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

A Phase II Trial of Myeloablative Conditioning and Transplantation of Partially HLA-mismatched Bone Marrow for Patients With Hematologic Malignancies

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

Study Overview

• Status: Completed
• Conditions: MDS; Lymphomas; Leukemias
• Intervention / Treatment: Drug: Busulfan; Drug: Cyclophosphamide; Radiation: Total body irradiation

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.

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: 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.; Drug: Cyclophosphamide; Patient will receive Cy by IV once a day for 2 days.; Other Names: Cytoxan; CTX; Cy; Radiation: Total body irradiation; Patients will receive TBI once a day for 4 days.; Other Names: TBI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Engraftment as Measured by Donor Chimerism	Percentage of participants who achieved donor chimerism >=95%.	Day 60

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-relapse Mortality	Number of participants deceased for reasons other than disease relapse or progression.	Day 100, 1 year
Acute GVHD	Percentage of participants who experience grade II-IV or III-IV acute graft-versus-host-disease (GVHD) by Przepiorka criteria. The stages are defined as follows: Stage II: Rash on >50% of skin, bilirubin 2-3 mg/dL, or diarrhea 500-1000 mL/day; Stage III: Bilirubin 3-15 mg/dL or diarrhea >1000 mL/day; Stage IV: Generalized erythroderma with bullae or bilirubin >15 mg/dL This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999)	Day 100
Chronic GVHD	Percentage of participants who experience chronic GVHD. Chronic GVHD is graded using NIH consensus criteria and Seattle criteria. This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999)	6 months, 12 months
Survival	Percentage of participants alive (overall survival) and alive without disease relapse, progression, or diagnosis of myeloid malignancy (event-free survival). Estimated using Kaplan-Meier method.	1 year, 2 years, 3 years
Relapse	Percentage of participants who experienced disease progression or relapse. This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999)	1 year, 3 years

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Center for Research Resources (NCRR); Otsuka Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Heather Symons, M.D., Johns Hopkins University

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2008
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: November 20, 2008
• First Submitted That Met QC Criteria: November 21, 2008
• First Posted (Estimate): November 24, 2008

Study Record Updates

• Last Update Posted (Actual): March 14, 2019
• Last Update Submitted That Met QC Criteria: March 13, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Lymphoma; AML; ALL; Cyclophosphamide; Tacrolimus; Leukemia; TBI; Transplantation; MDS; Haploidentical; CML; JMML; Hematologic malignancies; Busulfan; Cellcept; Mismatched; CMMOL
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Busulfan
• Other Study ID Numbers: J0820; NA_00015795 (Other Identifier: JHMIRB); KL2RR025006 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO