Juvenile Myelomonocytic Leukemia
Conditions
Brief summary
This randomized phase II trial studies how well giving busulfan, cyclophosphamide, and melphalan or busulfan and fludarabine phosphate before donor hematopoietic cell transplant works in treating younger patients with juvenile myelomonocytic leukemia. Giving chemotherapy before a donor hematopoietic transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. It is not yet known whether giving busulfan, cyclophosphamide, and melphalan or busulfan and fludarabine phosphate before a donor stem cell transplant is more effective in treating juvenile myelomonocytic leukemia.
Detailed description
PRIMARY OBJECTIVES: I. To compare ? in a randomized fashion ? the day 100 treatment related mortality (TRM) incidence for two myeloablative conditioning regimens, busulfan-fludarabine (fludarabine phosphate) (BU-FLU) and busulfan-cyclophosphamide-melphalan (BU-CY-MEL), prior to hematopoietic cell transplant (HCT) for children with juvenile myelomonocytic leukemia (JMML), in order to determine the preferred regimen for future trials. II. To compare ? in a randomized fashion ? the 18-month event-free survival (EFS) following two different myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML, in order to determine the preferred regimen for future trials. SECONDARY OBJECTIVES: I. To determine the 18-month relapse incidence (RI) following two different myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML. II. To determine the graft failure rates following two different myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML. TERTIARY OBJECTIVES: I. To determine the rates of severe toxicities (grade 3/4) at day 100 post-HCT between the two myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL). II. To determine the rates of acute and chronic (at 18 months post-HCT) graft-versus-host disease (GVHD) following HCT using two different conditioning regimens (BU-FLU vs. BU-CY-MEL) in children with JMML. III. To create a JMML-specific pre-HCT index to allow better risk-stratification of future patients. IV. To determine the feasibility of assessing post-transplant disease burden by donor chimerism measurements and allele-specific polymerase chain reaction (PCR) in mononuclear and sorted cell subsets. V. To validate gene expression and methylation classifiers predictive of relapse in patients with JMML. VI. To comprehensively assess genetic and biochemical alterations amongst patients with JMML who are treated on this transplant protocol. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: CONDITIONING REGIMEN: Patients receive busulfan intravenously (IV) over 2-3 hours once daily (QD), every 12 hours, or every 6 hours on days -8 to -5, cyclophosphamide IV over 60 minutes QD on days -4 and -3, and melphalan IV over 15-30 minutes on day -1. TRANSPLANT: Patients undergo allogeneic HCT on day 0. Patients receive tacrolimus IV or orally (PO) on days -1 to 98 (related donor) or 180 (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related donor) or 45 (unrelated donor). ARM II: CONDITIONING REGIMEN: Patients receive busulfan as in Arm I and fludarabine phosphate IV over 30-60 minutes on days -5 to -2. TRANSPLANT: Patients undergo allogeneic HCT as in Arm I. Patients receive tacrolimus IV or PO on days -1 to 98 (related donor) or 180 (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related donor) or 45 (unrelated donor). After completion of study treatment, patients are followed up for 5 years.
