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A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Hematologic Malignancies Using Two Related Donors

Phase 2
18 Years
Open (Enrolling)
Hematologic Malignancy, Leukemia, Acute Lymphoblastic Leukemia, ALL, Acute Myelogenous Leukemia, AML, Chronic Lymphocytic Leukemia, CLL, Lymphoma, Hodgkin's Lymphoma, Non-hodgkin's Lymphoma, Myeloma

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Trial Information

A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Hematologic Malignancies Using Two Related Donors

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.

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

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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

One Year Relapse-Free Survival

Outcome Description:

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.

Outcome Time Frame:

one year

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:

March 2012

Completion Date:

March 2019

Related Keywords:

  • Hematologic Malignancy
  • Leukemia
  • Acute Lymphoblastic Leukemia
  • ALL
  • Acute Myelogenous Leukemia
  • AML
  • Chronic Lymphocytic Leukemia
  • CLL
  • Lymphoma
  • Hodgkin's Lymphoma
  • Non-Hodgkin's Lymphoma
  • Myeloma
  • hematologic malignancy
  • leukemia
  • Acute lymphoblastic leukemia
  • ALL
  • Acute myelogenous leukemia
  • AML
  • Chronic lymphocytic leukemia
  • CLL
  • lymphoma
  • hodgkin's lymphoma
  • non-hodgkin's lymphoma
  • myeloma
  • allogeneic stem cell transplant
  • TJU 2-step
  • Hematopoietic stem cell transplant
  • HSCT
  • bone marrow transplant
  • Cyclophosphamide
  • MMF
  • Mycophenolate Mofetil
  • Neoplasms
  • Hodgkin Disease
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Hematologic Neoplasms



Thomas Jefferson UniversityPhiladelphia, Pennsylvania  19107-6541