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\begin{document}

\title{Treatment practices and response in Kaposiform hemangioendothelioma: a
multi-center cohort study}



\author[1]{Alexandra Borst}%
\author[2]{Whitney Eng}%
\author[2]{Morgan Griffin}%
\author[3]{Kiersten Ricci}%
\author[3]{Elissa Engel}%
\author[1]{Denise Adams}%
\author[1]{Jillian Dayneka}%
\author[4]{Sally J. Cohen-Cutler}%
\author[5]{Steven M. Andreoli}%
\author[6]{Melinda D. Wu}%
\author[7]{Allison P. Wheeler}%
\author[8]{Kenneth Heym}%
\author[9]{Shelley Crary}%
\author[10]{Taizo Nakano}%
\author[11]{Rachael  Schulte}%
\author[12]{Bhuvana Setty}%
\author[13]{Thomas McLean}%
\author[14]{Kristy S. Pahl}%
\author[15]{Stefanos Intzes}%
\author[16]{Irina Pateva}%
\author[17]{Max Teitelbaum}%
\author[1]{Zili Zong}%
\author[1]{Yimei Li}%
\author[18]{Michael Jeng}%
\affil[1]{The Children's Hospital of Philadelphia}%
\affil[2]{Dana-Farber/Boston Children's Cancer and Blood Disorders Center}%
\affil[3]{Cincinnati Children's Hospital Medical Center}%
\affil[4]{Children's Hospital Los Angeles}%
\affil[5]{Nemours Children's Specialty Care Jacksonville}%
\affil[6]{Oregon Health \& Science University Doernbecher Children's Hospital}%
\affil[7]{Monroe Carell Junior Children's Hospital at Vanderbilt}%
\affil[8]{Cook Children's Medical Center}%
\affil[9]{Arkansas Children's Hospital}%
\affil[10]{Children's Hospital Colorado}%
\affil[11]{Riley Children's Foundation}%
\affil[12]{Nationwide Children's Hospital}%
\affil[13]{Atrium Health Wake Forest Baptist}%
\affil[14]{Duke Children's Hospital and Health Center}%
\affil[15]{Providence Sacred Heart Medical Center}%
\affil[16]{University Hospitals Rainbow Babies \& Children's Hospital}%
\affil[17]{Byram Hills High School}%
\affil[18]{Lucile Salter Packard Children's Hospital at Stanford General Pediatrics}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\selectlanguage{english}
\begin{abstract}
Background and Objectives: Kaposiform hemangioendothelioma (KHE) and
tufted angioma (TA) are rare vascular tumors in children historically
associated with significant morbidity and mortality. This study was
conducted to determine first line therapy in the absence of available
prospective clinical trials. Methods: Patients from 17 institutions
diagnosed with KHE/TA between 2005-2020 with \textgreater{} 6 months
follow-up were included. Response rates to sirolimus and vincristine
were compared at 3 and 6 months. Durability of response and response to
other treatment modalities were also evaluated. Results: Of 159 unique
KHE/TA subjects, Kasabach-Merritt phenomenon (KMP) was present in 64
(40.3\%) and only 2 patients were deceased (1.3\%). Over 60\% (n=96)
demonstrated treatment response at 3 months and \textgreater{}70\%
(n=114) by 6 months (no significant difference across groups). The
vincristine group had higher radiologic response at 3 months compared to
sirolimus (72.7\% vs 20\%, p=0.03) but there was no differences between
these groups at 6 months. There were no differences in rates of
recurrent or progressive disease between vincristine and sirolimus.
Conclusions: In this large, multicenter cohort of 159 patients with
KHE/TA, rates of KMP were consistent with historical literature but the
mortality rate (1.3\%) was much lower. Overall treatment response rates
were high (\textgreater{}70\%) and there were no significant difference
in treatment response or durability of disease comparing sirolimus to
vincristine. Our results support individualized treatment decision plans
depending on clinical scenario and patient/physician preferences.
Response criteria and response rates reported here will be useful for
guiding future treatment protocols for vascular tumors.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare
vascular tumors that primarily present in young children and are
considered locally aggressive or borderline malignant
tumors.\textsuperscript{1,2} TA and KHE may be a continuum of one
disease as they both share histologic features and key to their
pathophysiology is disrupted vasculogenesis and abnormal endothelial
cell proliferation.\textsuperscript{3,4} KHE/TA are uniquely associated
with Kasabach Merritt Phenomenon (KMP), which manifests as
thrombocytopenia and a consumptive coagulopathy (hypofibrinogenemia and
elevated d-Dimer), with variable bleeding\textsuperscript{5--7}. KMP is
considered a risk factor for severe KHE/TA and has a historical
mortality rate of 20-30\%\textsuperscript{5--8}. Apart from the known
risks with KMP, a validated risk stratification in KHE/TA has not been
established\textsuperscript{3,9}.

KHE and TA tumors rarely completely resolve, and full surgical resection
is typically not possible given the infiltrative nature of this tumor.
More than half of patients experience recurrence of symptoms or KMP
after cessation of therapy.\textsuperscript{10--14} Front-line medical
therapy for KHE/TA is not standardized, but steroids, vincristine, and
sirolimus are the most commonly used systemic
medications.\textsuperscript{4,15} The optimal therapy (ies), schedule,
dosing, and duration of treatment are
unknown\textsuperscript{10,11,16--27}. Experts have proposed either
vincristine and steroids or sirolimus as standard
treatment\textsuperscript{4,28}. A multi-center, prospective, randomized
trial (NCT02110069) was recently undertaken to determine optimal
front-line therapy (sirolimus vs vincristine) for high risk KHE/TA but
closed early due to poor enrollment. Future prospective studies will
likely be limited by disease rarity as well as the availability of
sirolimus as a highly efficacious oral agent. It is unlikely that
prospective data will be generated to establish a standard optimal
treatment and to determine durability of response to treatment.

This study was designed and conducted to address these existing gaps in
knowledge about treatment for KHE/TA. The primary objective of this
multicenter retrospective cohort study was to compare 3-month and
6-month response rates to sirolimus versus vincristine. Secondary
objectives included comparison of other treatment regimens and
assessment of durability of treatment response.

