Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
Leukemia, AML, ALL, MDS
Brief summary
Phase II trial evaluating the safety & efficacy of Atorvastatin for prophylaxis of Acute Graft Versus Host Disease (GVHD) in patients with hematological malignances undergoing human leukocyte antigen (HLA)-Matched Related Donor Hematopoietic Stem Cell Transplant (HSCT).
Detailed description
The study is a single-arm phase II single institutional trial evaluating the safety and efficacy of atorvastatin for the prophylaxis of acute GVHD in patients with hematological malignancies undergoing HLA matched related donor HSCT. This study will explore a two-pronged acute GVHD prophylaxis strategy, consisting of pre-treating consenting related donors with atorvastatin before stem cell mobilization and collection, followed by atorvastatin plus methotrexate/tacrolimus-based GVHD prophylaxis in transplant recipient patients.
Interventions
DRUGatorvastatin
donors-will receive atorvastatin 40 mg/day orally at least 14 days before anticipated first day of stem cell leukapheresis (LP) until successful completion of leukapheresis according to institutional guidelines. Patients-will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first.
DRUGTacrolimus
beginning on Day -2 through approximately Day +180 (that is, approximately 6 months after Day 0)
DRUGmethotrexate
Day +1, +3, and +6 and +11
Sponsors
Ohio State University Comprehensive Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Donor Eligibility Criteria * The donor must be at least 18 years of age, and willing/able to provide informed consent. Complete medication list will be reviewed for potential negative interaction with atorvastatin. * The donor must be an HLA-matched sibling or relative. * Syngeneic donors are not eligible. * Female donors of child-bearing potential should have a negative pregnancy test, and must not be breast feeding. * Bilirubin, AST and ALT must be \< 2 x normal; and absence of hepatic fibrosis/cirrhosis. * Adequate renal function as defined by a serum creatinine clearance of ≥ 40% of normal calculated by Cockcroft-Gault equation. * Adequate cardiac function with no history of congestive heart failure, uncontrolled atrial fibrillation or ventricular tachyarrhythmias. Patient Eligibility Criteria * Have hematologic malignancy requiring allogeneic HSCT, have adequate organ function, a serologic (or higher resolution) 6/6 class I human leukocyte antigen (HLA)-A and B and molecular class II DRB1 matched related donor, and are able to give informed consent. * Patients \> 18 and ≤ 65 years with comorbidity score ≤ 3 will be eligible for myeloablative conditioning (MAC), while patients \> 65 years of age, those with previous history of autologous transplantation, or high comorbidity index (\>3) will be eligible for reduced intensity conditioning (RIC) transplantation . * All patients must have at least one 6/6 HLA-matched sibling donor. * Patient must provide informed consent * Patients must have left ventricular ejection fraction \> 30%, no uncontrolled arrhythmias or New York Heart Association class III-IV heart failure. * Bilirubin must be \< 2 x normal; and absence of hepatic fibrosis/cirrhosis. * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be \<2 x normal; and absence of hepatic fibrosis/cirrhosis. * Serum creatinine clearance of ≥40% of normal calculated by Cockcroft-Gault equation. * Forced expiratory volume in one second (FEV1)and diffusion capacity; corrected for hemoglobin(DLCO) ≥ 50% and 40% of predicted respectively. * Karnofsky performance status \> 70. * A negative pregnancy test will be required for all women of child bearing potential. Breast feeding is not permitted. * No HIV infection. Patients with immune dysfunction are at a significantly higher risk of toxicities from intensive immunosuppressive therapies. * No evidence of active bacterial, viral or fungal infection at the time of transplant conditioning. * No active alcohol or substance abuse within 6 months of study entry. * Prior allogeneic transplant is acceptable. * No history of intolerance or allergic reactions with atorvastatin or other statins. * Patients who have previously been taking atorvastatin or any other statin will be eligible as long as there is no contraindication to switch to atorvastatin 40mg/day in the opinion of the treating physician.
