Donor Lymphocyte Infusion With Azacitidine to Prevent Hematologic Malignancy Relapse After Stem Cell Transplantation

Phase 2

Completed

Conditions: Juvenile Myelomonocytic Leukemia
Myelodysplastic Syndrome
Acute Myelogenous Leukemia
Acute Lymphoid Leukemia

Interventions: Drug: azacitidine
Biological: donor lymphocyte infusion

Registration Number: NCT02458235

Lead Sponsor: University of California, San Francisco

Brief Summary: The goal of this study is to determine whether post-transplant consolidation with azacitidine combined with donor lymphocyte infusion (DLI) is a safe and effective approach for the prevention of relapse in pediatric and young adult patients with hematologic malignancies who have undergone hematopoietic stem cell transplantation (HSCT).

Detailed Description: This is a phase II single-arm trial of azacitidine (IV or SC) in combination with escalating donor lymphocyte infusion (DLI). Patients will be enrolled on the study by day +28 +/- 7 post-transplant, prior to withdrawal of immunosuppression or administration of donor lymphocyte infusion (DLI). They will have donor chimerism and minimal residual disease (MRD) testing from peripheral blood (PB) and bone marrow (BM) on day +28 ± 7. Patients will be stratified according to risk categories (low, standard and high), defined by GVHD status, mixed versus full donor chimerism, and positive versus negative MRD results. Depending on risk assessment, immunosuppression will be tapered according to standard or fast schedules, and patients (with the exception of low-risk ALL patients) will receive one cycle of low-dose azacitidine (40mg/m2 IV/SC daily x 4 days). After tapering immunosuppression, chimerism will be repeated and patients will receive up to 6 additional cycles of low-dose azacitidine, depending on risk assessment. For patients who meet criteria for high risk of relapse, azacitidine will be combined with escalating doses of DLI for a maximum of 7 cycles in total. Risk and safety assessments, including routine laboratory parameters, donor chimerism, minimal residual disease, and GHVD activity will be assessed following each cycle. Chimerism and minimal residual disease testing will be repeated every cycle by peripheral blood (PB), and bone marrow (BM) will be tested every other cycle. Patients will be followed by laboratory monitoring and physician evaluation prior to each cycle, and will be followed for two years post-transplant to study toxicity and GVHD outcomes.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 17

Inclusion Criteria

Patients age 0 - 29.9 years undergoing allogeneic peripheral blood stem cell transplant
Patients with acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL)
Patients with juvenile myelomonocytic leukemia (JMML)
Patients with myelodysplastic syndrome (MDS)

Exclusion Criteria

Patients who have had a prior transplant.
Patients with Fanconi anemia or other cancer-predisposition syndromes
Patients with expected survival <12 weeks
Lansky score <60%

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Azacitidine/donor lymphocyte infusion	donor lymphocyte infusion	Patients will be stratified according to risk categories (low, standard and high), defined by GVHD status, mixed versus full donor chimerism, and positive versus negative Minimal Residual Disease (MRD) results. Patients will receive up to 7 cycles of low-dose azacitidine (40mg/m2 IV/SC daily x 4 days) at 6 weekly intervals, except for low risk ALL patients who may not receive treatment after withdrawal of immunosuppression. Standard risk patients will receive an additional 6 cycles of azacitidine alone. High risk patients will receive an additional 6 cycles of azacitidine plus escalating DLI.
Azacitidine/donor lymphocyte infusion	azacitidine	Patients will be stratified according to risk categories (low, standard and high), defined by GVHD status, mixed versus full donor chimerism, and positive versus negative Minimal Residual Disease (MRD) results. Patients will receive up to 7 cycles of low-dose azacitidine (40mg/m2 IV/SC daily x 4 days) at 6 weekly intervals, except for low risk ALL patients who may not receive treatment after withdrawal of immunosuppression. Standard risk patients will receive an additional 6 cycles of azacitidine alone. High risk patients will receive an additional 6 cycles of azacitidine plus escalating DLI.

Primary Outcome Measures

Name	Time	Method
Proportion of Participants With Acute and Chronic Graft Versus Host Disease (GVHD)	Up to 2 years	Proportion of participants with Grade 3-4 acute GVHD and moderate to severe chronic GVHD will be reported.
Frequency of System Specific Grade 3 or Higher Treatment-related Adverse Events	Up to 2 years	Frequency of system specific adverse events of interest include renal, hepatic, cardiac, pulmonary, or neurologic toxicities. Toxicities will be graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Relapse Rate	Up to 2 years	Relapse rate will be estimated using a percentage of participants who relapsed. It is assumed that the rate of relapse in pediatric acute leukemia post-transplant would be 40%, azacitidine +/- Donor Lymphocyte Infusion (DLI) would reduce the 2-year relapse rate by approximately 40% to a rate of 25%.
Proportion of Participants With Severe Hematologic Toxicity Including Graft Failure	Up to 2 years	The proportion of participants will be reported for Grade 4 severe hematologic toxicities including graft failure
Number of Participants Whom Had >2 Dose Reductions for Any Reason	Up to 2 years	The number of participants whom had greater than 2 dose reductions for any reason.
Proportion of Participants With Serious Infection	Up to 2 years	The proportion of participants will be reported for Grade 3-4 invasive fungal infection or disease caused by viral infections

Secondary Outcome Measures

Name	Time	Method
Median Relapse-free Survival	Up to 2 years	Release-free survival rate is defined as the median length of time after beginning treatment that the participant survives without progression or relapse, reported in months
Median Time to Relapse	Up to 2 years	Time to relapse is defined as the length of time after beginning treatment until the participant has experienced a relapse in disease, measured in months.