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

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01824693
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 30
• Locations: 50
• Arms: 2
• Actual Duration (Months): 54.2
• Patients Per Site: 0.6
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Juvenile Myelomonocytic Leukemia	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	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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.

2. 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:

1. 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.

2. 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:

1. 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).

2. 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.

3. To create a JMML-specific pre-HCT index to allow better risk-stratification of future patients.

4. 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.

5. To validate gene expression and methylation classifiers predictive of relapse in patients with JMML.

6. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: Jun 24, 2013
• Actual Primary Completion Date: Dec 31, 2017
• Actual Study Completion Date: Dec 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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).	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic HCT; Other Names: Allogeneic Hematopoietic Cell Transplantation Allogeneic Stem Cell Transplantation HSC HSCT ; Drug: Busulfan; Given IV; Other Names: 1, 4-Bis[methanesulfonoxy]butane BUS Bussulfam Busulfanum Busulfex Busulphan CB 2041 CB-2041 Glyzophrol GT 41 GT-41 Joacamine Methanesulfonic Acid Tetramethylene Ester Methanesulfonic acid, tetramethylene ester Mielucin Misulban Misulfan Mitosan Myeleukon Myeloleukon Myelosan Mylecytan Myleran Sulfabutin Tetramethylene Bis(methanesulfonate) Tetramethylene bis[methanesulfonate] WR-19508 ; Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Melphalan; Given IV; Other Names: Alanine Nitrogen Mustard CB-3025 L-PAM L-Phenylalanine Mustard L-sarcolysin L-Sarcolysin Phenylalanine mustard L-Sarcolysine Melphalanum Phenylalanine Mustard Phenylalanine nitrogen mustard Sarcoclorin Sarkolysin WR-19813 ; Drug: Mycophenolate Mofetil; Given IV or PO; Other Names: Cellcept MMF ; Other: Pharmacological Study; Correlative studies; Drug: Tacrolimus; Given IV or PO; Other Names: FK 506 Fujimycin Hecoria Prograf Protopic
Experimental: 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).	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic HCT; Other Names: Allogeneic Hematopoietic Cell Transplantation Allogeneic Stem Cell Transplantation HSC HSCT ; Drug: Busulfan; Given IV; Other Names: 1, 4-Bis[methanesulfonoxy]butane BUS Bussulfam Busulfanum Busulfex Busulphan CB 2041 CB-2041 Glyzophrol GT 41 GT-41 Joacamine Methanesulfonic Acid Tetramethylene Ester Methanesulfonic acid, tetramethylene ester Mielucin Misulban Misulfan Mitosan Myeleukon Myeloleukon Myelosan Mylecytan Myleran Sulfabutin Tetramethylene Bis(methanesulfonate) Tetramethylene bis[methanesulfonate] WR-19508 ; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)- Beneflur Fludara SH T 586 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Mycophenolate Mofetil; Given IV or PO; Other Names: Cellcept MMF ; Other: Pharmacological Study; Correlative studies; Drug: Tacrolimus; Given IV or PO; Other Names: FK 506 Fujimycin Hecoria Prograf Protopic

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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).

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Months to 18 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
3	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
4	Mattel Children's Hospital UCLA	Los Angeles	California	United States	90095
5	Children's Hospital of Orange County	Orange	California	United States	92868
6	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
7	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
8	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
9	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
10	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
11	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
12	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
13	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
14	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
15	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
16	Norton Children's Hospital	Louisville	Kentucky	United States	40202
17	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
18	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
19	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
20	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
21	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
22	The Childrens Mercy Hospital	Kansas City	Missouri	United States	64108
23	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri	United States	63104
24	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
25	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
26	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
27	Columbia University/Herbert Irving Cancer Center	New York	New York	United States	10032
28	University of Rochester	Rochester	New York	United States	14642
29	New York Medical College	Valhalla	New York	United States	10595
30	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
31	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
32	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
33	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
34	Oregon Health and Science University	Portland	Oregon	United States	97239
35	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
36	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
37	Medical University of South Carolina	Charleston	South Carolina	United States	29425
38	Medical City Dallas Hospital	Dallas	Texas	United States	75230
39	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
40	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
41	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
42	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
43	Seattle Children's Hospital	Seattle	Washington	United States	98105
44	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
45	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
46	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
47	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
48	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
49	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
50	Starship Children's Hospital	Grafton	Auckland	New Zealand	1145

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Christopher Dvorak, Children's Oncology Group

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 5, 2014

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT01824693
• Other Study ID Numbers: ASCT1221; NCI-2013-00738; COG-ASCT1221; ASCT1221; ASCT1221; ASCT1221; U10CA180886; U10CA098543
• First Posted: Apr 5, 2013
• Last Update Posted: Dec 5, 2018
• Last Verified: Nov 1, 2018

