Acute Myeloid Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
Conditioning regimens, Stem Cell Transplantation, Hematopoietic Stem Cell Transplantation, Allogeneic Stem Cell Transplantation, Nonmyeloablative conditioning, Clofarabine, Cytarabine, Anti-thymocyte globulin
Brief summary
This study will test the combination of clofarabine, cytarabine, and thymoglobulin as a non-myeloablative conditioning regimen for patients with myelodysplastic syndromes or acute myeloid leukemia undergoing allogeneic stem cell transplant.
Detailed description
Current reduced intensity conditioning regimens have been able to decrease TRM (treatment related mortality) but suffer from increased rates of disease relapse. Disease burden at transplantation, as measured by percent myeloblasts, predicts relapse. Current regimens employ fludarabine and busulfan with various adjutants, but these agents are not part of the usual armamentarium used versus leukemia and have questionable anti-leukemic activity. By substituting clofarabine and cytarabine, a combination with proven anti-leukemic activity in the relapsed and refractory setting as well as activity versus MDS, as the back bone of the regimen we hope overcome residual disease and improve post-transplant relapse rates. Furthermore the principal toxicity of this regimen is myelosuppression, which should be abrogated by the infusion of stem cells. Thymoglobulin is included due to its minimal contribution to toxicity but significant benefits in engraftment, and controlling acute and chronic GVHD, which are major contributors to TRM and disease specific activity in MDS.
Interventions
DRUGClofarabine
DRUGCytarabine
DRUGThymoglobulin
PROCEDUREStem cell infusion
Sponsors
Washington University School of Medicine
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
(Patient): 1. Myelodysplastic Syndrome (MDS), as defined by the World Health Organization criteria, OR Chronic Myelomonocytic Leukemia (CMML) as defined by the French American British classification OR Acute Myeloid Leukemia (AML) in complete remission \[excluding FAB-M3\] diagnosed by standard criteria and meet the criteria below: 1. Patients may be in any CR 2. No more than 2 cycles of consolidation. Any consolidation regimen may be used. 3. No more than 6 months from documented CR to transplant. 2. Age 18 years or older. 3. ECOG performance status \<=2 4. Identification of suitable donor 5. DLCO \>=40% with no symptomatic pulmonary disease 6. LVEF by MUGA \>= 30% 7. Serum creatinine \<=1.0 mg/dL; if serum creatinine \>1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be \>60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient is female) x (1.212 if patient is black). 8. Bilirubin \<=2 times the upper limit of normal 9. AST \<=3 times the upper limit of normal Donor criteria: 1. HLA-Matched Sibling: The donor must be an adequate HLA match as determined by serologic typing for class (A, B) and low resolution molecular typing for class II (DRB1) as defined by institutional standards. 2. Matched Unrelated Donor: An acceptable match per NMDP standards based on high resolution molecular typing. 3. The donor must be healthy and must be an acceptable donor as per institutional standards for stem cell collection. 4. The donor must have no significant cardiopulmonary, renal, endocrine, or hepatic disease. 5. There is no upper age restriction for donors, but they must be at least 18 years of age. 6. Syngeneic donors are not eligible. 7. No known HIV.
Exclusion criteria
1. Pregnant or nursing. 2. Active systemic infection considered opportunistic, life threatening or clinically significant at the time of treatment. 3. Severe concurrent disease, including severe insulin-dependent diabetes, uncontrolled hypertension, transient ischemic attacks, uncontrolled symptomatic coronary artery disease, or symptomatic CNS involvement or psychiatric illness/social situations that would limit compliance with study requirements. 4. Known HIV disease. 5. History of other malignancy except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast unless the subject has been off treatment and free from disease for \> 3 years. 6. Active disease at the time of transplant.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Six-month Treatment Related Mortality | 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Engraftment as Measured by Percent Donor Chimerism | Day +30 | — |
| Overall Survival | 5 years from time of restaging | — |
| Disease-free Survival | 5 years from time of restaging | Disease-free survival is defined as the length of time after treatment ends that the participant survives without any signs or symptoms of that cancer. |
| Disease Specific Response Rates | One, three, six and twelve months. | Disease-specific partial response and complete response. |
| Rate of Chronic Graft-versus-host Disease (GVHD) | 100 days-1 year after transplant | — |
| Use Conventional STR-PCR Method for Monitoring Engraftment | Up to 1 year after transplant | Includes assessment of mixed chimerism in the whole blood, myeloid cells, T cells, and B cells. |
| Median Time to Progression | 5 years from time of restaging | Time to progression is defined as the length of time from the start of treatment until the disease starts to get worse or spread to other parts of the body. |
| Rate of Acute Graft-versus-host Disease (GVHD) | Up to 100 days after transplant | Acute GVHD occurs within 100 days of transplant. |
Countries
United States
Participant flow
Recruitment details
Enrollment to the study opened on 11/21/2007 and enrollment to the study closed on 08/11/2008
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Non-myeloablative Conditioning Regimen * Clofarabine 40mg/m2/day IV over two hours daily x 5 days on Days -6 thru -2
* Cytarabine 1gm/m2/day IV over two hours daily x 5 days on Days -6 thru -2 after the START of Clofarabine.
* Thymoglobulin 1.0mg/kg IV over 6 hours X 1 day on Day -4, then 2.5mg/kg/day x 2 days on Days -3 and -2.