\textbf{Methods}

\emph{Cohort}

Members of the American Society of Pediatric Hematology/Oncology (ASPHO)
Vascular Anomalies Special Interest Group (VA SIG) were invited to
participate by submitting clinical data of patients diagnosed with
KHE/TA between January 2005 and January 2020 with at least 6 months of
follow-up. Subjects who died within 6 months of diagnosis and met all
other eligibility criteria were included. This study was IRB approved at
each local institution, and patient clinical and treatment information
was collected securely in a REDCap database.\textsuperscript{29} Data
from each center, excluding protected health information, were
adjudicated by Drs. Borst, Jeng, and Adams and sent to the coordinating
center for analysis.

\emph{Definitions}

Clinical: Kasabach-Merritt phenomenon (KMP) was defined strictly as
severe thrombocytopenia with a platelet count [?] 50,000/uL at diagnosis
or prior to systemic medical therapy. Coagulopathy was defined less
strictly and could include hypofibrinogenemia with a fibrinogen
\textless{} 150mg/dL and/or D-dimer \textgreater{} 2 times the upper
limit of normal at diagnosis or prior to systemic medical therapy.

Therapy: Treatment groups included: sirolimus (Siro), vincristine (VCR),
Siro and VCR together (Siro+VCR), steroids only, and a minimal treatment
group that received either beta-blocker, aspirin, or no medical therapy.
Treatment groups were determined by the primary agent started within the
first 30 days following treatment initiation. Patients in the Siro, VCR,
or Siro+VCR categories were allowed to have also received steroids, but
the primary drug therapy must have been initiated less than 30 days
after steroids. Patients in the Steroid treatment group did not receive
additional therapies. Patients in the Siro+VCR group received both drugs
up-front within the 30 days. Patients included in the
surgery/interventional radiology (IR) group had either surgical
resection or IR embolization as their initial primary mode of treatment,
even if they received medical therapy later in their course.

Response: Time to response was determined by number of days since first
systemic therapy was initiated. For patients who received no systemic
medical therapy, time to response was determined as the time from
diagnosis or surgical intervention. Responses were categorized as
subjective clinical response (ClinR), radiologic response (RadR), and
hematologic response (HemR; in patients with KMP only). ClinR was
defined as resolution of symptoms related to tumor, functional deficit,
or decrease in size of tumor by visual inspection, even if not a
complete response. RadR was defined as any measurable decrease in tumor
size on radiographic imaging. If tumor measurements were available, the
RECIST criteria for partial response could be used\textsuperscript{30}.
HemR in patients with KMP was defined as a platelet count \textgreater{}
100,000/\selectlanguage{greek}μ\selectlanguage{english}l x 2 consecutive lab measurements without transfusion.
Durability of response was determined as time from first response to
recurrent disease. Time from diagnosis and treatment initiation to
persistent disease or progressive disease were also measured.
Progressive disease was defined as any clinically significant increase
in volume of tumor by history, exam, or radiologic imaging, worsening or
persistence of KMP, or clinically significant worsening of pain or
functional status as determined by treatment team. Investigators
reported their criteria in determining recurrent, persistent, or
progressive disease when applicable.

\emph{Statistical analysis}

Data were analyzed with the support of two biostatisticians (ZZ and YL)
at the Children's Hospital of Philadelphia. Demographic and clinical
characteristics were summarized for the overall cohort and by presence
or absence of KMP using descriptive statistics. Outcome variables
including response rates (e.g., objective hematologic response at 3
months), durability of response (e.g., time to persistent disease from
objective hematologic response), and adverse events were summarized
overall and by treatment groups. For group (either KMP or treatment
groups) comparisons, Wilcoxon rank sum test was used for continuous
variables and Fisher's exact test was used for categorical variables.
All analyses were performed in R 3.6.3 and a two-sided p-value
\textless{} 0.05 was considered statistically significant.

\textbf{Results}

\emph{Demographic and Clinical Characteristics of Patients with KHE and
TA}

Investigators from 17 institutions submitted data on 179 patients and
159 met full eligibility criteria after central review (Table 1). Of the
159 patients, 138 (86.8\%) carried a diagnosis of KHE, 18 (11.3\%) TA,
and 3 (1.9\%) diagnosed with a combined KHE/TA spectrum. Gender, race,
and ethnicity were equivalent across groups. Sixty-four patients
(40.3\%) had KMP at presentation. Patients with KMP were diagnosed (49.5
versus 293 days, p\textless{}0.001) and started treatment (48 versus 300
days, p\textless{}0.001) at a younger age than those without KMP. Biopsy
for pathologic diagnosis was more common in those without KMP compared
to those with KMP (91.6\% versus 71.9\%, p=0.002). Non-truncal lesions
were the most common location in all groups, but more common in those
without KMP (65.3\% versus 50\%, p=0.029). Tumor size was larger in the
individuals with KMP, and tumors associated with KMP were more likely to
involve more than one anatomic body area. Only 2 patients (1.3\%) were
described to have multifocal tumors. Some patients without KMP were
determined to have coagulopathy (fibrinogen \textless{} 150mg/dL and/or
D-dimer \textgreater{} 2 times the upper limit of normal) at diagnosis,
but this was more common in the those with KMP (79.7\% versus 14.7\%,
p\textless{}0.001). Number of hospitalizations, hospital length of stay,
and ICU length of stay were all higher for individual with KMP (all
p\textless{}0.001). Only 2 patients (1.3\%) in the cohort were deceased
and both had KMP, large tumors ([?] 5cm in size), and had tumor extension
across more than one body region. As expected, hematologic parameters
were more abnormal in patients with KMP, with lower hemoglobin nadir,
lower platelet count nadir, lower fibrinogen nadir, and higher maximum
prothrombin time and partial thromboplastin time (all p\textless{}0.001,
Supplemental Table 1).

