Treatment of Dyslipidemia in Allogeneic Hematopoietic Stem Cell Transplant Patients

Biol Blood Marrow Transplant 21 (2015) 809e820

Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org

Treatment of Dyslipidemia in Allogeneic Hematopoietic Stem Cell Transplant Patients Bernard Lawrence Marini 1, *, Sung Won Choi 2, Craig Alan Byersdorfer 2, Simon Cronin 3, David G. Frame 1 1 2 3

Department of Pharmacy Services and Clinical Sciences, University of Michigan Health System and College of Pharmacy, Ann Arbor, Michigan Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Michigan Health System, Ann Arbor, Michigan Department of Pharmacy, Karmanos Cancer Institute, Detroit, Michigan

Article history: Received 28 August 2014 Accepted 29 October 2014 Key Words: Graft-versus-host disease Dyslipidemia Allogeneic transplantation Statins Late complications

a b s t r a c t As survival rates in allogeneic hematopoietic stem cell transplantation (HSCT) continue to improve, attention to long-term complications, including cardiovascular disease, becomes a major concern. Cardiovascular disease and dyslipidemia are a common, yet often overlooked occurrence post-HSCT that results in significant morbidity and mortality. Also, increasing evidence shows that several anti-hyperlipidemia medications, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in particular, may have a role in modulating graft-versus-host disease (GVHD). However, factors such as drugedrug interactions, adverse effect profiles, and the relative efficacy in lowering cholesterol and triglyceride levels must be taken into account when choosing safe and effective lipid-lowering therapy in this setting. This review seeks to provide guidance to the clinician in the management of dyslipidemia in the allogeneic HSCT population, taking into account the recently published American College of Cardiology/American Heart Association guidelines on hyperlipidemia management, special considerations in this challenging population, and the evidence for each agent’s potential role in modulating GVHD. Ó 2015 American Society for Blood and Marrow Transplantation.

INTRODUCTION Allogeneic hematopoietic stem cell transplantation (HSCT) represents a potentially curative therapy for a number of lifethreatening conditions. Because of advances in patient care, survival outcomes in allogeneic HSCT have improved substantially over the years [1-3]. The National Marrow Donor Program analysis reported that 1-year survival rates for patients receiving a transplant from an unrelated donor have increased from 42.2% from 1996 to 2001 to 61.8% in the most recent 2008-2010 dataset [4]. Survival for unrelated donor transplants has even been shown to be comparable with related donor transplants in certain populations [5-7]. With continued improvements in HLA matching, supportive care measures, and control of graft-versus-host disease (GVHD), this trend is not expected to cease. Despite this improvement in peritransplant and immediate post-transplant survival, life expectancy for patients who survive more than 5 years post-transplant is approximately 30% lower than the

Financial disclosure: See Acknowledgments on page 818. * Correspondence and reprint requests: Bernard Lawrence Marini, PharmD, Department of Pharmacy, 1111 E. Catherine St., Rm 330, Ann Arbor, MI 48109-2054. E-mail address: [email protected] (B.L. Marini).

http://dx.doi.org/10.1016/j.bbmt.2014.10.027 1083-8791/Ó 2015 American Society for Blood and Marrow Transplantation.

general population, regardless of age [8]. This excess mortality has been attributed to the many long-term complications of allogeneic HSCT, including chronic GVHD, infection, and end-organ dysfunction, which may affect the respiratory, endocrine, hepatic, skeletal, ophthalmologic, renal, and cardiovascular systems [9]. Cardiovascular disease (CVD) is one of the more significant long-term complications of allogeneic HSCT, contributing to considerable morbidity and mortality [10-14]. Risk factors for CVD in the general population include age, hypertension, smoking, diabetes, and dyslipidemia [15]. Hypertension and smoking are the leading risk factors in terms of attributable mortality (13% and 9% of annual global deaths, respectively) [16]. However, these risk factors tend to cluster together, and dyslipidemia is estimated to be responsible for approximately 2.6 million deaths (4.5% of attributable global deaths) and one third of ischemic heart disease globally [16]. Management of modifiable cardiovascular risk factors, particularly dyslipidemia, can be challenging in the allogeneic HSCT population. Pharmacologic agents for dyslipidemia are not without serious side effects, and there are a number of clinically significant drug interactions the transplant provider must take into account. In a population particularly prone to adverse reactions and

810

B.L. Marini et al. / Biol Blood Marrow Transplant 21 (2015) 809e820

polypharmacy, proper management of drug therapy becomes increasingly important. Growing evidence also shows that statins and other antihyperlipidemia medications possess immunomodulatory properties; thus, the choice of lipid-lowering agent may have implications for GVHD outcomes post-transplant [17]. No guidelines exist at this time for the treatment of hyperlipidemia in allogeneic HSCT patients, and because of increasing survival post-transplant, a growing number of these individuals are no longer under the continuous care of transplant centers. Thus, awareness of the magnitude of cardiovascular risk and optimal pharmacotherapy of dyslipidemia in this challenging patient population is crucial. In this review, we summarize literature surrounding the treatment of dyslipidemia in allogeneic HSCT patients, with a focus on pharmacotherapy and the potential for immunomodulation with anti-hyperlipidemia medications. SCOPE OF THE PROBLEM IN HSCT PATIENTS In 2011, an international HSCT working group convened to update the recommendations for screening and preventive practices in long-term survivors of HSCT [18]. They noted that compared with other post-transplant complications, CVD is relatively rare. However, the notion that cardiovascular complications after HSCT may be underestimated was acknowledged [18]. Indeed, based on the most recent data available, this appears to be the case. The increased cardiovascular risk among survivors of HSCT was first well described in 2007 by Baker et al. [19]. In a retrospective analysis, 1089 survivors of HSCT were evaluated using 389 siblings as a matched control group. The age- and body mass indexeadjusted risk of diabetes mellitus and hypertension were 2 to 3 times higher (odds ratios, 2.31 [95% confidence interval, 1.45 to 3.67] and 3.42 [95% confidence interval, 1.55 to 7.52], respectively) in allogeneic HSCT patients. Another retrospective cohort study of 85 long-term survivors of HSCT found a similar high risk of CVD and metabolic syndrome (according to National Cholesterol Education Program-Adult Treatment Panel III criteria) [13]. The prevalence of metabolic syndrome was approximately double that expected from an age-adjusted general population cohort (29 cases versus 12.8 expected, P < .0001). Hypertriglyceridemia was present in 24 of 29 cases of metabolic syndrome in the HSCT group [13]. Not only is the risk of CVD greater in patients post-HSCT, evidence increasingly shows that the onset of CVD in HSCT patients occurs more quickly. A retrospective single-center cohort study by Tichelli et al. [12] found a cumulative incidence of CVD of 22% at 25 years, with a median age at onset of 49 years for the first cardiovascular event. Hyperlipidemia was associated with the development of CVD in a univariate analysis, and in a multivariate analysis the presence of 2 or more cardiovascular risk factors, including hyperlipidemia, was associated with the development of CVD [12]. A larger, multicenter, retrospective cohort study found similar premature adverse cardiovascular outcomes after HSCT, and the median age at onset was 54 [11]. The presence of hyperlipidemia was significantly associated with the incidence of an arterial cardiovascular event within 15 years post-transplant (12% versus 2%, P ¼ .0001) [11]. A nested case-control study of 3287 consecutive patients who survived at least 1 year post-transplant also found that post-HSCT hyperlipidemia was a risk factor for development of CVD [14]. Thus, HSCT patients are at risk for premature CVD, and hyperlipidemia is a significant risk factor for this serious post-transplant complication.

