Hematologic Malignancies
Conditions
Keywords
Hematologic Malignancies, GVHD, Graft-Versus-Host-Disease, LLME, CD34+ stem cell infusions, CD34- fraction, Cyclosporine, Mycophenolate Mofetil, HSCT, Hematopoietic stem cell transplantation
Brief summary
The purpose of this research study is to determine if an experimental agent, LLME can decrease the incidence and severity of Graft-Versus-Host-Disease (GVHD) following blood (hematopoietic) stem cell transplantation
Detailed description
We believe that the risks of allogeneic transplant can be drastically reduced if the following criteria can be met: (1) consistent engraftment, (2) little or no GVHD with the ability to rapidly withdraw immune suppression, (3) rapid recovery of CD4 counts to levels greater than 200 cells/micro liter. Our prior (ongoing) trial attempts to address how LLME treated T cells given as donor lymphocyte infusion (DLI) can address points 2 and 3 above. The current study addresses how treatment of the CD34- fraction of the graft attempts to address points 1 and 2 (and to a lesser extent point 3) above. We believe that if these points can be consistently achieved that the mortality of allogeneic HSCT may be reduced to levels more akin to those of autologous HSCT. We propose to test the hypothesis that LLME-treated T cells will be safe with regard to reducing GVHD or other infusion related toxicities and that their administration as part of the transplant will facilitate engraftment. We believe that this approach will ultimately be an important step in a variety of transplant settings ranging from matched siblings to haplodisparate donors.
Interventions
Infusion of L-leucyl-L-leucine methyl ester (LLME) treated donor white blood cells
DRUGFludarabine
Fludarabine 30 mg/m2 prior to HSCT infusion
DRUGCytarabine
Cytarabine 2gm/m2 prior to HSCT infusion
DRUGCyclophosphamide
Cyclophosphamide 1gm/m2 prior to HSCT infusion
DRUGTacrolimus
Tacrolimus given before and after HSCT infusion
DRUGMesna
Mesna 1gm/m2/day given prior to HSCT infusion.
GM-CSF given post HSCT infusion
PROCEDUREHematopoietic stem cell transplantation (HSCT)
CD34 selected allogeneic stem cell infusion with 5x104/kg untreated T cells
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
* Patients must be \> 18 years of age, with no upper age limit. * Patients must have an ECOG performance status of 0 or 1. * Any patient with a hematologic malignancy which is unlikely to be cured by conventional treatment is eligible for this study. * Patients for whom a disease specific protocol exists will be transplanted on those protocols as discussed in the introduction. * Patients who have had prior autografts may be treated on this protocol. * Patients must have adequate physical function as measured by the following criteria: * Cardiac: Asymptomatic or, if symptomatic, then left ventricular ejection fraction at rest must be \>40%. * Hepatic: Aspartate transaminase (AST) micro 3x the upper limits of normal and total serum bilirubin \< 2.5 mg/dL. Patients with a higher bilirubin from benign conditions such as Gilbert's disease may still be eligible for the study. * Renal: Serum creatinine within the normal range or if creatinine outside normal range then creatinine clearance \> 60 ml/min/1.73m2. Serum creatinine must be less than or equal to 2.0 mg/dl. * Pulmonary: Asymptomatic or, if symptomatic, DLCO (diffusion capacity) \> 45% of predicted (corrected for hemoglobin) * The patient or guardian(s) must be able to give informed consent to the study. * Patient must have a suitable donor who is identical for HLA (human leukocyte antigens) -A, -B, -C, -DR. Single antigen mismatches for HLA-A, -B, -C, -DR are also permitted. Donors obtained through the National Marrow Donor Program (NMDP) will follow NMDP guidelines.