\emph{Treatment Regimens}

The majority of patients (n=136, 85.5\%) received systemic medical
therapy (Table 2) and systemic therapy was more common in patients with
KMP versus those without KMP (95.3\% vs. 70\%, p=0.05). Siro was the
most common treatment (n=51, 32.1\%), followed by steroids (n=32,
20.1\%), beta-blocker or minimal/none (n=27, 17\%), VCR (n=25, 15.7\%),
surgical/interventional radiology (IR) (n=17, 10.7\%), and Siro+VCR
(n=7, 4.4\%). Time from initial symptoms to treatment initiation (16 vs
169 days, p\textless{}0.001) and time from diagnosis to treatment
initiation (3 vs. 21 days, p \textless{}0.001) were both shorter for
patients with KMP compared to those without KMP. Patients with KMP
received more blood product transfusions (78.1\% vs 6.3\%,
p\textless{}0.001) and more opioid medication use (29.7\% vs. 14.7\%,
p=0.028). Attempts at surgical procedures or IR embolization were
equivalent across groups (p=0.2).

\emph{Rationale for Therapy}

The most common indications for initiating therapy included extent of
disease (n=87, 54.7\%), coagulopathy (n=65, 40.9\%), pain (n=61,
38.4\%), and thrombocytopenia (n=59, 37.1\%). Reported range for
thrombocytopenia for patients starting medical therapy for this
indication was 3,000-107,000/uL. Patients with KMP were more likely to
have initiated therapy for coagulopathy, anemia, thrombocytopenia,
cardiac dysfunction, and airway compression (Table 2). Pain and cosmesis
were more likely to prompt therapy initiation for patients without KMP.
Other reasons for treatment initiation included avoidance of
scarring/contracture, rapid tumor growth, coagulopathy, functional
impairment, hypertension (compression of renal vasculature), high
output-cardiac failure, airway involvement, proximity to critical
structures, and pleural and pericardial effusions.

\emph{Treatment Response}

Of patients determined to be evaluable for response, 85.7\% (96/112)
demonstrated a treatment response at 3 months and 89.1\% (114/128) by 6
months. The vincristine treatment group had higher RadR at 3 months
compared to sirolimus (72.7\% vs 20\%, p=0.03), but equal at 6 months
(76.9\% vs 68\%, p=0.7). There were no other significant differences in
overall response, HemR, or ClinR between the sirolimus and vincristine
groups at 3 or 6 months (Table 3). Similarly, there were no significant
differences in overall response, RadR, HemR, or ClinR across all
treatment groups (Supplemental Table 2) except RadR in the surgical
resection group at 3 months only.

Based on previously published data showing improved outcomes in patients
with KHE treated with combination of sirolimus and steroids versus
sirolimus alone, we also compared these groups in our cohort (Table
4).\textsuperscript{31} Small patient numbers precluded statistical
comparisons, but 11 of 15 (73.3\%) patients who received sirolimus plus
steroid had response by 3 months compared to only 1 of 4 (25\%) patients
who received sirolimus. Treatment responses were not significantly
different amongst those who received sirolimus and steroid in comparison
to those who received vincristine and steroid.

\emph{Treatment Durability}

\emph{Recurrent and Progressive Disease:}

There were no differences in rates of recurrent or progressive disease
at 3 and 6 months between the Siro and VCR treatment groups (Table 5).
Time to recurrent or progressive disease from start of therapy or from
initial treatment response were also equivalent between vincristine and
sirolimus. Comparing all treatment groups (Supplemental Table 3), the
rate of recurrent disease at 3 months was higher in patients treated
with steroids alone (p=0.042), but across all treatment groups, there
was no difference in rates of recurrent or progressive disease at 6
months. Although not statistically different from other groups, it was
notable that of the 17 patients treated with surgery or IR embolization,
100\% had a treatment response by 3 months, but five (29.4\%) had
recurrent disease within 6 months requiring initiation of systemic
medical therapy.

\emph{Persistent Disease:}

Given the chronic nature of KHE/TA, we also tried to define disease
persistence in response to therapy (Supplemental Table 3). We found that
rates of persistent disease at 3 months (28.6\%, p=0.024) were higher in
patients receiving a combination of Siro+VCR compared to those receiving
steroids alone (and a significantly higher proportion of patients in the
Siro+VCR group required continuation of therapy at 3 months for
persistent disease (71.4\%, p\textless{}0.001). However, by 6 months,
rates of persistent disease were equivalent across groups.

When looking at just the VCR and Siro groups (Table 5), a higher
proportion of patients in the Siro group were reported to require
continuation of therapy at 3 months for persistent disease (27.5\% vs.
0\%, p=0.003). However, of the VCR group, 22/25 (88\%) received
adjunctive therapy including 9 (36\%) who had Siro added to their
regimen and time to initiation of Siro ranged from 29 days to 863 days.
Rationale for adding Siro included severity of disease in 5 patients,
VCR toxicity in 2 patients (hoarse cry, neutropenia), and loss of
central venous access in 2 patients. In the sub-analysis of sirolimus or
vincristine treatment with or without steroid use (Table 6), more
patients had persistent disease in the two vincristine groups, but small
numbers precluded statistical comparison. It was notable that in the VCR
+ steroid group, 9/19 (47.4\%) patients had Siro added to their
treatment regimen later.

\emph{Adverse Events}

Adverse events evaluated in the cohort included multi-organ failure,
serious infection, and significant bleeding (Supplemental Table 4).
Rates of multi-organ failure and significant bleeding were low across
all treatment groups, except combined Siro+VCR treatment group
(p=0.002). Infection rates were increased in the vincristine only group
compared to sirolimus (24\% vs 11.8\%, p=0.033). Other adverse events
included ptosis secondary to vincristine in 2 patients (one primarily
treated with steroids, VCR added later), major airway compromise in 1
patient requiring intubation (Siro+VCR), necrotizing enterocolitis in 1
patient (primary treatment VCR), biliary tract obstruction due to tumor
in 1 patient (surgical resection), and severe lymphedema in one Siro
patient.

\textbf{Discussion}

KHE and TA are aggressive vascular tumors that are associated with
significant morbidity and are rarely cured. Until the discovery of
efficacy of mTOR inhibition with sirolimus in KHE in mid-2000s,
vincristine and steroids were the mainstay of medical therapy. The rare
nature and widely heterogenous clinical presentation of KHE/TA have made
comparison of treatment modalities difficult. This study compares
treatment response and durability in the largest cohort of children with
KHE/TA to date.

