapy.

\textbf{CASE REPORT}

In April 2019, a 22 year old male with no past medical history presented
with increasing pain in the right pelvis and inferior limb. Pain was at
first managed by his general practitioner with nonsteroidal
anti-inflammatory drugs (NSAIDs) and steroids with no clear clinical
benefit. In February 2020, a magnetic resonance (MRI) of right hip bone
was performed, which detected a 9cm lesion extended from the femoral
head to the bone neck, hyperintense on T2-weighted images suggesting
intraspongious edema. A computed-tomography (CT) scan subsequently
performed confirmed the presence of a vast, irregular osteolytic area
and a hyperdense tissue in the great trochanter region, with a maximum
depth of 15mm. In March 2020, a biopsy of the osteolytic area was
performed: the histological specimen showed a proliferation of
undifferentiated, small round cell positive for CD99, FLI1, vimentin and
focal CD56, suggestive of Ewing sarcoma. The molecular analysis
confirmed the presence of EWSR1-ERG rearrangement (21q22.2). Staging
chest and abdomen CT and PET-CT scan did not detect any distant
metastases; right femur head, neck, intertrochanteric region and
proximal diaphysis showed a pathological hypermetabolism (SUV max 7.16),
but bone marrow fine needle aspiration was negative for neoplastic
cells. From April to June 2020, patient received four courses of
induction chemotherapy: two cycles of vincristine, doxorubicin and
cyclophosphamide (VDC), one cycle of vincristine, actinomycin-D and
ifosfamide (VAI) and one cycle of etoposide and ifosfamide (IE). The
following radiological assessment (chest, abdomen and right inferior
limb CT scan and right hip MRI) showed disease stability. In July 2020,
patient underwent surgical resection of right femur and global modular
replacement system prosthesis implant. Pathological response was good,
although not complete, with a 95\% necrosis rate and 5\% of residual
sarcomatous cells. Between August 2020 and March 2021, the patient
received adjuvant chemotherapy: 3 cycles of VDC, 3 cycles of VAI and 3
cycles of IE. Afterwards, follow up was started with trimestral chest,
abdomen and right inferior limb CT scan and blood tests. Radiological
assessments didn't detect any signs of disease relapse; blood samples
showed persistently stable G2 neutropenia, G1 anemia and G1
lymphocytopenia, consistent with recent chemotherapy. The patient
experienced slowly increasing pain at his right thigh, refractory to
analgesics and opioids. After one year, in August 2022, blood tests
showed pancytopenia, with neutropenia G1 (N 1750 /mm3), lymphocytopenia
G1 (LYMPH 0.97/mm3), thrombocytopenia G2 (PLT 74000/mm3) and anemia G1
(11.4 g/dl). Lactate dehydrogenase (655 U/L) and ferritin (1505 ug/l)
levels were increased. Peripheral blood smear identified the presence of
immature cells (myelocytes 4\%, metamyelocytes 0.5\%). Lymphocytes flow
cytometry analysis, vitamin B12, protein electrophoresis, alkaline
phosphatase, renal and hepatic function were preserved. At this time,
MRI of right inferior limb displayed intraspongious edema of iliopubic
branch, CT scan was persistently negative. No signs of recent bleeding
were objectifiable. A bone marrow fine needle aspiration and a biopsy
were then performed. The myelogram showed the presence of big,
pleomorphic non hematopoietic cells. Ewing sarcoma bone marrow relapse
was confirmed by the biopsy, where most bone marrow space was occupied
by a high-grade neoplasm composed of small round cells, arranged in
sheets, characterized by monotonous nuclear appearance and scant
cytoplasm with focal areas of cytoplasmic clearing. Brisk mitotic
activity, areas of hemorrhage and necrosis were present throughout the
biopsy specimen. By immunohistochemistry, the neoplastic cells showed
strong crisp membranous CD99 immunostaining and diffuse NKX2.2 nuclear
immunopositivity. Conversely, terminal deoxynucleotidyl transferase
(TdT), desmin and myogenin (Myf4) were negative. {[}Figure 1{]} A PET-CT
was then performed, showing an intense bone marrow glucidic
hypermetabolism in spine, scapulae, sternum, ribs, hipbone, humeri and
femurs. At the end of August 2022 blood cell counts rapidly dropped (in
particular, Hb 8 g/dL, PLT 33.000/mm3). Given the low blood cell counts
which contraindicated standard polychemotherapy regimens, we decided to
start first line chemotherapy with high dose ifosfamide at the dose of
1g/m2 per day, administered as a continuous infusion over 14 days,
followed by a 14 days pause. The first course of such chemotherapy was
started on August 24, 2022, with a 50\% precautionary dose-reduction
(total dose: 7 g/m2 over 2 weeks). A strict, daily monitoring of blood
count was performed both during infusion and in the 2 weeks off;
toxicity nadir was reached on day 17, with anemia G3 (7.3 g/dl) and
thrombocytopenia G4 (PLT 21000 /mm3). Persistent hematological toxicity
required one platelet and multiple red blood cells transfusions. At the
beginning of the second course, blood counts improved with neutrophil
count back to normal, improved hemoglobin (10.3 g/dl) and lymphocyte
count (0.82 /mm3) but persisting severe thrombocytopenia (32000 /mm3).
Following the second course, administered at the same reduced dose,
platelet count started to slowly increase; no platelet and less red
blood cell transfusions were needed. On the third cycle,
thrombocytopenia was restored to G1 level (85000 /mm3), and chemotherapy
dosage was increased to 80\% (total dose 11 g/m2), with a good
hematological and subjective tolerance. {[}Figure 2{]} After three
cycles, PET-CT scan showed metabolic response. {[}Figure 3{]} Due to the
persistently improved blood tests, and the normalization of platelet
count, chemotherapy was prosecuted at full dose for three more cycles.
Metabolic and hematological responses were associated with clinical
benefit on pain and deambulation. In February 2023, after six total
courses of high-dose ifosfamide, PET-CT showed progressive bone marrow
disease and once again blood tests abruptly dropped, with G3
neutropenia, G2 lymphocytopenia, G1 anemia and G1 thrombocytopenia.
Moreover, the patient developed vision problems, hyposthenia and
hypoesthesia of lower limbs, and a brain MRI demonstrated a diffuse
meningeal invasion. In March 2023, a new line of chemotherapy with
Irinotecan and Temozolomide was started. Although it was administered at
a reduced dose, therapy was complicated by persistent neutropenia G3
needing frequent treatment delays and dose adjustments. In July 2023,
the patient was hospitalized due to paraparesis, acute urinary retention
and pain; a CT scan confirmed new bone progression. He received
palliative radiotherapy on painful sites and was started on oral
etoposide with only minor benefits. Palliative care team was then
involved, and the patient died two months later at home.

