ABSTRACT
Background
Alemtuzumab can be an alternative to rabbit anti‐thymocyte globulin (rATG) to treat severe or glucocorticoid‐resistant acute T cell‐mediated kidney transplant rejection (TCMR). Yet, there are few reports in which these two treatments are evaluated let alone, compared. This study describes the real‐world clinical experience of both therapies and compares their efficacy and toxicity.
Methods
Kidney transplant recipients of two Dutch transplant centers who received lymphocyte‐depleting antibody therapy for severe or glucocorticoid‐resistant TCMR were retrospectively evaluated. In the first, alemtuzumab was the standard treatment for this indication, in the second, it was rATG. Patient survival, graft survival and function, and the occurrence of infections and malignancies were reported and compared.
Results
One hundred and forty‐three patients treated with alemtuzumab and 57 patients with rATG were evaluated. Patient survival was not significantly different during follow‐up (p = 0.55), and 5‐year survival rates were 71.0% (95% confidence interval [CI]: 63.0–79.9) after alemtuzumab and 70.7% (95% CI: 58.3–85.7) after rATG. Graft survival was not significantly different during follow‐up either (p = 0.24), and 5‐year graft loss rates were 32.3% (95% CI: 24.2–40.5) after alemtuzumab and 29.2% (95% CI: 16.0–42.4) after rATG. The occurrence of infections and malignancies did not differ between groups.
Conclusion
Mostly, severe TCMRs have good long‐term graft survival and function after either alemtuzumab or rATG therapy. No significant differences between the two therapies were found in this real‐world clinical experience. Alemtuzumab is an effective alternative to rATG for the treatment of severe TCMR.
Keywords: alemtuzumab, efficacy, rabbit anti‐thymocyte globulin, T cell‐mediated kidney transplant rejection, toxicity
Abbreviations
- BKV
BK‐virus
- CI
confidence interval
- CMV
cytomegalovirus disease
- DSA
donor-specific antibody
- EMC
Erasmus MC, University Medical Center Rotterdam
- HR
hazard ratio
- IQR
interquartile range
- IV
intravenous
- IVIG
intravenous immunoglobulin
- PH
proportional hazards
- PNF
primary non‐functioning
- rATG
rabbit anti‐thymocyte globulin
- TCMR
T cell‐mediated rejection
- UMCG
University Medical Center Groningen
1. Introduction
Lymphocyte‐depleting antibody therapy with either rabbit anti‐thymocyte globulin (rATG) or alemtuzumab is recommended for severe or glucocorticoid‐resistant acute T cell‐mediated kidney transplant rejection (TCMR) [1, 2]. Unfortunately, some patients develop resistance to rATG therapy through the formation of anti‐ATG antibodies, which significantly reduces therapy efficacy [3]. Alemtuzumab is an off‐label alternative to rATG, which holds certain advantages over rATG. First, alemtuzumab has fewer infusion‐related side effects [4]. Second, alemtuzumab can be administered subcutaneously [4]. Third, alemtuzumab can be given as a single dose [2], which enables treatment in day‐care setting, thereby reducing healthcare‐associated costs [4].
Both rATG and alemtuzumab cause profound depletion of T lymphocytes [5, 6]. Lymphocyte depletion after alemtuzumab is prolonged and puts patients at risk for infection and malignancy [6]. It is, however, unclear how these risks compare to rATG treatment. It is also unknown if alemtuzumab has superior efficacy over rATG as these drugs have only been compared head‐to‐head in randomized, controlled trials when used as induction therapy [7].
Reports concerning the outcomes of lymphocyte‐depleting therapy for severe TCMR are scarce and outdated [8], and comparisons of alemtuzumab and rATG are even rarer. Previous, retrospective analyses suggested that rATG and alemtuzumab may be comparable in terms of efficacy when used as anti‐rejection therapy [9]. The analysis by van der Zwan et al., however, was limited by the fact that the rATG and alemtuzumab cohorts dated from different eras with the rATG group predating the alemtuzumab group by 10 years. In the present study, the efficacy and safety of alemtuzumab and rATG for TCMR were compared by investigating two contemporaneous groups in a two‐center study.
2. Materials and Methods
2.1. Study Design
This is a retrospective study that was performed in two kidney transplant centers in the Netherlands: the Erasmus MC, University Medical Center Rotterdam (EMC), and the University Medical Center Groningen (UMCG). Both centers have comparable transplant protocols (as described below), but different treatments for TCMR. At the EMC, the treatment for severe or glucocorticoid‐resistant TCMR is alemtuzumab (Sanofi), whereas at the UMCG, it is rATG (Sanofi). The study was approved by the medical ethical review board of the EMC (protocol number MEC‐2021‐0924) and classified as not subjected to the Dutch Medical Research Involving Human Subjects Act [10]. Data were retrieved from the Dutch Organ Transplant Registry, local hospital transplant registries, and individual medical records.