In this cohort, we found similar rates of KMP (40.3\%) but a much lower
mortality rate (1.3\%) compared to historical cohorts. This may be
attributed to the introduction of sirolimus for long-term tumor
control.\textsuperscript{4,12,32,33} Sirolimus was the most common
treatment and overall treatment response rates were high
(\textgreater{}70\% overall by 6 months), and there were no differences
in radiologic, hematologic, or clinical response between the VCR and
Siro treatment groups at 6 months. Due to chronicity of KHE/TA we also
felt it was important to try to evaluate durability of treatment
response. We found no significant differences in the rates of
progressive or recurrent disease at 3 and 6 months between the VCR and
Siro treatment groups. While increased rates of reported persistent
disease were noted in the Siro group compared to VCR, we think the lack
of a standardized definition of persistent disease across investigators
and the frequent addition of sirolimus to patients on VCR regimen
precludes confirming this as a valid finding. KHE/TA can be considered a
chronic tumor, requiring months to years of therapy with infrequent
complete cures, and persistent disease needs to be defined more
effectively in future studies.

A recent prospective trial in 73 patients with KHE with KMP showed that
upfront sirolimus therapy in combination with steroids improves time to
resolution of KMP, durability of platelet response, and overall tumor
response at 12 months.\textsuperscript{31} In this retrospective cohort,
low patient numbers limited comparison of regiments with and without
steroids. More patients reported persistent disease in the Siro +
steroid group compared to the VCR + steroid treatment group, however
again noting that nearly 50\% of the patients in the VCR + steroid group
added sirolimus to their regimen later.

Different side effect profiles often influence the choice of medical
agent. Sirolimus is associated with concerns for delayed wound healing,
mucositis, neutropenia, and lymphopenia. Vincristine is associated with
constipation, jaw pain, and peripheral neuropathy. Sirolimus may be an
agent of choice or an agent of transition for some due to its increased
ease of administration, lack of need for central venous access, and
demonstrated efficacy. Although there are concerns about
immunosuppression secondary to sirolimus, we found a lower rate of
infectious complications in the Siro group compared to patients
receiving vincristine. However, high adverse event rates in the groups
receiving vincristine (VCR and VCR+Siro) could be confounded if these
patients had more severe disease leading their physicians to elect
treatment with vincristine.

With equivalent treatment response and durability at 6 months, the
decision to treat with vincristine or sirolimus, with or without
steroids, should account for additional clinical factors, including
route of administration, side effects, perceived severity of KMP or
urgency to treat, and patient/family preference. While vincristine may
bring about more rapid radiologic response and perhaps should be
considered for high urgency situations, this is not associated with
improved longer-term outcomes in these indolent tumors. Although full
surgical resection of KHE is the only curative option, we found that
many patients who underwent surgery ultimately ended up needing systemic
medical therapy. Fortunately, the high overall treatment response rates
and low mortality highlighted in this cohort demonstrate that individual
patient factors and family and physician preferences can be encouraged
in the management of this rare vascular tumor.

This study represents the largest cohort to date investigating treatment
practices and short-term response rates in patients with KHE/TA. Results
are limited by the retrospective nature of this study, the clinical
heterogeneity of KHE/TA, and variable investigator experience and
clinical perspective. Although KHE and TA have overlapping clinical and
histopathologic features, their presentation and the urgency for medical
therapy can be quite distinct, which may affect assessment of treatment
choices and duration in this cohort. Many patients with mild TA are
observed only or treated with monotherapy initially, whereas patients
who present more acutely with large KHE causing clinical compromise or
KMP, multi-modal therapy may be the initial approach. Due to this
significant disease heterogeneity, determining baseline response
parameters for this population will allow for historical comparison in
future treatment protocols. These results augment the ability to make
educated decisions for individualized medical management for patients
with KHE/TA with and without KMP, particularly when complete surgical
excision is not possible or successful. Given the rarity of these
tumors, multi-institutional studies are needed to further knowledge of
the natural history of KHE/TA and optimal treatment modalities.

\textbf{Conclusions}

In patients diagnosed with KHE/TA, about 40\% will exhibit KMP,
confirming established rates. Currently, a lower mortality rate (1.3\%)
exists likely owing to earlier recognition and treatment implementation
with improved medical therapy options. Overall treatment response rates
are high at \textgreater{} 70\% by 6 months. There was no significant
difference in treatment response or durability of disease response
comparing sirolimus to vincristine. Our results support individualized
treatment decision plans based on disease severity, side effect profile,
patient clinical situation, and physician experience. Response criteria
and response rates reported here will be useful for guiding future
treatment protocols for vascular tumors.

\textbf{Conflict of Interest Statement:}

The authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a
potential conflict of interest.

\textbf{Acknowledgements}

The authors wish to all of the members of the American Society of
Pediatric Hematology/Oncology (ASPHO) Vascular Anomalies Special
Interest Group (VA SIG) and the thank the patients and families who make
this work possible.

\textbf{References}

1. Wassef M, Blei F, Adams D, et al. Vascular Anomalies Classification:
Recommendations From the International Society for the Study of Vascular
Anomalies. \emph{Pediatrics} . 2015;136(1):e203-214.
doi:10.1542/peds.2014-3673

2.~~~~~~~~ ISSVA Classification of Vascular Anomalies \selectlanguage{ngerman}©2018
International Society for the Study of Vascular Anomalies Available at
``issva.org/classification'' Accessed May 2023. Accessed May 5, 2023.
https://www.issva.org/classification

3.~~~~~~~~ Putra J, Gupta A. Kaposiform haemangioendothelioma: a review
with emphasis on histological differential diagnosis. \emph{Pathology
(Phila)} . 2017;49(4):356-362. doi:10.1016/j.pathol.2017.03.001

4.~~~~~~~~ Ji Y, Chen S, Yang K, Xia C, Li L. Kaposiform
hemangioendothelioma: current knowledge and future
perspectives.\emph{Orphanet J Rare Dis} . 2020;15(1):39.
doi:10.1186/s13023-020-1320-1

5.~~~~~~~~ Kasabach HH, Merritt KK. Capillary Hemangioma With Extensive
Purpura: Report of a Case. \emph{Am J Dis Child} . 1940;59(5):1063-1070.
doi:10.1001/archpedi.1940.01990160135009

6.~~~~~~~~ Enjolras O, Wassef M, Mazoyer E, et al. Infants with
Kasabach-Merritt syndrome do not have ``true'' hemangiomas. \emph{J
Pediatr} . 1997;130(4):631-640. doi:10.1016/s0022-3476(97)70249-x

