Bone Marrow Transplantation of Patients in Remission Using Partially Matched Relative Donor

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Brief Title

Bone Marrow Transplantation of Patients in Remission Using Partially Matched Relative Donor

Official Title

A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematologic Malignancies in Remission From HLA Partially-Matched Related Donors

Brief Summary

      The primary hypothesis of this research study is that patients in remission undergoing
      myeloablative haploidentical hematopoietic stem cell transplantation (HSCT) on the Thomas
      Jefferson University (TJU) 2 Step treatment regimen will have a disease-free survival (DFS)
      rate at 1 year that is the same or better than the historical DFS of patients with similar
      diagnoses and ages undergoing matched sibling HSCT. Based on a review of the literature a DFS
      rate of 50% or better at 1 year would meet the criterion for an effective alternative
      therapy. A DFS rate of 75% or better would imply superior efficacy of the TJU 2 Step approach
      over T-replete matched sibling HSCT.
    

Detailed Description

      The primary rationale for the development of this research study is to find out if the Thomas
      Jefferson University (TJU) 2 Step approach to stem cell transplant is an effective treatment
      for patients with blood cancers who require transplant for long-term survival but are without
      an available matched-sibling donor. Historically, survival rates for patients undergoing
      half-matched stem cell transplant have been much lower than those observed after matched
      sibling stem cell transplant. This may be due to the poor-risk disease features of the
      patients by the time they are referred for hematopoietic stem cell transplantation (HSCT).
      Survival post half-matched stem cell transplant has also been affected by the requirement to
      remove or soothe donor T cells resulting in higher rates of infection and relapse. Newer
      approaches to haploidentical HSCT, such as the TJU 2 Step approach, utilize cyclophosphamide
      (CY) to tolerize donor lymphocytes instead of removing them completely from the donor
      product. This has resulted in less infection without concomitant increase in severe
      graft-versus-host disease (GVHD) and has increased overall survival as compared to older
      haploidentical treatment approaches due to decreases in regimen-related morbidity.

      Because of the historically low overall survival (OS) after haploidentical HSCT, it has
      become a procedure of last resort with most centers unwilling to consider it unless all other
      options are exhausted. With the recent development of regimens such as the TJU 2 Step
      approach which provide safe, alternative platforms for HSCT, it is now feasible, and
      ethically more acceptable, for patients without matched sibling donors to undergo HSCT prior
      to being heavily pretreated or developing resistant disease. In this setting, i.e. equivalent
      regimen safety profiles and more homogenous patient comparison groups, it is possible to more
      accurately compare antitumor effects between matched sibling donors and haploidentical
      donors. There is ample evidence in the literature that HLA mismatching causes GVHD. There is
      not a large body of evidence supporting the notion that HLA mismatching provides superior
      tumor control translating into greater relapse free survival. As compared to more common
      types of transplants where donor T cells are given to the recipient, the investigators would
      surmise that the T cell tolerization associated with the TJU 2 Step approach may decrease the
      anti-tumor effects of the donor immune system. Conversely, the greater degree of human
      leukocyte antigen (HLA) mismatch with exploitation of NK effects may mitigate some of the
      attenuated T cell alloreactivity.

      Thus, in the context of comparable regimen-related toxicity, our major aim in this research
      study is to compare graft versus tumor effects as measured by disease-free survival (DFS)
      between matched sibling HSCT and the TJU 2 Step haploidentical HSCT. If DFS is similar
      despite T cell tolerization, than the TJU 2 Step haploidentical approach should be considered
      an effective alternative therapy for those patients in remission without a matched sibling
      donor. The widespread benefit of this outcome would be the enfranchisement of segments of the
      population who are without available matched donors resulting in a delay or a failure to
      receive this potentially life-saving therapy. If DFS survival after treatment on the TJU 2
      Step haploidentical approach is superior to what would be expected after matched sibling
      HSCT, then one could conclude that haploidentical HSCT confers greater tumor control forming
      the basis for future studies regarding the potential benefits of utilizing haploidentical
      donors over matched sibling donors when both types of donors are available.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Disease-Free Survival (DFS)


Condition

Acute Myeloid Leukemia

Intervention

Total Body Irradiation (TBI)

Study Arms / Comparison Groups

 TJU 2 Step Regimen
Description:  All patients treated on this trial will have hematological malignancies that are in remission at the time of the transplant. Their diseases would be expected to relapse with standard therapy alone.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Radiation

Estimated Enrollment

28

Start Date

July 2010

Completion Date

May 2014

Primary Completion Date

May 2013

Eligibility Criteria

        Inclusion Criteria:

          1. Any patient with a hematologic or oncologic diagnosis without morphological evidence
             of disease in which allogeneic HSCT is thought to be beneficial.

               -  Diagnoses include:

             Acute Myeloid Leukemia Myelodysplastic Syndromes Biphenotypic Leukemia Acute
             Lymphocytic Leukemia Chronic Myeloid Leukemia Chronic Lymphocytic Leukemia Plasma Cell
             Neoplasms Lymphoma Hodgkin Disease Aplastic Anemia

          2. Patients must have a related donor who is a two or more allele mismatch at the HLA-A;
             B; C; DR loci.

          3. Patients must adequate organ function:

               -  LVEF of > or = 50%

               -  DLCO > or = 50% of predicted corrected for hemoglobin

               -  Adequate liver function as defined by a serum bilirubin < or = 1.8, AST or ALT <
                  or = 2.5X upper limit of normal

               -  Creatinine clearance of > or = 60 ml/min

          4. Performance status > or = 70% (TJU Karnofsky)

          5. HCT-CI Score < 5 Points

          6. Patients must be willing to use contraception if they have childbearing potential

          7. Able to give informed consent

        Exclusion Criteria:

          1. Performance status < or = 70% (TJU Karnofsky)

          2. HCT-CI Score > 5 Points

          3. Combination of Performance status of < 80% (TJU Karnofsky) and an HCT-CI of 4 points
             or more.

          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

          8. Patients with life expectancy of < or = 6 months for reasons other than their
             underlying hematologic/oncologic disorder

          9. Patients who have received alemtuzumab within 8 weeks of the transplant admission, or
             who have recently received horse or rabbit ant-thymocyte globulin and have an ATG
             level of > or = 2 ugm/ml

         10. Patients who cannot receive cyclophosphamide

         11. Patients with evidence of another malignancy, exclusive of a skin cancer that requires
             only local treatment, should not be enrolled on this protocol.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Dolores Grosso, DNP, CRNP, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01350245

Organization ID

10D.219

Secondary IDs

2010-10

Responsible Party

Sponsor

Study Sponsor

Sidney Kimmel Cancer Center at Thomas Jefferson University


Study Sponsor

Dolores Grosso, DNP, CRNP, Principal Investigator, Thomas Jefferson University


Verification Date

October 2016