Five-year Outcome of an Early Everolimus-based Quadruple Immunosuppression in Lung Transplant Recipients: Follow-up of the 4EVERLUNG Study : Transplantation

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Original Clinical Science—General

Five-year Outcome of an Early Everolimus-based Quadruple Immunosuppression in Lung Transplant Recipients: Follow-up of the 4EVERLUNG Study

Kneidinger, Nikolaus MD, PhD1; Valtin, Christina2; Hettich, Ina MD3; Frye, Björn Christian MD3; Wald, Alexandra MD4; Wilkens, Heinrike MD5; Bessa, Vasiliki MD, PhD6; Gottlieb, Jens MD2

Author Information
Transplantation 106(9):p 1867-1874, September 2022. | DOI: 10.1097/TP.0000000000004095

Abstract

INTRODUCTION

Chronic kidney disease is a common and significant comorbidity in lung transplant recipients. Within 10 y following transplantation, the incidence of severe renal dysfunction (creatinine, >2.5 mg/dL) and chronic dialysis is 14.8% and 6.4%, respectively, according to the latest International Society for Heart and Lung Transplantation report1; however, in many cases, multifactorial, calcineurin inhibitor (CNI)–based immunosuppression frequently causes nephrotoxicity by short-term and long-term damages.2

To improve immunosuppressant-associated side effects and subsequently outcome, there is a need to develop strategies to preserve long-term renal function while maintaining immunosuppressive efficacy. In this respect, the Efficacy of Everolimus in Combination with Specific Standard Immunosuppressive Regimen Lung Transplant Recipients (4EVERLUNG) study (NCT01404325) demonstrated efficacy and safety of an early everolimus-based quadruple low CNI immunosuppression regimen.3 The primary endpoint (estimated glomerular filtration rate [eGFR] after 12 mo) demonstrated superiority of the quadruple low CNI regimen: 64.5 versus 54.6 mL/min for the standard triple group. Key efficacy parameters (biopsy-proven acute cellular rejection, chronic lung allograft dysfunction [CLAD], and death) and safety endpoints were similar between both groups.3

However, it is unclear whether the reported beneficial effect of an everolimus-based quadruple low CNI immunosuppression early after lung transplantation remains effective and safe for a long-term follow-up.

Therefore, the aim of the study was to assess efficacy and safety of an everolimus-based quadruple low CNI immunosuppression during standard triple therapy up to 5 y after randomization in the former prospective, randomized, controlled trial (NCT01404325).

MATERIALS AND METHODS

The 4EVERLUNG study was performed at 8 lung transplant centers in Germany between February 2012 (first patient in) and January 2017 (last patient out) as reported previously.3 In this 12-mo, prospective, open-label study, patients with mild-to-moderate renal dysfunction (eGFR, ≥50 and ≤90 mL/min/1.73 m2 according to the Chronic Kidney Disease Epidemiology Collaboration formula) were randomized at 3 to 18 mo after lung transplantation to a regimen of everolimus with reduced CNI exposure (quadruple low CNI) or to standard CNI therapy (standard triple CNI, prednisolone, and antimetabolites). In the quadruple low CNI arm, an immediate reduction of the current CNI dose by 50% was recommended, and a target trough level of 3 to 5 and 25 to 75 ng/mL was anticipated for tacrolimus and cyclosporine, respectively. Simultaneously, everolimus was initiated, and a trough target level of 3 to 5 ng/mL was anticipated while antimetabolites were kept unchanged. In the standard triple CNI arm, a target trough level of 8 to 12 and 100 to 150 ng/mL was anticipated for tacrolimus and cyclosporine, respectively. After completion of the 12-mo visit, the immunosuppression regimen was at the discretion of the investigator. Anticipated trough target levels were retrospectively reported by the participating center. Although in patients on the quadruple low CNI regimen, trough target level remained unchanged compared with the core study, in the standard triple CNI regimen, CNI was reduced to 6 to 10 and 50 to 100 ng/mL for tacrolimus and cyclosporine, respectively.

