Is Minimal, [Almost] Steroid-Free Immunosuppression a Safe Approach in Adult Liver Transplantation? Long-term Outcome of a Prospective, Double Blind, Placebo-Controlled, Randomized, Investigator-Driven Study

Lerut, Jan; Pinheiro, Rafael Soares; Lai, Quirino; Stouffs, Valentine; Orlando, Giuseppe; Juri, Juan Manuel Rico; Ciccarelli, Olga; Sempoux, Christine; Roggen, Francine; Reyck, Chantal De; Latinne, Dominique; Gianello, Pierre

doi:10.1097/sla.0000000000000969

Cited by 50 publications

(32 citation statements)

References 48 publications

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“…Third, more relaxed monitoring for rejection and less aggressive treatment of rejection, may have contributed to chronic allograft injury in the more recent era. 12–14 This hypothesis is supported by our finding that, while rejection at any time period impacted survival, late rejection was particularly associated with worse outcomes, corroborating findings from other smaller single-center studies. 15–20 In this later time period, donor-specific antibodies in combination with lower medication adherence may be contributing, akin to other organ recipients.…”

Section: Discussionsupporting

confidence: 87%

Acute Rejection Increases Risk of Graft Failure and Death in Recent Liver Transplant Recipients

Levitsky

Goldberg

Smith

et al. 2017

Clinical Gastroenterology and Hepatology

169

154

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Background & Aims Acute rejection is detrimental to most transplanted solid organs, but is considered to be less of a consequence for transplanted livers. We evaluated risk factors for and outcomes after biopsy-proven acute rejection (BPAR) based on an analysis of a large national sample of recipients of liver transplants from living and deceased donors. Methods We analyzed data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) from 2003 through 2014 as the exploratory cohort and the Scientific Registry of Transplant Recipients (SRTR) from 2005 through 2013 as the validation cohort. We examined factors associated with time to first BPAR using multivariable Cox regression or discrete-survival analysis. Competing risks methods were used to compare causes of death and graft failure between recipients of living vs deceased donors. Results At least 1 BPAR episode occurred in 239/890 recipients in A2ALL (26.9%) and 7066/45,423 recipients in SRTR (15.6%). In each study, risk of rejection was significantly lower when livers came from biologically related living donors (A2ALL hazard ratio [HR], 0.57; 95% CI, 0.43–0.76 and SRTR HR, 0.78; 95% CI, 0.66–0.91) (P<.001) and higher in liver transplant recipients with primary biliary cirrhosis, of younger age, or with hepatitis C. In each study, BPAR was associated with significantly higher risks of graft failure and death. The risks were highest in the 12 month post-BPAR period in patients whose first episode occurred more than 1 year after liver transplantation. The HRs for graft failure were 6.79 in A2ALL (95% CI, 2.64–17.45) and 4.41 in SRTR (95% CI, 3.71–5.23). The HRs for death were 8.81 in A2ALL (95% CI, 3.37–23.04) and 3.94 in SRTR (95% CI, 3.22–4.83). In analyses of cause-specific mortality, associations were observed for liver-related (graft failure) causes of death but not for other causes. Conclusions Contrary to previous data, acute rejection after liver transplant is associated with significantly increased risk of graft failure, all-cause mortality and graft failure-related death. LDLT from a biologically related donor is associated with decreased risk of rejection.

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Section: Discussionsupporting

confidence: 87%

Acute Rejection Increases Risk of Graft Failure and Death in Recent Liver Transplant Recipients

Levitsky

Goldberg

Smith

et al. 2017

Clinical Gastroenterology and Hepatology

169

154

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“…It is of great importance to be aware of the possibility and severity of these side effects, and take appropriate precautions to avoid them since patients who discontinued chemotherapy owing to toxicity had poor outcome. Liver graft recipients generally require less immunosuppression compared to other solid organ transplant recipients . Since we did not observe any graft rejection after administration of chemotherapy, dose reduction of immunosuppressive treatment or even termination of immunosuppressive treatment during chemotherapy may be considered in selected cases.…”

Section: Discussionmentioning

confidence: 85%

Transplant oncology: assessment of response and tolerance to systemic chemotherapy for metastatic colorectal cancer after liver transplantation – a retrospective study

et al. 2019

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Summary Solid organ recipients have a 2–5 fold increased risk of malignancy compared to the general population. Because of the broader indications for transplantation, it is anticipated that an increasing number of organ graft recipients will present with malignancy. There are limited data about responses and tolerance to chemotherapy in solid organ transplanted patients. Twenty‐three of 46 colorectal cancer (CRC) patients with nonresectable liver metastases who had undergone liver transplantation (LT) in three different studies were included. All patients had received chemotherapy both prior to LT and after LT, at recurrence of metastatic CRC (mCRC). Adverse reactions (grades 3–4) and clinical and radiological outcome were retrospectively registered. Overall survival was determined from start of palliative chemotherapy after LT. No graft rejection was observed. Chemotherapy for mCRC was overall well‐tolerated and there was no increased bone marrow toxicity registered after LT; however, mucositis and diarrhea were more frequent in post‐LT chemotherapy. Median overall survival from start of palliative chemotherapy after LT was 13 months. No graft loss was observed when chemotherapy for mCRC was given to LT recipients who had developed nonresectable metastases. Overall, the chemotherapy for mCRC was well‐tolerated, induced responses, and long‐term survival was obtained in some patients.

