Methotrexate or Pentostatin for Graft-versus-host Disease Prophylaxis in Risk-adapted Allogeneic Bone Marrow Transplantation for Hematologic Malignancies

• Sponsor: St. Jude Children's Research Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01188798
• Collaborator: (none)
• Enrollment: 6
• Location: 1
• Arms: 2
• Duration (Months): 17
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of the study is to determine if participants who receive the GVHD prophylaxis medication pentostatin will have less severe hepatic toxicities than those receiving MTX. The study is estimated to have sufficient statistical power to ascertain at least a 20% improvement in day 42 NCI CTC grade 2 or above hepatic toxicity-free survival in pentostatin recipients.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia; Acute Myelocytic Leukemia; Chronic Myelocytic Leukemia; Hodgkin's Disease; Myelodysplastic Syndrome	Drug: Methotrexate; Drug: Pentostatin	Phase 3

Detailed Description

Participants will be randomized to receive either methotrexate (MTX) or pentostatin for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor. All participants will receive a standard backbone GVHD prophylaxis regimen (tacrolimus and sirolimus) and conditioning (cyclophosphamide/TBI). A risk-adapted approach will be used during conditioning to further minimize the risk of leukemia relapse based on two factors:

1. Lymphoid versus myeloid primary disease.

2. KIR compatibility between donor and host.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Methotrexate or Pentostatin for Graft-versus-host Disease Prophylaxis in Risk-adapted Allogeneic Bone Marrow Transplantation for Hematologic Malignancies
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Transplant recipients receiving Methotrexate Participants will be biologically stratified according to disease, donor, and KIR match. In addition to a standard backbone of 2 GVHD prophylactics, a computer generated randomization procedure will assign participants to a third GVHD prophylactic medication (MTX or pentostatin)	Drug: Methotrexate; Participants will be randomized to receive either methotrexate (MTX) or pentostatin for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor.
Experimental: Transplant recipients receiving Pentostatin Participants will be biologically stratified according to disease, donor, and KIR match.between donor and host.In addition to a standard backbone of 2 GVHD prophylactics, a computer generated randomization procedure will assign participants to a third GVHD prophylactic medication (MTX or pentostatin)	Drug: Pentostatin; Participants will be randomized to receive either methotrexate (MTX) or pentostatin for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor.

Outcome Measures

Primary Outcome Measures

1. Determining Whether the Hepatic Adverse Event-free (NCI Grades II-IV) Survival at Day 42 After an HLA-matched Transplant for Hematologic Malignancy Can be Improved by Using a GVHD Prophylaxis Regimen That Includes Pentostatin Rather Than MTX. [42 days post-transplant]

   The hypothesis was that individuals receiving the drug pentostatin as GVHD prophylaxis would experience less severe hepatic toxicity than those receiving methotrexate as GVHD prophylaxis. The study is estimated to have sufficient statistical power to ascertain at least a 20% improvement in day 42 grade 2 or above hepatic toxicity-free survival in pentostatin recipients

Secondary Outcome Measures

1. Assess Overall Survival, Relapse, Engraftment, and Regimen-related Morbidity and Estimating Cumulative Incidence of Pulmonary Adverse Events and Mucositis. [42 days post- transplant]

   To characterize the pharmacokinetic-pharmacodynamic relationships of pentostatin in this patient population and to assess the relationship between pre-transplant minimal residual disease (MRD) and transplant outcomes.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Months to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

*Age less than or equal to 21 years old

High risk malignancy as follows:

• High-risk ALL in CR1. Examples include, but not limited to: Induction failure or > 1% leukemic lymphoblasts in the bone marrow on remission date;> 0.1% leukemic lymphoblasts in the bone marrow in week 7 of continuation treatment (i.e. before reinduction I); re-emergence of leukemic lymphoblasts by MRD (at any level) in patients previously MRD negative; persistently detectable MRD at lower levels;early T-cell precursor (ETP) ALL.

• High-risk ALL beyond CR1, or with refractory disease. "Beyond CR1" denotes any CR following CR1, or any relapsed state. "Refractory disease" includes induction failure.

• High-risk de novo AML in CR1.Examples include but are not limited to:evidence of a high-risk genetic abnormality or high-risk MRD features.

• AML beyond CR1, or with refractory disease. "Beyond CR1" denotes any CR following CR1, or any relapsed state. "Refractory disease" includes induction failure.

• Therapy-related AML.

• MDS, primary or secondary, at any stage.