Quadruple low CNI was compared with standard triple CNI. Patients in whom the assigned immunosuppressive regimen was switched to an alternative regimen were analyzed as the intention-to-treat (ITT) population. Patients who remained on the assigned regimen until the end of observation were analyzed as the per protocol (PP) population. Significant changes of the immunosuppressive regimen referred to as “switch” were as follows: (1) from quadruple low CNI to standard triple, (2) from standard triple to quadruple low CNI, (3) from cyclosporine to tacrolimus and vice versa, (4) from mycophenolic acid to everolimus in a triple regimen, and (5) to a CNI-free regimen.

In all participant centers, universal cytomegalovirus (CMV) prophylaxis was performed according to CMV serology of donor (D) and recipients (R) and respective risk for CMV infection. In brief, patients with high risk (D+R-) received valganciclovir in a prophylactic dose for up to 12 mo. Patients with intermediate risk (R+) received valganciclovir in a prophylactic dose for 3 mo.

Patient data were retrospectively assessed from the participating sites until death or 5-y follow-up. eGFR according to Chronic Kidney Disease Epidemiology Collaboration was collected from randomization (baseline) yearly until 5-y follow-up or last measurement available. Malignancy was defined as any malignant disease including basal cell carcinoma of the skin. Thrombotic events were defined as venous thrombosis or thromboembolism, acute thrombotic stroke, or acute myocardial infarction. CLAD was defined as reported recently.4-6 Furthermore, CLAD-free survival and graft survival (time to death or retransplantation) were assessed.

The study was approved by the central institutional ethics committee (Munich, Germany; registration number 21-0029) and by institutional review boards at the participating sites. This was an investigator-initiated study where the sponsor of the original study (Novartis Pharma GmbH) was not involved.

Statistics

Statistical analysis was performed using IBM SPSS V.26 (IBM SPSS Statistics, Armonk, NY). Data are presented as absolute numbers with percentages or median with 25th and 75th percentile. Differences between groups were compared univariately by using the Mann-Whitney U test for continuous variables and the Fisher exact test or Pearson chi-square test as appropriate for categorical variables. Survival analysis was performed using the Kaplan-Meier method, and the differences in survival outcomes between groups were compared using the log-rank test. All reported P values are 2 sided unless indicated otherwise; P values of <0.05 were considered statistically significant. For final eGFR after 5 y, last observation carried forward method was used to impute missing values. Results are presented both as observed and after imputation.

RESULTS

Patient Characteristics

A complete data set of 123 participants (94.6%) of the 130 patients randomized in the 4EVERLUNG study (NCT01404325) was available for analysis. Two of 8 centers did not provide data of their patients (n = 7, 5.4%). In total, 45 patients (36.6%) were female, and mean age at the time of transplantation was 57 (51–61) y. Underlying lung diseases categories were as follows: obstructive (n = 54, 44%), restrictive (n = 58, 47%), and suppurative (cystic fibrosis/bronchiectasis; n = 11, 9%). Mean time from transplantation to randomization was 10 mo. Fifty-seven out of 123 patients (46%) were randomized to the standard triple and 66 patients (54%) to the quadruple low CNI regimen, respectively.

During the 5-y period, switch of the immunosuppressive regimen was performed in 41 patients (33%). Type of switch was from quadruple to a standard triple regimen (n = 30, 24%), from triple to quadruple low CNI regimen (n = 4, 3%), from cyclosporine to tacrolimus (n = 5, 4%), and from mycophenolic acid to everolimus (n = 1, 1%) and to a CNI-free regimen (n = 1, 1%). None of these patients was switched back or switched more than once.