2.2. Patients
This study concerned all consecutive adult kidney transplant recipients who were treated with alemtuzumab (at the EMC) or rATG (at the UMCG) for TCMR between January 1, 2012 and January 1, 2023. TCMR was histologically proven in all cases and classified according to the Banff classification actual at the time of the biopsy. Only pure TCMR was included. Patients were excluded if they had any history of prior exposure to either alemtuzumab or rATG. At the EMC, patients were identified through hospital pharmacy records [6]. At the UMCG, patients were identified through the local kidney transplant registry.
2.3. Outcomes and Follow‐Up
Several separate study outcomes were investigated, namely, patient survival, graft loss, kidney function, the occurrence and type of serious infections, the occurrence of cytomegalovirus (CMV) and BK‐virus (BKV) viremia, and the occurrence and type of malignancies.
Graft loss was defined as return to dialysis, transplant nephrectomy, or re‐transplantation, whichever occurred first. All community‐acquired infections that necessitated hospitalization, and any hospital‐acquired infection were scored and analyzed as serious infections. The cutoff of a positive PCR for BKV was 250 IU/mL in both centers. For CMV, the cutoff was 50 IU/mL at the EMC and 100 copies/mL at the UMCG. Dermatologic malignancies were only scored if radiotherapy, systemic therapy, or surgery for tissue‐invasive disease was indicated.
Follow‐up started on the first day of lymphocyte‐depleting antibody therapy and ended with death, loss to follow‐up, or treatment with a T lymphocyte‐depleting agent for a new graft. Additionally, the follow‐up of infections ended with a new kidney transplantation. If neither occurred, the end of the follow‐up was the date of the last correspondence up to January 1, 2024.
2.4. Immunosuppressive Therapy
Standard induction therapy in both centers was 20 mg intravenous (IV) basiliximab on Days 0 and 4. Both centers used the combination of tacrolimus, mycophenolate mofetil, and prednisolone as standard maintenance immunosuppression with tapering of the prednisolone dose until 5 mg/day at month 3. However, at the EMC, prednisolone was completely withdrawn around week 16 except for immunologically high‐risk patients, whereas triple maintenance therapy was continued indefinitely at the UMCG. Tacrolimus target pre‐dose concentrations were 10–15 µg/L (weeks 1–2), 8–12 µg/L (weeks 3–4), 5–10 µg/L (weeks 5–12), and 4–8 µg/L from month 4 onward at the EMC and 8–12 µg/L (weeks 1–6), 6–10 µg/L (week 7 to month 6) and 4–6 µg/L from month 6 onward at the UMCG.
First‐line anti‐rejection therapy in both centers consisted of 1000 mg IV methylprednisolone for three consecutive days. At the EMC, intravenous immune globulin (IVIG) was empirically added if an antibody‐mediated component was suspected. The indication for lymphocyte‐depleting therapy was determined at the discretion of the treating nephrologist and included glucocorticoid resistance (i.e., insufficient clinical response to glucocorticoids) and rejection severity (e.g., TCMR grade IIA or higher, severe loss of graft function) or both. At the EMC, patients were treated with alemtuzumab. Alemtuzumab was initially dosed as 30 mg subcutaneously for two consecutive days, but the dosing protocol was changed to a single dose of 30 mg from 2013 onward. At the UMCG, solely T lymphocyte‐depleting therapy‐naive patients were treated with rATG. Importantly, at the UMCG rATG was not considered for patients with antibody‐mediated rejection. Originally, rATG was dosed as 2 mg/kg of body weight every other day for five times and alternated with sessions of plasmapheresis, but from 2014 onward the protocol was adapted to 1.5 mg/kg of body weight for seven consecutive days.
Both centers started antimicrobial prophylaxis after anti‐rejection therapy with sulfamethoxazole/trimethoprim and valganciclovir; at the EMC until T lymphocytes repopulated to >200 × 106 cells/L and at the UMCG for a period of 6 months.
2.5. Statistical Analysis
Baseline characteristics were presented by the treatment group. Characteristics were described as proportions with percentages for categorical variables and medians with interquartile range (IQR) for continuous variables. Categorical variables were compared between the groups with Fisher's exact test and continuous variables with the Mann–Whitney U test. Additionally, to assess imbalances between the two groups, the standardized mean differences of each variable were calculated and reported.
To assess patient survival, the Kaplan–Meier estimate was computed and the survival function was plotted for visualization. Survival times were compared between the two groups with the multidirectional log‐rank test if the survival curves crossed [11]. The association between the treatment group and patient death was analyzed with multivariable Cox proportional hazard (PH) regression, after checking for the PH assumption visually (Supporting Materials).