• NK cell lymphoblastic leukemia in any CR

• Biphenotypic bilineage, or undifferentiated leukemia.

• CML in any phase

• Hodgkin lymphoma beyond CR1 or with refractory disease. "Beyond CR1" denotes any CR following CR1, or any relapsed state.

• Non-Hodgkin lymphoma beyond CR1 or with refractory disease. "Beyond CR1" denotes any CR following CR1, or any relapsed state.

• Juvenile Myelomonocytic Leukemia (JMML).

• All patients with prior evidence of CNS leukemia must be treated and be in CNS CR to be eligible for study.

• Has a suitable HLA matched sibling or unrelated volunteer donor available for stem cell donation.A "matched" donor is defined as allele matching at 7/8 to 8/8 HLA loci at A, B, C and DRB1.For the purpose of this study, the term "matched sibling" also refers to an HLA matched family member.

• Does not have any other active malignancy other than the one for which this transplant is indicated.

• Left ventricular ejection fraction > 40%,or shortening fraction > 26%.

• Forced vital capacity (FVC) greater than or equal to 50% of predicted value (corrected for hemoglobin), or if patient is unable to perform pulmonary function testing, pulse oximetry greater than or equal to 92% on room air.

• Creatinine clearance greater than or equal to 70 ml/min/1.73m2

• Karnofsky or Lansky (age-dependent) performance score of greater than or equal to 70.

• Bilirubin less than or equal to 2.5 mg/dL.

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase less than or equal to 5 times upper limit of normal

• Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment.

• Not lactating.

• Has not had a prior allogeneic HSCT.

Exclusion Criteria:

• Pregnant and lactating females are excluded from participation as the short and long-term effects of the protocol interventions and infusion on a fetus or a nursing child through breast milk are not entirely known at this time.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St . Jude Children's Research Hospital	Memphis	Tennessee	United States	38105

Sponsors and Collaborators

• St. Jude Children's Research Hospital

Investigators

• Principal Investigator: Asha Pillai, MD, St. Jude Children's Research Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• St. Jude Children's Research Hospital

Publications

None provided.

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT01188798
• Other Study ID Numbers: MUDSIB
• First Posted: Aug 25, 2010
• Last Update Posted: Mar 21, 2013
• Last Verified: Feb 1, 2012

• Keywords provided by St. Jude Children's Research Hospital: Allogeneic Bone Marrow Transplantation; Graft versus host disease; Tacrolimus; Sirolimus; Methotrexate; Pentostatin
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematologic Neoplasms; Hodgkin Disease; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myelodysplastic Syndromes; Graft vs Host Disease; Methotrexate; Pentostatin

Study Results

Participant Flow

Recruitment Details	Six transplant patients were recruited between December, 2010 through March, 2011. Participants will be biologically stratified according to disease, donor, and KIR match.

Arm/Group Title	Methotrexate	Pentostatin
Arm/Group Description	Participants will be biologically stratified according to disease, donor, and KIR match. In addition to a standard backbone of 2 GVHD prophylactics, a computer generated randomization procedure will assign participants to a third GVHD prophylactic medication (MTX or pentostatin) Participants were randomized to receive methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor.	Participants will be biologically stratified according to disease, donor, and KIR match between donor and host. In addition to a standard backbone of 2 GVHD prophylactics, a computer generated randomization procedure will assign participants to a third GVHD prophylactic medication (MTX or pentostatin) Participants were randomized to receive pentostatin for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor.
Period Title: Overall Study
STARTED	2	4
COMPLETED	0	1
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Methotrexate	Pentostatin	Total
Arm/Group Description	Participants will be biologically stratified according to disease, donor, and KIR match. In addition to a standard backbone of 2 GVHD prophylactics, a computer generated randomization procedure will assign participants to a third GVHD prophylactic medication (MTX or pentostatin) Methotrexate: Participants were randomized to receive methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor.	Participants will be biologically stratified according to disease, donor, and KIR match between donor and host. In addition to a standard backbone of 2 GVHD prophylactics, a computer generated randomization procedure will assign participants to a third GVHD prophylactic medication (MTX or pentostatin) Pentostatin: Participants were randomized to receive pentostatin for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor.	Total of all reporting groups
Overall Participants	2	4	6
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.35 (0.07)	12.95 (6.65)	12.08 (5.32)
Sex: Female, Male (Count of Participants)
Female	1 50%	4 100%	5 83.3%
Male	1 50%	0 0%	1 16.7%