ITT Population

Patient characteristics before randomization did not differ between the groups as shown in Table 1. The course of eGFR during the study period is shown in Figure 1A. eGFR at randomization was not different between the groups (64 [58–74] versus 61 [57–72] mL/min/1.73 m2; P = 0.384). Only at 1 y after randomization, at the end of the 4EVERLUNG study, eGFR was higher in the quadruple low CNI regimen (58 [50–69] versus 67 [57–77] mL/min/1.73 m2; P = 0.007). eGFR at 5 y was not different between the groups (56 [48–73] versus 58 [48–69] mL/min/1.73 m2; P = 0.951). Results were similar after imputation of missing values (57 [48–73] versus 58 [48–68] mL/min/1.73 m2; P = 0.806). Median changes of eGFR from randomization to the end of the observation period (5 y) did not differ statistically significant (–8 [–17 to 6] versus –3 [–14 to 5] mL/min/1.73 m2; P = 0.492) between the groups; however, median decrease of eGFR from 1 y to the end of the observation period was higher in the quadruple low CNI regimen (–2 [–10 to 12] versus –10 [–18 to 0] mL/min/1.73 m2; P = 0.006). An analysis where patients were presented until the actual switch in the respective group is shown in Figure S1 (SDC, https://links.lww.com/TP/C376). Similar to the ITT cohort, no difference was found between the groups except for 1 y after randomization (Figure S1, SDC, https://links.lww.com/TP/C376). Finally, the number of patients with end-stage renal disease requiring chronic renal replacement therapy was low and did not differ (Table 1).

TABLE 1. - Characteristics of the intention-to-treat population according to the randomized immunosuppressive regimen
Characteristics Triple (n = 57; 46%) Quadruple (n = 66; 54%) P
Gender (female), n (%) 18 (32) 27 (41) 0.284
Age (y), median (25th–75th percentile) 57 (52–61) 58 (50–61) 0.933
Primary diagnosis, n (%) 0.660
 Obstructive 24 (42) 30 (45)
 Restrictive 29 (51) 29 (44)
 Cystic fibrosis 4 (7) 7 (11)
Thromboembolism prerandomization, n (%) 2 (4) 5 (8) 0.451
CMV risk status prerandomization, n (%) 0.172
 Low risk, DR 11 (19) 16 (25)
 Intermediate risk, R+ 33 (58) 34 (52)
 High risk, D+R 13 (23) 15 (23)
Donor-specific antibodies postrandomization, n (%) 9 (16) 6 (9) 0.258
Switch after randomization, n (%) 11 (19) 30 (46) 0.002
Reason for switch, n (%) 0.740
 Patient preference 2 (3)
 Wound healing 1 (2) 7 (11)
 Acute or chronic rejection 4 (7) 8 (12)
 Side effects 4 (7) 9 (14)
 Infections 2 (4) 3 (5)
 Other 1 (2)
Days switch after randomization, median (25th–75th percentile) 462 (182–809) 299 (79–779) 0.274
No. of acute rejections (≥A1) postrandomization, n (%) 7 (12) 11 (17) 0.493
Dialysis, n (%) 2 (4) 1 (2) 0.596
Renal transplant, n (%)
Malignancy, n (%) 8 (14) 14 (21) 0.300
Thrombotic events postrandomization, n (%) 6 (11) 16 (24) 0.048
CMV infections, n (%) 25 (44) 22 (33) 0.231
CMV hospitalizations, n (%) 6 (11) 4 (6) 0.511
Community-acquired respiratory viral infections, n (%) 20 (35) 29 (44) 0.317
No. of hospitalizations, median (25th–75th percentile) 1 (0–3) 2 (0–3) 0.148
Hospitalization days, median (25th–75th percentile) 9 (0–32) 14 (0–36) 0.336
Hospitalization for bacterial/fungal infections, n (%) 17 (30) 22 (33) 0.677
Chronic lung allograft dysfunction, n (%) 16 (28) 17 (26) 0.773
 Phenotype 0.247
  Bronchiolitis obliterans syndrome 8 (14) 8 (12)
  Restrictive allograft syndrome 2 (4) 4 (6)
  Mixed 3 (5) 5 (8)
  Undefined/unclassified 3 (5)
Redo lung transplant, n (%) 2 (4) 0.213
Deceased, n (%) 8 (14) 15 (23) 0.218
 Cause of death, n (%) 0.675
  Unknown 1 (2)
  Chronic lung allograft dysfunction 4 (7) 8 (12)
  Infection 1 (2) 2 (3)
  Malignancy 2 (3)
  Cardiovascular 1 (2) 2 (3)
  Other 1 (2) 1 (2)
Data are presented as median (25th–75th percentile) and number and percentage, respectively. Bold type indicates significant values.
CMV, cytomegalovirus.

F1
FIGURE 1.:
eGFR during the observation period for the ITT (A) and PP (B) population. CNI, calcineurin inhibitor; eGFR, estimated glomerular filtration rate formula; ITT, intention-to-treat; PP, per protocol.