7.~~~~~~~~ Sarkar M, Mulliken JB, Kozakewich HP, Robertson RL, Burrows
PE. Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is
associated with Kaposiform hemangioendothelioma and not with common
infantile hemangioma. \emph{Plast Reconstr Surg} .
1997;100(6):1377-1386. doi:10.1097/00006534-199711000-00001

8.~~~~~~~~ Gruman A, Liang MG, Mulliken JB, et al. Kaposiform
hemangioendothelioma without Kasabach-Merritt phenomenon. \emph{J Am
Acad Dermatol} . 2005;52(4):616-622. doi:10.1016/j.jaad.2004.10.880

9.~~~~~~~~ Croteau SE, Gupta D. The clinical spectrum of kaposiform
hemangioendothelioma and tufted angioma. \emph{Semin Cutan Med Surg} .
2016;35(3):147-152. doi:10.12788/j.sder.2016.048

10.~~~~~~ Adams DM, Trenor CC, Hammill AM, et al. Efficacy and Safety of
Sirolimus in the Treatment of Complicated Vascular
Anomalies.\emph{PEDIATRICS} . 2016;137(2):e20153257-e20153257.
doi:10.1542/peds.2015-3257

11.~~~~~~ Drolet BA, Trenor CC, Brandão LR, et al. Consensus-Derived
Practice Standards Plan for Complicated Kaposiform
Hemangioendothelioma.\emph{J Pediatr} . 2013;163(1):285-291.
doi:10.1016/j.jpeds.2013.03.080

12.~~~~~~ Croteau SE, Liang MG, Kozakewich HP, et al. Kaposiform
hemangioendothelioma: atypical features and risks of Kasabach-Merritt
phenomenon in 107 referrals. \emph{J Pediatr} . 2013;162(1):142-147.
doi:10.1016/j.jpeds.2012.06.044

13.~~~~~~ Sakata N, Suenobu S ichi, Okano M, Ueda S, Kimura M, Takemura
T. Impact of sirolimus treatment for refractory kaposiform
hemangioendothelioma with exacerbation of the disease 10\selectlanguage{english} years after
initial diagnosis. \emph{Rare Tumors} . 2018;10.
doi:10.1177/2036361318776185

14.~~~~~~ Schaefer BA, Wang D, Merrow AC, Dickie BH, Adams DM. Long-term
outcome for kaposiform hemangioendothelioma: A report of two
cases.\emph{Pediatr Blood Cancer} . 2017;64(2):284-286.
doi:10.1002/pbc.26224

15.~~~~~~ Tower R l. Kaposiform haemangioendothelioma: new insights and
old problems. \emph{Br J Dermatol} . 2018;179(2):253-254.
doi:10.1111/bjd.16834

16.~~~~~~ Adams DM, Wentzel MS. The role of the hematologist/oncologist
in the care of patients with vascular anomalies. \emph{Pediatr Clin
North Am} . 2008;55(2):339-355, viii. doi:10.1016/j.pcl.2008.01.007

17.~~~~~~ Ricci KW. Advances in the Medical Management of Vascular
Anomalies. \emph{Semin Interv Radiol} . 2017;34(3):239-249.
doi:10.1055/s-0037-1604297

18.~~~~~~ Adams DM, Ricci KW. Vascular Anomalies: Diagnosis of
Complicated Anomalies and New~Medical Treatment Options. \emph{Hematol
Oncol Clin North Am} . 2019;33(3):455-470. doi:10.1016/j.hoc.2019.01.011

19.~~~~~~ Liu XH, Li JY, Qu XH, et al. Treatment of kaposiform
hemangioendothelioma and tufted angioma. \emph{Int J Cancer} .
2016;139(7):1658-1666. doi:10.1002/ijc.30216

20.~~~~~~ Haisley-Royster C, Enjolras O, Frieden IJ, et al.
Kasabach-merritt phenomenon: a retrospective study of treatment with
vincristine. \emph{J Pediatr Hematol Oncol} . 2002;24(6):459-462.
doi:10.1097/00043426-200208000-00010

21.~~~~~~ Barlow CF, Priebe CJ, Mulliken JB, et al. Spastic diplegia as
a complication of interferon Alfa-2a treatment of hemangiomas of
infancy. \emph{J Pediatr} . 1998;132(3 Pt 1):527-530.
doi:10.1016/s0022-3476(98)70034-4

22.~~~~~~ Morad AB, McClain KL, Ogden AK. The role of tranexamic acid in
the treatment of giant hemangiomas in newborns. \emph{Am J Pediatr
Hematol Oncol} . 1993;15(4):383-385.

23.~~~~~~ Hauer J, Graubner U, Konstantopoulos N, Schmidt S, Pfluger T,
Schmid I. Effective treatment of kaposiform hemangioendotheliomas
associated with Kasabach-Merritt phenomenon using four-drug
regimen.\emph{Pediatr Blood Cancer} . 2007;49(6):852-854.
doi:10.1002/pbc.20750

24.~~~~~~ Blei F, Karp N, Rofsky N, Rosen R, Greco MA. Successful
multimodal therapy for kaposiform hemangioendothelioma complicated by
Kasabach-Merritt phenomenon: case report and review of the
literature.\emph{Pediatr Hematol Oncol} . 1998;15(4):295-305.
doi:10.3109/08880019809014013

25.~~~~~~ Blatt J, Stavas J, Moats\selectlanguage{english}-Staats B, Woosley J, Morrell DS.
Treatment of childhood kaposiform hemangioendothelioma with
sirolimus.\emph{Pediatr Blood Cancer} . 2010;55(7):1396-1398.
doi:10.1002/pbc.22766

26.~~~~~~ Hammill AM, Wentzel M, Gupta A, et al. Sirolimus for the
treatment of complicated vascular anomalies in children. \emph{Pediatr
Blood Cancer} . 2011;57(6):1018-1024. doi:10.1002/pbc.23124

27.~~~~~~ Peng S, Yang K, Xu Z, Chen S, Ji Y. Vincristine and sirolimus
in the treatment of kaposiform haemangioendothelioma. \emph{J Paediatr
Child Health} . 2019;55(9):1119-1124. doi:10.1111/jpc.14370