• Additional relevant MeSH terms: Leukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Mycophenolic Acid; Cyclophosphamide; Melphalan; Busulfan; Mechlorethamine; Nitrogen Mustard Compounds; Fludarabine; Fludarabine phosphate; Tacrolimus

Study Results

Participant Flow

Arm/Group Title	Arm I (Busulfan, Cyclophosphamide, Melphalan)	Arm II (Busulfan, Fludarabine Phosphate)	ARM III (Non-Randomized)
Arm/Group Description	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	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	Patients who were not randomized and did not proceed to transplant because they did not meet all the protocol requirement for randomization
Period Title: Overall Study
STARTED	6	9	15
COMPLETED	5	2	0
NOT COMPLETED	1	7	15

Baseline Characteristics

Arm/Group Title	Arm I (Busulfan, Cyclophosphamide, Melphalan)	Arm II (Busulfan, Fludarabine Phosphate)	ARM III (Non-Randomized)	Total
Arm/Group Description	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	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	Patients who were not randomized and did not proceed to transplant because they did not meet all the protocol requirement for randomization	Total of all reporting groups
Overall Participants	6	9	15	30
Age (Count of Participants)
<=18 years	6 100%	9 100%	15 100%	30 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	0.50 (0.84)	2.33 (3.71)	1.27 (1.75)	1.00 (2.42)
Sex: Female, Male (Count of Participants)
Female	3 50%	2 22.2%	5 33.3%	10 33.3%
Male	3 50%	7 77.8%	10 66.7%	20 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 22.2%	2 13.3%	4 13.3%
Not Hispanic or Latino	6 100%	7 77.8%	13 86.7%	26 86.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	1 6.7%	1 3.3%
Asian	2 33.3%	1 11.1%	2 13.3%	5 16.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	1 6.7%	1 3.3%
White	3 50%	8 88.9%	10 66.7%	21 70%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 16.7%	0 0%	1 6.7%	2 6.7%
Region of Enrollment (Count of Participants)
United States	6 100%	8 88.9%	9 60%	23 76.7%
Canada	0 0%	0 0%	3 20%	3 10%
Australia	0 0%	0 0%	1 6.7%	1 3.3%
Kuwait	0 0%	1 11.1%	0 0%	1 3.3%
New Zealand	0 0%	0 0%	2 13.3%	2 6.7%

Outcome Measures

1. Primary Outcome

Title	Percent Probability of Event-free Survival (EFS)
Description	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

Outcome Measure Data

Analysis Population Description

All eligible randomized patients

Arm/Group Title	Arm I (Busulfan, Cyclophosphamide, Melphalan)	Arm II (Busulfan, Fludarabine Phosphate)
Arm/Group Description	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	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
Measure Participants	6	9
Number (95% Confidence Interval) [percent probability]	83	22

2. Primary Outcome

Title	Number of Participants Who Experience Treatment-Related Mortality (TRM) by Day 100
Description	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

Outcome Measure Data

Analysis Population Description

All eligible randomized patients

Arm/Group Title	Arm I (Busulfan, Cyclophosphamide, Melphalan)	Arm II (Busulfan, Fludarabine Phosphate)
Arm/Group Description	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	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
Measure Participants	6	9
Count of Participants [Participants]	0 0%	1 11.1%

3. Secondary Outcome

Title	Percentage of Participants Who Experience Primary Graft Failure Event Between Arms
Description	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

Outcome Measure Data

Analysis Population Description

All Eligible randomized patients

Arm/Group Title	Arm I (Busulfan, Cyclophosphamide, Melphalan)	Arm II (Busulfan, Fludarabine Phosphate)
Arm/Group Description	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	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
Measure Participants	6	9
Number [percentage of patients]	0	0

4. Secondary Outcome

Title	Percent Probability of 18 Months-relapse Event Between Arms
Description	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

Outcome Measure Data

Analysis Population Description

All eligible randomized patients

Arm/Group Title	Arm I (Busulfan, Cyclophosphamide, Melphalan)	Arm II (Busulfan, Fludarabine Phosphate)
Arm/Group Description	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	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
Measure Participants	6	9
Number (95% Confidence Interval) [percent probability]	17	55