An analysis by Kagoya et al. [20] sought to characterize the prevalence and risk factors for dyslipidemia in allogeneic HSCT patients. Of the 194 adult patients followed for a median of 77 months, 42.8% developed hypercholesterolemia and 50.8% developed hypertriglyceridemia. Again, the onset of dyslipidemia was rapid, with the median interval to occurrence of hypercholesterolemia and hypertriglyceridemia of 11 and 8 months post-allogeneic HSCT, respectively. In a multivariate analysis, family history of hyperlipidemia, the incidence of chronic GVHD, chronic liver disease, and steroid use were all independently associated with the development of hypercholesterolemia. The most comprehensive analysis of the incidence and course of hyperlipidemia post-allogeneic HSCT to date was a retrospective chart review by Blaser et al. [21] of 761 patients who survived >100 days after allogeneic HSCT and had lipid measurements in the post-transplant period. Patients received tacrolimus-based GVHD prophylaxis, and sirolimus was included in 50% of regimens. The incidence of dyslipidemia post-transplant was substantial; 73.4% of patients developed hyperlipidemia and 72.5% hypertriglyceridemia. In a multivariate analysis, being overweight and developing grades II to IV acute GVHD were both associated with posttransplant hyperlipidemia and hypertriglyceridemia. Among those with grades II to IV acute GVHD, 81% with hyperlipidemia and 73% with hypertriglyceridemia were on corticosteroids at the time of peak lipid and triglyceride values. As survival outcomes continue to improve post-HSCT, management of long-term complications becomes increasingly important. Clearly, the preponderance of the literature suggests that the risk of hyperlipidemia and adverse cardiovascular outcomes post-transplant are significant and worthy of treatment consideration. PATHOPHYSIOLOGY CVD and coronary artery disease involves a complex interplay between a number of factors, including obesity, dyslipidemia, and inflammation [22]. Adipose tissue increases the production of inflammatory cytokines and chemokines, including monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor (TNF)-a, and IL-6 [23]. Free fatty acids released by adipose tissue also generate reactive oxygen species, leading to the oxidation of low-density lipoprotein (LDL) [23]. The oxidized LDL is ultimately taken up by activated macrophages, leading to the formation of foam cells characteristic of atherosclerotic lesions. Oxidized LDL also promotes endothelial activation, adhesion molecule expression, a reduction in vasodilator production (nitric oxide), and recruitment of platelets and inflammatory cells [23]. Such an inflammatory environment promotes plaque instability, ultimately resulting in plaque rupture, thrombus formation, and infarction [22]. Thus, both inflammation and dyslipidemia contribute significantly to the development of coronary artery disease. The pathophysiology of dyslipidemia in allogeneic HSCT patients is multifactorial. Allogeneic HSCT patients are on immunosuppression for extended periods of time, and many of these agents are well known for altering lipid homeostasis. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor used both for the prevention and treatment of GVHD, is associated with a high incidence of hyperlipidemia and hypertriglyceridemia [24]. Sirolimus, in its original studies in renal transplantation, was associated with a 45% to 57% incidence of hypertriglyceridemia and a 43% to 46% incidence of hyperlipidemia at over 1 year post-transplant [24].

B.L. Marini et al. / Biol Blood Marrow Transplant 21 (2015) 809e820

The incidence of these lipid abnormalities may be even more pronounced in allogeneic HSCT patients. In a study by Couriel et al. [25], the use of sirolimus in the treatment of steroid refractory chronic GVHD was associated with a 77% incidence of hypertriglyceridemia and a 34% incidence of hypercholesterolemia. Many of these patients had pronounced dyslipidemia. For example, 44% of patients with hypertriglyceridemia had levels 2 to 5 times the upper limit of normal and half of patients with hyperlipidemia had levels greater than 11.637 mmol/L (normal level, <5.172 mmol/L). Lipid abnormalities were also quick to arise, occurring within 1 month of initiation of therapy. Sirolimus-induced hyperlipidemia may involve several different mechanisms [26-29]. Morrisett et al. [26] found that sirolimus treatment resulted in a dose-dependent expansion of the free fatty acid pool and an increase in hepatic very-low-density lipoprotein (VLDL) synthesis. This study and several other analyses of lipid metabolism indicate that inhibition of mTOR by sirolimus results in increased lipolysis via augmentation of hormone-sensitive lipase (increasing circulating free fatty acids), interference with triglyceride metabolism, decreased triglyceride storage, and a disruption of the insulin-signaling pathway [26-29]. The calcineurin inhibitor cyclosporine is also associated with lipid abnormalities. A double-blind, randomized, placebo-controlled trial of 36 nontransplanted patients treated with cyclosporine for only 2 months resulted in 21% and 31% mean increases in total cholesterol and LDL, respectively [30]. It is thought that cyclosporine impairs the conversion of cholesterol into bile acids via inhibition of steroid 26-hydroxylase. Furthermore, cyclosporine, transported by lipoproteins, has been shown to block LDL receptors, resulting in an elevated serum LDL [31]. Finally, similar to sirolimus, cyclosporine has been shown to affect VLDL and LDL clearance via alterations in lipase activities [31]. Tacrolimus, a calcineurin inhibitor with more potent immunosuppressive activity than cyclosporine, may induce less hyperlipidemia when compared with cyclosporine. For example, in kidneyepancreas transplant recipients with elevated pretransplant lipid values, tacrolimus-based immunosuppression resulted in significant reductions in serum cholesterol and triglycerides to levels consistent with the general population, indicating tacrolimus may have a lipid-neutral effect [32]. Crossover studies in solid organ transplant switching from cyclosporine- to tacrolimus-based immunosuppression have resulted in improved lipid values, further demonstrating the potential differences between the 2 calcineurin inhibitors’ effects on lipid metabolism [31]. Large phase III studies in allogeneic HSCT patients, however, have not reported differences in rates of hyperlipidemia between cyclosporine- and tacrolimus-treated patients [33-35]. Glucocorticoids, often used in high doses for the treatment of GVHD, besides being known for their hyperglycemic and appetite-stimulating effects, are also associated with the development of dyslipidemia. Indeed, the study by Blaser et al. [21] discussed above found that although acute GVHD was associated with the development of hyperlipidemia and hypertriglyceridemia post-transplant, most of these patients were on corticosteroids at the time of peak measurements. Thus, in this setting, corticosteroids may be the underlying cause of dyslipidemia. The mechanism by which corticosteroids cause dyslipidemia is multifactorial. They result in alterations in lipase activity, increases in de novo lipogenesis, and an increase in VLDL export, resulting in increased cholesterol and triglyceride levels [36]. Furthermore, glucocorticoids down-regulate the LDL receptor, further

811

perturbing lipid levels [31]. An excellent review of glucocorticoid effects on lipid metabolism has been published, and a full discussion of the impact of glucocorticoids on lipid and glucose homeostasis is beyond the scope of this review [36]. Not only do immunosuppressants contribute to dyslipidemia in allogeneic HSCT patients, but post-transplant complications can also affect lipid homeostasis. For example, chronic GVHD of the liver can result in severe elevations in serum total cholesterol and triglycerides, caused by the inability of bile salts and cholesterol to be cleared through the bile duct. This causes a backup of cholesterol into the serum, transported by an abnormal lipoprotein particle, lipoprotein X [37]. Nephrotic syndrome, a rare but serious complication associated with chronic GVHD, has also been known to cause significant dyslipidemia [38,39]. Finally, post-transplant endocrine complications, including hypogonadism and hypothyroidism, are well known to contribute to dyslipidemia [40,41]. These abnormalities are particularly common in those patients who receive total body irradiation as a part of the conditioning regimen [9]. Thus, both immunosuppressants and the transplant process itself contribute to the pathogenesis of dyslipidemia in allogeneic HSCT patients. TREATMENT Traditionally, the paradigm in the management of dyslipidemia has been to treat to an LDL target. However, the ideal target LDL has not been established. It has been assumed that the lower the LDL cholesterol, the better, but this does not take into account the potential for increased adverse events with increasing doses of drugs and implementing combination drug therapy to achieve LDL goals. Clearly, this approach was not supported by strong clinical evidence. In November 2013 the American Heart Association (AHA) released new cholesterol management guidelines that replace the older National Heart, Lung and Blood Institute guidelines [42]. Although lifestyle modifications remain a critical component to therapy and risk reduction, the new guidelines simplify management by focusing on treating patients who are most likely to benefit from drug therapy based on the literature. According to the guidelines, 4 groups of patients should be treated with statin therapy: (1) patients with clinical atherosclerotic CVD (coronary heart disease, stroke, and peripheral artery disease), (2) patients with familial (primary) hyperlipidemia and an LDL > 4.913 mmol/L (normal level, <2.586 mmol/L), (3) patients age 40 to 75 years with type 2 diabetes, and (4) patients with an estimated 10-year cardiovascular risk 7.5% [42]. The Pooled Cohort Risk Assessment Equations developed by the AHA’s Risk Assessment Work Group are used to estimate this risk and are available online as a downloadable spreadsheet on the AHA website (http:// my.americanheart.org/professional/StatementsGuidelines/ PreventionGuidelines/Prevention-Guidelines_UCM_45769 8_SubHomePage.jsp) [42]. Most patients in these categories should be treated with moderate- or high-intensity statin therapy, taking into account the patient’s age, ability to tolerate high-intensity statin therapy (eg, drugedrug interactions, history of statin intolerance), and clinical trial evidence. Statins that lower LDL by more than 50% on average are considered highintensity statins, and those that lower LDL by approximately 30% to 50% are considered moderate-intensity statins (Table 1) [42]. Because there is less evidence for nonstatin drugs, and trials to date have not demonstrated significant reductions in atherosclerotic CVD, the guidelines do not

812

B.L. Marini et al. / Biol Blood Marrow Transplant 21 (2015) 809e820

Table 1 Classification of Statin Therapy High-Intensity Statin Therapy Daily Dose Lowers LDL > 50%