28.~~~~~~ Ji Y, Chen S, Xiang B, et al. Sirolimus for the treatment of
progressive kaposiform hemangioendothelioma: A multicenter retrospective
study. \emph{Int J Cancer} . 2017;141(4):848-855. doi:10.1002/ijc.30775

29.~~~~~~ Harris PA, Taylor R, Minor BL, et al. The REDCap consortium:
Building an international community of software platform
partners.\emph{J Biomed Inform} . 2019;95:103208.
doi:10.1016/j.jbi.2019.103208

30.~~~~~~ Eisenhauer EA, Therasse P, Bogaerts J, et al. New response
evaluation criteria in solid tumours: Revised RECIST guideline (version
1.1). \emph{Eur J Cancer} . 2009;45(2):228-247.
doi:10.1016/j.ejca.2008.10.026

31.~~~~~~ Ji Y, Chen S, Zhou J, et al. Sirolimus plus prednisolone vs
sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized
clinical trial. \emph{Blood} . 2022;139(11):1619-1630.
doi:10.1182/blood.2021014027

32.~~~~~~ Ji Y, Yang K, Peng S, et al. Kaposiform haemangioendothelioma:
clinical features, complications and risk factors for Kasabach-Merritt
phenomenon. \emph{Br J Dermatol} . 2018;179(2):457-463.
doi:10.1111/bjd.16601

33.~~~~~~ Rodriguez V, Lee A, Witman PM, Anderson PA. Kasabach-merritt
phenomenon: case series and retrospective review of the mayo clinic
experience. \emph{J Pediatr Hematol Oncol} . 2009;31(7):522-526.
doi:10.1097/MPH.0b013e3181a71830

TABLE 1 Demographic and Clinical Characteristics of Patients with KHE/TA\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Total (n=159)\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Patients with KMP (n=64)\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Patients without KMP (n=95)\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
p-value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age at diagnosis (days), median {[}IQR{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
154.0 {[}32.0, 510.5{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
49.5 {[}10.8, 150.8{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
293.0 {[}96.0, 794.0{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age at treatment initiation (days), median {[}IQR{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
159.5 {[}34.5, 539.8{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
48.0 {[}18.0, 156.0{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
300.00{[}125.0, 1016.0{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Female Sex, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
61 (38.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
22 (34.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
39 (41.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Diagnosis confirmed by biopsy, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
133 (83.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
46 (71.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
87 (91.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.002\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Tumor Location, n (\%) Truncal Non-truncal Other\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
46 (28.9\%) 94 (59.1\%) 19 (12.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
26 (40.6\%) 32 (50.0\%) 6 (9.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
20 (21.1\%) 62 (65.3\%) 13 (13.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.029\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Tumor Size, n (\%) \textless{} 5cm [?] 5cm Unmeasured/unknown\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
50 (31.5\%) 95 (59.8\%) 14 (8.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
7 (10.9\%) 53 (82.8\%) 4 (6.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
43 (45.3\%) 42 (44.2\%) 10 (10.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Tumor Extent, n (\%) Localized/well-circumscribed or superficial
(\textless{}3cm) Localized but not well-circumscribed, infiltrative
(\textgreater{}3cm) Extensive across 1 body area Extensive, involving
more than 1 body area Multifocal Other\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
21 (13.2\%) 66 (41.5\%) 40 (25.2\%) 28 (17.6\%) 2 (1.3\%) 2
(1.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0 (0\%) 23 (35.9\%) 19 (29.7\%) 20 (31.3\%) 0 (0\%) 2 (3.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
21 (22.1\%) 43 (45.3\%) 21 (22.1\%) 8 (8.4\%) 2 (2.1\%) 0 (0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Presence of Coagulopathy at Diagnosis, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
65 (40.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
51 (79.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
14 (14.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
[?] 1 Hospitalizations, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
45 (28.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27 (42.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
18 (19.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hospital Length of Stay (days), median {[}IQR{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2.0 {[}0.0, 11.0{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13.5 {[}5.0, 30.5{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.0 {[}0.0, 2.0{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Length of ICU Stay (days), median {[}IQR{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.0 {[}0.0, 3.0{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4.0 {[}0.0, 16.0{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.0 {[}0.0, 0.0{]}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Deceased, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 (1.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 (3.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.2\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

KHE = Kaposiform hemangioendothelioma, TA = tufted angioma, KMP =
Kasabach-Merritt phenomenon, IQR = interquartile range

*p-value denotes comparison between the ``Patients with KMP'' and
``Patients without KMP'' groups. Fisher's exact tested used for
comparison of categorical variables and Wilcoxon rank sum test for
continuous variables.

Other Tumor Location: included abdominal wall, tongue, mons pubis, back,
mesenteric, iliacus muscle, cheek, and axilla, sacroiliac, intraspinal,
mandible, and liver/bile duct

Other Tumor Extent: included a tumor that was \textgreater{} 16cm in
size but confined to axilla and a 3cm tumor that was localized but
intra-connected to multiple visceral organs (pancreas, liver, bile duct)

