Immunosuppressive regimens for adult liver transplant recipients in real-life practice: consensus recommendations from an Italian Working Group

Low-risk patients with a Model for End-Stage Liver Disease (MELD) score < 25 and no autoimmune disease, HCC, or history of renal dysfunction.

Early (30 ± 5 days post-transplant) or very early (≤ 10 days post-transplant) mTOR inhibitor introduction to reduce exposure to CNI has been reported to improve estimated glomerular filtration rate (eGFR) by 8–12 mL/min/1.73 m² at 1 year after transplantation [15]. In the H2304 study, which investigated de novo use of everolimus in 719 liver transplant recipients who were randomized at 30 ± 5 days post-transplant, the adjusted change in eGFR at 12 months was superior in the everolimus plus reduced tacrolimus group using the Modification of Diet in Renal Disease (four-variable) (MDRD4) formula (difference of 8.5 mL/min/1.73 m²; p < 0.001) [11], and remained significantly superior at 24 months (difference of 6.7 mL/min/1.73 m²; p = 0.002) [12] compared with the standard tacrolimus-based regimen. An extension of the H2304 study demonstrated significantly improved renal function preservation for up to 3-years post-transplantation in 282 liver transplant recipients receiving everolimus plus reduced tacrolimus, with mean eGFR decreasing from randomization to month 36 by 7.0 ± 31.3 mL/min/1.73 m² versus 15.5 ± 22.7 mL/min/1.73 m² in the tacrolimus-control group (p = 0.005) [18].

In the PROTECT trial, in which 203 liver transplant patients were randomized at 4 weeks post-transplant to discontinue CNI therapy and start everolimus or to continue their current CNI-based regimen, an eGFR treatment difference of 7.8 mL/min (p = 0.021) in favor of everolimus was identified at 12 months after transplantation using the MDRD4 formula [19]. At month 35 after randomization, a 10.1 mL/min benefit in the adjusted mean eGFR in favor of everolimus was identified using the Cockcroft-Gault formula (p = 0.082 vs. CNI), 9.4 mL/min/1.73 m² (p = 0.053) using the MDRD4 formula, and 9.5 mL/min/1.73 m² (p = 0.028) using the Nankivell formula [14].

A separate study, in which 78 liver transplant patients were randomized to early CNI withdrawal followed by everolimus as monotherapy (with the initial dose of everolimus started on day 10 after liver transplantation) or to cyclosporine, identified a significant improvement in renal function at 12 months after transplantation in patients treated with everolimus compared with cyclosporine (mean eGFR values [MDRD formula] were 87.6 ± 26.1 mL/min vs. 59.9 ± 12.6 mL/min, respectively; p < 0.001) [20].

In addition, evidence from randomized studies and retrospective analyses shows that the improvement in renal function is limited if CNI-reducing strategies are postponed until renal function has deteriorated (eGFR < 60 mL/min/1.73 m²) [10, 21‐23].

In standard patients (Fig. 1), immunosuppression is based on CNIs, usually tacrolimus; cyclosporine can also be used. Tacrolimus monotherapy is not recommended. Early CNI reduction is feasible with the introduction of everolimus or mycophenolic acid derivatives, and may be further facilitated by the administration of induction agents (usually basiliximab for liver transplant recipients). Overall, a steroid-free approach is recommended.

Patients with one or more of the conditions listed in Fig. 2, namely high MELD-Na (i.e., MELD-Na > 29 or MELD-Na 25–29 with concomitant renal dysfunction/dialysis or chronic encephalopathy), national high urgency, acute gastroesophageal bleeding, renal dysfunction/dialysis, hepato-renal syndrome, sepsis, spontaneous bacterial peritonitis, colonization by multidrug-resistant organisms, portal thrombosis, metabolic syndrome or non-alcoholic steatohepatitis, thoracic ascites, urinary tract infection and/or ventilatory support and/or inotropic support, or high surgical risk are considered as high-risk patients. Frail patients, with sarcopenia as a distinctive characteristic, also belong to this category [24‐27].

Studies in this patient category are lacking, as most trials enroll low-risk patients (e.g., patients with no renal impairment).

Induction therapy (basiliximab) is recommended in these patients to delay the introduction of CNI to 3–5 days post-transplantation. In patients with elevated MELD-Na (> 29), the use of induction therapy should be carefully considered; CNI should be initiated at lower doses as compared to standard patients. CNI monotherapy is not recommended, and cyclosporine is a possible alternative to tacrolimus in particular in patients with dysmetabolic abnormalities and decompensated diabetes. For CNI reduction, the available options include mycophenolic acid derivatives and everolimus. CNI discontinuation can be considered for patients with signs of CNI-induced neuro-nephrotoxicity. Everolimus is particularly indicated in patients at risk of renal dysfunction or with renal dysfunction confirmed by eGFR assessments; among these patients, those with diabetes or metabolic disease may particularly benefit from everolimus, as this mTOR inhibitor has cardiovascular protective effects beside nephroprotective properties. Hyperlipidemia and hypertriglyceridemia, if present, can be treated before or after the introduction of everolimus. Proteinuria requires accurate renal function work-up and can be treated with appropriate strategies.