\textbf{DISCUSSION}

Thrombocytopenia is a frequent event in oncological patients. According
to Common terminology criteria for adverse events (CTCAE) v5.0, it is
defined as a decrease in number of platelets in a blood specimen, and 4
severity categories are recognized: grade 1 for counts ranging between
the upper normal level and 75 \selectlanguage{ngerman}×\selectlanguage{english} 10\^{}9/L, grade 2 between 75 and
50\selectlanguage{english} x\selectlanguage{english} 10\^{}9/L, grade 3 between 50 and 25\selectlanguage{english} x\selectlanguage{english} 10\^{}9/L and grade 4 under
25\selectlanguage{english} x\selectlanguage{english} 10\^{}9/L. {[}7{]}

Its incidence is estimated to range from 10\% to 68\%, according to
different studies. {[}8{]} About 21\% of patients with hematologic
malignancies and up to 6\% of patients with solid tumors present
thrombocytopenia before chemotherapy. The most frequently associated
histotypes are acute leukemia (37.3\%) and multiple myeloma (24.4\%);
among solid tumors, melanoma (21.4\%), ovarian (14.7\%) and lung
(14.3\%) cancer. After three months of chemotherapy, the reported
incidence rates increase to 28.2\% and 12.8\% for hematological and
solid neoplasms, respectively. {[}9{]}

