This study will examine the safety and effectiveness of stem cell transplantation for
treating patients with sarcomas (tumors of the bone, nerves, or soft tissue). Stem cells are
immature cells in the bone marrow and blood stream that develop into blood cells. Stem cells
transplanted from a healthy donor travel to the patient's bone marrow and begin producing
normal cells. In patients with certain cancers, such as leukemia and lymphoma, the donor's
immune cells attack the patient's cancer cells in what is called a "graft-versus-tumor"
effect, contributing to cure of the disease. This study will determine whether this
treatment can be used successfully to treat patients with sarcomas.
Patients between 4 and 35 years of age with a sarcoma that has spread from the primary site
or cannot be removed surgically, and for whom effective treatment is not available, may be
eligible for this study. Candidates must have been diagnosed by the age of 30 at the time of
enrollment. They must have a matched donor (usually a sibling). Participants undergo the
Donors: Stem cells are collected from the donor. To do this, the hormone granulocyte colony
stimulating factor (G-CSF) is injected under the skin for several days to move stem cells
out of the bone marrow into the bloodstream. Then, the cells are collected by apheresis. In
this procedure the blood is drawn through a needle placed in one arm and pumped into a
machine where the stem cells are separated out and removed. The rest of the blood is
returned to the donor through a needle in the other arm.
Patients: For patients who do not already have a central venous catheter (plastic tube), one
is placed into a major vein. This tube can stay in the body the entire treatment period for
giving medications, transfusing blood, , withdrawing blood samples, and delivering the
donated stem cells. Before the transplant procedure, patients receive from one to three
cycles of "induction" chemotherapy, with each cycle consisting of 5 days of fludarabine,
cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone followed by at least a
17-day rest period. All the drugs are infused through the catheter except prednisone, which
is taken by mouth. After the induction therapy, the patient is admitted to the hospital for
5 days of chemotherapy with high doses of cyclophosphamide, melphalan, and fludarabine. Two
days later, the stem cells are infused. The anticipated hospital stay is about 3 weeks, but
may be longer if complications arise. Patients are discharged when their white cell count is
near normal, they have no fever or infection, they can take sufficient food and fluids by
mouth, and they have no signs of serious graft-versus-host disease (GVHD)-a condition in
which the donor's cells "see" the patient's cells as foreign and mount an immune response
After hospital discharge, patients are followed in the clinic at least once or twice weekly
for a medical history, physical exam, and blood tests for 100 days. They receive medications
to prevent infection and GVHD and, if needed, blood transfusions. If GVHD has not developed
by about 120 days post transplant, patients receive additional white cells to boost the
immune response. After 100 days, follow-up visits may be less frequent. Follow-up continues
for at least 5 years. During the course of the study, patients undergo repeated medical
evaluations, including blood tests and radiology studies, to check on the cancer and on any
treatment side effects. On four occasions, white blood cells may be collected through
apheresis to see if immune responses can be generated against the sarcomas treated in this
study. Positron emission tomography (PET) scans may be done on five occasions. This test
uses a radioactive material to produce images useful in detecting primary tumors and cancer
that has spread.
- Treatment of pediatric sarcomas has enjoyed progress in the past 25 years for patients
with localized, chemosensitive disease and prognostic factors are now available to
identify subsets of patients who have very dismal prognoses; patients with primary
metastatic disease, especially those with bone and bone marrow metastases.
- Patients with primary chemoresistant disease and early recurrence also have very poor
prognoses and lack suitable treatment options. For these patients, it is critical that
alternative approaches to cytotoxic chemotherapy be identified.
- Basic laboratory studies have shown that Ewing's sarcoma is susceptible to immune
mediated mechanisms of cytolysis in vitro. Interestingly, for Ewing's sarcoma this
appears to be true for both chemosensitive and chemoresistant cell lines.
- Recent progress in the field of bone marrow transplantation has identified approaches
that can reproducibly induce allogeneic peripheral blood stem cell engraftment in
adults with hematologic malignancies. In some cases, this same approach has shown
beneficial effects for patients with solid tumors as a result of the development of
allogeneic, immune-mediated graft versus tumor effects.