* Stem Cell Transplant - On day 0 a minimum of total CD34+ cell dose of 2 x10E6/kg (actual weight of recipient) will be infused. | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Arm 1: Non-myeloablative Conditioning Regimen |
|---|---|
| Age, Continuous | 54 years |
| Diagnosis Acute myeloid leukemia | 4 participants |
| Diagnosis Myelodysplastic syndrome | 3 participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 5 / 7 |
Outcome results
Primary
Six-month Treatment Related Mortality
Time frame: 6 months
Population: This outcome was not analyzed.~Enrollment to the trial was halted after three of the first seven patients expired. This fulfilled the predefined stopping rule as it was unlikely that we would achieve our primary end point of a 6 month treatment-related mortality of 10%.
Secondary
Disease-free Survival
Disease-free survival is defined as the length of time after treatment ends that the participant survives without any signs or symptoms of that cancer.
Time frame: 5 years from time of restaging
Population: None of the patients analyzed survived without any signs or symptoms of that cancer.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Non-myeloablative Conditioning Regimen | Disease-free Survival | 0 participants |
Secondary
Disease Specific Response Rates
Disease-specific partial response and complete response.
Time frame: One, three, six and twelve months.
Population: This outcome was not analyzed due to terminating the study after 7 participants were enrolled.~We felt that the engraftment as measured by percent donor chimerism provided better response details than the limited data that was collected for the disease specific partial and complete response rates.
Secondary
Engraftment as Measured by Percent Donor Chimerism
Time frame: Day +30
Population: 2 participants were not analyzed because they expired prior to Day +30.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: Non-myeloablative Conditioning Regimen | Engraftment as Measured by Percent Donor Chimerism | Not done | 2 participants |
| Arm 1: Non-myeloablative Conditioning Regimen | Engraftment as Measured by Percent Donor Chimerism | 50% donor (bone marrow) | 1 participants |
| Arm 1: Non-myeloablative Conditioning Regimen | Engraftment as Measured by Percent Donor Chimerism | 100% donor (bone marrow) | 1 participants |
| Arm 1: Non-myeloablative Conditioning Regimen | Engraftment as Measured by Percent Donor Chimerism | 23.5% donor (FISH) | 1 participants |
Secondary
Engraftment as Measured by Percent Donor Chimerism
Time frame: Day +40-+60
Population: 3 participants were not analyzed because they were expired.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: Non-myeloablative Conditioning Regimen | Engraftment as Measured by Percent Donor Chimerism | 60% donor (bone marrow) | 1 participants |
| Arm 1: Non-myeloablative Conditioning Regimen | Engraftment as Measured by Percent Donor Chimerism | 70% donor (bone marrow) | 1 participants |
| Arm 1: Non-myeloablative Conditioning Regimen | Engraftment as Measured by Percent Donor Chimerism | 75% donor (bone marrow) | 1 participants |
| Arm 1: Non-myeloablative Conditioning Regimen | Engraftment as Measured by Percent Donor Chimerism | 100% donor (peripheral blood) | 1 participants |
Secondary
Engraftment as Measured by Percent Donor Chimerism
Time frame: Day +80-+90
Population: 3 participants were not analyzed as they were deceased.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: Non-myeloablative Conditioning Regimen | Engraftment as Measured by Percent Donor Chimerism | 0% donor | 1 participants |
| Arm 1: Non-myeloablative Conditioning Regimen | Engraftment as Measured by Percent Donor Chimerism | 33% donor - myeloid (peripheral blood) | 1 participants |
| Arm 1: Non-myeloablative Conditioning Regimen | Engraftment as Measured by Percent Donor Chimerism | 67% donor (bone marrow) | 1 participants |
| Arm 1: Non-myeloablative Conditioning Regimen | Engraftment as Measured by Percent Donor Chimerism | 100% donor (bone marrow) | 1 participants |
Secondary
Median Time to Progression
Time to progression is defined as the length of time from the start of treatment until the disease starts to get worse or spread to other parts of the body.
Time frame: 5 years from time of restaging
Population: Of the four surviving patients, three relapsed. One patient remained in remission on day +120.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Non-myeloablative Conditioning Regimen | Median Time to Progression | 152 days |
Secondary
Overall Survival
Time frame: 5 years from time of restaging
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Non-myeloablative Conditioning Regimen | Overall Survival | 237 days |
Secondary
Rate of Acute Graft-versus-host Disease (GVHD)
Acute GVHD occurs within 100 days of transplant.
Time frame: Up to 100 days after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Non-myeloablative Conditioning Regimen | Rate of Acute Graft-versus-host Disease (GVHD) | 0 percentage of participants |
Secondary
Rate of Chronic Graft-versus-host Disease (GVHD)
Time frame: 100 days-1 year after transplant
Population: None of the participants had chronic graft-versus-host disease (GVHD). 3 participants expired prior to day 100.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Non-myeloablative Conditioning Regimen | Rate of Chronic Graft-versus-host Disease (GVHD) | 0 percentage of participants |
Secondary
Use Conventional STR-PCR Method for Monitoring Engraftment
Includes assessment of mixed chimerism in the whole blood, myeloid cells, T cells, and B cells.
Time frame: Up to 1 year after transplant
Population: This outcome was not analyzed specifically as the conventional STR-PCR method was used for monitoring engraftment.