Acute Myelogenous Leukemia, Acute Lymphoid Leukemia, Juvenile Myelomonocytic Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
pediatric leukemia myelodysplastic syndrome azacitidine
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.
Interventions
DRUGazacitidine
40mg/m2 IV/SC daily x 4 days, maximum of 7 cycles at 6 weekly intervals
BIOLOGICALdonor lymphocyte infusion
For patients with cells available for DLI who are in the high risk group and do not have graft-versus-host disease (GVHD), DLI will be adminstered on day 5 of each cycle.
Sponsors
Hellman Foundation
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 29 Years
Healthy volunteers
No
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%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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%. |
| 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. |
| 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. |
| 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 |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azacitidine/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: 40mg/m2 IV/SC daily x 4 days, maximum of 7 cycles at 6 weekly intervals
donor lymphocyte infusion: For patients with cells available for DLI who are in the high risk group and do not have graft-versus-host disease (GVHD), DLI will be adminstered on day 5 of each cycle. | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | Azacitidine/Donor Lymphocyte Infusion |
|---|---|
| Age, Customized 0-9 years | 7 Participants |
| Age, Customized 10-19 years | 9 Participants |
| Age, Customized 20-29 years | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 17 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 17 |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 10 / 17 |
Outcome results
Primary
Frequency of System Specific Grade 3 or Higher Treatment-related Adverse Events
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.
Time frame: Up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azacitidine/Donor Lymphocyte Infusion | Frequency of System Specific Grade 3 or Higher Treatment-related Adverse Events | 0 Participants |
Primary
Number of Participants Whom Had >2 Dose Reductions for Any Reason
The number of participants whom had greater than 2 dose reductions for any reason.
Time frame: Up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azacitidine/Donor Lymphocyte Infusion | Number of Participants Whom Had >2 Dose Reductions for Any Reason | 0 participants |
Primary
Proportion of Participants With Acute and Chronic Graft Versus Host Disease (GVHD)
Proportion of participants with Grade 3-4 acute GVHD and moderate to severe chronic GVHD will be reported.
Time frame: Up to 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine/Donor Lymphocyte Infusion | Proportion of Participants With Acute and Chronic Graft Versus Host Disease (GVHD) | Acute GVHD | 0.176 proportion of participants |
| Azacitidine/Donor Lymphocyte Infusion | Proportion of Participants With Acute and Chronic Graft Versus Host Disease (GVHD) | Moderate to severe chronic GVHD | 0.411 proportion of participants |
Primary
Proportion of Participants With Serious Infection
The proportion of participants will be reported for Grade 3-4 invasive fungal infection or disease caused by viral infections
Time frame: Up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azacitidine/Donor Lymphocyte Infusion | Proportion of Participants With Serious Infection | 0.41 proportion of participants |
Primary
Proportion of Participants With Severe Hematologic Toxicity Including Graft Failure
The proportion of participants will be reported for Grade 4 severe hematologic toxicities including graft failure
Time frame: Up to 2 years
Population: No participants experienced a severe hematologic toxicity including graft failure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azacitidine/Donor Lymphocyte Infusion | Proportion of Participants With Severe Hematologic Toxicity Including Graft Failure | 0.00 proportion of participants |
Primary
Relapse Rate
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%.
Time frame: Up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azacitidine/Donor Lymphocyte Infusion | Relapse Rate | 23.5 percentage of participants |
Secondary
Median Relapse-free Survival
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
Time frame: Up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine/Donor Lymphocyte Infusion | Median Relapse-free Survival | 22 months |
Secondary
Median Time to Relapse
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.
Time frame: Up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine/Donor Lymphocyte Infusion | Median Time to Relapse | 3 months |