Moderate-Intensity Statin Therapy Daily Dose Lowers LDL 30%-50%

Atorvastatin 40-80 mg Atorvastatin 10-20 mg Rosuvastatin 20-40 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin 40 mg b.i.d. (or XL 80 mg daily) Pitavastatin 2-4 mg

Low-Intensity Statin Therapy Daily Dose Lowers LDL < 30% Simvastatin 10 mg Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg Pitavastatin 1 mg

Data from [42].

support the routine use of these agents. However, in patients who are unable to completely tolerate statin therapy, the addition of nonstatin cholesterol-lowering therapy may be considered [42]. Furthermore, in patients with very high triglyceride levels or with a history of triglyceride-induced pancreatitis, nonstatin therapies (eg, fibrates, niacin, n-3 polyunsaturated fatty acids) are reasonable in addition to intensive therapeutic lifestyle changes [43]. Table 2 summarizes the AHA recommendations for the treatment of hyperlipidemia. From the evidence discussed thus far, it is clear that allogeneic HSCT patients are at a significantly higher risk of early CVD relative to the general population [11-14]. To put the numbers in context with the new AHA guidelines and the 7.5% cutoff, the retrospective analysis of allogeneic HSCT patients by Tichelli et al. [12] demonstrated a 4.1% rate of CVD at 10 years. The 7.5% cutoff in the AHA guidelines was based on placebo group cardiovascular event rates from large, multicenter trials that demonstrated a significant reduction in the risk of major cardiovascular events with statin therapy in patients without baseline CVD [42]. Of note, patients were significantly older in these trials (mean age of 58 in the MEGA and AFCAPS/TexCAPS trials and median age of 66 in the JUPITER trial) compared with a median age of 27 in the Tichelli et al. study of allogeneic HSCT patients [12,44-46]. When adjusting for age, allogeneic HSCT patients have an almost 7-fold increase in the risk of an arterial cardiovascular event [12]. To further illustrate the profound increase in CVD, at 25 years post-transplant, where the age of patients is similar to those in the statin primary prevention trials, the cumulative incidence of CVD was 22% [12]. Based on the significantly increased ageadjusted risk for CVD in this population, it appears that

Table 2 Recommendations for Statin Therapy Indications for Statin Therapy

Clinical Considerations

Recommendation

Clinical ASCVD

Age  75 yr Age > 75 yr

High-intensity statin Moderate-intensity statin High-intensity statin Moderate-intensity statin High-intensity statin

FH with LDL  4.913 mmol/L Diabetes, ages 40-75 yr

7.5% estimated 10-year ASCVD risk, ages 40-75 yr

10-year ASCVD risk < 7.5% 10-year ASCVD risk  7.5%

Moderate- to highintensity statin

Data from [42]. ASCVD indicates atherosclerotic CVD; FH, familial (primary) hyperlipidemia.

treatment of all allogeneic HSCT patients able to tolerate moderate- to high-intensity statin therapy is reasonable and in line with AHA guidelines for targeting high-risk patients. Long-term post-transplant adverse outcomes such as these are likely to become increasingly important as strategies in the management and prevention of GVHD continue to be optimized. As the studies by Blaser et al. [21] and Kagoya et al. [20] indicated, development of GVHD is associated with the development of hyperlipidemia post-transplant. Although this may be related to increased immunosuppression to manage GVHD, the role of inflammation in CVD and atherosclerosis has been well described [47]. Both inflammation due to the alloimmune process of GVHD and the high prevalence of hyperlipidemia post-HSCT may contribute to the negative cardiovascular outcomes in this population. Theoretically, the reverse may also be true. Inflammatory cytokines known to be involved in the process of atherosclerosis, including TNF-a and IL-6, are also those involved in the development of GVHD [47,48]. Thus, a potential strategy in the management of hyperlipidemia in HSCT could involve agents that also target the inflammatory changes of both atherosclerosis and GVHD. Furthermore, there is increasing evidence that effector T cells rely on lipid-biosynthetic pathways to meet the high metabolic demand of rapid clonal expansion through a complex interplay of the sterol regulatory element-binding proteins and liver X receptor signaling [49-51]. This reliance on fat oxidation as a key fuel source is not seen in homeostatic T cell proliferation or in the hematopoietic stem cell population (which rely primarily on aerobic glycolysis) [49,50]. Targeting hyperlipidemia in allogeneic HSCT patients thus may help to limit the primary fuel source of pathogenic T cells implicated in GVHD [52]. Finally, factors such as drugedrug interactions, adverse effect profiles, and the relative efficacy in lowering cholesterol and triglyceride levels must be taken into consideration when choosing safe and effective lipid-lowering therapy. The remainder of this section discusses the pros and cons of the various agents used in the treatment of hyperlipidemia and the evidence for their use in this patient population. Statins Statins exert their anti-hyperlipidemic effects by competitively inhibiting the rate-limiting enzyme in the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, preventing the conversion of HMG-CoA to mevalonic acid [53]. This inhibition reduces cholesterol production in the liver, resulting in an upregulation of LDL receptors and an increased clearance of LDL from the blood [53]. Depending on the statin and dosage used, these agents result in a 25% to 60% reduction in LDL cholesterol and a 10% to 37% reduction in triglycerides in the general population [54]. Thus, they are most effective in patients with LDL-predominant hyperlipidemia. The pleiotropic effects of statins have interested researchers for decades, and these alternative mechanisms are what makes these agents attractive for the treatment of hyperlipidemia in allogeneic HSCT patients. The inhibition of the mevalonate pathway not only reduces cholesterol synthesis, but also decreases the isoprenylation and formation of active cell signaling proteins, including Ras, Rac, and Rho [55]. This process preferentially skews CD4þ T cell differentiation from a pro-inflammatory, T helper type 1 (TH1) phenotype pathognomonic of acute GVHD to a noninflammatory TH2 phenotype. These effects were best demonstrated in a study by Zeiser et al. [56] using a murine bone marrow transplant

B.L. Marini et al. / Biol Blood Marrow Transplant 21 (2015) 809e820

model. Researchers found that pretreatment of either donor or recipient mice with atorvastatin provided partial protection from acute GVHD and resulted in 43% and 40% mean survival rates, respectively, compared with a 0% survival rate for placebo-treated mice. When both donor and recipient mice were treated, the survival benefit was additive, with a 65% survival rate in this group [56]. Because researchers were able to show the protective effects of statins were reversed by administration of mevalonate, it provides strong evidence that inhibition of isoprenylation plays a significant role in the anti-GVHD effect of statins. Indeed, levels of prenylated RAS, RAP-1, and Rho-B were reduced in T cells exposed to atorvastatin [56]. Zeiser et al. [56] also showed that, in vitro, atorvastatin pretreatmentddespite promoting TH2 polarization in CD4þ T lymphocytesddid not impair the graft-versustumor effects of cytotoxic T lymphocytes. Finally, statins have been shown to induce the development of anti-inflammatory T regulatory cells [57]. As a drug class, statins have the most evidence for use in allogeneic HSCT patients; a retrospective review of 761 allogeneic HSCT patients found that 29% of patients were prescribed a statin within 2 years post-HSCT. Use of statins in this population resulted in significant reductions in total cholesterol, LDL, and triglycerides with only a 3% incidence of possible statin toxicity and only 1 case of rhabdomyolysis [21]. Although prevention of isoprenylation clearly contributes to the anti-GVHD effects of statins, additional immunomodulatory mechanisms involving T cell trafficking and costimulation have been described. Two agents in particular, lovastatin and simvastatin, have been shown to inhibit leukocyte function-associated antigen-1 (LFA-1), an integrin molecule involved in regulating lymphocyte trafficking and activation. Activation of T cells induces a conformational change in LFA-1, allowing it to bind with high affinity to its ligands on antigen-presenting cells (APCs), resulting in T cell trafficking and further activation [58]. Simvastatin and

813

lovastatin bind allosterically to LFA-1, forcing it to remain in a low-affinity state. In a murine bone marrow transplantation model, Wang et al. [59] were able to demonstrate that blocking LFA-1 activation in recipient mice with lovastatin resulted in a reduction in T cell homing to lymph nodes, a decrease in donor derived T cell proliferation, and, ultimately, protection against acute GVHD mortality compared with pravastatin controls. There is also abundant evidence that statins may alter APC function and proliferation. In particular, statins have been shown to reduce IFN-geinduced MHC class II expression in APCs, decrease the expression of costimulatory molecules and chemokine receptors on APCs, and ultimately result in decreased APC maturation and activity [17,60,61]. Figure 1 depicts the hypothesized immunomodulatory activity of statins in the setting of GVHD. In addition to the robust in vitro and animal data indicating the potential utility of these agents in treating hyperlipidemia and preventing GVHD, the evidence in allogeneic HSCT patients has been equally promising. The first indication that statins may be useful in the setting of allogeneic HSCT was actually a prospective trial evaluating the effects of pravastatin in the treatment of refractory chronic GVHD [62]. In this study, 18 patients with pathology-proven chronic GVHD that did not respond to corticosteroids or cyclosporine were treated with pravastatin titrated to a maximum dose of 40 mg/day for 8 weeks. Pravastatin treatment was associated with a significant reduction in serum total cholesterol (6.36 mmol/L to 4.75 mmol/L [normal level <5.17 mmol/L], P ¼ .0001) and an overall response rate of 28% in chronic GVHD scores [62]. In the setting of acute GVHD, Hamadani et al. [63] conducted a retrospective analysis assessing the impact of statin use on 67 patients who underwent allogeneic HSCT for acute leukemia. Patients who were taking greater than 40 mg/day of statins for at least 1 month before and 3 months after allogeneic HSCT (n ¼ 10) had a numerical reduction in the incidence of grades II to IV

Figure 1. Mechanism of statin immunomodulation in GVHD [17,55-58,60,61]. Treg indicates regulatory T cell; LFA1, leukocyte function-associated antigen-1; ICAM, intercellular adhesion molecule; CIIA, MHC class II transactivator; TCR, T cell receptor; MHCII, MHC complex class II; PP, pyrophosphate.

