Hematological Malignancies
Conditions
Keywords
hematopoietic stem cell transplantation, HSCT, allogeneic marrow transplantation, cyclophosphamide, graft-versus-host disease, GVHD
Brief summary
It is hypothesized that engraftment when administering cyclophosphamide post the stem cell infusion will increase, the incidence of graft versus host disease (GVHD) and day 100 mortality will decrease, and the use of cyclophosphamide post stem cell infusion with alternative donors will be as safe and as effective as traditional matched transplants.
Detailed description
The primary rationale for the development of this research study is to find out if the use of cyclophosphamide after a blood 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 partially matched related or unrelated donor transplants (henceforth to be called alternative donor transplants) have been much lower than those observed after matched sibling stem cell transplants. Survival post alternative donor stem cell transplant has also been affected by the requirement to remove or reduce the numbers of donor T cells resulting in higher rates of infection, graft rejection, and relapse. One significant limitation to conventional donor transplants with HLA matched siblings has been that over 50% of patients do not have HLA matched siblings so that increasing the safety of alternative donor transplants could have a significant influence on the number of patients who could safely receive transplants. Because of the historically low overall survival (OS) after alternative donor transplants, it has become a procedure of last resort in many centers unwilling to consider it unless all other options are exhausted. There fore several centers including ours have sought to overcome problems using various strategies. The strategy the investigators have proposed for this study (which has been used similarly by other centers) has been to administer cyclophosphamide post the stem cell infusion (traditionally it is given before the stem cell infusion) thereby hopefully destroying the activated T-cells causing graft-versus host disease (GVHD) and allow T cell tolerization and engraftment; but, not the inactivated T cells thereby hopefully preserving the anti-tumor effects of the donor immune system. Thus, the major aim of this study will be to measure the engraftment with this regimen and secondarily to measure incidence of GVHD and day 100 mortality. The goal is to see if in the first 3 months the use of cyclophosphamide post stem cell infusion with alternative donors is as safe and as effective as traditional matched transplants.
Interventions
RADIATIONTotal Body Irradiation
Myeloablative HSCT Arm: Total body irradiation (TBI) is given in 8 fractions over 4 days (total dose of 12 Gy) Reduced Intensity HSCT Arm: TBI is given in one fraction (total dose of 2 Gy)
DRUGCyclophosphamide
Cyclophosphamide is administered on the third day after the hematopoietic stem cell transplantation (HSCT) to help reduce graft-versus-host disease (GVHD). It is given at a dose of 60 mg/kg/d for 2 days on days +3 and +4.
DRUGTacrolimus
Started the fifth day after the transplant to help prevent graft-versus-host disease (GVHD).
DRUGMycophenolate mofetil
Started the fifth day after the transplant to help prevent graft-versus-host disease (GVHD).
DRUGFludarabine
Started the fifth day before the transplant. Given for four days at 30 mg/m2/d.
DRUGBusulfan
Started the fourth day before the transplant. Given for two days at 3.2 mg/kg.
GENETICHematopoietic stem cell transplantation
Allogeneic marrow transplantation given after the last dose of total body irradiation (TBI)
Sponsors
Sidney Kimmel Cancer Center at Thomas Jefferson University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
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 hematological or oncological diagnosis in which allogeneic hematopoietic stem cell transplantation (HSCT) is thought to be beneficial. 1. Patients without morphological or molecular evidence of disease 2. For patients with indolent diseases, if the patient has evidence of disease the disease burden must be minimal (at least PR) and the disease must be chemoresponsive. Thus for example patients with acute leukemia (not an indolent disease) must be in a morphological CR or CRp. 2. For patients with MDS the inclusion criteria is specifically as follows: * For patients with RA or RARS or isolated 5q- they can proceed to transplant without any treatment. * For patients with RAEB-1, RCMD+/-RS, or MDS NOS must have stable disease for 6 months (as documented by serial bone marrow examinations) in the absence of any therapy but growth factors or transfusion support. Patients who require treatment to control their disease must show chemo-responsiveness * For patients with CMML or RAEB-2 they must demonstrate chemo-responsiveness * Chemo-responsiveness is defined as a blast percentage decrease by at least 5 percentage points and there must be less than 10% blasts after treatment and at the time of transplant, if there are more than 10% blasts at any point during the disease course * Chemo-responsiveness must also include at least one of the following if applicable: * A cytogenetic response * A well-documented decrease in transfusion requirements. 3. Patients must have a related donor who is zero, one, two, three, or four antigen mismatched at the HLA-A; B; C; DR loci or an unrelated donor up to a two antigen mismatch. DNA will be retained by the tissue typing laboratory for possible typing for DQ and DP. When multiple related donor options are available donor selection will be determined the same as in the TJU two-step protocols. When multiple unrelated donors are available care will be made to avoid HLA-A and HLA-B mismatches if possible based on data from the Japanese Marrow Donor Registry studies. An HLA antibody screen will be performed on each patient. 