Thrombotic events after randomization occurred more frequently in the quadruple low CNI regimen (11% versus 24%; P = 0.048). Prevalence of acute cellular rejections, CLAD, CLAD phenotypes, and estimated CLAD-free survival did not differ between the groups (Table 1; Figure 2A). Finally, more deaths occurred in the quadruple low CNI regimen without being statistically different (14% versus 23%; P = 0.218). Estimated graft survival did not differ between the groups (P = 0.347), as shown in Figure 3A. All outcome variables are reported in Table 1.

F2
FIGURE 2.:
CLAD-free survival by Kaplan-Meier analysis for the ITT (A) and PP (B) populations. CLAD, chronic lung allograft dysfunction; CNI, calcineurin inhibitor; ITT, intention-to-treat; PP, per protocol.
F3
FIGURE 3.:
Graft survival by Kaplan-Meier analysis for the ITT (A) and PP (B) populations. CNI, calcineurin inhibitor; ITT, intention-to-treat; PP, per protocol.

PP Population

Baseline characteristics between the groups did not differ, as shown in Table 2. Similar to the ITT analysis, eGFR at randomization was not different between the groups (65 [58–74] versus 61 [55–70] mL/min/1.73 m2; P = 0.145). The course of eGFR during the study period is shown in Figure 1B. Only at 1 y after randomization, at the end of the 4EVERLUNG study, eGFR was higher in the quadruple low CNI regimen (58 [51–70] versus 68 [58–80] mL/min/1.73 m2; P = 0.023). eGFR at 5 y was not different between the groups (59 [50–73] versus 59 [48–69] mL/min/1.73 m2; P = 0.946). Results were similar in the last observation carried forward analysis (60 [50–73] versus 59 [48–69] mL/min/1.73 m2; P = 0.779). Median changes of eGFR from randomization to the end of the observation period (5 y) did not differ statistically significant (–7 [–15 to 6] versus –2 [–14 to 10] mL/min/1.73 m2; P = 0.424) between the groups; however, median decrease of eGFR from 1 y to the end of the observation period (5 y) was higher in the quadruple low CNI regimen (–2 [–9 to 12] versus –10 [–20 to 0] mL/min/1.73 m2; P = 0.010). None of the patients developed end-stage renal disease (Table 2).

TABLE 2. - Characteristics of the per protocol population according to the randomized immunosuppressive regimen
Characteristics Triple (n = 46) Quadruple (n = 36) P
Gender (female), n (%) 17 (37) 15 (42) 0.664
Age (y), median (25th–75th percentile) 56 (50–61) 59 (49–61) 0.779
Primary diagnosis, n (%) 0.755
 Obstructive 20 (43) 15 (42)
 Restrictive 22 (48) 16 (44)
 Cystic fibrosis 4 (9) 5 (14)
Thromboembolism prerandomization, n (%) 2 (5) 2 (6) 1.000
CMV risk status prerandomization, n (%) 0.365
 Low risk, DR 8 (17) 7 (20)
 Intermediate risk, R+ 30 (65) 20 (56)
 High risk, D+R 8 (17) 8 (23)
Donor-specific antibodies postrandomization, n (%) 5 (11) 1 (3) 0.223
No. of acute rejections (≥A1) postrandomization, n (%) 2 (4) 2 (6) 1.000
Dialysis, n (%)
Renal transplant, n (%)
Malignancy, n (%) 7 (15) 8 (22) 0.416
Thrombotic events postrandomization, n (%) 5 (11) 8 (22) 0.162
CMV infection, n (%) 19 (41) 9 (25) 0.122
CMV hospitalizations, n (%) 3 (7) 1 (3) 0.627
Community-acquired respiratory viral infections, n (%) 16 (35) 12 (33) 0.891
No. of hospitalizations, median (25th–75th percentile) 1 (0–2) 1 (0–3) 0.911
Hospitalization days, median (25th–75th percentile) 9 (0–22) 6 (0–28) 0.689
Hospitalization for bacterial/fungal infections, n (%) 14 (30) 9 (25) 0.587
Chronic lung allograft dysfunction, n (%) 14 (30) 5 (14) 0.078
 Phenotype 0.613
  Bronchiolitis obliterans syndrome 8 (17) 4 (11)
  Restrictive allograft syndrome 2 (4)
  Mixed 2 (4) 1 (3)
  Undefined/unclassified 2 (4)
Redo lung transplant, n (%) 2 (4) 0.501
Deceased, n (%) 5 (11) 4 (11) 1.000
 Cause of death, n (%) 0.353
  Unknown 1 (2)
  CLAD 3 (7) 1 (3)
  Malignancy 1 (3)
  Cardiovascular 1 (2) 2 (6)
Data are presented as median (25th–75th percentile) and number and percentage, respectively.
CLAD, chronic lung allograft dysfunction; CMV, cytomegalovirus.

