Graft vs Host Disease
Conditions
Keywords
Graft vs Host Disease, GVHD, Allogeneic hematopoietic stem cell transplantation, HSCT, Atorvastatin
Brief summary
Hematopoietic stem cell transplantation is a procedure in which a person receives blood forming stem cells from a person called a donor. The stem cells can be obtained from the hollow part of the hip bone or from blood. A serious problem with this treatment is graft-versus-host disease (GVHD). This happens when stem cells from the donor attack normal cells of the recipient. Currently, there is no universal standard of care in the United States to prevent GVHD. This study is being done to see if a medicine that is used to lower cholesterol can also help in reducing GVHD. Patients will receive atorvastatin daily by mouth starting 14 days before stem cell transplant. They will continue to take atorvastatin until 180 days after transplant. This medicine may be stopped earlier if there is a bad side effect or a severe GVHD. Patients will also receive standard treatment to prevent GVHD. Patients will undergo many tests that are standard for their treatment at West Virginia University (WVU), including blood tests to check blood counts, kidney function and HIV status; blood test to check for pregnancy; Multi Gated Acquisition Scan (MUGA scan)or echocardiogram to test heart function; lung function testing; and bone marrow aspirate or biopsy. Patients will also have the option to provide blood samples for optional research related to the study.
Detailed description
Acute graft-versus-host disease (GVHD) is one of the most frequent complications after allogeneic hematopoietic stem cell transplantation (HSCT).(1) It develops in 30-75% of recipients of allogeneic HSCT depending on the degree of histocompatibility between the donor and the recipient, number of T-cells in the graft, recipient's age and GVHD prophylactic regimen used. (2-4) Novel strategies designed to effectively prevent the development of this life threatening complication of allogeneic transplantation are urgently needed.
Interventions
DRUGAtorvastatin calcium
40 mg PO daily
Sponsors
West Virginia University
Mehdi Hamadani
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients with a history of a hematological malignancy or bone marrow failure syndrome suitable for allogeneic stem cell transplantation in the opinion of treating transplant physician. * Patients aged 18-75 years of age are eligible. Patients with age \> 18 and ≤ 50 years will be eligible for myeloablative conditioning (MAC), while patients \> 50 years of age, or those with previous history of autologous transplantation, high hematopoietic cell transplant comorbidity index (HCT-CI) score (\>2), and baseline diagnosis of hodgkin's lymphoma, chronic lymphocytic leukemia and follicular lymphoma will be suitable for reduced intensity conditioning (RIC) transplantation (however intensity of conditioning regimen will remain at the discretion of treating physician). * All patients must have at least one suitable human leukocyte antigen (HLA)-matched sibling or unrelated donor according to transplant center's guidelines (for selection of appropriate sibling donor). * Patient must provide informed consent. * Left ventricular ejection fraction ≥ 40%. * Bilirubin ≤ 2 x the upper limit of normal (ULN) and aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤ 3 x ULN; and absence of hepatic cirrhosis. For patients with Gilbert's syndrome, bilirubin ≤ 3 x ULN is permitted. * Adequate renal function as defined by a serum creatinine clearance of ≥ 40% of normal calculated by Cockcroft-Gault equation. * Carbon monoxide diffusing capacity (DLCOcor) corrected for hemoglobin or forced expiratory volume at one second (FEV1) or DL/VA ≥ 40% of predicted (a pulmonary function test). * Karnofsky performance status \> 70. * A negative pregnancy test will be required for all women of child bearing potential. Breast feeding is not permitted. * Patients with positive HIV serology are eligible. * Patients who have previously been taking atorvastatin or any other statin drug will be eligible as long as there is no contraindication to switch to atorvastatin (40mg/day) in the opinion of the treating physician. * Method of stem-cell collection from the sibling donor will be at the discretion of the treating physician. Although it is anticipated that majority of sibling donors will undergo Granulocyte colony-stimulating factor(G-CSF) induced stem cell mobilization; however donors undergoing bone marrow harvest or stem cell mobilization with experimental agents (e.g. plerixafor) will remain eligible for the study.