814

B.L. Marini et al. / Biol Blood Marrow Transplant 21 (2015) 809e820

acute GVHD, although this was not statistically significant (10% versus 40%, P ¼ .08) [63]. In a subgroup analysis of 47 acute myeloid leukemia patients, this decrease in acute GVHD reached statistical significance (0% versus 43%, P ¼ .02) [63]. There were no differences in chronic GVHD between the 2 groups and no statistically significant difference in progression-free survival in patients with acute myeloid leukemia, indicating possible preservation of the graftversus-leukemia effect with statin therapy [63]. To elucidate the impact of both donor and recipient statin treatment on GVHD, Rotta et al. conducted 2 retrospective analyses in allogeneic HSCT patients [64,65]. The first study retrospectively analyzed the impact of both donor and recipient statin treatments on the incidence of acute GVHD in 567 individuals undergoing allogeneic HSCT with HLA-matched sibling grafts [64]. Specific statins used by recipients included atorvastatin (n ¼ 22), simvastatin (n ¼ 5), and rosuvastatin (n ¼ 1), and statins used by donors included atorvastatin (n ¼ 49), simvastatin (n ¼ 23), rosuvastatin (n ¼ 4), pravastatin (n ¼ 6), lovastatin (n ¼ 4), and fluvastatin (n ¼ 1) [64]. In a multivariate analysis, donor statin treatment (n ¼ 87) was associated with a reduction in grades III to IV acute GVHD (hazard ratio [HR] ¼ .28) [64]. When analyzed by subtype of acute GVHD, researchers found that donor statin use was associated with a significant reduction in gastrointestinal GVHD (P ¼ .02) but not other subtypes [64]. Of note, protection against GVHD was statistically significant in patients who received cyclosporine-based immunosuppression but not in those who received tacrolimus-based immunosuppression [64]. Recipient statin treatment was not associated with a reduction in the risk of GVHD; however, only 28 recipients had used statins regularly before allogeneic HSCT [64]. Researchers also examined the composition of peripheral blood stem cell grafts in 312 patients, and, interestingly, donor statin exposure was associated with a reduced content of dendritic cells of the type 2 variety (1.46  106  .46  106 cells/kg, P ¼ .002) and no change in the amount of CD34þ stem cells (.78  106  .48  106 cells/kg, P ¼ .11) [64]. Given the low amount of recipient statin use in the first study, Rotta et al. conducted a second study [65] to examine the effects of recipient statin treatment by analyzing outcomes in both related and unrelated donors (N ¼ 1206). Statins used by recipients in this study included atorvastatin (n ¼ 40), simvastatin (n ¼ 16), pravastatin (n ¼ 10), lovastatin (n ¼ 6), and rosuvastatin (n ¼ 4). A multivariate analysis, adjusted for a number of potential GVHD risk factors, revealed that statin use was associated not with a reduction in acute GVHD but with a decreased risk of chronic GVHD (HR ¼ .62, P ¼ .05) [65]. Similar to the previous retrospective trial, the decreased risk of GVHD was restricted to patients who received cyclosporine-based immunosuppression [65]. The authors suggested that this may be a result of synergy between statins and cyclosporine. Cyclosporine, but not tacrolimus, interacts with cyclophilins, which affect the calcium-dependent mitochondrial membrane permeability transition, a key process in the apoptotic pathway [64]. Statins also affect this process. However, because the literature suggests that tacrolimus may be more effective than cyclosporine at preventing GVHD, this may simply reflect the relatively lower potency of statins in preventing GVHD compared with the choice of calcineurin inhibitor [33]. Additionally, concomitant use of many statins and cyclosporine results in significantly increased statin exposure, most likely because of inhibition of the organic anion transporting polypeptide 1B1 (OATP1B1), a membrane transporter

involved in statin uptake into the liver [66]. Thus, this difference may be the result of increased statin exposure in patients being treated with concomitant cyclosporine. In a subset analysis of patients on cyclosporine-based prophylaxis who survived beyond day 100 post-transplant, statin use was even more strongly associated with protection against chronic GVHD (HR ¼ .40, P ¼ .02) [65]. However, there was also a statistically significant increased risk of recurrent malignancy (HR ¼ 2.53, P ¼ .009) in this subset [65]. This increased risk of disease relapse was not seen in the overall cohort of patients who received statins or in those who had received tacrolimus-based GVHD prophylaxis; however, given that only 76 patients were treated with statins, the study was likely underpowered to detect a difference in this outcome [65]. The implications of the increased risk of disease relapse in this specific subset of patients are unclear but certainly warrant further investigation. Most recently, statins have been evaluated prospectively in a phase II, single-arm clinical trial as a component of the GVHD prophylaxis regimen in matched sibling allogeneic HSCTs (N ¼ 30) [67]. Donors received atorvastatin 40 mg daily for 14 to 28 days before leukapheresis, and recipients received atorvastatin 40 mg daily starting on day 14 and continuing until immunosuppression was stopped, day þ180, development of grades II to IV acute GVHD, or the development of severe chronic GVHD. The cumulative rates of grades II to IV acute GVHD were 3.3% at 100 days and 11.1% at 180 days post-transplant [67]. Although difficult to draw definitive conclusions with this small sample size, the rates of acute GVHD are considerably lower than those published in the literature (30% to 50%) [67]. There was also an increase in IL10 concentrations after atorvastatin treatment, although this was not statistically significant (n ¼ 17, 5.6 versus 7.1 pg/mL, P ¼ .06) [67]. IL-10 is an anti-inflammatory cytokine characteristic of the TH2 phenotype associated with a reduction in acute GVHD [68,69]. This increase in IL-10 concentrations is promising and further supports a possible mechanism for statin immunomodulation in this setting. Rates of chronic GVHD were in line with what is expected in this population, with a 1-year cumulative incidence of 52.3% [67]. Of note, recipients stopped statin therapy once immunosuppression was stopped, day þ180, or the development of grades II to IV acute or severe chronic GVHD. Because the data by Rotta et al. [65] suggest that statin use post-transplant may reduce chronic GVHD, it is possible that extending statin therapy beyond the acute setting may affect chronic GVHD while also potentially impacting cardiovascular morbidity in this at-risk population. Further, larger studies are required to test this theory and to confirm any benefits with regards to lowering of acute GVHD. Most importantly, treatment with statins was safe. Although the study was not adequately powered to fully assess safety outcomes, no serious adverse events, increases in infection, or increases in relapse were noted [67]. The evidence for statin use in allogeneic HSCT patients is certainly expanding; however, clinicians must be cognizant of potential drugedrug interactions and adverse reactions associated with these agents. The major adverse effects associated with statins include asymptomatic elevations in hepatic transaminases and myopathy [70]. In the study by Blaser et al. [21] mentioned previously, 220 allogeneic HSCT patients were treated with statins within 2 years of transplantation and only 7 patients (3%) discontinued therapy secondary to potential statin toxicity. Two patients (1%) developed myopathies, and only 1 patient (.5%) had liver function test elevations attributable to statin toxicity.