Chemotherapy has a well-known impact on platelet and other blood cell
counts, through an acute damage and apoptosis of hematopoietic cells.
{[}10{]} Acute thrombocytopenia generally occurs within 10 days from the
infusion and is of short duration due to the bone marrow replication
reserve. {[}11{]} A long term bone marrow injury may occur when
chemotherapy inhibits the self-renewal potential of hematopoietic stem
cells, causing their senescence. {[}12, 13{]} Moreover, chemotherapy
drugs may interfere with the hematopoietic microenvironment, resulting
in bone marrow loss and adipogenic differentiation of stem cells.
{[}14{]}

Gemcitabine is associated with the highest risk of thrombocytopenia,
followed by platinum-based regimens; on the opposite, anthracyclines and
taxanes have lower rates. {[}9, 15, 16{]} High dose ifosfamide has a
well-known hematological toxicity, with a grade 3-4 thrombocytopenia
occurrence rate of almost 30\% in some studies {[}17{]} A recent study
has also showed that a low platelet count was significantly associated
with ifosfamide and etoposide chemotherapy in Ewing sarcoma patients.
{[}18{]}

While most cases are asymptomatic, a decrease in platelet count may lead
to minor and major bleeding, especially when platelet counts drop to
grade 2 and lower. A study by Elting and colleagues demonstrated how
bleeding episodes complicated 9\% of chemotherapy cycles in patients
with a history of previous bleeding and who had baseline platelet count
lower than 75000/mm3, bone marrow metastases or poor performance status.
{[}19{]}

No clear guidelines on management of patients with bone marrow
infiltration are available: most data are obtained by case reports or
small retrospective studies of patients treated with different
cytotoxics according to histology, with a great heterogeneity on
outcomes. A French retrospective study showed the efficacy and
feasibility of weekly, low dose paclitaxel in 26 patients with breast
cancer BMI. {[}20{]} Similarly, analogous cases of breast cancer BMI
have been successfully treated with continuous infusion doxorubicin
{[}21{]} or weekly nab-paclitaxel {[}22{]}. On the other hand, a patient
with neuroblastoma did not derive any benefit from combination therapy
of standard dose topotecan and cyclophosphamide {[}23{]}.

Among mesenchymal tumors, Ewing sarcoma and pediatric rhabdomyosarcoma
BMI is not uncommon {[}24-25{]}; more rarely, bone marrow infiltration
from other histologic subtypes like angiosarcoma {[}26{]}, epithelioid
sarcoma {[}27{]}~and follicular dendritic cell sarcoma {[}28{]} has been
reported. Given the aggressiveness of such sarcoma subtypes, most cases
were treated with high dose, multidrug regimens with poor responses and
severe hematological toxicity, often fatal. {[}29{]} Of note, one
patient with alveolar rhabdomyosarcoma treated with schedule-adapted
VDC/IE had an optimal response with 15-months PFS {[}30{]} Chemotherapy,
acting on the very first cause of thrombocytopenia, surely has a leading
role in the treatment of bone marrow infiltration. All the reported
successful cases have in common the administration of low dose,
continuous infusion or weekly fractionated chemotherapy regimens, with
the aim of reducing the negative impact on hematopoietic bone marrow
cells.

To our knowledge, this is the first described case of management of bone
marrow infiltration from Ewing sarcoma presenting with severe
thrombocytopenia successfully managed with low-dose continuous infusion
ifosfamide, providing almost 7 months of progression-free survival.

Such results are highly clinically significant, considering the poor
prognosis of relapsed Ewing sarcoma, and might be of help when
decision-making is required in this setting.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}\selectlanguage{english}
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\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Figure 1.} H\&E bone marrow biopsy showing extensive
infiltration by Ewing sarcoma. Small round cells with scant cytoplasm
arranged in sheets fill the marrow space (1A and 1B). Strong membranous
CD99 (1C) and diffused NKX2.2 (1D) immunopositivity.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Figure 2.} Platelet and hemoglobin levels during treatment with
HD-ifosfamide and required transfusions. Blood tests progressively
improved during treatment, until progression after cycle 6 when platelet
count abruptly dropped.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image7/image7}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image8/image8}

\end{center}
\end{figure}

\textbf{Figure 3.} PET-CT performed before (a) and after (b) three
cycles of HD-ifosfamide, showing metabolic response to treatment on bone
marrow infiltration.

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