Outcome Measures

1. Primary Outcome

Title	Determining Whether the Hepatic Adverse Event-free (NCI Grades II-IV) Survival at Day 42 After an HLA-matched Transplant for Hematologic Malignancy Can be Improved by Using a GVHD Prophylaxis Regimen That Includes Pentostatin Rather Than MTX.
Description	The hypothesis was that individuals receiving the drug pentostatin as GVHD prophylaxis would experience less severe hepatic toxicity than those receiving methotrexate as GVHD prophylaxis. The study is estimated to have sufficient statistical power to ascertain at least a 20% improvement in day 42 grade 2 or above hepatic toxicity-free survival in pentostatin recipients
Time Frame	42 days post-transplant

Outcome Measure Data

Analysis Population Description

Insufficient data was available to answer objectives

Arm/Group Title	Methotrexate	Pentostatin
Arm/Group Description	Participants will be biologically stratified according to disease, donor, and KIR match. In addition to a standard backbone of 2 GVHD prophylactics, a computer generated randomization procedure will assign participants to a third GVHD prophylactic medication (MTX or pentostatin) Merthotrexate: Participants were randomized to receive methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor.	Participants will be biologically stratified according to disease, donor, and KIR match between donor and host. In addition to a standard backbone of 2 GVHD prophylactics, a computer generated randomization procedure will assign participants to a third GVHD prophylactic medication (MTX or pentostatin) Pentostatin: Participants were randomized to receive pentostatin for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor.
Measure Participants	0	0

2. Secondary Outcome

Title	Assess Overall Survival, Relapse, Engraftment, and Regimen-related Morbidity and Estimating Cumulative Incidence of Pulmonary Adverse Events and Mucositis.
Description	To characterize the pharmacokinetic-pharmacodynamic relationships of pentostatin in this patient population and to assess the relationship between pre-transplant minimal residual disease (MRD) and transplant outcomes.
Time Frame	42 days post- transplant

Outcome Measure Data

Analysis Population Description

Insufficient data was available to answer objectives.

Arm/Group Title	Methotrexate	Pentostatin
Arm/Group Description	Participants will be biologically stratified according to disease, donor, and KIR match. In addition to a standard backbone of 2 GVHD prophylactics, a computer generated randomization procedure will assign participants to a third GVHD prophylactic medication (MTX or pentostatin) Merthotrexate: Participants were randomized to receive methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor.	Participants will be biologically stratified according to disease, donor, and KIR match between donor and host. In addition to a standard backbone of 2 GVHD prophylactics, a computer generated randomization procedure will assign participants to a third GVHD prophylactic medication (MTX or pentostatin). Pentostatin: Participants were randomized to receive pentostatin for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor.
Measure Participants	0	0