4. All patients must have adequate organ function: 1. Patients with related donors must have an LVEF of \>35%. Patients with unrelated donors must have an LVEF \>45%. Patients with LVEF ≤50% and all patients with symptoms or history of heart failure or coronary artery disease must have a stress echo or equivalent test and a cardiological evaluation. 2. Patients with related donors must have a DLCO \>35% of predicted corrected for hemoglobin. Patients with unrelated donors must have a DLCO \>45% of predicted corrected for hemoglobin. For related donors if the DLCO is less than 45% the EF must be greater than 45% and vice versa. 3. Patients with related donors must have an adequate liver function as defined by a serum bilirubin \<3.0, AST and ALT \<3.0X upper limit of normal. Patients with unrelated donors must have an adequate liver function as defined by a serum bilirubin \<1.8, AST and ALT \< 2.5X upper limit of normal. Exceptions may be granted for patients with benign liver disorders such as Gilbert's disease. 4. Patients with related donors or with unrelated donors must have a creatinine clearance of \> 60 ml/min/1.73 m\^2. 5. Patients with related donors must have a performance status \> 60% (TJU Karnofsky14) (Appendix A). Patients with unrelated donors must have a Performance status \> 70% (TJU Karnofsky). 6. Patients with related donors must have a HCT-CI Score \< 6 Points (Appendix B). Patients with unrelated donors must have a HCT-CI Score \< 5 Points. 7. Patients must be willing to use contraception if they are of childbearing potential. 8. Patients must be able to give informed consent or have a care giver who can give consent. 9. Patients that are HIV positive will be eligible for the study if they have an undetectable viral load and meet the above criteria for patients with unrelated donors.
Exclusion criteria
1. Patients with related donors who have a combination of Performance status of \< 70% (TJU Karnofsky) and an HCT-CI of 4 points or more. Patients with unrelated donors with a combination of Performance status of \< 80% (TJU Karnofsky) and an HCT-CI of 4 points or more. 2. Patients with active involvement of the central nervous system with malignancy. Patients with a disease with potential for CNS involvement should have documentation of the lack of CNS involvement via lumbar puncture or similar procedure performed within two months of admission or as per TJU standard practice guidelines. 3. Patients with a psychiatric disorder that would preclude patients from complying with the protocol even with a caregiver. Patients with a lack of social support that would interfere with the ability to receive appropriate medical care will also be excluded. 4. Pregnancy 5. Patients with life expectancy of \< 6 months for reasons other than their underlying hematological/oncological disorder. 6. 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 \> 2 μg/ml. Patients on systemic corticosteroids at a dose equivalent of prednisone 7.5mg/day or higher. 7. Patients who cannot receive cyclophosphamide. 8. Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol. 9. Patients with refractory disease. 10. Patients with clinically significant preformed antibodies to their donors. 11. Patients who require supplemental oxygen other than for sleep apnea will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Successful Engraftment Using Cyclophosphamide Post-Transplant | Through 100 days post-transplant | Successful Hematopoietic engraftment will be assessed by determining the incidence of participants who achieve both of the following criteria within the 100 days post-transplant: ANC \>/= 0.5x10e9/L for at least 3 days. Platelet engraftment \>20,000 with no transfusions X 7 days. The incidence will be calculated as the number of participants who meet both engraftment criteria. Results will be presented as a proportion/percentage/probability not as an incidence rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of Grade III-IV GVHD | Through 100 days post-transplant | The cumulative incidence of Grade III-IV graft-versus-host disease (GVHD) within 100 days post-transplant will be estimated; goal is less than 10%. The cumulative incidence represents the probability that a participant experiences Grade III-IV GVHD by day 100. Results will be reported as proportion/percentage/probability. |
| Incidence of GVHD Unresponsive to Corticosteroids and Photopheresis | Through 100 days post-treatment | This outcome will estimate the cumulative incidence (probability) of graft-versus-host disease (GVHD) that is considered unresponsive to corticosteroids and photopheresis within 100 days after treatment; goal is less than 15%. The cumulative incidence will be calculated as the number of participants meeting these criteria. Results will be reported as a proportion/percentage. |
| Transplant-Related Mortality | 100 days post-transplant | The cumulative incidence of transplant related mortality (TRM) by day 100 post-transplant will be estimated. Assess day 100 transplant-related mortality; goal is less than 15%. TRM is defined as death that results from medical treatment rather than from the underlying disease itself. The cumulative incidence reflects the probability of TRM by day 100. The result will be reported as a proportion/percentage/probability, not an incidence rate. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Myeloablative HSCT Myeloablative Hematopoietic Stem Cell Transplantation (HSCT): Patients will receive myeloablative transplants or nonmyeloablative transplants depending on their disease type.
Total Body Irradiation: Myeloablative HSCT Arm: Total body irradiation (TBI) is given in 8 fractions over 4 days (total dose of 12 Gy)
Cyclophosphamide: Cyclophosphamide is administered on the third day after the hematopoietic stem cell transplantation (HSCT) to help reduce graft-versus-host disease (GVHD). It is given at a dose of 60 mg/kg/d for 2 days on days +3 and +4.
