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

This study has suspended participant recruitment.
(Slow accrual)
Information provided by (Responsible Party):
Thomas Jefferson University
ClinicalTrials.gov Identifier:
First received: February 6, 2012
Last updated: August 5, 2014
Last verified: August 2014

The majority of patients who undergo allogeneic transplant with active or resistant disease at the time of the transplant will relapse afterwards. Therefore, new strategies to prevent relapse are needed in this patient population.

Since 2006, the majority of patients undergoing half-matched hematopoietic stem cell transplant (HSCT) at Jefferson have received their transplants in 2 steps. At Jefferson, this type of transplant is referred to as the 2 step approach. Patients undergoing HSCT who were in remission at HSCT did very well using the 2 step approach, but many patients with resistant disease at the time of HSCT relapsed later.

Post-transplant relapse is associated with tumor escape mechanisms such as the downregulation or loss of HLA antigens. This results in the inability of the donor immune system to recognize the malignant cells. In this phase II trial, patients will undergo HSCT using the Jefferson 2 step approach, but will receive cells from 2 donors instead of one. It is hypothesized that it will be harder for tumor cells to escape from 2 different donor immune systems after HSCT.

Condition Intervention Phase
Hematologic Malignancy
Acute Lymphoblastic Leukemia
Acute Myelogenous Leukemia
Chronic Lymphocytic Leukemia
Hodgkin's Lymphoma
Non-hodgkin's Lymphoma
Radiation: Total Body Irradiation (TBI)
Biological: Donor Lymphocyte Infusion (DLI)
Drug: Cyclophosphamide (CY)
Drug: Tacrolimus
Drug: Mycophenolate Mofetil (MMF)
Biological: Hematopoietic Stem Cell Transplant (HSCT)
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Hematologic Malignancies Using Two Related Donors

Resource links provided by NLM:

Further study details as provided by Thomas Jefferson University:

Primary Outcome Measures:
  • One Year Relapse-Free Survival [ Time Frame: one year ] [ Designated as safety issue: No ]

    To assess one year relapse-free survival (RFS) in patients undergoing HSCT (hematopoietic stem cell transplantation) using the TJU 2 step-approach with two donors.

    Survival will be estimated by the Kaplan-Meier method. All estimates of rates will be presented with corresponding confidence intervals. For 1 year RFS rates, the method of Atkinson and Brown will be used to allow for the two-stage design; otherwise the method of Conover.

Secondary Outcome Measures:
  • Chimerism assessment [ Time Frame: one year ] [ Designated as safety issue: No ]
    To assess chimerism to ascertain whether one donor is emerging as dominant at regular intervals beginning at the time of engraftment.

  • Assessment of dominance [ Time Frame: one year ] [ Designated as safety issue: No ]
    If dominance is observed, to compare the 2 donors with regard to degree of HLA mismatch, KIR types, CD 34+ cell doses, infusion order, donor age, and donor alloreactivity points in an effort to identify potential biologic factors that predict for dominance. To determine if trends toward dominance occur in T cell, NK cell, or other cellular subsets prior to emerging in the graft as a whole.

  • Relapse rates [ Time Frame: One Year ] [ Designated as safety issue: No ]
    To assess if establishment of a dominant donor versus persistent chimerism of both donors is associated with a lower relapse rate.

  • Engraftment [ Time Frame: One Year ] [ Designated as safety issue: No ]
    To assess the consistency and pace of engraftment of both donors.

  • Immune Reconstitution [ Time Frame: one year ] [ Designated as safety issue: No ]
    Assess T and B cell Reconstitution

  • Non-relapse morbidity and mortality [ Time Frame: One year ] [ Designated as safety issue: Yes ]
    Assessment of regimen related toxicity, GVHD incidence and severity, and overall survival.

  • Tolerance of DLI [ Time Frame: 2-6 days prior to transplant ] [ Designated as safety issue: Yes ]
    Assessment of the tolerance of the period of fever, diarrhea, and rash after the introduction of second donor and qualitatively compare it to prior patient groups or concurrent patient groups

  • Assessment for tumor escape mechanisms [ Time Frame: one year post transplant ] [ Designated as safety issue: No ]
    To test for loss of one or both HLA haplotypes in patients who relapse post-transplant and examine the relapse in the context of the characteristics of the 2 donors

Enrollment: 4
Study Start Date: March 2012
Estimated Study Completion Date: March 2019
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Allogeneic HSCT Using Two Related Donors
Allogeneic hematopoietic stem cell transplant (HSCT) is a lifesaving therapy for patients with hematopoietic malignancies. The ability of HSCT to control an underlying hematologic malignancy is based on three variables, the intrinsic sensitivity/resistance of the malignancy, treatment regimen intensity, and graft versus tumor effects. The use of two donors instead of one is intended to increase graft versus tumor effects.
Radiation: Total Body Irradiation (TBI)
TBI twice daily for 4 days and occurs 6 to 9 days prior to the transplant. Total radiation dose is 12 Gy.
Other Names:
  • TBI
  • radiotherapy
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:
  • CY
  • Endoxan
  • Cytoxan
  • Neosar
  • Procytox
  • Revimmune
  • cytophosphane
Drug: Tacrolimus
Tacrolimus is started the day before the transplant and stops a few months after transplant.
Other Names:
  • FK-506
  • fujimycin
  • Prograf
  • Advagraf
  • Protopic
Drug: Mycophenolate Mofetil (MMF)
MMF is started the day before transplant and stops a few weeks after transplant.
Other Names:
  • MMF
  • CellCept
  • Myfortic
Biological: Hematopoietic Stem Cell Transplant (HSCT)

CD34+ selected Hematopoietic Stem Cell Transplant (HSCT) is performed using donor cells from two related donors.

