Safety Study of Bone Marrow Transplant Using Mismatched Tissue Followed by Chemotherapy

NCT ID: NCT00796562

Last Updated: 2019-03-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 107 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-12-31
• Study Completion Date: 2016-11-30

Brief Summary

The purpose of this study is to see if giving high dose chemotherapy and total body irradiation before and repeating high dose chemotherapy after a bone marrow transplant could reduce the incidence of graft rejection and disease for patients with blood cancers

Detailed Description

Allogeneic blood or marrow transplantation (alloBMT), following either marrow-ablative or nonmyeloablative conditioning, is a potentially curative treatment for a variety of hematologic malignancies and non-malignant hematologic disorders. Of all the potential sources of allografts, transplantation of stem cells from a human leukocyte antigen (HLA)-matched sibling has generally produced the best overall outcomes, i.e. overall and progression-free survival. Unfortunately, only about a third of candidates for alloBMT have HLA-matched siblings.

For patients who lack HLA-matched siblings, there are three alternative sources of stem cells for alloBMT: 1) volunteer unrelated donors; 2) umbilical cord blood; and 3) partially HLA-mismatched, or haploidentical, related donors. Since any patient shares exactly one HLA haplotype with each biological parent or child and half of siblings, an eligible haploidentical donor can be identified rapidly in nearly all cases. However, haploidentical BMT has been associated with significant risks of graft rejection and severe GVHD, which are manifestations of excessive alloreactivity by host and donor T cells, respectively.

The risk of severe GVHD may be reduced in intensively conditioned recipients of grafts that have been rigorously depleted of mature T cells or selectively depleted of alloreactive T cells, but the risks of serious infection and death from prolonged immune compromise in these patients remains high. Cyclophosphamide(Cy) is a highly immunosuppressive antineoplastic agent that has an established role in conditioning for alloBMT.

Typically, the drug is administered prior to transplantation to prevent graft rejection by suppressing the host immune system. However, pre-transplantation conditioning with Cy increases the risk of GVHD following allogeneic T cell infusion in mouse models. In contrast, administration of a properly timed, high dose of Cy after BMT inhibits both graft rejection and GVHD.

Conditions

MDS; Leukemias; Lymphomas

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Myeloablative haploidentical BMT

• All participants except those with acute lymphoblastic leukemia and lymphoblastic lymphoma: Busulfan will be administered 1 mg/kg oral (or 0.8 mg/kg IV) four times per day for four days, followed by cyclophosphamide 50 mg/kg once per day for two days.
• Participants with acute lymphocytic leukemia or lymphoblastic lymphoma: Cyclophosphamide will be administered 50 mg/kg once per day for two days, followed by total body irradiation at 300 cGy per day for four days.

Group Type: EXPERIMENTAL

Busulfan

Intervention Type: DRUG

Participant will receive Busulfan injections, 4 times a day for 4 days with dilantin prophylaxis (in patients 10 years of age or older). Busulfan levels in the blood will be measured and dose adjusted, if needed.

Cyclophosphamide

Intervention Type: DRUG

Patient will receive Cy by IV once a day for 2 days.

Total body irradiation

Intervention Type: RADIATION

Patients will receive TBI once a day for 4 days.

Interventions

Busulfan

Participant will receive Busulfan injections, 4 times a day for 4 days with dilantin prophylaxis (in patients 10 years of age or older). Busulfan levels in the blood will be measured and dose adjusted, if needed.

Intervention Type: DRUG

Cyclophosphamide

Patient will receive Cy by IV once a day for 2 days.

Intervention Type: DRUG

Total body irradiation

Patients will receive TBI once a day for 4 days.

Intervention Type: RADIATION

Other Intervention Names

Cy; Cytoxan; CTX; TBI

Eligibility Criteria

Inclusion Criteria

• Acute lymphocytic leukemia in high risk CR1
• Acute myeloid leukemia in CR1
• Therapy-related AML
• RAEB with >5% and <20% bone marrow blasts
• Chronic myelogenous leukemia beyond 1st chronic phase; Patients cannot be in blast crisis
• CMMoL
• JMML
• Chemotherapy-resistant Hodgkins Lymphoma or intermediate or high grade Non-Hodgkins lymphoma (Less than a PR after standard or salvage chemotherapy)
• Mantle cell lymphoma: chemotherapy refractory (Less than a PR after standard or salvage chemotherapy) or patients beyond CR1 with chemosensitive disease
• Follicular Lymphoma, Grade 3
• Transformed indolent lymphomas

Exclusion Criteria

• Poor cardiac function: left ventricular ejection fraction <45% as determined by MUGA or ECHO. For pediatric patients LVEF <45% or a shortening fraction below normal limits for age.
• Poor pulmonary function: FEV1 and FVC <50% predicted for patients who have not received thoracic or mantle irradiation. For patients who have received thoracic or mantle irradiation, FEV1 and FVC <70% predicted or DLCO < 50 of predicted. For children unable to perform PFTs because of developmental stage pulse oximetry < 85% on RA
• Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary malignancy)
• Poor renal function: Creatinine >2.0mg/dl or creatinine clearance
• HIV-positive
• Positive leukocytotoxic crossmatch
• Women of childbearing potential who currently are pregnant or who are not practicing adequate contraception
• Uncontrolled viral, bacterial, or fungal infections Patients with symptoms consistent with RSV, influenza A, B, or parainfluenza at the time of enrollment will be assayed for the above viruses and if positive are not eligible for the trial until they are no longer symptomatic (patients may have continued assay positivity for a period of time post resolution of symptoms secondary to the nature of the assay.
• Indolent lymphomas (Follicular Grade 1 and 2, marginal zone, chronic lymphocytic leukemia, small lymphocytic lymphoma, MALT)

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Otsuka Pharmaceutical Co., Ltd.

INDUSTRY

Sponsor Role: collaborator

National Center for Research Resources (NCRR)

NIH

Sponsor Role: collaborator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Heather Symons, M.D.

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Countries

United States

References

Fine J.P. and Gray, R.J. (1999), A proportional hazards model for the subdistribution of a competing risk, Journal of the American Statistical Association, 94:496-509.

Reference Type: BACKGROUND

Symons HJ, Zahurak M, Cao Y, Chen A, Cooke K, Gamper C, Klein O, Llosa N, Zambidis ET, Ambinder R, Bolanos-Meade J, Borrello I, Brodsky R, DeZern A, Gojo I, Showel M, Swinnen L, Smith BD, Luznik L, Jones RJ, Fuchs EJ. Myeloablative haploidentical BMT with posttransplant cyclophosphamide for hematologic malignancies in children and adults. Blood Adv. 2020 Aug 25;4(16):3913-3925. doi: 10.1182/bloodadvances.2020001648.

Reference Type: DERIVED

PMID: 32813874 (View on PubMed)

Other Identifiers

NA_00015795

Identifier Type: OTHER

Identifier Source: secondary_id

KL2RR025006

Identifier Type: NIH

Identifier Source: secondary_id

View Link

J0820

Identifier Type: -

Identifier Source: org_study_id