Exclusion criteria
* Patients undergoing a T-cell depleted allogeneic transplantation will not be eligible. * Patients receiving another investigational drug are not eligible unless cleared by Principal Investigator. Patients with prior malignancies except resected basal cell carcinoma, treated carcinoma in-situ, or other hematologic diseases for which allogeneic HSCT is a treatment strategy, are not eligible. Cancer treated with curative intent \< 5 years previously will not be allowed unless approved by the Principal Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Grades II to IV aGVHD at Day +100 of Atorvastatin Administration | Up through day 100 following transplant | The incidence of grades II to IV aGVHD at day +100 of atorvastatin administration. The grading of aGVHD and cGVHD were done using the Consensus Conference criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Atorvastatin in Transplant Recipients in Terms of Adverse Events and Toxicities. | Patients: Baseline, weekly for 9 weeks and then on days 84, 91-100, 180 and 365. Donors: at apheresis and then 30 days later. | Adverse events and toxicities were monitored in patients using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria. |
| Time to Neutrophil and Platelet Engraftment | weekly for 12 weeks, 100 days, 6 months, and 12 months | Neutrophil engraftment will be defined as first of three consecutive days with ANC ≥ 0.5 x 109/L post-conditioning regimen induced nadir. Similarly platelet engraftment is defined as first day of platelet count ≥ 20,000 x 109/L, without transfusion for 7 consecutive days. |
| Percentage of Patients With Chronic Graft Versus Host Disease (cGVHD) | up 1 year post transplant | cGVHD occurring anytime after day 100 post transplant will be termed chronic GVHD, and evaluated in patients who were followed for at least 100 days without early progression or death. Grading of cGVHD was done using the National Institutes of Health Consensus Development Project Criteria |
| Non Relapse Mortality (NRM) at One Year | up to 12 months post transplant | Cumulative incidence of NRM will be calculated as the time from transplant until death not related to disease, where the competing risk for NRM was death due to disease. Patients who had not died were censored at last follow up. |
Countries
United States
Participant flow
Recruitment details
Patients who are candidates for HSCT using HLA matched related donors were eligible to be enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Patients Patients will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first. Standard post transplant care will be administered. | 40 |
| Donor Related donors will receive atorvastatin 40 mg/day orally at least 14 days before anticipated first day of stem cell leukapheresis (LP) until successful completion of leukapheresis according to institutional guidelines. Peripheral blood stem cells will not be manipulated or T-depleted prior to administration. | 40 |
| Total | 80 |
Baseline characteristics
| Characteristic | Patients | Donor | Total |
|---|---|---|---|
| Age, Continuous | 51 years | 50 years | 51 years |
| Region of Enrollment United States | 40 patients | 40 patients | 80 patients |
| Sex: Female, Male Female | 20 Participants | 20 Participants | 40 Participants |
| Sex: Female, Male Male | 20 Participants | 20 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 36 / 36 |
| serious Total, serious adverse events | 5 / 36 |
Outcome results
Primary
Percentage of Participants With Grades II to IV aGVHD at Day +100 of Atorvastatin Administration
The incidence of grades II to IV aGVHD at day +100 of atorvastatin administration. The grading of aGVHD and cGVHD were done using the Consensus Conference criteria.
Time frame: Up through day 100 following transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients | Percentage of Participants With Grades II to IV aGVHD at Day +100 of Atorvastatin Administration | 30 percentage of patients |
Secondary
Non Relapse Mortality (NRM) at One Year
Cumulative incidence of NRM will be calculated as the time from transplant until death not related to disease, where the competing risk for NRM was death due to disease. Patients who had not died were censored at last follow up.
Time frame: up to 12 months post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients | Non Relapse Mortality (NRM) at One Year | 5.5 percentage of patients |
Secondary
Percentage of Patients With Chronic Graft Versus Host Disease (cGVHD)
cGVHD occurring anytime after day 100 post transplant will be termed chronic GVHD, and evaluated in patients who were followed for at least 100 days without early progression or death. Grading of cGVHD was done using the National Institutes of Health Consensus Development Project Criteria
Time frame: up 1 year post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients | Percentage of Patients With Chronic Graft Versus Host Disease (cGVHD) | 43 percentage of patients |
Secondary
Safety of Atorvastatin in Transplant Recipients in Terms of Adverse Events and Toxicities.
Adverse events and toxicities were monitored in patients using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria.
Time frame: Patients: Baseline, weekly for 9 weeks and then on days 84, 91-100, 180 and 365. Donors: at apheresis and then 30 days later.
Population: Only patients with evaluable data reported
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients | Safety of Atorvastatin in Transplant Recipients in Terms of Adverse Events and Toxicities. | Grade 2 elevated liver enzymes | 2 patients |
| Patients | Safety of Atorvastatin in Transplant Recipients in Terms of Adverse Events and Toxicities. | Grade 4 elevated liver enzymes | 1 patients |
Secondary
Time to Neutrophil and Platelet Engraftment
Neutrophil engraftment will be defined as first of three consecutive days with ANC ≥ 0.5 x 109/L post-conditioning regimen induced nadir. Similarly platelet engraftment is defined as first day of platelet count ≥ 20,000 x 109/L, without transfusion for 7 consecutive days.
Time frame: weekly for 12 weeks, 100 days, 6 months, and 12 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Patients | Time to Neutrophil and Platelet Engraftment | Neutrophil engraftment | 18 days |
| Patients | Time to Neutrophil and Platelet Engraftment | Platelet engraftment | 14 days |