Exclusion criteria
* Uncontrolled arrhythmias or uncontrolled New York Heart Association class III-IV heart failure. * Evidence of active bacterial, viral or fungal infection at the time of transplant conditioning. * History of intolerance or allergic reactions with atorvastatin will not be eligible. * Undergoing a T-cell depleted allogeneic transplantation * Receiving conditioning regimens containing anti-thymocyte globulin, and/or campath
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Matched Related Transplants Who Develop Grade II-IV Acute Graft Versus Host Disease (GVHD). | Day 100 | The number of subjects in the matched sibling cohort who develop grades II-IV acute GVHD will be assessed by consensus criteria and graded on Bone Marrow Transplant Clinical Trials Network Manual of Procedures suggested grading sheets. Grade I is mild GVHD involving up to 25% of the subject's skin; Grade II is moderate GVHD. involving 25 to 50% of the subject's skin and can include mild changes in liver and/or mild diarrhea; Grade III is severe GVHD involving over 50% of the subject's skin. Liver involvement is likely as are stomach cramps and diarrhea; and Grade 4 is very severe GvHD. Skin may be blistered and may have broken down in places. Skin may be yellow due to liver injury. Severe diarrhea is common. Subjects in the matched unrelated donors are not included in this analysis. |
| Matched Unrelated Donors Transplants Who Develop Grade II-IV Acute GVHD. | Day 100 | The number of subjects in the matched unrelated donor cohort who develop grade II-IV acute GVHD. Acute GVHD will be assessed by consensus criteria and graded on Bone Marrow Transplant Clinical Trials Network Manual of Procedures suggested grading sheets. Grade I is mild GVHD involving up to 25% of the subject's skin; Grade II is moderate GVHD. involving 25 to 50% of the subject's skin and can include mild changes in liver and/or mild diarrhea; Grade III is severe GVHD involving over 50% of the subject's skin. Liver involvement is likely as are stomach cramps and diarrhea; and Grade 4 is very severe GvHD. Skin may be blistered and may have broken down in places. Skin may be yellow due to liver injury. Severe diarrhea is common. Subjects in the matched related donors are not included in this analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Matched Related Transplants Who Develop Grade II-IV Chronic GVHD. | 1 year | The number of subjects who develop grade II-IV chronic GVHD. Chronic GVHD diagnosis and grading I to IV will be according to National Institutes of Health (NIH) Criteria rating progressively intense symptoms involving: skin (asymptomatic to deep sclerosis, impaired mobility, ulceration, or pruritus), oral cavity (asymptomatic to symptoms limiting oral intake), eyes (asymptomatic to severe dry eye, inability to work, or loss of vision due to keratoconjunctivitis), gastrointestinal tract (asymptomatic to significant weight loss \[\>15%\] or esophageal dilation), liver (normal function to bilirubin or enzymes \>5 times ULN), lungs (asymptomatic to severe shortness of breath requiring supplemental oxygen), joints and fascia (asymptomatic to contractures with reduced range of motion and limited ability to perform daily care), and genital tract (asymptomatic to strictures and severe pain). Subjects in the matched unrelated donors are not included in this analysis. |
| Matched Unrelated Donors Transplants Who Develop Grade II-IV Chronic GVHD. | 1 year | The number of subjects who develop grade II-IV chronic GVHD. Chronic GVHD diagnosis and grading I to IV will be according to National Institutes of Health (NIH) Criteria rating progressively intense symptoms involving: skin (asymptomatic to deep sclerosis, impaired mobility, ulceration, or pruritus), oral cavity (asymptomatic to symptoms limiting oral intake), eyes (asymptomatic to severe dry eye, inability to work, or loss of vision due to keratoconjunctivitis), gastrointestinal tract (asymptomatic to significant weight loss \[\>15%\] or esophageal dilation), liver (normal function to bilirubin or enzymes \>5 times ULN), lungs (asymptomatic to severe shortness of breath requiring supplemental oxygen), joints and fascia (asymptomatic to contractures with reduced range of motion and limited ability to perform daily care), and genital tract (asymptomatic to strictures and severe pain). Subjects in the matched related donors are not included. |
Countries
United States
Participant flow
Recruitment details
75 subjects signed consent. Six did not meet eligibility criteria and were not treated.
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin Calcium (Lipitor) Atorvastatin will be administered at a dose of 40 mg orally daily starting on day -14, to permit an approximately 1-week observation period to rule out any acute atorvastatin-induced side effects before the initiation of transplant conditioning.
Patients will receive atorvastatin until +180 days or until the patient develops grade II-IV acute GVHD, extensive chronic GVHD, or any grade 3-4 toxicity related to atorvastatin.
Atorvastatin calcium: 40 mg PO daily | 30 |
| Unrelated Donor Atorvastatin will be administered at a dose of 40 mg orally daily starting on day -14, to permit an approximately 1-week observation period to rule out any acute atorvastatin-induced side effects before the initiation of transplant conditioning.
Patients will receive atorvastatin until +180 days or until the patient develops grade II-IV acute GVHD, extensive chronic GVHD, or any grade 3-4 toxicity related to atorvastatin.