Interventions
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic HCT
DRUGBusulfan
Given IV
DRUGCyclophosphamide
Given IV
DRUGFludarabine Phosphate
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGMelphalan
Given IV
DRUGMycophenolate Mofetil
Given IV or PO
OTHERPharmacological Study
Correlative studies
DRUGTacrolimus
Given IV or PO
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have a strong clinical suspicion of JMML, based on a modified category 1 of the revised diagnostic criteria; specifically, eligible patients must have all of the following: * Splenomegaly * Absolute monocyte count (AMC) \> 1000/uL * Blasts in peripheral blood (PB)/bone marrow (BM) \< 20% * For the 7-10% of patients without splenomegaly, the diagnostic entry criteria must include all other features described above and at least 2 of the following criteria: * Circulating myeloid precursors * White blood cell (WBC) \> 10,000/uL * Increased fetal hemoglobin (HgbF) for age * Sargramostim (GM-CSF) hypersensitivity OR, patients must have been previously diagnosed with JMML * Patients must be previously untreated with HCT * All patients and/or their parents or legal guardians must sign a written informed consent * All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion criteria
* Patients with a known germline mutation of PTPN11 (Noonan?s Syndrome) are not eligible * Patients with a known history of NF1 (Neurofibromatosis Type 1) and either * A history of a tumor of the central nervous system (astrocytoma or optic glioma), or * A malignant peripheral nerve sheath tumor with a complete remission of \< 1 year are not eligible * Human immunodeficiency virus (HIV) positive patients are not eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Probability of Event-free Survival (EFS) | From transplant up to 18 months | Probability of Event-free Survival (EFS) for Patients after 18 months. An event is either treatment related mortality (TRM), primary or secondary graft failure, or relapse/non-response (as defined in protocol section 10). Time to event is time from transplant with patients who die between the start of the conditioning regimen and transplant given a time to event of zero. |
| Number of Participants Who Experience Treatment-Related Mortality (TRM) by Day 100 | From transplant up to 100 days | The number of patients who experience TRM on day 100. Treatment-Related Mortality (TRM) an event defined as a death prior to relapse or non-response. Time to TRM is defined as time from transplants to TRM. Patients who die between the start of the conditioning regimen and transplant will be considered a TRM with time to TRM of zero. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experience Primary Graft Failure Event Between Arms | Day 0 - day 540 (18 months) following completion of stem cell transplant | Primary Graft failure is defined as the failure to achieve an ANC \>= 500/uL after 42 days, determined by 3 consecutive measurements on different days; OR \< 5% donor cells in blood or bone marrow by day +42 (as demonstrated by a chimerism assay), without evidence of Juvenile Myelomonocytic Leukemia (JMML). |
| Percent Probability of 18 Months-relapse Event Between Arms | From transplant up to 18 months | Probability of patients relapsing at 18 months. A relapse event is defined in protocol section 10.2.3. Time to relapse/non-response is defined as time from transplant to when all criteria of section 10.2.3 are met. |
Countries
Australia, Canada, New Zealand, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Busulfan, Cyclophosphamide, Melphalan) CONDITIONING REGIMEN: Patients receive busulfan IV QD, every 12 hours, or every 6 hours over 2-3 hours on days -8 to -5, cyclophosphamide IV QD over 60 minutes on days -4 and -3, and melphalan IV over 15-30 minutes on day -1.
TRANSPLANT: Patients undergo allogeneic HCT no sooner than 24 hours after the last dose of chemotherapy.
Patients receive tacrolimus IV or PO on days -1 to 98 (related donor) or 180 (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related donor) or 45 (unrelated donor).
Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic HCT
Busulfan: Given IV
Cyclophosphamide: Given IV
Laboratory Biomarker Analysis: Correlative studies
Melphalan: Given IV
Mycophenolate Mofetil: Given IV or PO
Pharmacological Study: Correlative studies
Tacrolimus: Given IV or PO | 6 |
| Arm II (Busulfan, Fludarabine Phosphate) CONDITIONING REGIMEN: Patients receive busulfan as in Arm I and fludarabine phosphate IV over 1 hour on days -5 to -2.
TRANSPLANT: Patients undergo allogeneic HCT as in Arm I.
Patients receive tacrolimus IV or PO on days -1 to 98 (related donor) or 180 (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related donor) or 45 (unrelated donor).
Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic HCT
Busulfan: Given IV
Fludarabine Phosphate: Given IV
Laboratory Biomarker Analysis: Correlative studies
Mycophenolate Mofetil: Given IV or PO
Pharmacological Study: Correlative studies
Tacrolimus: Given IV or PO | 9 |
| ARM III (Non-Randomized) Patients who were not randomized and did not proceed to transplant because they did not meet all the protocol requirement for randomization | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Ineligible | 0 | 0 | 3 |
| Overall Study | No Transplant Planned | 0 | 0 | 10 |
| Overall Study | Physician Decision | 1 | 1 | 1 |
| Overall Study | Progressive Disease | 0 | 5 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Arm I (Busulfan, Cyclophosphamide, Melphalan) | Arm II (Busulfan, Fludarabine Phosphate) | ARM III (Non-Randomized) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 9 Participants | 15 Participants | 30 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 0.50 years STANDARD_DEVIATION 0.84 | 2.33 years STANDARD_DEVIATION 3.71 | 1.27 years STANDARD_DEVIATION 1.75 | 1.00 years STANDARD_DEVIATION 2.42 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 7 Participants | 13 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 3 Participants | 8 Participants | 10 Participants | 21 Participants |
| Region of Enrollment Australia | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Canada | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Kuwait | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment New Zealand | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United States | 6 Participants | 8 Participants | 9 Participants | 23 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 10 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 5 / 9 | 1 / 12 |
| other Total, other adverse events | 5 / 6 | 7 / 9 | 0 / 12 |
| serious Total, serious adverse events | 1 / 6 | 1 / 9 | 0 / 12 |
Outcome results
Primary
Number of Participants Who Experience Treatment-Related Mortality (TRM) by Day 100
The number of patients who experience TRM on day 100. Treatment-Related Mortality (TRM) an event defined as a death prior to relapse or non-response. Time to TRM is defined as time from transplants to TRM. Patients who die between the start of the conditioning regimen and transplant will be considered a TRM with time to TRM of zero.
Time frame: From transplant up to 100 days
Population: All eligible randomized patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Busulfan, Cyclophosphamide, Melphalan) | Number of Participants Who Experience Treatment-Related Mortality (TRM) by Day 100 | 0 Participants |
| Arm II (Busulfan, Fludarabine Phosphate) | Number of Participants Who Experience Treatment-Related Mortality (TRM) by Day 100 | 1 Participants |
Primary
Percent Probability of Event-free Survival (EFS)
Probability of Event-free Survival (EFS) for Patients after 18 months. An event is either treatment related mortality (TRM), primary or secondary graft failure, or relapse/non-response (as defined in protocol section 10). Time to event is time from transplant with patients who die between the start of the conditioning regimen and transplant given a time to event of zero.
Time frame: From transplant up to 18 months
Population: All eligible randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Busulfan, Cyclophosphamide, Melphalan) | Percent Probability of Event-free Survival (EFS) | 83 percent probability |
| Arm II (Busulfan, Fludarabine Phosphate) | Percent Probability of Event-free Survival (EFS) | 22 percent probability |
Secondary
Percentage of Participants Who Experience Primary Graft Failure Event Between Arms
Primary Graft failure is defined as the failure to achieve an ANC \>= 500/uL after 42 days, determined by 3 consecutive measurements on different days; OR \< 5% donor cells in blood or bone marrow by day +42 (as demonstrated by a chimerism assay), without evidence of Juvenile Myelomonocytic Leukemia (JMML).
Time frame: Day 0 - day 540 (18 months) following completion of stem cell transplant
Population: All Eligible randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Busulfan, Cyclophosphamide, Melphalan) | Percentage of Participants Who Experience Primary Graft Failure Event Between Arms | 0 percentage of patients |
| Arm II (Busulfan, Fludarabine Phosphate) | Percentage of Participants Who Experience Primary Graft Failure Event Between Arms | 0 percentage of patients |
Secondary
Percent Probability of 18 Months-relapse Event Between Arms
Probability of patients relapsing at 18 months. A relapse event is defined in protocol section 10.2.3. Time to relapse/non-response is defined as time from transplant to when all criteria of section 10.2.3 are met.
Time frame: From transplant up to 18 months
Population: All eligible randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Busulfan, Cyclophosphamide, Melphalan) | Percent Probability of 18 Months-relapse Event Between Arms | 17 percent probability |
| Arm II (Busulfan, Fludarabine Phosphate) | Percent Probability of 18 Months-relapse Event Between Arms | 55 percent probability |