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

Primary Purpose

Acute Leukemia, Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Withdrawal of immunosuppression and donor lymphocyte infusion
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Leukemia focused on measuring Hematologic, Malignancy, Leukemia, Pre-leukemic, Allogeneic, Transplant, Pediatric

Eligibility Criteria

6 Months - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of California
  • All Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Experimental

Arm Label

Group I: Observation

Group II: Intervention

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Relapse at 2 Years Post-transplant.
Definition of relapse was >5 % blasts in bone marrow

Secondary Outcome Measures

2 Years Post-transplant Survival.
The Incidence of Acute Graft Versus Host Disease (aGVHD).
Definition and diagnostic criteria of aGVHD according to: 1994 Consensus Conference on Acute GVHD Grading. Przepiorka D1, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. Bone Marrow Transplant. 1995 Jun;15(6):825-8. In this system, patients are divided into one of four grades (I-IV) depending on the degree, or stage, of involvement in three organs. The skin is staged with percent body surface involved, the liver is staged with degree of bilirubin elevation, and the gastrointestinal tract is staged with amount of diarrhea.
The Incidence of Chronic GVHD (cGVHD).
Diagnostic criteria of cGVHD from: Filipovich AH, Weisdorf D, Pavletic S et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-host disease: I Diagnosis and Staging Working Group Report. Biology of Blood and Marrow Transplantation 2005;11:945-955. The diagnosis of chronic GVHD requires the following: 1) Distinction from acute GVHD; 2) Presence of at least 1 diagnostic clinical sign of chronic GVHD or presence of at least 1 distinctive manifestation confirmed by pertinent biopsy or other relevant tests; 3) Exclusion of other possible diagnoses. Scoring of organ manifestations requires careful assessment of signs, symptoms, laboratory values, and other study results. A clinical scoring system (0-3) is used for evaluation of the involvement of individual organs and sites. Global assessment of severity (mild, moderate, or severe) is derived by combining organ- and site-specific scores.

Full Information

First Posted
December 17, 2009
Last Updated
May 18, 2016
Sponsor
University of California, San Francisco
Collaborators
Johns Hopkins All Children's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01036009
Brief Title
A Study of Withdrawal of Immunosuppression and Donor Lymphocyte Infusions Following Allogeneic Transplant for Pediatric Hematologic Malignancies
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2016
Overall Recruitment Status
Completed
Study Start Date
October 2009 (undefined)
Primary Completion Date
July 2014 (Actual)
Study Completion Date
July 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, San Francisco
Collaborators
Johns Hopkins All Children's Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
Keywords
Hematologic, Malignancy, Leukemia, Pre-leukemic, Allogeneic, Transplant, Pediatric

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
43 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group I: Observation
Arm Type
No Intervention
Arm Description
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.
Arm Title
Group II: Intervention
Arm Type
Experimental
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
Withdrawal of immunosuppression and donor lymphocyte infusion
Intervention Description
Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.
Primary Outcome Measure Information:
Title
Relapse at 2 Years Post-transplant.
Description
Definition of relapse was >5 % blasts in bone marrow
Time Frame
2 years post transplant.
Secondary Outcome Measure Information:
Title
2 Years Post-transplant Survival.
Time Frame
2 years post transplant
Title
The Incidence of Acute Graft Versus Host Disease (aGVHD).
Description
Definition and diagnostic criteria of aGVHD according to: 1994 Consensus Conference on Acute GVHD Grading. Przepiorka D1, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. Bone Marrow Transplant. 1995 Jun;15(6):825-8. In this system, patients are divided into one of four grades (I-IV) depending on the degree, or stage, of involvement in three organs. The skin is staged with percent body surface involved, the liver is staged with degree of bilirubin elevation, and the gastrointestinal tract is staged with amount of diarrhea.
Time Frame
2 years post transplant
Title
The Incidence of Chronic GVHD (cGVHD).
Description
Diagnostic criteria of cGVHD from: Filipovich AH, Weisdorf D, Pavletic S et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-host disease: I Diagnosis and Staging Working Group Report. Biology of Blood and Marrow Transplantation 2005;11:945-955. The diagnosis of chronic GVHD requires the following: 1) Distinction from acute GVHD; 2) Presence of at least 1 diagnostic clinical sign of chronic GVHD or presence of at least 1 distinctive manifestation confirmed by pertinent biopsy or other relevant tests; 3) Exclusion of other possible diagnoses. Scoring of organ manifestations requires careful assessment of signs, symptoms, laboratory values, and other study results. A clinical scoring system (0-3) is used for evaluation of the involvement of individual organs and sites. Global assessment of severity (mild, moderate, or severe) is derived by combining organ- and site-specific scores.
Time Frame
2 years post transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Biljana Horn, M.D.
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
All Children's Hospital
City
St. Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
18955982
Citation
Horn B, Soni S, Khan S, Petrovic A, Breslin N, Cowan M, Pelle-Day G, Cooperstein E, Baxter-Lowe LA. Feasibility study of preemptive withdrawal of immunosuppression based on chimerism testing in children undergoing myeloablative allogeneic transplantation for hematologic malignancies. Bone Marrow Transplant. 2009 Mar;43(6):469-76. doi: 10.1038/bmt.2008.339. Epub 2008 Oct 27.
Results Reference
background
PubMed Identifier
25644958
Citation
Horn B, Petrovic A, Wahlstrom J, Dvorak CC, Kong D, Hwang J, Expose-Spencer J, Gates M, Cowan MJ. Chimerism-based pre-emptive immunotherapy with fast withdrawal of immunosuppression and donor lymphocyte infusions after allogeneic stem cell transplantation for pediatric hematologic malignancies. Biol Blood Marrow Transplant. 2015 Apr;21(4):729-37. doi: 10.1016/j.bbmt.2014.12.029. Epub 2015 Jan 31.
Results Reference
derived

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

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