Tacrolimus: Started the fifth day after the transplant to help prevent graft-versus-host disease (GVHD).
Mycophenolate mofetil: Started the fifth day after the transplant to help prevent graft-versus-host disease (GVHD).
Hematopoietic stem cell transplantation: Allogeneic marrow transplantation given after the last dose of total body irradiation (TBI) | 33 |
| Reduced Intensity HSCT Reduced Intensity Hematopoietic Stem Cell Transplantation (HSCT): Patients who have received a previous transplant, patients who have received dose limiting radiation, and patients with a DLCO \<45% will receive the reduced intensity conditioning regimen.
Total Body Irradiation: Reduced Intensity HSCT Arm: TBI is given in one fraction (total dose of 2 Gy)
Cyclophosphamide: Cyclophosphamide is administered on the third day after the hematopoietic stem cell transplantation (HSCT) to help reduce graft-versus-host disease (GVHD). It is given at a dose of 60 mg/kg/d for 2 days on days +3 and +4.
Tacrolimus: Started the fifth day after the transplant to help prevent graft-versus-host disease (GVHD).
Mycophenolate mofetil: Started the fifth day after the transplant to help prevent graft-versus-host disease (GVHD).
Fludarabine: Started the fifth day before the transplant. Given for four days at 30 mg/m2/d.
Busulfan: Started the fourth day before the transplant. Given for two days at 3.2 mg/kg.
Hematopoietic stem cell transplantation: Allogeneic marrow transplantation given after the last dose of total body irradiation (TBI) | 45 |
| Total | 78 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 8 |
| Overall Study | Disease Progression | 1 | 1 |
Baseline characteristics
| Characteristic | Myeloablative HSCT | Reduced Intensity HSCT | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 28 Participants | 28 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 17 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 44 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 5 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) White | 21 Participants | 38 Participants | 59 Participants |
| Sex: Female, Male Female | 17 Participants | 21 Participants | 38 Participants |
| Sex: Female, Male Male | 16 Participants | 24 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 33 | 8 / 45 |
| other Total, other adverse events | 33 / 33 | 45 / 45 |
| serious Total, serious adverse events | 5 / 33 | 5 / 45 |
Outcome results
Primary
Successful Engraftment Using Cyclophosphamide Post-Transplant
Successful Hematopoietic engraftment will be assessed by determining the incidence of participants who achieve both of the following criteria within the 100 days post-transplant: ANC \>/= 0.5x10e9/L for at least 3 days. Platelet engraftment \>20,000 with no transfusions X 7 days. The incidence will be calculated as the number of participants who meet both engraftment criteria. Results will be presented as a proportion/percentage/probability not as an incidence rate.
Time frame: Through 100 days post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Myeloablative HSCT | Successful Engraftment Using Cyclophosphamide Post-Transplant | 1.00 Cumulative Probability of Engraftment |
| Reduced Intensity HSCT | Successful Engraftment Using Cyclophosphamide Post-Transplant | 0.93 Cumulative Probability of Engraftment |
Secondary
Cumulative Incidence of Grade III-IV GVHD
The cumulative incidence of Grade III-IV graft-versus-host disease (GVHD) within 100 days post-transplant will be estimated; goal is less than 10%. The cumulative incidence represents the probability that a participant experiences Grade III-IV GVHD by day 100. Results will be reported as proportion/percentage/probability.
Time frame: Through 100 days post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Myeloablative HSCT | Cumulative Incidence of Grade III-IV GVHD | 0.5152 Cumulative Probability of Grade III-IV G |
| Reduced Intensity HSCT | Cumulative Incidence of Grade III-IV GVHD | 0.3111 Cumulative Probability of Grade III-IV G |
Secondary
Incidence of GVHD Unresponsive to Corticosteroids and Photopheresis
This outcome will estimate the cumulative incidence (probability) of graft-versus-host disease (GVHD) that is considered unresponsive to corticosteroids and photopheresis within 100 days after treatment; goal is less than 15%. The cumulative incidence will be calculated as the number of participants meeting these criteria. Results will be reported as a proportion/percentage.
Time frame: Through 100 days post-treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Myeloablative HSCT | Incidence of GVHD Unresponsive to Corticosteroids and Photopheresis | 0.0625 Cumulative Probability of GVHD |
| Reduced Intensity HSCT | Incidence of GVHD Unresponsive to Corticosteroids and Photopheresis | 0.0233 Cumulative Probability of GVHD |
Secondary
Transplant-Related Mortality
The cumulative incidence of transplant related mortality (TRM) by day 100 post-transplant will be estimated. Assess day 100 transplant-related mortality; goal is less than 15%. TRM is defined as death that results from medical treatment rather than from the underlying disease itself. The cumulative incidence reflects the probability of TRM by day 100. The result will be reported as a proportion/percentage/probability, not an incidence rate.
Time frame: 100 days post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Myeloablative HSCT | Transplant-Related Mortality | 0.0909 Cumulative Probability of Mortality |
| Reduced Intensity HSCT | Transplant-Related Mortality | 0.1951 Cumulative Probability of Mortality |