- To determine if the transplantation of human leukocyte antigen (HLA) matched,
peripheral blood stem cells can result in full donor engraftment (greater than 95
percent by day 100) in patients with high risk-pediatric sarcomas.
- To identify and characterize the toxicities of HLA-matched peripheral blood stem cell
transplant (PBSCT) in patients with high-risk pediatric sarcomas. In particular we will
identify the incidence of graft versus host disease (GVHD) and the pace of immune
reconstitution in this population.
- To determine if allogeneic graft-versus-tumor responses following allogeneic PBSCT can
induce clinically significant anti-tumor effects as measured by radiographic evidence
of antitumor responses following PBSCT in patients with measurable disease and improved
clinical outcome compared to historical controls in this patient population with a
universally poor outcome.
- Patients, age of greater than 4 years at enrollment to less than 30 years at diagnosis
and age less than 35 at enrollment, with ultra-high risk Ewing's sarcoma family of
tumors, desmoplastic small round cell tumor or alveolar rhabdomyosarcoma.
- Patients must have completed standard front-line therapy and salvage therapy.
- Patient must have the availability of a 5 or 6 antigen HLA-matched first-degree
relative donor or a genotypically identical twin.
- Patients must have adequate cardiac, pulmonary, renal, liver, and marrow function.
-Donor will be prepared for peripheral blood stem cell harvest with Filgrastim mobilization,
10 microg/kg per day subcutaneous (SQ) for 5-7 days until they have stem cell collected by
apheresis. The stem cells will then be cryopreserved.
Patients will receive 1 to 3 21 day cycles of Fludarabine-EPOCH induction chemotherapy. The
preparative regimen will consist of cyclophosphamide, fludarabine and melphalan followed by
stem cell infusion. GVHD prophylaxis will consist of sirolimus and tacrolimus.
- INCLUSION CRITERIA: PATIENT
The following diagnoses will be considered:
1. Patients with Ewing's sarcoma family of tumors, or alveolar
rhabdomyosarcoma in one of the following categories:
- Patients who present at the time of initial diagnosis with bone or bone marrow
metastases may be enrolled after completion of standard front-line therapy.
Standard front line therapy for alveolar rhabdomyosarcoma should include
vincristine and cyclophosphamide, plus actinomycin D and/or adriamycin. For
patients with Ewing's sarcoma, standard front line therapy should include
vincristine, cyclophosphamide, adriamycin, ifosfamide and etoposide.
- Patients with recurrence of tumor at any site less than one year after
completing standard front-line therapy or with a second or subsequent recurrence
at any time after completing standard front-line therapy.
- Patients with progression or persistence of disease while receiving standard
front-line chemotherapy who cannot achieve a complete response (CR) with local
2. The following patients with desmoplastic small round cell tumor are eligible after
receiving front line standard therapy, which is defined as a regimen containing at
least vincristine, cyclophosphamide, and adriamycin:
- unresectable disease
- metastatic tumor (abdominal and extra-abdominal disease)
- progressive or persistent while receiving standard therapy
- recurrence within one year of completing therapy
- Patients without evaluable tumor at the time of enrollment are eligible
- Patients who have previously received high-dose chemotherapy with
autologous stem cell rescue are eligible for this trial.
- Patient age 5-35 at enrollment.
- Availability of a 5 or 6 antigen human leukocyte antigen (HLA)-matched
first-degree relative donor (single HLA-A or B mismatch allowed).
Genotypically identical twins may serve as stem cell donors. Genotypic
identity must be confirmed by restrictive fragment length polymorphism
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
or, for children less than or equal 10 years of age, Lansky greater than or
- Cardiac function: Left ventricular ejection fraction greater than or equal
to 45% by multi-gated acquisition scan (MUGA), fractional shortening
greater than or equal 28% by echocardiogram (ECHO) or left ventricular
ejection fraction greater than or equal 55% by ECHO.
- Pulmonary function: carbon monoxide diffusing capacity (DLCO) greater than
or equal to 50% of the expected value corrected for alveolar volume.