There were less CMV infections in the quadruple low CNI regimen. More malignancies and thrombotic events occurred in the quadruple low CNI regimen without being statistically different (Table 2). Prevalence of CLAD at the end of observation was lower in the quadruple low CNI regimen (30% versus 14%; P = 0.078). Furthermore, estimated CLAD-free survival by Kaplan-Meier analysis was higher in the quadruple low CNI regimen (P = 0.082) as shown in Figure 2B. Overall survival did not differ between the standard triple and the quadruple low CNI regimens, as shown in Figure 3B. All outcome variables are reported in Table 2.

Switch Population

Over the 5-y follow-up in 11 patients (19%) of the standard triple regimen and in 30 patients (46%) of the quadruple low CNI regimen, the immunosuppressive regimen was switched (P = 0.002). Mean time of switch was 362 (99–787) d after randomization. Reasons for a switch did not differ between the groups, as depicted in Table 1. Baseline characteristics of the switch population did not differ between standard triple and quadruple low CNI regimens, respectively (Table S1, SDC, https://links.lww.com/TP/C376). Switch patients were more likely to have de novo donor-specific antibodies, acute cellular rejections, and end-stage renal disease. Furthermore, switch patients were more often hospitalized, and total time in the hospital was longer (Table S1, SDC, https://links.lww.com/TP/C376). Finally, overall survival (P = 0.008) and estimated graft survival (P = 0.013; Figure S2, SDC, https://links.lww.com/TP/C376) were significantly lower in patients switched.

DISCUSSION

In this retrospective long-term analysis of an open-label randomized control trial, an everolimus-based quadruple low CNI maintenance immunosuppression after transplantation was not associated with improved long-term renal function. The initial benefit was lost over time in both patients who were being switched back to a standard triple regimen and patients who remained on a quadruple low CNI regimen. The immunosuppressive efficacy and safety profiles were overall comparable with the standard triple regimen.

The primary endpoint of the core study was renal function at month 12 after randomization expressed as eGFR, which was superior in the quadruple low CNI regimen compared with the standard triple regimen.3 In our analysis, this effect was not sustained during the course of up to 5 y after randomization. This was mainly because of a decrease of eGFR in the quadruple low CNI regimen after the first year in both the ITT and PP populations. In contrast, eGFR in the standard triple regimen did not further decrease and remained stable during the follow-up. A possible explanation could not be elucidated in our study but might be associated with the differing anticipated drug target levels. Whereas in a standard triple regimen, the CNI target level was decreased during the posttransplant period, in a quadruple low CNI regimen, the dose was meant to remain stable for both the CNI and everolimus. In the core study, patients have been enrolled 3 to 18 mo after transplantation with a mean tacrolimus level of ≈10 ng/mL throughout the study3; thereafter, anticipated tacrolimus trough levels were 6 to 10 ng/mL. Therefore, most of the patients in the standard triple regimen will have experienced a reduction of the CNI trough level during the observation period. Trough levels were not obtained in this study; however, as reported in the core study, there was a high level of adherence to the anticipated targets during the first year with a mean trough level of approximately 4 and 5 ng/mL everolimus and tacrolimus, respectively.3

