Hematopoietic/Lymphoid Cancer
Conditions
Brief summary
This phase II trial studies how well total-body irradiation, donor lymphocyte infusion, and cyclophosphamide before donor stem cell transplant works in treating patients with high-risk hematologic malignancies. Giving total-body irradiation, donor lymphocyte infusion, and chemotherapy before a donor stem cell transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When certain stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Removing the T cells from the donor cells before transplant and giving tacrolimus and mycophenolate mofetil may stop this from happening.
Detailed description
PRIMARY OBJECTIVES: 1\) To assess 1 year relapse free survival in high risk patients undergoing hematopoietic stem cell transplant (HSCT) using the Thomas Jefferson University (TJU) 2 step approach with 2 days inserted between the last fraction of total-body irradiation (TBI) and the infusion of donor T cells (donor lymphocyte infusion \[DLI\]). SECONDARY OBJECTIVES: 1. To assess regimen related toxicity in this updated conditioning regimen, graft-versus-host disease (GVHD) incidence and severity, and overall survival in patients undergoing treatment on this protocol. 2. To assess the consistency and pace of engraftment. 3. To assess the pace of T cell and B cell immune recovery. OUTLINE: CONDITIONING REGIMEN: Patients undergo TBI twice daily (BID) on days -10 to -8, undergo DLI on day -6, and receive cyclophosphamide intravenously (IV) over 2 hours on days -3 and -2. TRANSPLANT: Patients undergo cluster of differentiation (CD) 34+ selected allogeneic HSCT on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV or orally (PO) beginning on day -1 with taper beginning by day 42, and mycophenolate mofetil IV BID on days -1 to 28. After completion of study treatment, patients are followed up for 1 year.
Interventions
RADIATIONTotal-Body Irradiation (TBI)
Undergo TBI
BIOLOGICALDonor Lymphocyte Infusion (DLI)
Undergo DLI
DRUGCyclophosphamide
Given IV
Undergo CD34+ selected allogeneic HSCT
DRUGMycophenolate mofetil
Given IV
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. This treatment is for patients with high risk hematologic malignancies. High risk is defined as: * 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 * Patients without morphologic evidence of disease but with high risk features which would predict for relapse despite remission at HSCT such as adverse cytogenetics, 3rd or greater CR (complete response), or failure to recover peripheral blood counts to normal ranges. While these patients do not have detectable disease by current methods, like all patients they have non-detectable disease which in their case is highly aggressive. 2. Patients must have one related donor who is HLA (human leukocyte antigen) mismatched in the GVHD direction at two or more HLA loci 3. Patients must adequate organ function: * LVEF (left ventricular ejection fraction) of \>50 % * Diffusing capacity of the lungs for carbon monoxide (DLCO) (adjusted for hemoglobin) \>50 % of predicted and forced expiration to the full FEV-1 \>50 % * Adequate liver function as defined by a serum bilirubin \<1.8, AST (aspartate aminotransferase) or ALT (alanine aminotransferase) \< 2.5X upper limit of normal * Creatinine clearance of \> 60 ml/min 4. Karnofsky Performance Status (KPS) of \> 80% 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) Karnofsky Performance status of \<80% 2. \> 5 Comorbidity Points on the Hematopoietic cell transplantation - specific comorbidity (HCT-CI) Index (See Appendix B) 3. Class I or II antibodies against donor human leukocyte antigens (HLA) 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. Anti-thymocyte globulin (ATG) level of \> 2 ugm/ml 11. Patients with active inflammatory processes 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Count of Participants That Experience 1 Year Relapse Free Survival After Undergoing Hematopoietic Stem Cell Transplantation (HSCT) Using the Thomas Jefferson University 2 Step Approach | Up to 1 year after HSCT |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Successful Engraftment | Up to 1 year after HSCT | Will be reported descriptively. Successful engraftment is defined as ANC (absolute neutrophil count, the number of white blood cells (WBCs) that are neutrophils) ≥ 0.5x109/L for at least 30 days and Platelet engraftment \> 20,000 with no transfusion x 7 days. |
| Count of Participants That Experienced Death as a Result of Graft-versus-host Disease (GVHD) | Up to 1 year after HSCT | Graft versus host disease was clinically characterized based on 4 stages of progression for three major body areas, skin, liver, gut. Subjects who experienced life threatening reactions in their skin, liver and gut ultimately experienced functional impairment and expired. Life threatening reactions in the Skin were characterized by desquamation (the shedding of the outer layers of skin) and bullae (a bubblelike cavity filled with air or fluid, in particular). Life threatening reactions in the Liver were characterized by Bilirubin, \> 15 mg/dl Life threatening reactions in the Gut were characterized by Pain +/- ileus (a painful obstruction of the ileum or other part of the intestine.) |
| Median Pace of T Cell Immune Recovery at 28 Days Post Hematopoietic Stem Cell Transplantation (HSCT) | At 28 days post HSCT | An excess amount of residual T-lymphocytes in the Peripheral Blood Stem Cell Collection (PBSC) product may increase the risk of GVHD. The ideal amount of T-cells left in the PBSC product is no greater than 5x104/kg. Every effort will be made to keep T-cell amounts to below this threshold. The median pace of T-cell immune recovery at 28 days will be monitored by collecting cluster of differentiation (CD24) and (CD38). |
| Median Pace of T Cell Immune Recovery at 90 Days Post Hematopoietic Stem Cell Transplantation (HSCT) | 90 days post HSCT | An excess amount of residual T-lymphocytes in the Peripheral Blood Stem Cell Collection (PBSC) product may increase the risk of GVHD. The ideal amount of T-cells left in the PBSC product is no greater than 5x104/kg. Every effort will be made to keep T-cell amounts to below this threshold. The median pace of T-cell immune recovery at 90 days will be monitored by collecting cluster of differentiation (CD24) and (CD38). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (TBI, DLI, Cyclophosphamide, CD34+ Donor HSCT) CONDITIONING REGIMEN: Patients undergo TBI BID on days -10 to -8, undergo DLI on day -6, and receive cyclophosphamide IV over 2 hours on days -3 and -2.