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“…A meta‐analysis of individual patient data and a network meta‐analysis from several RCTs using this information would be extremely valuable, particularly for those studies with interventional arms prematurely stopped due to increased early ACR rates. It is possible that these interventional arms, usually aiming at aggressive minimization or avoidance of CNI , show similar or even improved graft loss and mortality rates than more conventional immunosuppression protocols, as already reported in a long‐term follow‐up of a tacrolimus monotherapy RCT . In that case, such aggressive minimization protocols should not be discarded, but further investigated for a possible benefit on adverse events.…”

Section: Recommendations To Optimize the Assessment Of Acr Within Rctsmentioning

confidence: 79%

“…A recent RCT evaluating a combination of belatacept, basiliximab, mycophenolate, and steroids was prematurely terminated because of increased rates of graft loss and death compared with simpler regimes (tacrolimus±mycophenolate), although none of the deaths were attributable to ACR . In another double‐blind trial with protocol liver biopsies, 156 patients were randomized to tacrolimus monotherapy versus tacrolimus and steroids . Although at day 7 moderate–severe histological ACR was present in almost 50% of the study population, 5‐year incidence of chronic rejection was only 2.4%, while the 5‐year patient and graft survival rates were excellent (76% and 79% in each arm, respectively).…”

Section: Analysis Of Biopsy‐proven Acr As An Efficacy Endpoint For Rctsmentioning

confidence: 99%

“…The use of chronic rejection, graft loss, and mortality as the only primary efficacy endpoints would require an unbearable high number of patients with prolonged surveillances, thereby increasing costs exponentially and reducing feasibility. Nonetheless, an observational follow‐up of patients included in RCTs evaluating immunosuppressants should be systematically extended at least for 5 years to report graft loss and mortality rates, as these data may reinforce the justification of the evaluated strategy . A meta‐analysis of individual patient data and a network meta‐analysis from several RCTs using this information would be extremely valuable, particularly for those studies with interventional arms prematurely stopped due to increased early ACR rates.…”

Section: Recommendations To Optimize the Assessment Of Acr Within Rctsmentioning

confidence: 99%

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Biopsy-proven acute cellular rejection as an efficacy endpoint of randomized trials in liver transplantation: a systematic review and critical appraisal

et al. 2016

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Biopsy-proven acute cellular rejection (ACR) is the primary efficacy endpoint in most randomized trials evaluating immunosuppression in liver transplantation. However, ACR is not a major cause of graft loss, and a certain grade of immune activation may be even beneficial for long-term graft acceptance. Validated criteria to select candidates for liver biopsy are lacking, and routine clinical practice relies on liver tests, which are inaccurate markers of ACR. Indeed, both the agreement among clinicians to select candidates for liver biopsy and the correlation between the clinical suspicion of ACR and histological findings are poor. In randomized trials evaluating immunosuppression protocols, this concern grows exponentially due to the open-label and multicenter nature of most studies. Therefore, biopsy-proven ACR is a suboptimal efficacy endpoint given its limited impact on prognosis and the heterogeneous diagnosis, which may increase the risk of bias. Chronic rejection and/or graft loss would be more appropriate endpoints, but would certainly require larger studies with prolonged surveillances. An objective method to select candidates for liver biopsy is therefore urgently needed, and only severe episodes of histological ACR should be considered as potentially harmful. Emerging surrogate markers of ACR and antibody-mediated rejection require further investigation to determine their clinical role.

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Is Minimal, [Almost] Steroid-Free Immunosuppression a Safe Approach in Adult Liver Transplantation? Long-term Outcome of a Prospective, Double Blind, Placebo-Controlled, Randomized, Investigator-Driven Study

Abstract: Excellent long-term results can be obtained under minimal IS and absence of steroids. TAC-based monotherapy is feasible in most adult liver recipients until 5 years of follow-up.

Cited by 50 publications

References 48 publications

Acute Rejection Increases Risk of Graft Failure and Death in Recent Liver Transplant Recipients

Acute Rejection Increases Risk of Graft Failure and Death in Recent Liver Transplant Recipients

Transplant oncology: assessment of response and tolerance to systemic chemotherapy for metastatic colorectal cancer after liver transplantation – a retrospective study

Biopsy-proven acute cellular rejection as an efficacy endpoint of randomized trials in liver transplantation: a systematic review and critical appraisal

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