There might be alternate reasons for loss of kidney function under a quadruple regimen. Thrombotic microangiopathy (TMA) characterized by endothelial cell injury and formation of fibrin thrombi within capillary and arterioles is associated with the use of mammalian target of rapamycin (mTOR) inhibitors. The risk for TMA is particularly increased when CNI and mTOR inhibitors are used together and in the setting of high drug levels.7-9 TMA might also develop after long-term exposure, can be difficult to be established as diagnosis, and may cause irreversible renal failure.10 Furthermore, mTOR inhibitors may cause proteinuria or worsening proteinuria from preexisting glomerulopathies.11 Both may counteract the CNI sparing effect when used for a long period despite the initial benefit. CNI itself may cause irreversible renal functional deterioration as a result of progressive tubulointerstitial injury and glomerulosclerosis.12 mTOR inhibition in patients with preexisting nephropathy should be used with caution because it may accelerate the progression of renal disease.13 Whether long-term exposure of a combination of CNI and mTOR inhibitors or continuing exposure of mTOR inhibitors in the case of decreasing renal function has caused loss of the beneficial short-term effect in our study has to be established further.

In the line of the risk for endothelial injury, thromboembolic events were twice as many in the quadruple low CNI regimen than in the standard triple regimen. The increased risk of thrombotic events by mTOR inhibitors is known and is caused by endothelial activation, thrombin formation, and impaired fibrinolysis.14 A lower risk for CMV infections in patients treated with everolimus as the second immunosuppressive drug has been reported previously.15-17 This is supported by our observations, keeping the low number of affected individuals in mind.

Patients on a quadruple low CNI regimen were more frequently switched to an alternative immunosuppressive regimen, which was mainly back to a standard triple regimen. The reasons for a switch did not differ between the groups and were mainly associated with allograft dysfunction or side effects. Being switched was associated with worse outcomes, including increased mortality. This has to be interpreted with caution and does not indicate a causal relationship. The threshold to switch a patient if adverse events occur might have been lower in patients on the quadruple low CNI regimen than those on the standard triple regimen. This might have resulted in a selection of quadruple low CNI patients with an unfavorable course in the switch population. This is further supported by analysis of the PP population where switch patients were excluded. In this analysis, patients who remained on a quadruple low CNI regimen had a particularly uneventful course, with a low mortality rate (11%) and CLAD (14%) rate at 5 y.

In this respect, the risk for CLAD was lower in patients on the quadruple low CNI regimen than in those on the standard triple regimen in the PP population. Whether this is associated with the above-mentioned exclusion from patients with unfavorable courses from the PP population or whether this effect is associated with the different rates of de novo donor-specific antibodies has to be established.

In case of malignancy, a regimen with mTOR inhibitors to spare CNI is frequently used.18,19 Keeping in mind that the number of de novo malignancies was generally low, there was no statistical difference between the groups. In contrast, there were more malignancies in patients on a quadruple low CNI regimen.

Long-term therapeutic studies on immunosuppressive regimens have been challenging in the past.15,16,20-23 A high discontinuation rate is frequently observed. Most common and recurring reasons for early discontinuation are decreased therapeutic efficacy, renal insufficiency, myelosuppression, and gastrointestinal symptoms.16,22 All are inherent effects of any immunosuppressive regimen. Methodological problems arise from switching from the investigated to the comparative regimen, resulting in commingling of groups, which frequently limits clear discrimination between study populations. Furthermore, treatment contamination arises in particular in long-term interventions. Despite equal randomization and similar baseline characteristics, acquired comorbidities and other renal toxic drugs during the course of the long study period may have contaminated the effect of the investigated regimen. All the above have to be taken into account when interpreting our study. In this respect, the applied concept of ITT and PP populations to analyze long-term effect of the different regimens has to be cautiously interpreted in view of the study design and its limitations, which in particular include the retrospective study spanning a period of 5 y. Furthermore, some observations lack a clear explanation and need further assessment before implementation into the clinical routine. Although the foundation of the study was a randomized controlled trial, this is a retrospective analysis of several centers with potential differences in surveillance and management of lung transplant recipients.

In conclusion, the beneficial effect of an early quadruple low CNI regimen after transplantation for long-term follow-up could not be confirmed in our analysis with its respective limitations. Whether this indicates that a quadruple low CNI regimen has no role or that patients should be electively switched back to a standard triple regimen has to be assessed further.

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