Stem Cell Transplantation in Patients With High-Risk and Recurrent Pediatric Sarcomas

Background:

• 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.

Objectives:

• 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.

Eligibility:

• 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.

Design:

-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:

• 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 treatment modalities.
• 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 (RFLP) analysis.
• 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 equal 60
• 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 patients ineligible.
• 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 consent.
• 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 allogeneic transplantation).
• 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 l).
• 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 recipient.
• High risk of inability to comply with transplant protocol.