TRANSPLANT: Patients undergo CD34+ selected allogeneic HSCT on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 with taper beginning by day 42, and mycophenolate mofetil IV BID on days -1 to 28.
Total-Body Irradiation (TBI): Undergo TBI
Donor Lymphocyte Infusion (DLI): Undergo DLI
Cyclophosphamide: Given IV
Allogeneic hematopoietic stem cell transplantation (HSCT): Undergo CD34+ selected allogeneic HSCT
Mycophenolate mofetil: Given IV | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Treatment (TBI, DLI, Cyclophosphamide, CD34+ Donor HSCT) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 39 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Region of Enrollment United States | 41 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 16 / 40 |
| other Total, other adverse events | 40 / 40 |
| serious Total, serious adverse events | 32 / 40 |
Outcome results
Primary
Count of Participants That Experience 1 Year Relapse Free Survival After Undergoing Hematopoietic Stem Cell Transplantation (HSCT) Using the Thomas Jefferson University 2 Step Approach
Time frame: Up to 1 year after HSCT
Population: One subject was inevaluable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (TBI, DLI, Cyclophosphamide, CD34+ Donor HSCT) | Count of Participants That Experience 1 Year Relapse Free Survival After Undergoing Hematopoietic Stem Cell Transplantation (HSCT) Using the Thomas Jefferson University 2 Step Approach | 27 Participants |
Secondary
Count of Participants That Experienced Death as a Result of Graft-versus-host Disease (GVHD)
Graft versus host disease was clinically characterized based on 4 stages of progression for three major body areas, skin, liver, gut. Subjects who experienced life threatening reactions in their skin, liver and gut ultimately experienced functional impairment and expired. Life threatening reactions in the Skin were characterized by desquamation (the shedding of the outer layers of skin) and bullae (a bubblelike cavity filled with air or fluid, in particular). Life threatening reactions in the Liver were characterized by Bilirubin, \> 15 mg/dl Life threatening reactions in the Gut were characterized by Pain +/- ileus (a painful obstruction of the ileum or other part of the intestine.)
Time frame: Up to 1 year after HSCT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (TBI, DLI, Cyclophosphamide, CD34+ Donor HSCT) | Count of Participants That Experienced Death as a Result of Graft-versus-host Disease (GVHD) | 2 Participants |
Secondary
Median Pace of T Cell Immune Recovery at 28 Days Post Hematopoietic Stem Cell Transplantation (HSCT)
An excess amount of residual T-lymphocytes in the Peripheral Blood Stem Cell Collection (PBSC) product may increase the risk of GVHD. The ideal amount of T-cells left in the PBSC product is no greater than 5x104/kg. Every effort will be made to keep T-cell amounts to below this threshold. The median pace of T-cell immune recovery at 28 days will be monitored by collecting cluster of differentiation (CD24) and (CD38).
Time frame: At 28 days post HSCT
Population: 3 subjects were not evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (TBI, DLI, Cyclophosphamide, CD34+ Donor HSCT) | Median Pace of T Cell Immune Recovery at 28 Days Post Hematopoietic Stem Cell Transplantation (HSCT) | Median CD3/4 count at d+28 | 41.3 cells/ul |
| Treatment (TBI, DLI, Cyclophosphamide, CD34+ Donor HSCT) | Median Pace of T Cell Immune Recovery at 28 Days Post Hematopoietic Stem Cell Transplantation (HSCT) | Median cluster of diff. 38 (CD3/8) count at d+28 | 48 cells/ul |
Secondary
Median Pace of T Cell Immune Recovery at 90 Days Post Hematopoietic Stem Cell Transplantation (HSCT)
An excess amount of residual T-lymphocytes in the Peripheral Blood Stem Cell Collection (PBSC) product may increase the risk of GVHD. The ideal amount of T-cells left in the PBSC product is no greater than 5x104/kg. Every effort will be made to keep T-cell amounts to below this threshold. The median pace of T-cell immune recovery at 90 days will be monitored by collecting cluster of differentiation (CD24) and (CD38).
Time frame: 90 days post HSCT
Population: 5 subjects were not evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (TBI, DLI, Cyclophosphamide, CD34+ Donor HSCT) | Median Pace of T Cell Immune Recovery at 90 Days Post Hematopoietic Stem Cell Transplantation (HSCT) | Median CD3/4 count at d+90 | 141 cells/ul |
| Treatment (TBI, DLI, Cyclophosphamide, CD34+ Donor HSCT) | Median Pace of T Cell Immune Recovery at 90 Days Post Hematopoietic Stem Cell Transplantation (HSCT) | Median CD3/8 count at d+90 | 384 cells/ul |
Secondary
Number of Participants With Successful Engraftment
Will be reported descriptively. Successful engraftment is defined as ANC (absolute neutrophil count, the number of white blood cells (WBCs) that are neutrophils) ≥ 0.5x109/L for at least 30 days and Platelet engraftment \> 20,000 with no transfusion x 7 days.
Time frame: Up to 1 year after HSCT
Population: One subject was inevaluable
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (TBI, DLI, Cyclophosphamide, CD34+ Donor HSCT) | Number of Participants With Successful Engraftment | 37 Participants |