B.L. Marini et al. / Biol Blood Marrow Transplant 21 (2015) 809e820

Because this was a retrospective study not adequately powered to assess statin toxicity in allogeneic HSCT patients, clinicians must carefully monitor for liver function test elevations while results from larger, future prospective studies are awaited. However, it must be noted that these data are in line with what has been seen the general population, in which liver enzyme abnormalities occur infrequently (approximately 1% in postmarketing studies and large metaanalyses) [71,72]. This low rate of toxicity prompted the US Food and Drug Administration to remove the recommendation to routinely monitor liver function tests during statin therapy, given the paucity of this adverse reaction [73]. Nonetheless, there have been case reports of hepatic failure associated with statin use, and it is reasonable to monitor liver function tests periodically in allogeneic HSCT patients, given the lack of robust, prospective data in this setting [71]. Statin-induced myopathy, ranging from muscle aches to overt rhabdomyolysis, is also uncommon, occurring at a rate of .1% to .2% in clinical trials. Fatal rhabdomyolysis is even more rare, with an estimate occurrence rate of <1 death per million statin prescriptions [70]. The risk of myopathy appears to be dose- and concentration-related [70]. Thus, pharmacokinetic drugedrug interactions that elevate serum concentrations of statins increase the risk of myopathy. Most statins, with the exception of pitavastatin, pravastatin, and rosuvastatin, are highly dependent on cytochrome P-450 (CYP450) enzymes for metabolism and elimination [66]. Atorvastatin, lovastatin, and simvastatin are metabolized primarily through CYP3A4. Thus, allogeneic HSCT patients also on azole antifungals which are strong 3A4 inhibitors (itraconazole, posaconazole, and voriconazole), should be closely monitored for toxicity and consideration should be made for using a non-3A4 metabolized statin for lipid lowering. All statins appear to be substrates of hepatic transporter proteins, in particular the organic anion transporting polypeptide, which appears to be the most significant transporter involved in statin drugedrug interactions [66]. As mentioned previously, cyclosporine, an inhibitor of not only CYP3A4 but also of OATP1B1, increases the area under the curve of statins by 2- to 25-fold depending on the particular agent and individual genetic differences in statin metabolism and elimination [66]. Fluvastatin, a 2C9

815

substrate minimally affected by OATP1B1 in vivo, appears to be the least affected by cyclosporine, with concomitant use resulting in an area under the curve increase of approximately 2- to 4-fold [66]. The incidence of myopathy is significantly increased with concomitant cyclosporine and most statins; however, when used in the smallest possible doses with close monitoring, statins can be used safely in this setting. Tacrolimus, on the other hand, does not alter the pharmacokinetics of statins [66]. Table 3 summarizes the doses, efficacy, pharmacokinetic interaction potential, and common adverse events of anti-hyperlipidemia agents. By staying cognizant of potential drugedrug interactions (Table 4), clinicians can take full advantage of the emerging benefits of statin use in the setting of allogeneic HSCT. Other Agents There are very little data for other anti-hyperlipidemia medications in the setting of allogeneic HSCT, although this does not preclude their use in the proper clinical setting. In the retrospective analysis by Kagoya et al. [20] referenced above, 3 patients with dyslipidemia post-allogeneic HSCT were effectively treated with fibrates and 1 patient with niacin. There is also 1 case report of using bezafibrate in combination with ursodeoxycholic acid for severe lipoprotein X-mediated hypercholesterolemia caused by GVHD and cholestasis [74]. Fibrates act as agonists for peroxisome proliferator-activated receptor-a, a transcription factor that up-regulates lipolysis, reduces secretion of VLDL particles, increases free fatty acid uptake by the liver, and increases high-density lipoprotein (HDL) plasma levels [75]. Treatment with fibrates result in a 30% to 60% reduction in triglycerides, making these agents particularly attractive in the setting of sirolimus-induced dyslipidemia or lipoprotein-X mediated hypercholesterolemia, which are characteristically triglyceride-predominant conditions. Reductions in LDL and increases in HDL are comparatively smaller, averaging 5% to 31% and 9% to 20%, respectively [54]. In addition to the effects on lipids, bezafibrate has also been used as an effective treatment for chronic GVHD of the liver in patients unresponsive to ursodeoxycholic acid and immunosuppressants [76]. Thus, although the immunomodulatory effects of fibrates have never been fully evaluated in the setting of GVHD to the same scale as statins,

Table 3 Dosing, Efficacy, Drug Interaction Potential, and Adverse Events of Lipid-Lowering Agents Agent

Dosing Range

Lipid-Lowering Efficacy

Pharmacokinetic DDIs

LDL

HDL

Tg

Pravastatin Lovastatin Simvastatin Fluvastatin Pitavastatin Atorvastatin Rosuvastatin Fenofibrate Gemfibrozil

10-80 mg daily 10-80 mg daily 5-80 mg daily 20-80 mg daily 1-4 mg daily 10-80 mg daily 5-40 mg daily 67-200 mg daily 600 mg twice daily

()22-37% ()21-40% ()26-47% ()22-36% ()32-43% ()39-60% ()45-63% ()20-31% ()5-10%

(þ)2-12% (þ)5-10% (þ)8-16% (þ)3-6% (þ)5-8% (þ)5-9% (þ)8-14% (þ)9-14% (þ)10-20%

()11-24% ()10-19% ()12-33% ()12-18% ()15-19% ()19-37% ()10-35% ()30-50% ()40-60%

Niacin

1.5-6 g/day

()5-25%

Fish oil Ezetimibe Cholesterol absorption inhibitors

4 g daily (þ)44.5% (þ)9.1% 10 mg daily ()15-20% (þ)1-4% Cholestyramine: 4-24 g/day ()15-30% (þ)3-5% Colesevelam: 6-7 tabs/day Colestipol: 7-30 g/day

OATP substrate OATP, 3A4 substrate OATP, 3A4 substrate OATP, 2C9 substrate OATP, UGT substrate OATP, 3A4 substrate OATP substrate N/A Inhibits 1A2, 2C8, 2C9, 2C19, and OATP (þ)15-25% ()20-50% N/A ()44.9% ()5-8% (þ)0-20%

Significant AEs

Myopathy, increased transaminases

Dyspepsia, increased transaminases, increased SCr (fenofibrate)

Flushing, hepatotoxicity, glucose intolerance, hyperuricemia N/A Dyspepsia, increased bleeding risk OATP substrate Diarrhea May decrease absorption Constipation, bloating, flatulence of other agents

Data from [54,66,70,71,77-79,84,85]. Tg indicates triglycerides; DDIs, drugedrug interactions; AEs, adverse events; UGT, UDP-glucuronosyltransferase; N/A, not applicable; SCr, serum creatinine.

816

B.L. Marini et al. / Biol Blood Marrow Transplant 21 (2015) 809e820

Table 4 Drug Interactions with Common Allogeneic HSCT Medications Cyclosporine

Tacrolimus

Sirolimus Azole Antifungals

d

d

d

Lovastatin

XXX (limit pravastatin to 20 mg/day) CI/avoid

d

d

Simvastatin

CI/avoid

d

d

Fluvastatin

XXX (limit fluvastatin to 20 mg/day)

d

d

Pitavastatin Atorvastatin

CI/avoid CI/avoid

d

d

d

d

CI e itra, posa, vori XX e fluc CI e itra, posa, vori XX e fluc XXX e limit to 20 mg/day with fluc XX e vori d XXX e limit to 20 mg/day with itra, posa, vori d

Pravastatin

Rosuvastatin

XXX (limit rosuvastatin to 5 mg/day) XX (both can Fenofibrate cause renal and gemfibrozil dysfunction) Niacin d XXX (separate Cholesterol absorption administration) inhibitors Ezetimibe XXX

d XX (both can d cause renal dysfunction) d d d X (could theoretically decrease absorption) d

d

d

Data from [54]. XXX indicates strong interaction; d, no clinically significant interaction; CI, contraindicated; itra, itraconazole; posa, posaconazole; vori, voriconazole; XX, moderate interaction; fluc, fluconazole; X, mild interaction.

an anti-inflammatory benefit in this population cannot be ruled out. Fibrates are generally well tolerated, most commonly causing gastrointestinal upset and asymptomatic liver enzyme elevations [54]. However, concomitant use of these agents with statins does increase the risk for myopathy primarily through inhibition of hepatic uptake of statins via OATP1B1 [66]. In addition, fenofibrate has been associated with reversible increases in serum creatinine [77]. Niacin has been used for a number of years in the treatment of dyslipidemia, and its exact mechanism in this regard is complex and not fully understood [78]. Treatment with niacin results in a 5% to 25% reduction in LDL cholesterol, a 20% to 50% reduction in triglycerides, and is the most effective agent in raising HDL cholesterol, resulting in a 15% to 35% increase in levels [54]. Although niacin has significant favorable effects on all cholesterol subtypes, tolerability limits its widespread use. Niacin is associated with cutaneous flushing in up to 90% of patients [78]. Sustained-release preparations are associated with a lower incidence of this adverse reaction but have less of an impact on lipid parameters and pose an increased risk of rare hepatotoxicity. Other problematic adverse reactions include hyperuricemia, glucose intolerance, and gastrointestinal disturbances [79]. There is limited evidence for the use of niacin in the allogeneic HSCT population, but niacin is not associated with significant pharmacokinetic drugedrug interactions, making it a particularly attractive choice in patients on cyclosporine or azole antifungals. There is some emerging evidence that niacin possesses anti-inflammatory activity through its activity at the G proteinecoupled receptor GPR109A (hydroxylcarboxylic acid receptor 2) [78]. This receptor is expressed