- Renal function: Age-adjusted normal serum creatinine according to the
following table or a creatinine clearance greater than or equal to 60
ml/min/1.73 m^2. Age (years) Maximum serum creatinine (mg/dl) less than or
equal to 5 0.8 greater than 5, less than or equal to 10 1.0 greater than
10, less than or equal to15 1.2, greater than 15 1.5
- Liver function: Serum total bilirubin less than 2 mg/dl, serum aspartate
aminotransferase (AST) and alanine aminotransferase (ALT) less than or
equal to 2.5 times upper limit of normal.
- Marrow function: absolute neutrophil count (ANC) must be greater than
750/mm^3 (unless due to underlying disease in which case there is no grade
restriction), platelet count must be greater than or equal to 75,000/mm^3
(not achieved by transfusion) unless due to underlying disease in which
case there is no grade restriction). Lymphopenia, cluster of
differentiation 4 (CD4) lymphopenia, leukopenia, and anemia will not render
- Ability to give informed consent. For patients less than18 years of age
their legal guardian must give informed consent. Pediatric patients will be
included in age appropriate discussion in order to obtain verbal assent.
- Durable power of attorney form completed (patients greater than or equal
to18 years of age only).
INCLUSION CRITERIA: DONOR
- Weight greater than or equal 15 kilograms.
- First degree relative with genotypic identity at 5 or 6 HLA loci (single HLAA or B
locus mismatch allowed). Genotypically identical twins may serve as stem cell donors.
Genotypic identity must be confirmed by RFLP analysis.
- For donors less than 18 years of age, he/she must be the oldest suitable donor, their
legal guardian must give informed consent, the donor must give verbal assent, and
he/she must be cleared by social work and a mental health specialist to participate.
- For donors greater than or equal to 18 years of age, ability to give informed
- Adequate peripheral venous access for apheresis or consent to use a temporary central
venous catheter for apheresis.
- Donor selection criteria will be in accordance with National Institutes of Health
(NIH)/Clinical Center (CC) Department of Transfusion Medicine Standards.
EXCLUSION CRITERIA: PATIENT
- Uncontrolled fungal infection.
- History of untreated CNS tumor involvement. Extradural masses which have not invaded
the brain parenchyma (as is commonly observed in Ewing's sarcoma family of tumors) or
parameningeal tumors (as is commonly observed in rhabdomyosarcoma) without evidence
for leptomeningeal spread will not render the patient ineligible. Patients with
previous central nervous system (CNS) tumor involvement that has been treated and has
been stable for at least 6 weeks are eligible.
- Lactating or pregnant females.
- Human immunodeficiency virus (HIV) positive (due to unacceptable risk following
- Hepatitis B surface antigen (HBsAg) positive or hepatitis C antibody positive with
elevated liver transaminases. All patients with chronic active hepatitis (including
those on treatment) are ineligible.
- High risk of inability to comply with transplant protocol, or inability to give
appropriate informed consent in the estimation of the principal investigator (PI),
social work, or the stem cell transplant team.
- Fanconi Anemia
EXCLUSION CRITERIA: DONOR
- History of medical illness which poses a risk to donation in the estimation of the PI
or the Department of Transfusion Medicine physician including, but not limited to
stroke, hypertension that is not controlled with medication, or heart disease.
Individuals with symptomatic angina or a history of coronary bypass grafting or
angioplasty will not be eligible.
- History of congenital hematologic, immunologic, oncologic or metabolic disorder,
which poses a prohibitive risk to the recipient in the estimation of the PI.
- Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000/micro
- Lactating or pregnant females. Donors of childbearing potential must use an effective
method of contraception during the time they are receiving growth colony stimulating
factor (G-CSF). The effects of cytokine administration on a fetus are unknown and may
be potentially harmful. The effects upon breast milk are also unknown and may
potentially be harmful to the infant.
- Human immunodeficiency virus (HIV)-positive, hepatitis B surface antigen (HBsAg)
positive or hepatitis C antibody positive. Donors are providing an allogeneic blood
product and there is the potential risk of transmitting these viral illnesses to the
- High risk of inability to comply with transplant protocol.