Clinical trial NCT01665677: Atorvastatin as GVHD Prophylaxis for Allogeneic Hematopoietic Cell Transplantation
Official title: Phase II Study of Atorvastatin, Micro-dose Methotrexate and Tacrolimus Administered Only to Transplant Recipients for the Prophylaxis of Acute Graft-versus-host Disease Following Allogeneic Hematopoietic Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Graft vs Host Disease
Keywords: Graft vs Host Disease
GVHD
Allogeneic hematopoietic stem cell transplantation
HSCT
Atorvastatin
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: West Virginia University
First posted: 2012-08-15
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Matched Related Transplants Who Develop Grade II-IV Acute Graft Versus Host Disease (GVHD).
timeFrame: Day 100
measure: Matched Unrelated Donors Transplants Who Develop Grade II-IV Acute GVHD.
timeFrame: Day 100
Secondary outcomes:
measure: Matched Related Transplants Who Develop Grade II-IV Chronic GVHD.
timeFrame: 1 year
measure: Matched Unrelated Donors Transplants Who Develop Grade II-IV Chronic GVHD.
timeFrame: 1 year
Other outcomes:
Locations:
city: Morgantown
country: United States
facility: West Virginia University Hospitals Mary Babb Randolph Cancer Center
state: West Virginia
city: Milwaukee
country: United States
facility: Froedtert Hospital and the Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: West Virginia University
name: Michael Craig, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical College of Wisconsin
name: Mehdi Hamadani, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Deeg HJ. How I treat refractory acute GVHD. Blood. 2007 May 15;109(10):4119-26. doi: 10.1182/blood-2006-12-041889. Epub 2007 Jan 18.
citation: Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, van der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998 Oct 1;92(7):2303-14.
citation: Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM, Przepiorka D, Davies S, Petersen FB, Bartels P, Buell D, Fitzsimmons W, Anasetti C, Storb R, Ratanatharathorn V. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood. 2000 Sep 15;96(6):2062-8.
citation: Antin JH, Kim HT, Cutler C, Ho VT, Lee SJ, Miklos DB, Hochberg EP, Wu CJ, Alyea EP, Soiffer RJ. Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood. 2003 Sep 1;102(5):1601-5. doi: 10.1182/blood-2003-02-0489. Epub 2003 May 1.
citation: Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118. doi: 10.1146/annurev.pharmtox.45.120403.095748.
citation: Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8.
citation: Kanate AS, Hari PN, Pasquini MC, Visotcky A, Ahn KW, Boyd J, Guru Murthy GS, Rizzo JD, Saber W, Drobyski W, Michaelis L, Atallah E, Carlson KS, D'Souza A, Fenske TS, Cumpston A, Bunner P, Craig M, Horowitz MM, Hamadani M. Recipient Immune Modulation with Atorvastatin for Acute Graft-versus-Host Disease Prophylaxis after Allogeneic Transplantation. Biol Blood Marrow Transplant. 2017 Aug;23(8):1295-1302. doi: 10.1016/j.bbmt.2017.04.009. Epub 2017 Apr 12.