A Two-Step Approach to Bone Marrow Transplant Using Cells From A Partially-Matched Relative

A Two Step Approach To Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies From HLA Partially-Matched Related Donors

The purpose of this study is to develop a way of treating patients who do not have a completely matched family donor or a readily available unrelated donor with bone marrow transplant by using a partially-matched family donor. Patients receiving this type of transplant will receive chemotherapy and/or radiation to treat their disease. They will also receive their donor's cells in 2 parts. During the first part, the donor's lymphocytes will be exposed to one of the chemotherapy agents to help the patient become tolerant to the lymphocytes. In the second part of the transplant, the patient will receive their donor's stem cells to help recover their peripheral blood counts and establish long-term engraftment. The hypothesis of this study is that in partially-matched allogeneic transplant, there is a defined number of donor T-cells that can be treated and given to the recipient to avoid post-transplant infection without causing severe graft-versus-host disease.

Study Overview

• Status: Completed
• Conditions: Hematologic Malignancies
• Intervention / Treatment: Biological: Donor Lymphocyte Infusion (DLI); Drug: Cyclophosphamide (CY); Radiation: Total Body Irradiation (TBI); Drug: Tacrolimus; Drug: Mycophenolate Mofetil (MMF); Biological: Hematopoietic Stem Cell Transplant (HSCT)

Detailed Description

Haploidentical hematopoietic stem cell transplant is a life-saving therapy for patients who are without well matched donors. This type of therapy has been associated with poor outcomes in the past due to complications such as infection. The Jefferson 2 Step approach was designed to allow the infusion of an exact dose of tolerized lymphocytes in haploidentical transplant in order to allow for immune reconstitution post transplant to avoid infectious complications while still having acceptable rates of GVHD. In this approach, patients with high-risk hematological malignancies undergo 8 fractions of TBI (12 Gy) followed by an exact dose of donor lymphocytes. The phase I portion of the study determined the optimal dose of lymphocytes. Two days after receiving the donor lymphocytes, the patients receive 2 daily doses of cyclophosphamide. One day after receiving cyclophosphamide, the patients receive stem cell from their donor. Tacrolimus and mycophenylate mofetil are used as GVHD prophylaxis.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Any patient with a hematologic or oncologic diagnosis in which allogeneic HSCT is thought to be beneficial, and in whom front-line therapy has already been applied.
2. Patients must have a related donor who is either a one, two or three out of six antigen mismatch at the HLA-A;B;DR loci.
3. Patients without a well-matched unrelated donor or those who have a disease status that precludes a wait for an identified unrelated donor.

4. Patients must adequate organ function:

   • LVEF of >45%
   • FVC or FEV1 >45% of predicted
   • Adequate liver function as defined by a serum bilirubin <1.8, AST or ALT < 2.5X upper limit of normal
   • Serum creatinine < 2.0 mg/dl or creatinine clearance of > 40 ml/min
5. Performance status > 60% (Karnofsky)
6. Patients must be willing to use contraception if they have childbearing potential
7. Able to give informed consent

Exclusion Criteria:

1. An eligible HLA-identical sibling donor.
2. Performance status < 60% (Karnosfsky)
3. HIV positive
4. Active involvement of the central nervous system with malignancy
5. Psychiatric disorder that would preclude patients from signing an informed consent
6. Pregnancy
7. Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder.

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: Haploidentical Allogeneic Transplantation; Patients undergoing hematopoietic stem cell transplant from a partially matched related donor

Biological: Donor Lymphocyte Infusion (DLI); DLI given 6 days prior to transplant (HSCT).; Other Names: DLI; T cell infusion; Drug: Cyclophosphamide (CY); Cyclophosphamide given once daily at 60 mg/kg on days 2 and 3 prior to transplant (HSCT).; Other Names: Cytoxan; Endoxan; Neosar; Revimmune; Procytox; CY; cytophosphane; Radiation: Total Body Irradiation (TBI); TBI twice daily days 6-9 prior to transplant (HSCT); Other Names: TBI; radiotherapy; Drug: Tacrolimus; Tacrolimus given one day prior to transplant (HSCT).; Other Names: Prograf; Protopic; FK-506; Advagraf; fujimycin; Drug: Mycophenolate Mofetil (MMF); MMF given one day prior to transplant (HSCT).; Other Names: CellCept; Myfortic; MMF; Biological: Hematopoietic Stem Cell Transplant (HSCT); CD34+ selected Hematopoietic Stem Cell Transplant (HSCT) is performed. This is the day of transplantation.; Other Names: HSCT; stem cell transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival of Participants	To determine overall survival at 6 months post-transplant.	6 months
Optimal Dose of CD3+ Donor Lymphocytes (T-cells) for Consistent Engraftment Without GVHD	To determine the optimal dose of CD3+ donor lymphocytes required for consistent engraftment without the development of grade III/IV GVHD. Measured as CD3+ donor lymphocytes given as n x 10^8/kg. "n" was found to be 2 and was found to be the optimal dose and was the only dose given.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Engraftment Rates	To assess hematopoietic engraftment rates.	6 months
Lymphoid Recovery	To assess the pace of lymphoid recovery in this patient population.	6 months
Incidence of Grades III-IV GVHD	To determine the incidence and severity of GVHD in these patients using a combination of cyclophosphamide, tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis.' Severity was graded using CTCAE 3.0 (1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death)	6 months

Collaborators and Investigators

• Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University
• Investigators: Principal Investigator: Neal Flomenberg, MD, Thomas Jefferson University

Publications and helpful links

General Publications

• Grosso D, Carabasi M, Filicko-O'Hara J, Kasner M, Wagner JL, Colombe B, Cornett Farley P, O'Hara W, Flomenberg P, Werner-Wasik M, Brunner J, Mookerjee B, Hyslop T, Weiss M, Flomenberg N. A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing. Blood. 2011 Oct 27;118(17):4732-9. doi: 10.1182/blood-2011-07-365338. Epub 2011 Aug 25.

Helpful Links

• Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer Center
• Thomas Jefferson University Hospitals

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): August 1, 2009
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: January 29, 2007
• First Submitted That Met QC Criteria: January 30, 2007
• First Posted (Estimated): January 31, 2007

Study Record Updates

• Last Update Posted (Actual): May 4, 2025
• Last Update Submitted That Met QC Criteria: May 1, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Hematologic Malignancies; Haploidentical Transplant; Two Step Approach
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antibiotics, Antitubercular; Antitubercular Agents; Calcineurin Inhibitors; Cyclophosphamide; Mycophenolic Acid; Tacrolimus
• Other Study ID Numbers: 06U.20; 2005-84 (Other Identifier: CCRRC); JT 1157 (Other Identifier: JeffTrial Number)