Clinical trial NCT01036009: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Johns Hopkins All Children's Hospital
First posted: 2009-12-21
Enrollment: 43
Sex: ALL
Minimum age (years): 6
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Relapse at 2 Years Post-transplant.
timeFrame: 2 years post transplant.
Secondary outcomes:
measure: 2 Years Post-transplant Survival.
timeFrame: 2 years post transplant
measure: The Incidence of Acute Graft Versus Host Disease (aGVHD).
timeFrame: 2 years post transplant
measure: The Incidence of Chronic GVHD (cGVHD).
timeFrame: 2 years post transplant
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California
state: California
city: St. Petersburg
country: United States
facility: All Children's Hospital
state: Florida
Study officials:
affiliation: University of California, San Francisco
name: Biljana Horn, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.