In this group, we included less frequent or emerging indications to liver transplantation in Italy, as follows: patients with polycystic liver disease (PLD) with or without kidney involvement, patients necessitating combined liver-kidney transplantation, patients with autoimmune liver disease (AILD), patients with oncological indications to transplantation as neuroendocrine tumors (NET), metastatic colorectal cancer (metaCRC), or patients with cholangiocarcinoma (CCA) (Fig. 3).

Two inherited disorders associated with PLD can be distinguished: isolated polycystic liver disease (PCLD) and autosomal dominant polycystic kidney disease (ADPKD). Although PCLD is not associated with excess mortality when left untreated, the quality of life supports the choice of liver transplantation as a therapeutic option [28, 29].

Combined liver-kidney transplantation should be considered in patients with severe renal impairment or on renal replacement therapy [30, 31].

Liver transplantation for NET liver metastasis may be a viable treatment option in selected patients as 5-year post-transplant overall survival rates of 47–97% and disease-free survival rates of 32–87% have been reported [32‐34]. Survival outcomes after liver transplantation are similar for liver transplantation performed in “ideal” candidates and for those with HCC [33]. However, as recurrence rates remain higher, immunosuppressive treatment must be appropriate to the oncological status.

For patients with metaCRC, the role of liver transplantation requires further elucidation and definition by ongoing clinical trials and real-life practice [35]. Nonetheless, a Norwegian study of 21 patients with nonresectable colorectal liver metastases demonstrated a 5-year survival rate of 60% after liver transplantation, exceeding outcomes reported for chemotherapy [36]. In colorectal cancer patients with nonresectable liver-only metastases, the 5-year overall survival rate was 83% after liver transplantation, highlighting the importance of improved patient selection criteria for optimal survival rates [37].

CCA, the second most common liver cancer, is associated with a very poor prognosis [38]. Liver transplantation protocols for CCA show low survival rates, given that tumor size (> 2 cm) and multi-nodularity are risk factors for tumor recurrence and worse outcomes when compared with similar HCCs [39]. Nevertheless, clinically acceptable results were obtained in selected patients who underwent neoadjuvant chemoradiotherapy followed by liver transplantation [40]. In such cases, the immunosuppressive strategy must balance the risk of recurrence. There is also some experimental and clinical evidence on the antiproliferative effect of mTOR inhibitors in CCA-tumor cells [41] and in clinical studies [42].

Patients with isolated PCLD can be referred to the critical patient path, due to complex surgery. Patients with ADPKD and renal impairment and/or in renal replacement therapy are considered for simultaneous or delayed combined liver-kidney transplantation [43, 44]. In this case, the immunosuppressive therapy is directed towards the critical patient path or towards the standard case path depending on the clinical conditions and after a careful multidisciplinary evaluation [30, 31].

Everolimus-facilitated CNI reduction should be implemented as early as possible, to avoid further damage to the kidney. In patients with oncological issues, the early introduction of mTOR inhibitors should be considered, and their use is also recommended in the case of post-transplant recurrence [45]. This could apply also to patients with additional risk factors for post-transplant de novo malignancy development (i.e. alcohol-related liver disease).

AILD should be treated with tacrolimus and corticosteroids, adjusting the latter based on efficacy and side effects; everolimus or mycophenolates can also be added. Cyclosporine can be used instead of tacrolimus [46], mostly in case of relapse.

Patients undergoing liver transplantation due to HCC.

Antiproliferative properties of mTOR inhibitors and data from the literature support the use of this drug class in HCC patients. A large body of preclinical and clinical evidence has shown that mTOR inhibitors can limit HCC recurrence and progression in liver transplant recipients [47‐49]. Sirolimus-based immunosuppression was beneficial after liver transplantation with significantly higher patient survival post-transplantation for HCC in a multivariate analysis of 2491 patients (hazard ratio 0.53, 95% confidence interval [CI] 0.31–0.92; p ≤ 0.05) [48]. mTOR inhibitors were also associated with significantly lower rates of HCC recurrence after liver transplantation when compared with CNIs (8% vs. 13.8%; p < 0.001) in a systematic review of 3666 HCC liver transplant recipients [47]. However, significant benefits of mTOR inhibitors were only observed in patients within Milan criteria (i.e., low-risk patients) in a prospective, randomized, phase 3 clinical trial of sirolimus-based immunosuppression in 525 HCC liver transplant recipients [50]. Moreover, HCC recurrence-free and overall survival benefits of mTOR inhibitors were apparent for up to 3–5 years post-transplantation, but were not sustained thereafter. An analysis of the US Scientific Registry of Transplant Recipients suggested beneficial, albeit not statistically significant, outcomes in terms of lower rates of HCC recurrence and cancer-specific mortality in recipients of liver transplantations for HCC receiving sirolimus-based immunosuppression, however, effects appeared to be modified by patient age at transplantation, with better outcomes identified for transplant recipients > 55 years of age than those ≤ 55 years [51].