TABLE 2 Treatment Information\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& Total (n=159) & Patients with KMP (n=64) & Patients without KMP (n=95)
& p-value\tabularnewline
\midrule
\endhead
Systemic Therapy Given, n (\%) & 136 (85.5\%) & 61 (95.3\%) & 75
(79.0\%) & 0.005\tabularnewline
Primary Treatment Category, n (\%) Sirolimus Vincristine Siro+VCR
Steroids Minimal Surgery/IR & 51 (32.1\%) 25 (15.7\%) 7 (4.4\%) 32
(20.1\%) 27 (17.0\%) 17 (10.7\%) & 19 (29.7\%) 16 (25.0\%) 7 (10.9\%) 16
(25.0\%) 2 (3.1\%) 4 (6.3\%) & 32 (33.7\%) 9 (9.5\%) 0 (0\%) 16 (16.8\%)
25 (26.3\%) 13 (13.7\%) &\tabularnewline
Time Between Initial Symptoms and Treatment Initiation (days), median
{[}IQR{]} & 52.0 {[}9.5, 235.5{]} & 16.0 {[}3.0, 44.0{]} & 179.0
{[}64.5, 456.0{]} & \textless{}0.001\tabularnewline
Time Between Diagnosis and Treatment Initiation (days), median {[}IQR{]}
& 9.0 {[}1.0, 52.8{]} & 3.0 {[}1.0, 10.0{]} & 21.0 {[}6.0, 71.0{]} &
\textless{}0.001\tabularnewline
Received Blood Product Transfusions, n (\%) & 56 (35.2\%) & 50 (78.1\%)
& 6 (6.3\%) & \textless{}0.001\tabularnewline
Received Opioid Medication, n (\%) & 33 (20.8\%) & 19 (29.7\%) & 14
(14.7\%) & 0.028\tabularnewline
Interventional Radiology Procedure Attempted, n (\%) & 16 (10.1\%) & 8
(12.5\%) & 8 (8.4\%) & 0.2\tabularnewline
Surgical Resection Attempted, n (\%) & 28 (17.6\%) & 8 (12.5\%) & 20
(21.1\%) & 0.2\tabularnewline
Reason for Treatment Initiation, n (\%) Coagulopathy Thrombocytopenia
Anemia Pain Recurrent cellulitis Visceral or bone involvement Cardiac
dysfunction Airway compression Limb dysfunction Cosmetic look Extent of
disease & 65 (40.9\%) 59 (37.1\%) 22 (13.8\%) 61 (38.4\%) 2 (1.3\%) 12
(7.5\%) 5 (3.1\%) 11 (6.9\%) 29 (18.2\%) 34 (21.4\%) 87 (54.7\%) & 51
(79.7\%) 53 (82.8\%) 21 (32.8\%) 18 (28.1\%) 1 (1.6\%) 6 (9.4\%) 5
(7.8\%) 10 (15.6\%) 9 (14.1\%) 7 (10.9\%) 40 (62.5\%) & 14 (14.7\%) 6
(6.3\%) 1 (1.1\%) 43 (45.3\%) 1 (1.1\%) 6 (6.3\%) 0 (0\%) 1 (1.1\%) 20
(21.1\%) 27 (28.4\%) 47 (49.5\%) & \textless{}0.001 \textless{}0.001
\textless{}0.001 0.032 \textgreater{}0.9 0.5 0.010 \textless{}0.001 0.3
0.010 0.14\tabularnewline
\bottomrule
\end{longtable}

Siro = sirolimus, VCR = vincristine

*p-value denotes comparison between the ``Patients with KMP'' and
``Patients without KMP'' groups. Fisher's exact tested used for
comparison of categorical variables and Wilcoxon rank sum test for
continuous variables.

TABLE 3 Short and Long-Term Treatment Response with Sirolimus vs
Vincristine\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Treatment Group\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Treatment Group\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Treatment Group\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Treatment Group\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Treatment Response\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Total (N=76) n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Sirolimus (N=51) n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Vincristine (N=25) n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
p-value\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Any response at 3 months\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
53/63 (84.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30/39 (76.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23/24 (95.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.074\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
HemR at 3 months\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26/27 (96.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11/12 (91.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15/15 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
RadR at 3 months\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10/21 (47.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2/10 (20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8/11 (72.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.030\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ClinR at 3 months\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
50/57 (87.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
28/34 (82.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
22/23 (95.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Any response at 6 months\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
61/70 (87.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
38/46 (82.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23/24 (95.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
HemR at 6 months\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30/31 (96.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15/16 (93.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15/15 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textgreater{}0.9\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
RadR at 6 months\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27/38 (71.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
17/25 (68\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10/13 (76.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.7\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ClinR at 6 months\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
59/66 (89.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
36/42 (85.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23/24 (95.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.4\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

*p-value denotes comparison between the ``Sirolimus'' and
``Vincristine'' groups, Fisher's exact test

TABLE 4 Comparison of Steroid vs. No Steroid Groups -- Treatment
Response\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Treatment Group\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Treatment Group\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Treatment Group\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Treatment Group\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Treatment Response\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Sirolimus only (N=4) n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Siro + Steroids (N=15) n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
VCR only (N=5) n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
VCR + Steroids (N=19) n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
p-value* (steroid groups only)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Any response at 3 months?\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1/2 (50\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
11/12 (91.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
4/5 (80\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
17/17 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
HemR at 3 months?\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
7/8 (87.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3/3 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
12/12 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
RadR at 3 months?\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2/3 (66.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1/1 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5/7 (71.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.9\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ClinR at 3 months?\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1/2 (50\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
9/10 (90\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3/4 (75\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
16/16 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Any response at 6 months\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2/3 (66.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
13/14 (92.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
4/5 (80\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
17/17 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
HemR at 6 months?\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
10/11 (90.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3/3 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
12/12 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
RadR at 6 months?\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1/2 (50\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6/7 (85.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3/3 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6/8 (75\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}0.9\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ClinR at 6 months?\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2/3 (66.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
12/13 (92.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
4/5 (80\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
16/16 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.4\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Siro = sirolimus, VCR = vincristine

*p-value denotes comparison of Siro + Steroids to VCR + steroids only,
Fisher's exact test

HemR = hematologic response, in patients with KMP only (platelet count
\textgreater{} 100,000/\selectlanguage{greek}μ\selectlanguage{english}l x 2 consecutive lab measurements without
transfusion)

RadR = radiologic response (any measurable decrease in tumor size on
radiographic imaging, if tumor measurements were available, the RECIST
criteria for partial response was used)

ClinR = clinical response (resolution of symptoms, functional deficit,
or decrease in size of tumor by visual inspection, even if not a
complete response), radiologic response