Adverse Events

Time Frame	Up to 1 year after completion of transplant.
Adverse Event Reporting Description	Adverse event reporting is collected routinely using case report forms. SAE field contains NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. Ineligible patients are excluded from reporting of adverse events. 3 patients from ARM III (Non-Randomized) were excluded due to ineligibility.
Arm/Group Title	Arm I (Busulfan, Cyclophosphamide, Melphalan)		Arm II (Busulfan, Fludarabine Phosphate)		ARM III (Non-Randomized)
Arm/Group Description	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		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		Patients who have not met all protocol requirements to proceed to HCT
All Cause Mortality
	Arm I (Busulfan, Cyclophosphamide, Melphalan)		Arm II (Busulfan, Fludarabine Phosphate)		ARM III (Non-Randomized)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		5/9 (55.6%)		1/12 (8.3%)
Serious Adverse Events
	Arm I (Busulfan, Cyclophosphamide, Melphalan)		Arm II (Busulfan, Fludarabine Phosphate)		ARM III (Non-Randomized)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		1/9 (11.1%)		0/12 (0%)
General disorders
Multi-organ failure	0/6 (0%)	0	1/9 (11.1%)	1	0/12 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/6 (16.7%)	1	1/9 (11.1%)	1	0/12 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm I (Busulfan, Cyclophosphamide, Melphalan)		Arm II (Busulfan, Fludarabine Phosphate)		ARM III (Non-Randomized)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		7/9 (77.8%)		0/12 (0%)
Blood and lymphatic system disorders
Anemia	0/6 (0%)	0	1/9 (11.1%)	1	0/12 (0%)	0
Blood and lymphatic system disorders - Other, specify	2/6 (33.3%)	3	0/9 (0%)	0	0/12 (0%)	0
Febrile neutropenia	3/6 (50%)	5	3/9 (33.3%)	3	0/12 (0%)	0
Cardiac disorders
Sinus tachycardia	1/6 (16.7%)	2	0/9 (0%)	0	0/12 (0%)	0
Gastrointestinal disorders
Abdominal distension	2/6 (33.3%)	2	0/9 (0%)	0	0/12 (0%)	0
Abdominal pain	2/6 (33.3%)	2	1/9 (11.1%)	1	0/12 (0%)	0
Ascites	1/6 (16.7%)	1	1/9 (11.1%)	1	0/12 (0%)	0
Diarrhea	1/6 (16.7%)	1	1/9 (11.1%)	1	0/12 (0%)	0
Mucositis oral	2/6 (33.3%)	2	3/9 (33.3%)	3	0/12 (0%)	0
General disorders
Edema face	0/6 (0%)	0	1/9 (11.1%)	1	0/12 (0%)	0
Fatigue	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Fever	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Irritability	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Pain	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Edema limbs	0/6 (0%)	0	1/9 (11.1%)	1	0/12 (0%)	0
Infusion related reaction	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Infections and infestations
Catheter related infection	1/6 (16.7%)	1	1/9 (11.1%)	1	0/12 (0%)	0
Infections and infestations - Other, specify	3/6 (50%)	8	1/9 (11.1%)	1	0/12 (0%)	0
Sepsis	1/6 (16.7%)	2	2/9 (22.2%)	2	0/12 (0%)	0
Skin infection	0/6 (0%)	0	1/9 (11.1%)	1	0/12 (0%)	0
Investigations
Alanine aminotransferase increased	1/6 (16.7%)	1	2/9 (22.2%)	2	0/12 (0%)	0
Aspartate aminotransferase increased	1/6 (16.7%)	1	2/9 (22.2%)	2	0/12 (0%)	0
Blood bilirubin increased	2/6 (33.3%)	4	1/9 (11.1%)	2	0/12 (0%)	0
Weight gain	3/6 (50%)	4	0/9 (0%)	0	0/12 (0%)	0
Weight loss	0/6 (0%)	0	1/9 (11.1%)	1	0/12 (0%)	0
Urine output decreased	0/6 (0%)	0	1/9 (11.1%)	1	0/12 (0%)	0
Metabolism and nutrition disorders
Anorexia	3/6 (50%)	6	3/9 (33.3%)	3	0/12 (0%)	0
Dehydration	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Hyperglycemia	1/6 (16.7%)	1	2/9 (22.2%)	2	0/12 (0%)	0
Hypermagnesemia	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Hypoalbuminemia	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Hypocalcemia	0/6 (0%)	0	1/9 (11.1%)	1	0/12 (0%)	0
Hypokalemia	3/6 (50%)	3	1/9 (11.1%)	1	0/12 (0%)	0
Hypomagnesemia	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Hypophosphatemia	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Hoarseness	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Hypoxia	1/6 (16.7%)	1	1/9 (11.1%)	1	0/12 (0%)	0
Pneumonitis	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Respiratory, thoracic and mediastinal disorders - Other, specify	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0
Stridor	2/6 (33.3%)	2	0/9 (0%)	0	0/12 (0%)	0
Vascular disorders
Hypotension	2/6 (33.3%)	3	1/9 (11.1%)	1	0/12 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Must obtain sponsor approval