Exclusion criteria
* Patients who are eligible for a standard myeloablative transplant and for whom a standard myeloablative transplant is preferable will not be treated on this protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of CD34+ Stem Cell Infusions Followed by LLME as Measured by 100-Day Mortality | Through 100 days post-transplant or death | Determine the safety of CD34+ stem cell infusions followed by the LLME treated CD34- fraction. This includes monitoring the patients for any side effects associated with the LLME treated cell infusion or any other unexpected adverse events. This regimen will be gauged as to its safety using 100 day mortality as the measured endpoint. Deaths from all causes will be included. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Engraftment of Non-Myeloablative Transplants | Through 30 days post-transplant | Determine the engraftment rate of non-myeloablative transplants using CD34+ stem cells and LLME treated CD34- products. |
| Incidence of Grade II-IV Acute Graft-Versus-Host-Disease (GVHD) | Through 24 months post-treatment | Determine the incidence of grade II-IV acute GVHD after administration of grafts when combined with Cyclosporine/Mycophenolate Mofetil for GVHD prophylaxis. GVHD assessments occur daily as an in patient and at each out patient visit. |
| Rate of Serious Infectious Complications | Through 3 months post-transplant | Determine the rate of serious infectious complications. A serious infection will be defined as any requiring hospitalization or parenteral therapy. CD4 counts will be measured monthly for the first 3 months after transplant. |
| Number of Patients Who Achieve a CD4 Count > 200/Micro-liters | Through 60 Days Post Transplant | Determine the number of patients who achieve a CD4 count \> 200/micro-liters by 60 days after transplant. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LLME to Decrease GVHD Following HSC T To determine if an experimental agent, LLME, can decrease the incidence and severity of Graft-Versus-Host-Disease (GVHD) following hematopoietic stem cell transplantation (HSCT). | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | LLME to Decrease GVHD Following HSC T |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Age, Continuous | 54.65 years STANDARD_DEVIATION 9.74 |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 10 / 14 |
Outcome results
Primary
Safety of CD34+ Stem Cell Infusions Followed by LLME as Measured by 100-Day Mortality
Determine the safety of CD34+ stem cell infusions followed by the LLME treated CD34- fraction. This includes monitoring the patients for any side effects associated with the LLME treated cell infusion or any other unexpected adverse events. This regimen will be gauged as to its safety using 100 day mortality as the measured endpoint. Deaths from all causes will be included.
Time frame: Through 100 days post-transplant or death
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LLME to Decrease GVHD Following HSC T | Safety of CD34+ Stem Cell Infusions Followed by LLME as Measured by 100-Day Mortality | 1 participants |
Secondary
Incidence of Grade II-IV Acute Graft-Versus-Host-Disease (GVHD)
Determine the incidence of grade II-IV acute GVHD after administration of grafts when combined with Cyclosporine/Mycophenolate Mofetil for GVHD prophylaxis. GVHD assessments occur daily as an in patient and at each out patient visit.
Time frame: Through 24 months post-treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LLME to Decrease GVHD Following HSC T | Incidence of Grade II-IV Acute Graft-Versus-Host-Disease (GVHD) | Developed grade II-IV GVHD | 3 participants |
| LLME to Decrease GVHD Following HSC T | Incidence of Grade II-IV Acute Graft-Versus-Host-Disease (GVHD) | Developed cGVHD (Chronic GVHD) | 1 participants |
Secondary
Number of Patients Who Achieve a CD4 Count > 200/Micro-liters
Determine the number of patients who achieve a CD4 count \> 200/micro-liters by 60 days after transplant.
Time frame: Through 60 Days Post Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LLME to Decrease GVHD Following HSC T | Number of Patients Who Achieve a CD4 Count > 200/Micro-liters | 13 participants |
Secondary
Rate of Engraftment of Non-Myeloablative Transplants
Determine the engraftment rate of non-myeloablative transplants using CD34+ stem cells and LLME treated CD34- products.
Time frame: Through 30 days post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LLME to Decrease GVHD Following HSC T | Rate of Engraftment of Non-Myeloablative Transplants | 13 participants |
Secondary
Rate of Serious Infectious Complications
Determine the rate of serious infectious complications. A serious infection will be defined as any requiring hospitalization or parenteral therapy. CD4 counts will be measured monthly for the first 3 months after transplant.
Time frame: Through 3 months post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LLME to Decrease GVHD Following HSC T | Rate of Serious Infectious Complications | 2 participants |