Atorvastatin calcium: 40 mg PO daily | 39 |
| Total | 69 |
Baseline characteristics
| Characteristic | Atorvastatin Calcium (Lipitor) | Unrelated Donor | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 10 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 29 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 39 Participants | 69 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 38 Participants | 66 Participants |
| Region of Enrollment United States | 30 participants | 39 participants | 69 participants |
| Sex: Female, Male Female | 13 Participants | 12 Participants | 25 Participants |
| Sex: Female, Male Male | 17 Participants | 27 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 39 |
| other Total, other adverse events | 30 / 30 | 39 / 39 |
| serious Total, serious adverse events | 10 / 30 | 12 / 39 |
Outcome results
Primary
Matched Related Transplants Who Develop Grade II-IV Acute Graft Versus Host Disease (GVHD).
The number of subjects in the matched sibling cohort who develop grades II-IV acute GVHD will be assessed by consensus criteria and graded on Bone Marrow Transplant Clinical Trials Network Manual of Procedures suggested grading sheets. Grade I is mild GVHD involving up to 25% of the subject's skin; Grade II is moderate GVHD. involving 25 to 50% of the subject's skin and can include mild changes in liver and/or mild diarrhea; Grade III is severe GVHD involving over 50% of the subject's skin. Liver involvement is likely as are stomach cramps and diarrhea; and Grade 4 is very severe GvHD. Skin may be blistered and may have broken down in places. Skin may be yellow due to liver injury. Severe diarrhea is common. Subjects in the matched unrelated donors are not included in this analysis.
Time frame: Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Matched Related Donor | Matched Related Transplants Who Develop Grade II-IV Acute Graft Versus Host Disease (GVHD). | 3 Participants |
Primary
Matched Unrelated Donors Transplants Who Develop Grade II-IV Acute GVHD.
The number of subjects in the matched unrelated donor cohort who develop grade II-IV acute GVHD. Acute GVHD will be assessed by consensus criteria and graded on Bone Marrow Transplant Clinical Trials Network Manual of Procedures suggested grading sheets. Grade I is mild GVHD involving up to 25% of the subject's skin; Grade II is moderate GVHD. involving 25 to 50% of the subject's skin and can include mild changes in liver and/or mild diarrhea; Grade III is severe GVHD involving over 50% of the subject's skin. Liver involvement is likely as are stomach cramps and diarrhea; and Grade 4 is very severe GvHD. Skin may be blistered and may have broken down in places. Skin may be yellow due to liver injury. Severe diarrhea is common. Subjects in the matched related donors are not included in this analysis.
Time frame: Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Matched Related Donor | Matched Unrelated Donors Transplants Who Develop Grade II-IV Acute GVHD. | 12 Participants |
Secondary
Matched Related Transplants Who Develop Grade II-IV Chronic GVHD.
The number of subjects who develop grade II-IV chronic GVHD. Chronic GVHD diagnosis and grading I to IV will be according to National Institutes of Health (NIH) Criteria rating progressively intense symptoms involving: skin (asymptomatic to deep sclerosis, impaired mobility, ulceration, or pruritus), oral cavity (asymptomatic to symptoms limiting oral intake), eyes (asymptomatic to severe dry eye, inability to work, or loss of vision due to keratoconjunctivitis), gastrointestinal tract (asymptomatic to significant weight loss \[\>15%\] or esophageal dilation), liver (normal function to bilirubin or enzymes \>5 times ULN), lungs (asymptomatic to severe shortness of breath requiring supplemental oxygen), joints and fascia (asymptomatic to contractures with reduced range of motion and limited ability to perform daily care), and genital tract (asymptomatic to strictures and severe pain). Subjects in the matched unrelated donors are not included in this analysis.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Matched Related Donor | Matched Related Transplants Who Develop Grade II-IV Chronic GVHD. | 9 Participants |
Secondary
Matched Unrelated Donors Transplants Who Develop Grade II-IV Chronic GVHD.
The number of subjects who develop grade II-IV chronic GVHD. Chronic GVHD diagnosis and grading I to IV will be according to National Institutes of Health (NIH) Criteria rating progressively intense symptoms involving: skin (asymptomatic to deep sclerosis, impaired mobility, ulceration, or pruritus), oral cavity (asymptomatic to symptoms limiting oral intake), eyes (asymptomatic to severe dry eye, inability to work, or loss of vision due to keratoconjunctivitis), gastrointestinal tract (asymptomatic to significant weight loss \[\>15%\] or esophageal dilation), liver (normal function to bilirubin or enzymes \>5 times ULN), lungs (asymptomatic to severe shortness of breath requiring supplemental oxygen), joints and fascia (asymptomatic to contractures with reduced range of motion and limited ability to perform daily care), and genital tract (asymptomatic to strictures and severe pain). Subjects in the matched related donors are not included.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Matched Related Donor | Matched Unrelated Donors Transplants Who Develop Grade II-IV Chronic GVHD. | 15 Participants |