not only on adipocytes but also on neutrophils, macrophages, and Langerhans cells. Through this pathway, niacin has been shown to suppress secretion of inflammatory cytokines, including MCP-1, regulated on activation, normal T cell expressed and secreted (RANTES), fractalkine, TNF-a, and IL6 [78]. Because some of these cytokines play a clear role in the pathogenesis of GVHD, niacin may possess benefits beyond simply effective management of multiple lipid abnormalities. If tolerated, its use in the allogeneic HSCT setting should be accompanied by monitoring for glucose intolerance and hyperuricemia. n-3 Polyunsaturated fatty acids (n-3 PUFAs, or “fish oils”), including docosahexaenoic acid and eicosapentaenoic acid, are particularly effective agents at reducing triglycerides. Lovaza is a fish oil product approved by the US Food and Drug Administration as an adjunct to diet to reduce triglyceride levels in patients with severe hypertriglyceridemia [80]. Studies of Lovaza in this population resulted in a nearly 45% decrease in triglyceride levels [80]. The mechanism of lipid lowering by n-3 PUFAs is thought to be related to inhibition of fatty acid and triglyceride biosynthesis, reduction in hormone-sensitive lipase activity, and stimulation of fatty acid oxidation [81]. Interestingly, n-3 PUFAs are also thought to have immunomodulatory effects. n-3 PUFAs alter the phospholipid content of inflammatory cells, resulting in a decreased production of arachidonic acidederived inflammatory prostaglandins, thromboxanes, and leukotrienes and an increased production of the anti-inflammatory resolvins [82]. n-3 PUFAs have also been shown to decrease leukocyte chemotaxis, inflammatory cytokine production, adhesion molecule expression, and reactive oxygen species generation [82]. n-3 PUFAs have demonstrated clinical benefit in several inflammatory conditions, including rheumatoid arthritis, inflammatory bowel disease, asthma, and acute lung injury in intensive care unit patients [82,83]. Thus, although evidence for their use in the allogeneic HSCT population is lacking, a potential anti-inflammatory effect in patients at risk for GVHD is intriguing. Of note, n-6 PUFAs, including linoleic acid and arachidonic acid, have been shown to be pro-inflammatory. There are no expected pharmacokinetic interactions of n-3 PUFAs with commonly used transplant medications; the main concern with using these agents in the allogeneic HSCT setting is the potential for inhibition of platelet aggregation induced by PUFA byproducts [84]. Thus, allogeneic HSCT patients in whom n-3 PUFAs are used should be monitored closely for bleeding, and these agents should be used cautiously in patients with significant thrombocytopenia or other concomitant antiplatelet agents. Ezetimibe inhibits the Niemann-Pick C1-like transporter in the intestinal tract, preventing cholesterol absorption [85]. Treatment with ezetimibe results in a moderate decrease in LDL of approximately 20%, a decrease in triglycerides of up to 8%, and a 1% to 4% increase in HDL [54]. Ezetimibe is frequently combined with statins for additive LDL lowering. Ezetimibe has also been shown to reduce inflammatory markers in patients with hyperlipidemia, but the mechanism for this anti-inflammatory effect has not been elucidated [85,86]. The reduction in inflammation may simply result from a reduction in lipid values. Ezetimibe is typically well tolerated, with diarrhea being the most common complaint (occurring in approximately 4% of patients), and this agent can be used safely in combination with statins to gain additional LDL lowering efficacy [87,88]. Although this agent has not been systematically evaluated in the allogeneic HSCT population, it appears to be a safe and attractive option for

B.L. Marini et al. / Biol Blood Marrow Transplant 21 (2015) 809e820

add-on therapy when statin doses need to be limited in the setting of drugedrug interactions. Ezetimibe is not metabolized via CYP enzymes; however, like many statins, it is handled by the OATP1B1 transporter [89]. Cyclosporine, an OATP1B1 inhibitor, has been shown to increase ezetimibe concentrations 2- to 3-fold [54]. Thus, the combination of ezetimibe and cyclosporine should be used with caution. The gastrointestinal adverse effects of this agent may preclude its use in patients with gastrointestinal GVHD, and this agent should be discontinued if gastrointestinal GVHD is suspected. The final class of agents, the bile acid sequestrants, act by binding and preventing reabsorption of bile acids in the gastrointestinal lumen. This results in increased uptake and breakdown of LDL cholesterol in the liver for conversion into bile acids [85]. Treatment with bile acid sequestrants results in a 15% to 30% decrease in LDL and a 3% to 5% increase in HDL [54]. In combination with statins, these agents result in a nearly 50% lowering of LDL [85]. Unfortunately, bile acid sequestrants can result in up to a 20% increase in triglycerides, so caution must be used in patients with severe hypertriglyceridemia [85]. In addition, the bile acid sequestrants are sometimes difficult to tolerate and inconvenient, requiring multiple doses per day. The main side effects are gastrointestinal in nature and include constipation, bloating, and flatulence [85]. In addition to binding bile acids, these agents also bind many drugs in the gastrointestinal tract, resulting in decreased systemic exposure to some agents. Interacting medications, including cyclosporine, should be given at least 1 hour before and 4 hours after bile acid sequestrants [85]. These agents have also not been systematically evaluated in the allogeneic HSCT population. The hydrophilic bile acid ursodiol, although not typically thought of as a lipid-lowering agent, may have a similar mechanism of action to the bile acid sequestrants. It has been hypothesized that ursodiol may reduce gastrointestinal absorption of cholesterol, increase receptor-mediated LDL uptake in the liver, and potentially inhibit HMG-CoA reductase [90-92]. This agent also reduces the concentration of hepatotoxic hydrophobic bile acids and may possess immunomodulatory effects, including a reduction in the production of the inflammatory cytokines TNF-a, macrophage inflammatory protein 2, and IL-6 [93-96]. Accordingly, prophylactic ursodiol given for 90 days post-allogeneic HSCT (N ¼ 242) has been shown to result in a reduction in grades III to IV acute GVHD, grades II to IV and III to IV liver GVHD, grades III to IV skin GVHD, and grades II to IV gastrointestinal GVHD [96]. Most importantly, ursodiol given in this manner resulted in a significantly higher overall survival with 10 years of follow-up (38% versus 48%, P ¼ .037) with no difference in the incidence of relapse [97]. In patients with primary biliary cirrhosisdoften associated with hypercholesterolemiadtreatment with ursodiol has been shown to result in a 28% reduction in total cholesterol at 2 years [98]. To test whether this effect was due to improvement in the underlying cholestatic liver disease or an intrinsic lipid-lowering property of ursodiol, Braga et al. [99] conducted a multicenter, randomized, placebo-controlled, double-blind clinical trial in 125 patients with primary hypercholesterolemia without underlying liver disease. Unfortunately, ursodiol had no effect on lipid values throughout the 24 weeks of treatment. Thus, although ursodiol is a key agent that should be given posttransplant, it does not possess intrinsic lipid-lowering properties in those with hypercholesterolemia not induced by

817

Table 5 Potential Immunomodulatory Effects of Lipid-Lowering Agents Agent

Effects

Pravastatin Lovastatin

1. Promotes TH2 phenotype by inhibiting Ras, Rac, and Rho formation [55,56] 2. Blocks LFA-1, preventing T cell-to-APC interaction [58,59] 3. Alters APC function and proliferation [17,60,61] 4. Up-regulates anti-inflammatory T regulatory cell expression [57]

Simvastatin Fluvastatin Pitavastatin Atorvastatin Rosuvastatin

1. Promotes TH2 phenotype by inhibiting Ras, Rac, and Rho formation [55,56] 2. Alters APC function and proliferation [17,60,61] 3. Up-regulates anti-inflammatory T regulatory cell expression [57]

Fenofibrate Gemfibrozil

1. Bezafibrate shows evidence for chronic GVHD refractory to ursodeoxycholic acid [76]

Niacin

1. Suppresses secretion of inflammatory cytokines through the GPR109A receptor [78]

Fish oil (n-3 PUFAs)

1. Decreases production of prostaglandins, thromboxanes, and leukotrienes [82] 2. Increases production of the anti-inflammatory resolvins [82] 3. Decreases leukocyte chemotaxis, inflammatory cytokine production, adhesion molecule expression, and ROS generation [82] NOTE: n-6 PUFAs may be pro-inflammatory [84]

Ezetimibe

1. May decrease vascular inflammation [85,86]

N/A Cholesterol absorption inhibitors ROS indicates reactive oxygen species.