TABLE 5 Durability of Response at 3 months and 6 months (Vincristine vs.
Sirolimus)\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& Treatment Group & Treatment Group & Treatment Group & Treatment
Group\tabularnewline
\midrule
\endhead
Durability of Response & Total (N=76) & Sirolimus (N=51) & Vincristine
(N=25) & *p-value\tabularnewline
Persistent disease 3 months from start of therapy, n (\%) & 2/76 (2.6\%)
& 2/51 (3.9\%) & 0/25 (0\%) & \textgreater{}0.9\tabularnewline
Persistent disease 6 months from start of therapy, n (\%) & 5/76 (6.6\%)
& 5/51 (9.8\%) & 0/25 (0\%) & 0.2\tabularnewline
Time to persistent disease from start of systemic therapy (days), median
{[}IQR{]} & 566 {[}365.9-1493{]} & 414 {[}352-1148{]} & 1486
{[}1067-1902{]} & 0.2\tabularnewline
Persistent disease requiring change in treatment agent, n (\%) & 9/76
(11.8\%) & 7/51 (13.7\%) & 2/25 (8\%) & 0.7\tabularnewline
Persistent disease requiring continuation of current therapy, n (\%) &
14/76 (18.4\%) & 14/51 (27.5\%) & 0/25 (0\%) & 0.003\tabularnewline
Recurrent disease 3 months from start of therapy, n (\%) & 2/76 (2.6\%)
& 1/51 (2\%) & 1/25 (4\%) & \textgreater{}0.9\tabularnewline
Recurrent disease 6 months from start of therapy, n (\%) & 1/76 (1.3\%)
& 0/51 (0\%) & 1/25 (4\%) & 0.3\tabularnewline
Time to recurrent disease from start of systemic therapy (days), median
{[}IQR{]} & 825.5 {[}372.3-1273.5{]} & 1024 {[}583-1318{]} & 379
{[}231-913{]} & 0.3\tabularnewline
Recurrent disease requiring change in treatment agent, n (\%) & 8/76
(10.5\%) & 5/51 (9.8\%) & 3/25 (12\%) & \textgreater{}0.9\tabularnewline
Recurrent disease requiring re-initiation of prior therapy, n (\%) &
13/76 (17.1\%) & 11/51 (21.6\%) & 2/25 (8\%) & 0.2\tabularnewline
Progressive disease 3 months from start of therapy, n (\%) & 1/76
(1.3\%) & 1/51 (2\%) & 0/25 (0\%) & \textgreater{}0.9\tabularnewline
Progressive disease 6 months from start of therapy, n (\%) & 1/76
(1.3\%) & 1/51 (2\%) & 0/25 (0\%) & \textgreater{}0.9\tabularnewline
Time to progressive disease from start of systemic therapy (days),
median {[}IQR{]} & 730 {[}395-885{]} & 730 {[}562.5-1215{]} & 553
{[}387-719{]} & 0.8\tabularnewline
Progressive disease requiring change in treatment agent, n (\%) & 3/76
(3.9\%) & 2/51 (3.9\%) & 1/25 (4\%) & \textgreater{}0.9\tabularnewline
Progressive disease requiring re-initiation of prior therapy, n (\%) &
3/76 (3.9\%) & 2/51 (3.9\%) & 1/25 (4\%) &
\textgreater{}0.9\tabularnewline
\bottomrule
\end{longtable}

*p-value denotes comparison between the Vincristine and Sirolimus
groups, Fisher's exact test

TABLE 6 Comparison of Steroid vs. No Steroid Groups Durability of
Response\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& Treatment Group & Treatment Group & Treatment Group & Treatment Group
&\tabularnewline
\midrule
\endhead
Durability of Response & Sirolimus only (N=4) & Siro + Steroids (N=15) &
VCR only (N=5) & VCR + Steroids (N=19) & *p-value (steroid groups
only)\tabularnewline
Persistent disease 3 months from start of therapy, n (\%) & 0 (0\%) & 2
(13.3\%) & 5 (100\%) & 19 (100\%) & 0.2\tabularnewline
Persistent disease 6 months from start of therapy, n (\%) & 0 (0\%) & 3
(20\%) & 0 (0\%) & 1 (5.3\%) & 0.3\tabularnewline
Time to persistent disease from start of therapy (days), median
{[}IQR{]} & 1631.5 {[}977.3, 2285.8) & 257.5 {[}123.3, 551{]} & NA &
407.5 {[}286.8, 528.3{]} & 0.8\tabularnewline
Persistent disease requiring change in treatment agent, n (\%) & 1
(25\%) & 3 (20\%) & 0 (0\%) & 1 (5.3\%) & 0.3\tabularnewline
Persistent disease requiring continuation of current therapy, n (\%) & 2
(50\%) & 4 (26.7\%) & 0 (0\%) & 0 (0\%) & 0.029\tabularnewline
Recurrent disease 3 months from start of therapy, n (\%) & 0 (0\%) & 1
(6.7\%) & 1 (20\%) & 0 (0\%) & 0.4\tabularnewline
Recurrent disease 6 months from start of therapy, n (\%) & 0 (0\%) & 1
(6.7\%) & 1 (20\%) & 0 (0\%) & 0.4\tabularnewline
Time to recurrent disease from start of therapy (days), median {[}IQR{]}
& 1915.5 {[}1509.8, 2321.3{]} & 430.5 {[}268.5,637.8{]} & 379 {[}193.5,
646{]} & 231 {[}231, 231{]} & 0.8\tabularnewline
Recurrent disease requiring change in treatment agent, n (\%) & 1 (25\%)
& 3 (20\%) & 2 (40\%) & 0 (0\%) & 0.076\tabularnewline
Recurrent disease requiring re-initiation of prior therapy, n (\%) & 1
(25\%) & 4 (26.7\%) & 1 (20\%) & 2 (10.5\%) & 0.4\tabularnewline
Progressive disease 3 months from start of therapy, n (\%) & 0 (0\%) & 1
(6.7\%) & 0 (0\%) & 0 (0\%) & 0.4\tabularnewline
Progressive disease 6 months from start of therapy, n (\%) & 0 (0\%) & 1
(6.7\%) & 0 (0\%) & 0 (0\%) & 0.4\tabularnewline
Time to progressive disease from start of therapy (days), median
{[}IQR{]} & 730 {[}730, 730{]} & 1700 {[}1700, 1700{]} & NA & 553
{[}387, 719{]} & 0.7\tabularnewline
Progressive disease requiring change in treatment agent, n (\%) & 0
(0\%) & 1 (6.7\%) & 0 (0\%) & 1 (5.3\%) &
\textgreater{}0.9\tabularnewline
Progressive disease requiring re-initiation of prior therapy, n (\%) & 1
(25\%) & 0 (0\%) & 0 (0\%) & 1 (5.3\%) &
\textgreater{}0.9\tabularnewline
\bottomrule
\end{longtable}

Siro = sirolimus, VCR = vincristine

*p-value denotes comparison of Siro + Steroids to VCR + steroids only,
Fisher's exact test

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

