Hematologic Malignancies
Conditions
Keywords
Hematologic Malignancies, Two Step Approach, Haploidentical Transplant
Brief summary
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.
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.
Interventions
RADIATIONTotal Body Irradiation (TBI)
TBI twice daily days 6-9 prior to transplant (HSCT)
BIOLOGICALDonor Lymphocyte Infusion (DLI)
DLI given 6 days prior to transplant (HSCT).
Cyclophosphamide given once daily at 60 mg/kg on days 2 and 3 prior to transplant (HSCT).
DRUGTacrolimus
Tacrolimus given one day prior to transplant (HSCT).
DRUGMycophenolate Mofetil (MMF)
MMF given one day prior to transplant (HSCT).
BIOLOGICALHematopoietic Stem Cell Transplant (HSCT)
CD34+ selected Hematopoietic Stem Cell Transplant (HSCT) is performed. This is the day of transplantation.
Sponsors
Sidney Kimmel Cancer Center at Thomas Jefferson University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival of Participants | 6 months | To determine overall survival at 6 months post-transplant. |
| Optimal Dose of CD3+ Donor Lymphocytes (T-cells) for Consistent Engraftment Without GVHD | 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Engraftment Rates | 6 months | To assess hematopoietic engraftment rates. |
| Lymphoid Recovery | 6 months | To assess the pace of lymphoid recovery in this patient population. |
| Incidence of Grades III-IV GVHD | 6 months | 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) |
Countries
United States
Participant flow
Recruitment details
Patients presenting to Thomas Jefferson University with hematological malignancies requiring hematopoeitic stem cell transplantation without matched related donors. Opened January, 2006 through August, 2009
Participants by arm
| Arm | Count |
|---|---|
| Haploidentical Allogeneic Transplantation Patients undergoing hematopoietic stem cell transplant from a partially matched related donor | 27 |
| Total | 27 |
Baseline characteristics
| Characteristic | Haploidentical Allogeneic Transplantation |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age, Continuous | 50 years STANDARD_DEVIATION 12.9 |
| Region of Enrollment United States | 27 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 27 / 27 |
| serious Total, serious adverse events | 23 / 27 |
Outcome results
Primary
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.
Time frame: 6 months
Population: Two patients died prior to expected day of engraftment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Haploidentical Allogeneic Transplantation | Optimal Dose of CD3+ Donor Lymphocytes (T-cells) for Consistent Engraftment Without GVHD | 2 lymphocytes x 10^8/kg |
Primary
Overall Survival of Participants
To determine overall survival at 6 months post-transplant.
Time frame: 6 months
Population: 27 Patients undergoing haploidentical transplant at Thomas Jefferson University
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Haploidentical Allogeneic Transplantation | Overall Survival of Participants | 13 participants |
Secondary
Engraftment Rates
To assess hematopoietic engraftment rates.
Time frame: 6 months
Population: Two patients died prior to expected engraftment day
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Haploidentical Allogeneic Transplantation | Engraftment Rates | 23 participants |
Secondary
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)
Time frame: 6 months
Population: Two patients died prior to expected engraftment. Two patients who rejected were retransplanted and were evaluable for GVHD.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Haploidentical Allogeneic Transplantation | Incidence of Grades III-IV GVHD | 2 participants |
Secondary
Lymphoid Recovery
To assess the pace of lymphoid recovery in this patient population.
Time frame: 6 months
Population: Two patients did not engraft, two patients died prior to expected day of engraftment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Haploidentical Allogeneic Transplantation | Lymphoid Recovery | 23 participants |