cholestatic liver disease. Table 5 summarizes the hypothesized immunomodulatory activity of individual statins and other anti-hyperlipidemia medications. SUMMARY AND RECOMMENDATIONS The incidence of dyslipidemia and CVD post-allogeneic HSCT is coming to the forefront as a significant long-term complication worthy of serious consideration. Data indicate that these complications are not only frequent but occur much earlier than expected in the general population. Based on clinical practice guidelines for the management of dyslipidemia, patients at high risk of CVD should receive moderate to high doses of statins because of the reduction in mortality seen in this setting. Overwhelmingly, the data indicate that allogeneic HSCT patients are at a significantly greater risk of CVD compared with the general population and thus could potentially benefit from statin therapy, regardless of calculated risk based on age and traditional risk measures in the Pooled Cohort Equations. Of the antihyperlipidemia medications, statins have the most evidence in the allogeneic HSCT population and have been used safely to effectively manage dyslipidemia in this setting. Care should be taken to avoid drugedrug interactions that may increase the myopathy risk, especially with certain azole antifungals and the calcineurin inhibitor cyclosporine. With these considerations in mind, we recommend statins as firstline therapy. Other agents are reasonable choices in the case of severe isolated hypertriglyceridemia (fibrates) or intolerance, drug interactions, or contraindications to statins. We recommend monitoring lipid values before transplant and then every 3 to 4 months thereafter. Although lowering of cardiovascular risk should be a primary goal of lipid-lowering therapy in this population,

818

B.L. Marini et al. / Biol Blood Marrow Transplant 21 (2015) 809e820

several of these agents possess unique immunomodulatory effects that require further investigation. In particular, statins may modulate GVHD by down-regulating the TH1 response, up-regulating regulatory T cell development, and altering APC function, proliferation, and interaction with T cells. Phase II trials are currently underway to determine the effect of statins on GVHD, both as donor pretreatment (NCT01525407, NCT01527045) and recipient GVHD prophylaxis (NCT01175148, NCT01491958). Because of the benefits of statins with regards to CVD morbidity and mortality as well as the increasing clinical evidence for their role in modulation of GVHD, these agents should be strongly considered in patients undergoing allogeneic HSCT able to tolerate therapy. Clinicians must remain aware of the potential toxicities and drug interactions with statin therapy as well as the unknown effects on relapse. Ongoing trials will definitively answer this question in the near future. Finally, although management of dyslipidemia is a critical need in this population, CVD risk factors frequently coexist; thus, management and prevention of CVD should always occur as a part of a comprehensive cardiac risk management program that addresses all major modifiable risk factors.

ACKNOWLEDGMENTS C.A.B. and S.W.C. were co-recipients of a Hope on Wheels grant from the Hyundai Motor Company. Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report.

REFERENCES 1. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363: 2091-2101. 2. Hahn T, McCarthy PL, Hassebroek A, et al. Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol. 2013;31:2437-2449. 3. Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2013. Available at: http:// www.cibmtr.org. Accessed September 28, 2014. 4. Center for International Blood & Marrow Transplant Research. NMDP/Be the match unrelated transplants: improved survival over time. Available at: https://bethematchclinical.org/Clockwork/ DisplayInternal?id=4151. Accessed December 9, 2014. 5. Saarinen-Pihkala UM, Gustafsson G, Ringden O, et al. No disadvantage in outcome of using matched unrelated donors as compared with matched sibling donors for bone marrow transplantation in children with acute lymphoblastic leukemia in second remission. J Clin Oncol. 2001;19:3406-3414. 6. Moore J, Nivison-Smith I, Goh K, et al. Equivalent survival for sibling and unrelated donor allogeneic stem cell transplantation for acute myelogenous leukemia. Biol Blood Marrow Transplant. 2007;13: 601-607. 7. Davies SM, DeFor TE, McGlave PB, et al. Equivalent outcomes in patients with chronic myelogenous leukemia after early transplantation of phenotypically matched bone marrow from related or unrelated donors. Am J Med. 2001;110:339-346. 8. Martin PJ, Counts GW, Appelbaum FR, et al. Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation. J Clin Oncol. 2010;28:1011-1016. 9. Mohty M, Apperley JF. Long-term physiological side effects after allogeneic bone marrow transplantation. Hematology Am Soc Hematol Educ Program. 2010;2010:229-236. 10. Chow EJ, Mueller BA, Baker KS, et al. Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation. Ann Intern Med. 2011;155:21-32. 11. Tichelli A, Passweg J, Wójcik D, et al. Late cardiovascular events after allogeneic hematopoietic stem cell transplantation: a retrospective multicenter study of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2008;93: 1203-1210.

12. Tichelli A, Bucher C, Rovó A, et al. Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation. Blood. 2007; 110:3463-3471. 13. Annaloro C, Usardi P, Airaghi L, et al. Prevalence of metabolic syndrome in long-term survivors of hematopoietic stem cell transplantation. Bone Marrow Transplant. 2008;41:797-804. 14. Armenian SH, Sun C-L, Mills G, et al. Predictors of late cardiovascular complications in survivors of hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2010;16:1138-1144. 15. Pencina MJ, D’Agostino RB, Larson MG, et al. Predicting the 30-year risk of cardiovascular disease: the Framingham heart study. Circulation. 2009;119:3078-3084. 16. Mendis S, Puska P, Norrving B. Global atlas on cardiovascular disease prevention and control. Geneva; 2011. Available at: http://whqlib doc.who.int/publications/2011/9789241564373_eng.pdf. 17. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med. 2000;6:1399-1402. 18. Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18:348-371. 19. Baker KS, Ness KK, Steinberger J, et al. Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood. 2007;109:1765-1772. 20. Kagoya Y, Seo S, Nannya Y, Kurokawa M. Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on prognosis. Clin Transplant. 2012;26:E168-E175. 21. Blaser BW, Kim HT, Alyea EP, et al. Hyperlipidemia and statin use after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18:575-583. 22. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685-1695. 23. Roos CJ, Quax PHA, Jukema JW. Cardiovascular metabolic syndrome: mediators involved in the pathophysiology from obesity to coronary heart disease. Biomark Med. 2012;6:35-52. 24. Rapamune. Package insert. New York, NY: Wyeth Pharmaceuticals. Available at: http://labeling.pfizer.com/showlabeling.aspx?id¼139. Accessed April 20, 2013. 25. Couriel DR, Saliba R, Escalón MP, et al. Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. Br J Haematol. 2005;130:409-417. 26. Morrisett JD, Abdel-Fattah G, Hoogeveen R, et al. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res. 2002;43:1170-1180. 27. Soliman GA, Acosta-Jaquez HA, Fingar DC. mTORC1 inhibition via rapamycin promotes triacylglycerol lipolysis and release of free fatty acids in 3T3-L1 adipocytes. Lipids. 2010;45:1089-1100. 28. Hoogeveen RC, Ballantyne CM, Pownall HJ, et al. Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Transplantation. 2001;72:1244-1250. 29. Aggarwal D, Fernandez ML, Soliman GA. Rapamycin, an mTOR inhibitor, disrupts triglyceride metabolism in guinea pigs. Metabolism. 2006; 55:794-802. 30. Ballantyne CM, Podet EJ, Patsch WP, et al. Effects of cyclosporine therapy on plasma lipoprotein levels. JAMA. 1989;262:53-56. 31. Subramanian S, Trence DL. Immunosuppressive agents: effects on glucose and lipid metabolism. Endocrinol Metab Clin North Am. 2007; 36:891-905. vii. 32. McCauley J, Shapiro R, Jordan ML, et al. Long-term lipid metabolism in combined kidney-pancreas transplant recipients under tacrolimus immunosuppression. Transplant Proc. 2001;33:1698-1699. 33. Ratanatharathorn V, Nash RA, Przepiorka D, et al. 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; 92:2303-2314. 34. Nash RA, Antin JH, Karanes C, et al. 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;96:2062-2068. 35. Hiraoka A, Ohashi Y, Okamoto S, et al. Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant. 2001;28:181-185. 36. Macfarlane DP, Forbes S, Walker BR. Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome. J Endocrinol. 2008;197:189-204. 37. Turchin A, Wiebe DA, Seely EW, et al. Severe hypercholesterolemia mediated by lipoprotein X in patients with chronic graft-versus-host disease of the liver. Bone Marrow Transplant. 2005;35:85-89. 38. Reddy P, Johnson K, Uberti JP, et al. Nephrotic syndrome associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2006;38:351-357. 39. Kodner C. Nephrotic syndrome in adults: diagnosis and management. Am Fam Physician. 2009;80:1129-1134.

