Busulfan, Cyclophosphamide, and Melphalan or Busulfan and Fludarabine Phosphate Before Donor Hematopoietic Cell Transplant in Treating Younger Patients With Juvenile Myelomonocytic Leukemia

Study Overview
=================
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.

Official Title
-----------------
A Randomized Phase II Study Comparing Two Different Conditioning Regimens Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Children With Juvenile Myelomonocytic Leukemia (JMML)

Conditions
-----------------
Juvenile Myelomonocytic Leukemia

Intervention / Treatment
-----------------
* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Busulfan
* Drug: Cyclophosphamide
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Melphalan
* Drug: Mycophenolate Mofetil
* Other: Pharmacological Study
* Drug: Tacrolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 3 Months
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (busulfan, cyclophosphamide, melphalan)<br>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). | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic HCT<br>* Other names: HSCT;Drug: Busulfan<br>* Given IV<br>* Other names: WR-19508;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Drug: Mycophenolate Mofetil<br>* Given IV or PO<br>* Other names: MMF;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: Protopic;|
| Experimental: Arm II (busulfan, fludarabine phosphate)<br>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). | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic HCT<br>* Other names: HSCT;Drug: Busulfan<br>* Given IV<br>* Other names: WR-19508;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mycophenolate Mofetil<br>* Given IV or PO<br>* Other names: MMF;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: Protopic;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From transplant up to 18 months | 
| 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. | From transplant up to 100 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Day 0 - day 540 (18 months) following completion of stem cell transplant | 
| 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. | From transplant up to 18 months |