The CliniMACS® Plus Instrument will be used for the selection of human CD34+ hematopoietic stem cells.

Other Names:
  • HSCT
  • stem cell transplant
  • CliniMACS

Detailed Description:

At Jefferson, a 2 step process of performing bone marrow transplants (HSCT) was developed in 2005. In this process, subjects are given their donor cells at 2 different times. First, after receiving radiation and/or chemotherapy to help their immune system accept donor cells and further fight their disease, subjects receive a specific amount of donor T cells. (Step 1 of the HSCT). The donor T cells fight the cancer and help the subject fight infection and accept a new immune system. Donor T cells can also irritate the tissues of the subject's body, especially their skin, gut, and liver. This condition can be life threatening and is called graft versus host disease or GVHD. To decrease the incidence and severity of GVHD, after the subjects receive their donor's T cells, they are given a drug called cyclophosphamide (CY). This drug eliminates the most active donor T cells, but leaves behind some T cells to help fight infection. Step 2 of the HSCT occurs when the subject receives their donor's stem cells to help their blood counts recover.

There have been low rates of serious GVHD and toxicity using the 2 step approach. Over 100 transplants (using 1 donor) have been performed at TJUH using this method. Patients who go to transplant while their disease is under control have had good outcomes. However, subjects whose disease is active at the time of the HSCT (especially subjects with acute leukemia) have had a high incidence of relapsing after HSCT. Relapse after HSCT usually results in death. There have not been any significant advances in the field regarding improving outcomes for subjects with disease at HSCT.

The rationale for the current study is as follows. Transplants using donor cells work not just because the subject receives chemotherapy and radiation therapy, but because the donor cells themselves can recognize the cancer when it tries to come back and eradicate it. This is called a graft versus tumor effect or GVT. Therefore the recognition of the tumor by the donor cells is key to the prevention of relapse and long term survival. When a subject relapses after HSCT, it is because the cancer cells were able to avoid recognition by the new donor immune system. In this research study, the investigators will use two donors instead of one. Our hypothesis is that the cells from two donors will have a better chance at recognizing and eradicating the malignancy than cells from one donor.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Any patient with a hematologic malignancy with residual disease (morphological, cytogenetic, molecular, or radiographic) after treatment with 1 or more chemotherapy regimens in whom achievement of remission with additional chemoradiotherapy is felt to be unlikely or who is in 3rd or greater CR. Patients with marrow based diseases in which the marrow biopsy does not meet criteria for active disease (i.e. <5% blasts in acute leukemia) but who does not have full count recovery will be eligible for treatment on this high risk trial.
  2. Patients must have two related donors that meet an acceptable scenario as described above.
  3. Patients must adequate organ function:

    • LVEF of >= 50%
    • DLCO (adjusted for hemoglobin) >= 50% of predicted
    • Adequate liver function as defined by a serum bilirubin =< 1.8, AST or ALT < 2.5X upper limit of normal
    • Creatinine clearance of >= 60 ml/min
  4. Karnofsky Performance Status of > 80 % on the modified KPS tool (see Appendix A).
  5. Patients must be willing to use contraception if they have childbearing potential.
  6. Able to give informed consent

Exclusion Criteria:

  1. Modified KPS of < 80%
  2. >= 5 Comorbidity Points on the HCT-CI Index (See Appendix B)
  3. Class I or II antibodies against donor HLA antigens
  4. HIV positive
  5. Active involvement of the central nervous system with malignancy
  6. Psychiatric disorder that would preclude patients from signing an informed consent
  7. Pregnancy, or unwillingness to use contraception if they have child bearing potential
  8. Patients with life expectancy of =< 6 months for reasons other than their underlying hematologic/oncologic disorder
  9. Alemtuzumab treatment within 8 weeks of HSCT admission.
  10. ATG level of >= 2 ugm/ml
  11. Patients with active inflammatory processes (such as flair of an autoimmune disease) including T max > 101, or active tissue inflammation are excluded.
  12. Inability to tolerate cyclophosphamide or undergo total body irradiation at the doses specified in the treatment plan.
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01532635

United States, Pennsylvania
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
Sponsors and Collaborators
Thomas Jefferson University
Principal Investigator: Neal Flomenberg, MD Thomas Jefferson University
Principal Investigator: Dolores Grosso, DNP, CRNP Thomas Jefferson University
  More Information

Additional Information:
No publications provided

Responsible Party: Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT01532635     History of Changes
Other Study ID Numbers: 11D.570, 2011-101
Study First Received: February 6, 2012
Last Updated: August 5, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Thomas Jefferson University:
hematologic malignancy
Acute lymphoblastic leukemia
Acute myelogenous leukemia
Chronic lymphocytic leukemia
hodgkin's lymphoma
non-hodgkin's lymphoma
allogeneic stem cell transplant
TJU 2-step
Hematopoietic stem cell transplant
bone marrow transplant
Mycophenolate Mofetil

Additional relevant MeSH terms:
Hodgkin Disease
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Lymphoma, Non-Hodgkin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Leukemia, B-Cell
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Mycophenolate mofetil
Mycophenolic Acid
Alkylating Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists

ClinicalTrials.gov processed this record on October 21, 2014