Adverse Events

Time Frame	Adverse events were collected from diagnosis to day 100 post-transplant.
Arm/Group Title	Methotrexate		Pentostatin
Arm/Group Description	Participants will be biologically stratified according to disease, donor, and KIR match. In addition to a standard backbone of 2 GVHD prophylactics, a computer generated randomization procedure will assign participants to a third GVHD prophylactic medication (MTX or pentostatin) Merthotrexate: Participants were randomized to receive methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor.		Participants will be biologically stratified according to disease, donor, and KIR match between donor and host. In addition to a standard backbone of 2 GVHD prophylactics, a computer generated randomization procedure will assign participants to a third GVHD prophylactic medication (MTX or pentostatin) Pentostatin: Participants were randomized to receive pentostatin for graft-versus-host disease (GVHD) prophylaxis after receiving an allogeneic bone marrow transplant from an HLA-matched related or unrelated donor.
All Cause Mortality
	Methotrexate		Pentostatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Methotrexate		Pentostatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		4/4 (100%)
Gastrointestinal disorders
Ulcer of pharynx (disorder)	0/2 (0%)	0	1/4 (25%)	1
General disorders
Fever without Neutropenia	2/2 (100%)	4	2/4 (50%)	3
Hepatobiliary disorders
Failure, Hepatic	0/2 (0%)	0	1/4 (25%)	1
Veno-occlusive Disease, Hepatic	0/2 (0%)	0	1/4 (25%)	1
Immune system disorders
Graft Versus Host Disease (GVHD), Acute, Liver	0/2 (0%)	0	1/4 (25%)	1
Graft Versus Host Disease (GVHD), Joint, Chronic	0/2 (0%)	0	1/4 (25%)	1
Infections and infestations
Febrile Neutropenia	0/2 (0%)	0	1/4 (25%)	1
Infection, Klebsiella, Blood	0/2 (0%)	0	1/4 (25%)	1
Metabolism and nutrition disorders
Anemia	0/2 (0%)	0	1/4 (25%)	1
Nervous system disorders
Encephalopathy due to vitamin deficiency (disorder)	0/2 (0%)	0	1/4 (25%)	1
Other (Not Including Serious) Adverse Events
	Methotrexate		Pentostatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		4/4 (100%)
Blood and lymphatic system disorders
Bleeding/Hemorrhage, Gastrointestinal	0/2 (0%)	0	1/4 (25%)	1
Epistaxis	2/2 (100%)	3	2/4 (50%)	2
Hematemesis	1/2 (50%)	1	0/4 (0%)	0
Hemorrhagic Cystitis	0/2 (0%)	0	1/4 (25%)	1
Infection, Adenovirus, Blood	0/2 (0%)	0	1/4 (25%)	1
Cardiac disorders
Hypertension	1/2 (50%)	1	1/4 (25%)	1
Gastrointestinal disorders
Chronic gastritis (disorder)	0/2 (0%)	0	1/4 (25%)	1
Gallbladder Disease	0/2 (0%)	0	1/4 (25%)	1
Mucositis	1/2 (50%)	1	2/4 (50%)	2
Nausea (finding)	0/2 (0%)	0	1/4 (25%)	1
Ulcer of pharynx (disorder)	1/2 (50%)	1	0/4 (0%)	0
Vomiting (disorder)	0/2 (0%)	0	1/4 (25%)	1
General disorders
Fever without Neutropenia	1/2 (50%)	1	0/4 (0%)	0
Hepatobiliary disorders
Typhlitis	0/2 (0%)	0	1/4 (25%)	1
Immune system disorders
Cytokine Release Syndrome (Stem Cell Infusion)	0/2 (0%)	0	2/4 (50%)	2
Cytokine Release Syndrome (Thymoglobulin)	0/2 (0%)	0	1/4 (25%)	1
Infections and infestations
Febrile Neutropenia	2/2 (100%)	5	1/4 (25%)	1
Infection, Adenovirus, Stool	1/2 (50%)	1	1/4 (25%)	1
Infection, BK Virus, Blood	0/2 (0%)	0	2/4 (50%)	2
Infection, BK Virus, Urine	0/2 (0%)	0	1/4 (25%)	1
Infection, Clostridium Difficile, Stool	2/2 (100%)	2	1/4 (25%)	1
Infection, Cytomegalovirus, Urine	0/2 (0%)	0	1/4 (25%)	1
Infection, E. Coli, Blood	0/2 (0%)	0	1/4 (25%)	1
Infection, Helicobacter pylori, Stomach	1/2 (50%)	1	0/4 (0%)	0
Infection, Herpes Simplex Virus (HSV), Oral	0/2 (0%)	0	1/4 (25%)	1
Infection, Pseudomonas Aeruginosa, Blood	0/2 (0%)	0	1/4 (25%)	1
Infection, Staphylococcus Epidermidis, Blood	1/2 (50%)	1	0/4 (0%)	0
Infection, Varicella Zoster, Abdomen, Skin	0/2 (0%)	0	1/4 (25%)	1
Tracheitis	0/2 (0%)	0	1/4 (25%)	1
Metabolism and nutrition disorders
Hypertension	0/2 (0%)	0	1/4 (25%)	1
Metabolic Encephalopathy	0/2 (0%)	0	1/4 (25%)	1
Nervous system disorders
Mood Alteration	1/2 (50%)	1	0/4 (0%)	0
Sensory neuropathy	0/2 (0%)	0	1/4 (25%)	1
Renal and urinary disorders
Disease, Renal	0/2 (0%)	0	1/4 (25%)	1
Engraftment Syndrome	0/2 (0%)	0	1/4 (25%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/2 (0%)	0	1/4 (25%)	1
Nodule, Pulmonary, Left Lower Lobe	0/2 (0%)	0	1/4 (25%)	1
Skin and subcutaneous tissue disorders
Pruritis	0/2 (0%)	0	1/4 (25%)	1

Limitations/Caveats

This study was terminated prematurely. The Data Safety and Monitoring Board (DSMB) requested major scientific study changes. This was deemed infeasible by institutional leadership and study was terminated. Therefore, no final results exist to report.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.