Pilot Study of Non-Myeloablative, HLA-Matched Allogeneic Stem Cell Transplantation for Pediatric Hematopoietic Malignancies

NCT00013533 | Completed Early Phase 1

• 2 other identifiers: 01012501-C-0125
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Allogeneic blood and marrow stem cell transplantation (BMT) plays an important role in the curative treatment of a number of pediatric malignancies. Unfortunately, the success of conventional allogeneic BMT is limited in part by the multiple toxicities associated with myeloablative preparative regimens.
• Non-myeloablative pre-transplant regimens are associated with less toxic side effects than standard BMT. Recently, a novel immunosuppressive, non-myeloablative pre-transplant chemotherapy regimen has been shown to facilitate complete donor engraftment in an adult trial at the NCI. Objectives: The primary objective of this protocol is to evaluate the efficacy and safety of this treatment approach in pediatric patients with hematopoietic malignancies Eligibility: Inclusion Criteria Age: Patient must be greater than or equal to 5 years and less than 22 years of age. Diagnosis:
• Hodgkin s and Non-Hodgkin s Lymphoma: Refractory disease or relapse after salvage regimen.
• Acute Myelogenous Leukemia: History of bone marrow relapse in remission (CR) #2 or greater.
• Acute Lymphocytic Leukemia: History of bone marrow relapse in CR #2 or greater (CR#1 with Philadelphia chromosome positive or prior induction failure).
• Acute Hybrid Leukemia including mixed lineage, biphenotypic and undifferentiated: History of bone marrow relapse in CR #2 or greater (CR#1 with Philadelphia chromosome positive or prior induction failure).
• Myelodysplastic Syndrome: RAEB or RAEB-t with less than 10% blasts in marrow and blood.
• Chronic Myelogenous Leukemia: Chronic phase or accelerated phase with less than 10% blasts in marrow and blood.
• Juvenile Myelomonocytic Leukemia: less than 10% blasts in marrow and blood. Prior Therapy: Chemotherapy to achieve above criteria allowed. Prior BMT allowed as long as at least day 100+ post-prior BMT, no evidence of GVHD, and no detectable residual donor chimerism. Donor: First degree related donors, who are HLA matched (single HLA-A or B locus mismatch allowed), weight greater than or equal to 15 kilograms, and who meet standard donation criteria will be considered. The same donor from a prior BMT is allowed. ECOG Performance Status: 0, 1, or 2. and life expectancy: greater than 3 months. Liver Function: Serum direct bilirubin less than 2.0 mg/dL and serum ALT and AST values less than or equal to 2.5x upper limit of normal. (Values above these levels may be accepted if due to malignancy.) Renal Function: Age adjusted normal serum creatinine or Cr clearance greater than or equal to 60 mL/min/1.73 m(2). Pulmonary Function: DLCO greater than or equal to 50%. Cardiac Function: LVEF greater than or equal to 45% by MUGA or LVSF greater than or equal to 28% by ECHO Exclusion Criteria
• Active CNS malignancy: Tumor mass on CT or leptomeningeal disease. (Patients with a history of CNS involvement and no current evidence of CNS disease are allowed.)
• HIV infection, active hepatitis B or C infection: HbSAg or HCV seropositive and elevated liver transaminases.
• Fanconi Anemia.
• Lactating or pregnant females. Design: Pilot Study
• Initial evaluation: Patient and donor will be screened for eligibility. G-CSF primed bone marrow derived stem cells will be collected from the donor.
• Induction/Consolidation chemotherapy: 1 to 3 cycles will be given every 22 days depending on disease response, CD4 count, and toxicities.
• Lymphoma: fludarabine, etoposide, doxorubicin, vincristine, cyclophohamide, prednisone, and filgrastim (EPOCH-fludarabine).
• Leukemia and MDS: Fludarabine, cytarabine, and filgrastim (FLAG).
• Transplantation: Fludarabine and cyclophosphamide will be administered over 4 days followed by bone marrow transplant. Patients will remain hospitalized until bone marrow recovery. Patients will be monitored closely at the NIH for at least 100 days post-BMT.
• Post-transplant CNS prophylaxis for ALL: Standard post-transplant CNS prophylaxis will be employed with intrathecal methotrexate to decrease the risk of CNS relapse for all patients with ALL.
• Total number of recipient and donors to be accrued is 56.

Conditions

Hodgkin Lymphoma; Lymphocytic Leukemia; Mixed Cell Leukemia; Myelodysplastic Syndrome; Non Hodgkin's Lymphoma; CML; ALL; AML; Lymphoma

Keywords

Leukemia; Myelodysplastic Syndrome; Bone Marrow Transplant; Pediatric Oncology; Lymphoma; Efficacy; Safety; Childhood Cancer

Outcome Measures

Primary Outcomes (2)

• To determine the efficacy and safety of this chemotherapy regimen in facilitating donor engraftment after allogeneic bone marrow transplantation (BMT).