For patients with recurrent HCC post-transplantation, evidence from retrospective analyses and case reports suggests that mTOR inhibitors should be introduced to slow disease progression due to their antiproliferative activity [52‐54]. The addition of everolimus to sorafenib in a 46-year old male who experienced HCC recurrence 11 years after liver transplantation led to an approximately 50% reduction in tumor size after 3-months of treatment, with further reductions of tumor size after 8 months [52]. In a retrospective cohort study of 31 patients with recurrent HCC after liver transplantation, the combined use of mTOR inhibitor (everolimus or sirolimus) and sorafenib identified a median overall survival of 19.3 months after initiation of the combined treatment, with a median time to disease progression of 6.77 months [54]. In a retrospective analysis of 7 liver transplantation recipients with HCC recurrence who were switched to everolimus plus sorafenib, 5 patients were alive after a median follow-up of 6.5 months (interquartile range [IQR] 14 months), 4 patients with tumor progression; the median time to progression was 3.5 (IQR 12) months [53].

Compared with CNI-based immunosuppression, mTOR-inhibitor-based immunosuppression significantly increased recurrence-free-survival at both 1- and 3-years post-transplantation (risk ratio [RR] 1.09 and 1.1, respectively) in a systematic review and meta-analysis of 23 studies on the survival and recurrence of HCC in liver transplant recipients [55]. In addition, treatment with mTOR inhibitors conferred a significant survival advantage in overall survival at 1-, 3- and 5-years post-transplant (RR: 1.07, 1.1, and 1.18, respectively), and a significantly lower rate of HCC recurrence (RR: 0.67) compared with conventional CNI-based immunosuppression.

In all HCC patients (regardless of their risk of relapse), strategies to facilitate CNI reduction should be implemented to limit CNI-related renal toxicities and the impact of CNI exposure on cancer recurrence. Steroid-free immunosuppressive schedules are preferred (Fig. 4).

Liver transplant recipients who develop de novo malignancies any time following transplantation, including extrahepatic solid tumors, non-melanoma skin cancer, and lymphoproliferative diseases.

A relatively large body of evidence from studies in heart, kidney, and liver transplant recipients suggests that the use of mTOR inhibitors leads to a reduced incidence of de novo malignancies after solid organ transplantation [15, 56, 57]. The incidence of de novo malignancy within 963 days post-transplant was significantly lower in patients receiving sirolimus/everolimus compared with cyclosporine/tacrolimus (0.60% vs. 1.81%; p < 0.001) in a retrospective analysis of 33,249 kidney transplant recipients, with the risk of developing any de novo malignancy reduced by 60% with sirolimus/everolimus immunosuppression (relative risk 0.4, 95% CI 0.24–0.64; p = 0.0002) [56]. A retrospective cohort study of 7217 kidney transplant recipients demonstrated a 46% significantly reduced risk of de novo malignancies in recipients treated with mTOR inhibitors compared with those never treated (p < 0.05) [57].

Further evidence supports the use of mTOR inhibitors in patients with de novo malignancies after liver transplantation [58‐60]. In 6 liver transplantation patients who converted from CNI to everolimus due to de novo malignancies, which appeared 3–4 years post-transplantation, 83% (n = 5) of patients remained disease-free after a mean follow-up time of 10 ± 9 months; lung carcinoma recurred at 12-months following conversion in 1 patient [58]. From a total of 4 liver transplantation recipients who were converted to sirolimus-based immunosuppression due to the development of aggressive de novo malignancies, 3 patients who converted within 90–120 days after surgical removal of the malignancy remained tumor-free at 12–33 months post-conversion; 1 patient, who switched to sirolimus at 18 months after a mastectomy for breast cancer, died due to its recurrence [59].

In this setting, mTOR inhibitors may be used either as monotherapy or combined with reduced-exposure CNI, depending on individual risk factors (i.e., time post-transplantation, transplantation indication, age at transplantation, etc.) [15, 47, 48, 58‐60].

CNI reduction or discontinuation is recommended (Fig. 5). Given its antiproliferative properties, everolimus should be administered as soon as possible. mTOR inhibitor-based immunosuppression is warranted in all liver transplant recipients at high risk of de novo malignancies (i.e., human herpes virus-8-positive patients; patients with alcoholic cirrhosis; patients with concurrent inflammatory bowel disease; recipients of grafts from donors at risk of transmission of malignancies; Epstein Barr virus-DNA positivity after transplantation) [15].