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A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Hematologic Malignancies From One Versus Two HLA Partially-Matched Related Donors

Phase 2
18 Years
Open (Enrolling)
Hematologic Malignancy

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Trial Information

A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Hematologic Malignancies From One Versus Two HLA Partially-Matched Related Donors

Human leukocyte antigens (HLA) are expressed by every person's immune system. These antigens
help identify what is "self" and "non-self". The immune system recognizes and destroys germs
or tumor cells that do not express the same HLA antigen.. Each person inherits one set of
HLA antigens from each parent. Each set is called a haplotype. In haploidentical
transplant, the donor is matched to one haplotype and is mismatched to the other. Donor
cells destroy tumor after transplant by recognizing the mismatched HLA haplotype. Recent
research in haploidentical transplant demonstrated that for some patients who relapse after
transplant, tumor cells are able to escape detection by the transplanted donor immune system
by decreasing the expression of HLA antigens or by eliminating the mismatched HLA haplotype
all together. Once these antigens are diminished or gone, the donor immune system can no
longer recognize the tumor cell and thus does not destroy it allowing relapse. The purpose
of this treatment is to avoid relapse after transplant by using two partially matched
donors. Ideally, the donors will be mismatched to the patient at the opposite haplotype so
that the loss of one haplotype will not result in an escape of donor immune detection. A
certain percentage of patients will have a combination of donors in which this type of
matching can occur. Other patients will have two donor combinations in which both donors
recognize the same haplotype of the patient. In this setting the use of 2 donors may still
increase graft versus tumor responses through increased mismatching by other means such as
minor histocompatibility mismatching. Prior to use in this study, some donor combinations
will be tested in murine models to assess feasibility. These combinations involve the
targeting of both patients haplotypes, but also a complete mismatch of the donor to the
patient or the donors to each other.

A third group of patients may have only one eligible donor. For this group, to increase
donor effects on the malignant cells, one day will be added to the transplant regimen.
During the transplant regimen, donor lymphocytes are given to the patient before the actual
stem cells are given. These donor lymphocytes react with the patient's own residual
lymphocytes. During this "alloreaction" it is though that tumor cells are destroyed by the
activated donor lymphocytes. After 2 days, cyclophosphamide is given to delete the
activated lymphocytes. This helps prevent graft versus host disease (GVHD), a deleterious
condition in which the donor lymphocytes attack the normal tissues of the patient's body.
In this process, lymphocytes that are not activated remain. These non activated lymphocytes
provide immunity for the patient after transplant. It is this step in the TJU 2 step
process which allows the patients to gain immune function after transplant without
significant negative effects that would otherwise be caused by a half matched transplant.
In this study, the alloreaction period will be extended by one day for patients with only
one suitable donor to allow the activated donor lymphocytes more time to destroy tumor

In summary, patients on this protocol will undergo transplant using two donors if available
in a suitable combination. If two donors are not available, the donor lymphocytes of the
single donor will be allowed to react for an additional day to hopefully further treat the
resistant disease.

Inclusion Criteria:

1. Any patient with a hematologic malignancy with residual disease 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.

2. Patients must have at least one related donor who is HLA mismatched in the GVHD
direction at two or more HLA loci. Patients with any combination of eligible donors
fitting one of the acceptable double donor scenarios will be treated on the two donor
arm of this study. All other patients will be transplanted with one donor, whose
selected will be based on alloreactivity points. Our priorities for patient
assignments will be scenarios 1 or 2 > scenario 5 > one donor transplant.

3. Patients must adequate organ function:

1. LVEF of > or = 50 %

2. DLCO (adjusted for hemoglobin) > or = 50 % of predicted

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

4. Creatinine clearance of > or = 60 ml/min

4. Karnofsky Performance Status of > or = 70% on the modified KPS tool

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 < 70%

2. > or = 5 Comorbidity Points on the HCT-CI Index

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 < or = 6 months for reasons other than their
underlying hematologic/oncologic disorder

9. Alemtuzumab treatment within 8 weeks of HSCT admission.

10. ATG level of > or = 2 ugm/ml

11. Patients with active inflammatory processes including Tmax > 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Relapse-Free Survival (RFS)

Outcome Description:

To assess 1 year relapse free survival in patients undergoing HSCT using the TJU 2 Step approach using one partially matched donor with an extra day added to the transplant regimen, or by using two donors who are partially matched to each other and the patient.

Outcome Time Frame:

1 year post-transplant

Safety Issue:


Principal Investigator

Neal Flomenberg, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Thomas Jefferson University


United States: Food and Drug Administration

Study ID:




Start Date:

May 2010

Completion Date:

May 2015

Related Keywords:

  • Hematologic Malignancy
  • allogeneic stem cell transplant
  • TJU 2 Step
  • HSCT
  • Hematopoietic stem cell transplantation
  • Neoplasms
  • Hematologic Neoplasms



Thomas Jefferson University Philadelphia, Pennsylvania  19107-6541