A Study of Withdrawal of Immunosuppression and Donor Lymphocyte Infusions Following Allogeneic Transplant for Pediatric Hematologic Malignancies

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
All Children’s Hospital Johns Hopkins Medicine
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01036009
First received: December 17, 2009
Last updated: July 15, 2013
Last verified: July 2013
  Purpose

There is no curative therapy once acute leukemia patients relapse after transplant. Patients who develop clinically significant graft versus host disease (GVHD) have a lower rate of relapse than those who do not develop GVHD. We are initiating this study of post-transplant fast withdrawal of immunosuppression and donor lymphocyte infusions, with a goal of achieving full donor chimerism in children with hematologic malignancies. If our hypothesis that full donor chimerism results in leukemia-free survival is correct, using immune modulation to achieve full donor chimerism should decrease relapse rate and thus increase survival. The goal of this Phase II study is to identify if achieving full donor chimerism in whole blood CD3+ and leukemia-specific (CD14/15+, CD19+, CD33+ and CD34+) subset may decrease the risk of relapse of patients undergoing allogeneic transplant for hematologic malignancy.


Condition Intervention Phase
Acute Leukemia
Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Biphenotypic Leukemia
Pre-leukemic Syndromes
Monosomy 7
Bone Marrow Clonal Malformations
Juvenile Myelomonocytic Leukemia
Myelodysplastic Syndromes
Chronic Myelogenous Leukemia
Other: Withdrawal of immunosuppression and donor lymphocyte infusion
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Preemptive Fast Withdrawal of Immunosuppression and Donor Lymphocyte Infusions for Achieving Complete Donor Chimerism Following Allogeneic Transplant for Pediatric Hematologic Malignancies

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Relapse rate at 2 years post-transplant. [ Time Frame: 2 years post transplant. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 2 years post-transplant survival. The incidence of acute and chronic GVHD. [ Time Frame: 2 years post transplant ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 50
Study Start Date: October 2009
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Group I: Observation
Group I (observation): Patients with full donor chimerism and no evidence of MRD continue to undergo clinical monitoring for acute and chronic graft-vs-host disease and relapse until 3 years post-transplant. Patients undergo repeat chimerism testing at 12 and 24 months post-transplant.
Experimental: Group II: Intervention
Group II (intervention): Patients undergo withdrawal of immunosuppression and receive donor lymphocyte infusions between days 60-365 post-transplant (or until full donor chimerism is achieved). Patients also undergo clinical monitoring and repeat chimerism testing as in group I.
Other: Withdrawal of immunosuppression and donor lymphocyte infusion
Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.

Detailed Description:

The goal of this Phase II study is to identify if achieving full donor chimerism in whole blood, CD3+, and leukemia-specific subset (CD3+, CD14/15+, CD19+, CD33+ and CD34+ subset) may decrease the risk of relapse of patients undergoing allogeneic transplant for hematologic malignancy.

We estimate that total of 50 recipient patients will need to be enrolled. Of these 50 recipient patients an observation group and an intervention group will be formed. We want to enroll 25 recipient patients in the intervention group, this group will receive study intervention and their outcomes will be the focus of statistical analysis for this study. Intervention will involve fast withdrawal of immunosuppression following transplant and donor lymphocyte infusion (DLI) until full donor chimerism is achieved. Chimerism is a genetic test that measures the proportion of donor's and recipient's cells in blood or bone marrow. Twenty five patients will undergo fast withdrawal of immunosuppression and 33 -50% of them (8-13) will undergo DLI following fast withdrawal of immunosuppression.

Patients will have peripheral blood (PB) chimerism tested upon engraftment. A confirmatory test from PB and bone marrow (BM) will be done on day 45±7. Minimal residual disease (MRD) will be examined by immunoflow, FISH, cytogenetics or PCR. Patients with positive MRD will be on a faster schedule of immune intervention than patients with negative MRD. Interventions will be carried on until 1 year post transplant. If confirmatory testing shows no evidence of MRD and full donor chimerism is present in all subsets, the patient will be part of the "observation" group and be observed until 2 years post transplant. Chimerism will be repeated at 12 and 24 months post transplant. If the patient has mixed chimerism on both confirmatory tests (PB and BM), the patient will be part of the "intervention" group and fast withdrawal of immunosuppression will be initiated. If the patient has mixed chimerism on one of the confirmatory tests (PB or BM), the test will be repeated in 2 weeks and the patient will proceed with either observation or intervention, based on the result of the repeated test. Patients will be followed for the incidence of acute and chronic Graft Versus Host Disease (GVHD) and relapse until 2 years post transplant. The study will be considered successful if the relapse rate at 2 years post transplant is ≤20% for the entire study or ≤ 40% for the intervention group.

  Eligibility

Ages Eligible for Study:   6 Months to 25 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 6 months - 25 years.
  • Diagnoses of acute leukemia (AML, ALL, biphenotypic leukemia), pre-leukemic syndromes (monosomy 7 or other bone marrow clonal malformations), JMML, myelodysplastic syndromes or CML.
  • Undergoing an allogeneic transplant as standard care.
  • Performance status: Karnofsky/Lansky>60%.
  • Availability of pre-transplant recipient's DNA and donor's DNA for chimerism testing. This could be DNA or material from which DNA could be extracted. Frozen blood would be preferred. For some patients, post transplant specimens that are not infiltrated with donor cells may be used.
  • Bone marrow or PBMTC as stem cell source.HLA matching: donor and recipient should be matched at a minimum of 7/8 antigens (A,B,C and DrB1) for bone marrow and PBMTC transplants.
  • No history of ≥grade III acute GVHD.

Exclusion Criteria:

  • Treatment on other experimental protocols, if withdrawal of immunosuppression interferes with procedures of follow-up on the primary study.
  • Leukemia relapse defined as > 5% blasts on bone marrow exam or >1% leukemia cells by immunoflow MRD, or presence of extramedullary leukemia.
  • History of acute GVHD ≥ stage III or with any degree of active acute or cGVHD.
  • On steroids for any reason.
  • Any condition that compromises compliance with the objectives and procedures of this protocol, as judged by the principal investigator.
  • Cells for DLI cannot be obtained from the donor.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01036009

Locations
United States, California
University of California
San Francisco, California, United States, 94115
United States, Florida
All Children's Hospital
St. Petersburg, Florida, United States, 33701
Sponsors and Collaborators
University of California, San Francisco
All Children’s Hospital Johns Hopkins Medicine
Investigators
Principal Investigator: Biljana Horn, M.D. University of California, San Francisco
  More Information

Publications:
Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01036009     History of Changes
Obsolete Identifiers: NCT00975598
Other Study ID Numbers: CC# 09082
Study First Received: December 17, 2009
Last Updated: July 15, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of California, San Francisco:
Hematologic
Malignancy
Leukemia
Pre-leukemic
Allogeneic
Transplant
Pediatric

Additional relevant MeSH terms:
Congenital Abnormalities
Leukemia
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Neoplasms
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Preleukemia
Syndrome
Bone Marrow Diseases
Disease
Hematologic Diseases
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasms by Histologic Type
Pathologic Processes
Precancerous Conditions

ClinicalTrials.gov processed this record on October 23, 2014