B.L. Marini et al. / Biol Blood Marrow Transplant 21 (2015) 809e820

40. Guay AT. The emerging link between hypogonadism and metabolic syndrome. J Androl. 2009;30:370-376. 41. Pearce EN. Hypothyroidism and dyslipidemia: modern concepts and approaches. Curr Cardiol Rep. 2004;6:451-456. 42. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889-2934. 43. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123:2292-2333. 44. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615-1622. 45. Nakamura H, Arakawa K, Itakura H, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet. 2006;368:1155-1163. 46. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207. 47. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868-874. 48. Ferrara JLM, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373:1550-1561. 49. Gatza E, Wahl DR, Opipari AW, et al. Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graftversus-host disease. Sci Transl Med. 2011;3:67-68. 50. Kidani Y, Elsaesser H, Hock MB, et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol. 2013;14:489-499. 51. Bensinger SJ, Bradley MN, Joseph SB, et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell. 2008;134:97-111. 52. Byersdorfer CA, Tkachev V, Opipari AW, et al. Effector T cells require fatty acid metabolism during murine graft-versus-host disease. Blood. 2013;122:3230-3237. 53. Buhaescu I, Izzedine H. Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem. 2007;40:575-584. 54. Goldman M, Lance L, Lacy C, Armstrong L, editors. Drug information handbook. 20th ed. Hudson, Ohio: Lexi-Comp; 2011. 55. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118. 56. Zeiser R, Youssef S, Baker J, et al. Preemptive HMG-CoA reductase inhibition provides graft-versus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activity. Blood. 2007; 110:4588-4598. 57. Mausner-Fainberg K, Luboshits G, Mor A, et al. The effect of HMG-CoA reductase inhibitors on naturally occurring CD4þCD25þ T cells. Atherosclerosis. 2008;197:829-839. 58. Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med. 2001;7:687-692. 59. Wang Y, Li D, Jones D, et al. Blocking LFA-1 activation with lovastatin prevents graft-versus-host disease in mouse bone marrow transplantation. Biol Blood Marrow Transplant. 2009;15:1513-1522. 60. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006;6:358-370. 61. Yilmaz A, Reiss C, Tantawi O, et al. HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis. Atherosclerosis. 2004;172:85-93. 62. Hori A, Kanda Y, Goyama S, et al. A prospective trial to evaluate the safety and efficacy of pravastatin for the treatment of refractory chronic graft-versus-host disease. Transplantation. 2005;79:372-374. 63. Hamadani M, Awan FT, Devine SM. The impact of HMG-CoA reductase inhibition on the incidence and severity of graft-versus-host disease in patients with acute leukemia undergoing allogeneic transplantation. Blood. 2008;111:3901-3902. 64. Rotta M, Storer BE, Storb RF, et al. Donor statin treatment protects against severe acute graft-versus-host disease after related allogeneic hematopoietic cell transplantation. Blood. 2010;115:1288-1295. 65. Rotta M, Storer BE, Storb R, et al. Impact of recipient statin treatment on graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2010;16:1463-1466. 66. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipidlowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80:565-581. 67. Hamadani M, Gibson LF, Remick SC, et al. Sibling donor and recipient immune modulation with atorvastatin for the prophylaxis of acute graft-versus-host disease. J Clin Oncol. 2013;31:4416-4423. 68. Lin M-T, Storer B, Martin PJ, et al. Relation of an interleukin-10 promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation. N Engl J Med. 2003;349: 2201-2210.

819

69. Holler E, Roncarolo MG, Hintermeier-Knabe R, et al. Prognostic significance of increased IL-10 production in patients prior to allogeneic bone marrow transplantation. Bone Marrow Transplant. 2000;25: 237-241. 70. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation. 2004;109(23 Suppl 1):III50-III57. 71. Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis. 2009;29:412-422. 72. Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation. 2006;114:2788-2797. 73. US Food and Drug Administration. FDA drug safety communication: important safety label changes to cholesterol-lowering statin drugs. Available at: http://www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed May 29, 2013. 74. Inamoto Y, Teramoto T, Shirai K, et al. Severe hypercholesterolemia associated with decreased hepatic triglyceride lipase activity and pseudohyponatremia in patients after allogeneic stem cell transplantation. Int J Hematol. 2005;82:362-366. 75. Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998;98: 2088-2093. 76. Hidaka M, Iwasaki S, Matsui T, et al. Efficacy of bezafibrate for chronic GVHD of the liver after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2010;45:912-918. 77. McQuade CR, Griego J, Anderson J, Pai AB. Elevated serum creatinine levels associated with fenofibrate therapy. Am J Health Syst Pharm. 2008;65:138-141. 78. Digby JE, Ruparelia N, Choudhury RP. Niacin in cardiovascular disease: recent preclinical and clinical developments. Arterioscler Thromb Vasc Biol. 2012;32:582-588. 79. Vosper H. Niacin: a re-emerging pharmaceutical for the treatment of dyslipidaemia. Br J Pharmacol. 2009;158:429-441. 80. Lovaza. Package insert. Research Triangle Park, NC: GlaxoSmithKline. Available at: https://www.gsksource.com/gskprm/htdocs/documents/ LOVAZA-PI-PIL.PDF. Accessed June 5, 2013. 81. Toth PP, Dayspring TD, Pokrywka GS. Drug therapy for hypertriglyceridemia: fibrates and omega-3 fatty acids. Curr Atheroscler Rep. 2009;11:71-79. 82. Calder PC. n-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr. 2006;83(6 Suppl.):1505S-1519S. 83. McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2009;33:277-316. 84. Lagarde M, Chen P, Véricel E, Guichardant M. Fatty acid-derived lipid mediators and blood platelet aggregation. Prostaglandins Leukot Essent Fatty Acids. 2010;82:227-230. 85. Toth PP. Drug treatment of hyperlipidaemia: a guide to the rational use of lipid-lowering drugs. Drugs. 2010;70:1363-1379. 86. Tamaki N, Ueno H, Morinaga Y, et al. Ezetimibe ameliorates atherosclerotic and inflammatory markers, atherogenic lipid profiles, insulin sensitivity, and liver dysfunction in Japanese patients with hypercholesterolemia. J Atheroscler Thromb. 2012;19:532-538. 87. Leiter LA, Betteridge DJ, Farnier M, et al. Lipid-altering efficacy and safety profile of combination therapy with ezetimibe/statin vs. statin monotherapy in patients with and without diabetes: an analysis of pooled data from 27 clinical trials. Diabetes Obes Metab. 2011;13: 615-628. 88. Zetia. Package insert. Whitehouse Station, NJ: Merck. Available at: http:// www.merck.com/product/usa/pi_circulars/z/zetia/zetia_pi.pdf. Accessed October 1, 2014. 89. Oswald S, König J, Lütjohann D, et al. Disposition of ezetimibe is influenced by polymorphisms of the hepatic uptake carrier OATP1B1. Pharmacogenet Genomics. 2008;18:559-568. 90. Bouscarel B, Ceryak S, Robins SJ, Fromm H. Studies on the mechanism of the ursodeoxycholic acid-induced increase in hepatic low-density lipoprotein binding. Lipids. 1995;30:607-617. 91. Rosenbaum CL, Cluxton RJ. Ursodiol: a cholesterol gallstone solubilizing agent. Drug Intell Clin Pharm. 1988;22:941-945. 92. Maton PN, Ellis HJ, Higgins MJ, Dowling RH. Hepatic HMGCoA reductase in human cholelithiasis: effects of chenodeoxycholic and ursodeoxycholic acids. Eur J Clin Invest. 1980;10:325-332. 93. Yoshikawa M, Tsujii T, Matsumura K, et al. Immunomodulatory effects of ursodeoxycholic acid on immune responses. Hepatology. 1992;16: 358-364. 94. Kürktschiev D, Subat S, Adler D, Schentke KU. Immunomodulating effect of ursodeoxycholic acid therapy in patients with primary biliary cirrhosis. J Hepatol. 1993;18:373-377. 95. Ishizaki K, Iwaki T, Kinoshita S, et al. Ursodeoxycholic acid protects concanavalin A-induced mouse liver injury through inhibition of intrahepatic tumor necrosis factor-alpha and macrophage inflammatory protein-2 production. Eur J Pharmacol. 2008;578:57-64.

820

B.L. Marini et al. / Biol Blood Marrow Transplant 21 (2015) 809e820

96. Ruutu T, Eriksson B, Remes K, et al. Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Blood. 2002;100:1977-1983. 97. Ruutu T, Juvonen E, Remberger M, et al. Improved survival with ursodeoxycholic acid prophylaxis in allogeneic stem cell transplantation: long-term follow-up of a randomized study. Biol Blood Marrow Transplant. 2014;20:135-138.

98. Balan V, Dickson ER, Jorgensen RA, Lindor KD. Effect of ursodeoxycholic acid on serum lipids of patients with primary biliary cirrhosis. Mayo Clin Proc. 1994;69:923-929. 99. Braga MFB, Grace MGA, Lenis J, et al. Efficacy and safety of ursodeoxycholic acid in primary, type IIa or IIb hypercholesterolemia: a multicenter, randomized, double-blind clinical trial. Atherosclerosis. 2009; 203:479-482.