• Safety/Efficacy

  5 years

Secondary Outcomes (9)

• Toxicity of regimen

  5 years

• To determine the toxicity of this non-myelablative allogeneic BMT regimen.

• fludarabine-based induction reducing T-cells

  5 years

• immune suppression

  5 years

• IL-7 levels

  5 years

Study Arms (1)

1

EXPERIMENTAL

Transplant with Induction Therapy

Procedure: Stem cell transplantation

Interventions

Stem cell transplantation PROCEDURE

\>3 x 106/kg CD34+ stem cells by IV infusion

1

Eligibility Criteria

• Age: 4 Years - 20 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients with the following diagnoses will be considered:
• Hodgkin's and Non-Hodgkin's Lymphoma: Refractory (non-CR) to primary treatment regimen; Refractory (non-CR) to or relapse after salvage regimen.
• Acute Myelogenous Leukemia (AML): History of bone marrow relapse it CR number 2 or greater.
• Acute Lymphocytic Leukemia (ALL): History of bone marrow relapse in CR number 2 or greater; complete remission #1 with Philadelphia chromosome positive or prior induction failure (subsequent induction regimen required to achieve CR).
• Acute hybrid leukemia including mixed lineage, biphenotypic, and undifferentiated (AUL): History of bone marrow relapse in CR number 2 or greater; Complete remission #1 with Philadelphia chromosome positive or prior induction failure (second induction regimen required to achieve (CR).
• Myelodysplastic Syndrome (MDS) excluding refractory anemia (RA) and RA with ringed sideroblasts (RARS): blasts less than 10% in marrow and blood.
• Chronic Myelogenous Leukemia (CML): Chronic Phase; Accelerated Phase with blasts less than 10% in marrow and blood.
• Juvenile Myelomonocytic Leukemia (JMML, J-CML): Blasts less than 10% in marrow and blood.
• Patients must be greater than or equal to 4 years and less than 22 years of age.
• Prior chemotherapy: Chemotherapy to achieve above noted criteria allowed. Prior autologous BMT allowed. Prior allogeneic BMT allowed as long as at least day +100 post-prior BMT, and no evidence of ongoing active GVHD.
• Availability of 5 or 6 antigen genotypic HLA-matched first-degree relative donor (single HLA-A or B locus mismatch allowed).
• Performance status of 0,1, or 2.
• Life expectancy greater than 3 months.
• Liver function: serum direct bilirubin less than 2.0 mg/dL, and serum ALT and AST values less than or equal to 2.5 times the upper limit of normal. Values above these levels may be accepted, at the discretion of the PI, if such elevations are thought to be due to malignancy (excluding acute leukemia).
• Renal function: age-adjusted normal serum creatinine or a creatinine clearance greater than or equal to 60 mL/min/1.73 m(2).

You may not qualify if:

• History of medical illness which in the estimation of the PI or DTM physician poses prohibitive risk to donation including, but not limited to stroke, hypertension that is not controlled by medication, or heart disease. Individuals with symptomatic angina or a history of coronary artery bypass grafting or angioplasty will not be eligible. History of congenital hematologic, immunologic, or metabolic disorder which in the estimation of the PI poses prohibitive risk to the recipient.
• Anemia (Hb less than gm/dl) or thrombocytopenia (less than 100,000/ul).
• Lactating or pregnant females.
• HIV positive.
• Seropositive for hepatitis B (HbsAg) or hepatitis C.
• High risk of inability to comply with transplant protocol as determined by principal investigator, social work, and BMT team.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Kantarjian HM, Deisseroth A, Kurzrock R, Estrov Z, Talpaz M. Chronic myelogenous leukemia: a concise update. Blood. 1993 Aug 1;82(3):691-703. No abstract available.

  PMID: 8338938 BACKGROUND

• Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med. 1998 Aug 27;339(9):605-15. doi: 10.1056/NEJM199808273390907. No abstract available.

  PMID: 9718381 BACKGROUND

• Rivera GK, Buchanan G, Boyett JM, Camitta B, Ochs J, Kalwinsky D, Amylon M, Vietti TJ, Crist WM. Intensive retreatment of childhood acute lymphoblastic leukemia in first bone marrow relapse. A Pediatric Oncology Group Study. N Engl J Med. 1986 Jul 31;315(5):273-8. doi: 10.1056/NEJM198607313150501.

  PMID: 3523250 BACKGROUND

MeSH Terms

Conditions

Hodgkin Disease; Leukemia, Lymphoid; Leukemia, Biphenotypic, Acute; Myelodysplastic Syndromes; Lymphoma, Non-Hodgkin; Lymphoma; Leukemia; Neoplasms

Interventions

Stem Cell Transplantation

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Hematologic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative

Study Officials

• Terry J Fry, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 20, 2001
• First Posted: March 21, 2001
• Study Start: March 14, 2001
• Primary Completion: March 1, 2008
• Study Completion: May 7, 2015
• Last Updated: December 16, 2019

Record last verified: 2015-05-07

Locations

US (1)