To assess the association between the treatment group on the kidney function at 3 and 6 months and 1, 2, 3, and 5 years after therapy, a multivariable linear mixed‐effects model with subject‐specific intercept and slope was fitted. To compare kidney functions at each different time point, the mean of the predicted kidney function was computed with 95% confidence intervals (95% CI) and plotted per treatment group. For non‐functioning grafts, a kidney function of one was imputed at the first consecutive time point, and exclusion thereafter. To account for the effect of graft failure on the mean kidney function, a sensitivity analysis was also performed in which the imputed kidney function remained one for each time point until the end of follow‐up.
The cumulative incidences of graft loss, first serious infection, and first malignancy were computed with death as a competing risk to avoid overestimation of the event rate [12]. The cumulative incidences between groups were compared with Gray's test [13, 14]. A death‐censored, multivariable Cox PH regression analysis was performed for estimation of the association between treatment group and the incidence of graft loss, after checking for the PH assumption visually (Supporting Materials). To evaluate the total occurrence of serious infections and malignancies during follow‐up, the incidence rate per hundred person‐years was calculated and compared with the Poisson test for rate comparison. A multivariable, zero‐inflated negative binomial regression was performed to estimate the association between the treatment group on the incidence rate of serious infections. Additionally, the risk for recurrent serious infections was examined with the Andersen–Gill regression analysis.
For all multivariable analysis, the included variables were defined in a meeting with the co‐authors before the initiation of the outcome analysis. They were selected as potential confounders based on clinical experience. Because the aim of the multivariable analysis was to assess the relation between treatment group and outcome, no backward or forward inclusion of covariates was performed. The number of covariates to include was about one‐tenth of the number of events to reduce the risk of overfitting. They are listed with their definitions in the Supporting Materials. Variables were selected based on clinical relevance and apparent differences in the baseline characteristics. For statistical purposes, an adapted morbidity score was used, which scored for any presence of diabetes mellitus, peripheral arterial disease, cardiac disease, and cerebrovascular disease (0 = not present, 1 = present) and summed the total per patient.
The R statistical software (v4.3.2, [R Foundation for Statistical Computing, Vienna, Austria]) was used for statistical analysis. The applied packages were: cmprsk (v2.2.11), lme4 (v1.1.33), MASS (v7.3.60), mdir.logrank (v0.0.4), pscl (v1.5.9), reda (v0.5.4), splines (v4.3.2), survival (v3.5.5), tidyr (v1.3.0), and tidyselect (v1.2.0).
3. Results
3.1. Inclusion and Baseline Characteristics
Two thousand one hundred and twenty‐eight kidney transplantations were performed in the study period at the EMC and 1807 at the UMCG. During this period, 251 cases of rejection were treated with alemtuzumab at the EMC. A total of 66 cases of rATG were given at the UMCG. For the present analysis, 143 patients were eligible for inclusion in the alemtuzumab group, and 57 patients in the rATG group (Figure 1).
FIGURE 1.
Overview of study inclusion per group, with reasons for exclusion.
Patient characteristics are depicted in Table 1. The proportion of living donors was significantly higher in the alemtuzumab group. The number of donations after circulatory death donors was higher in the rATG group, and in this same group cold ischemia times were longer than in the alemtuzumab group (Table 2). Compared to the alemtuzumab group, in the rATG group patients more often received triple maintenance immunosuppressive therapy, and there were significant between‐center differences regarding the use of IVIG and antibody removal therapies (Table 3). The two groups were comparable in terms of the rejection characteristics (Table 3).
TABLE 1.
Patient characteristics at the time of therapy.
| Patient group | ||||
|---|---|---|---|---|
|
Alemtuzumab (n = 143) |
rATG (n = 57) |
SMD | ||
| Age at therapy | Median (IQR) | 57 (44−65) | 56 (37−65) | 0.16 |
| Sex a | Female/Male (%) |
50/93 (35/65) |
30/27 (53/47) |
0.36 |
| BMI | Median (IQR) | 27.9 (24−32) | 25.9 (23−31) | 0.30 |
| Unknown (%) | 4 (3) | 0 | ||
| Diabetes mellitus | No/Yes (%) |
79/64 (55/45) |
39/18 (68/32) |
0.27 |
| Hypertension | No/Yes (%) |
18/125 (13/87) |
8/57 (14/86) |
0.04 |
| Cardiac disease | No/Yes (%) |
113/30 (79/21) |
51/6 (89/11) |
0.29 |
| Peripheral arterial vascular disease | No/Yes (%) |
128/15 (90/10) |
51/6 (89/11) |
<0.01 |
| CVA | No/Yes (%) |
129/14 (90/10) |
56/1 (98/2) |
0.35 |
| COPD | No/Yes (%) |
134/9 (94/6) |
56/1 (98/2) |
0.23 |
| Primary disease | Diabetic nephropathy a (%) | 31/143 (22) | 4/57 (7) | 0.71 |
| Glomerulonephritis (%) | 19/143 (13) | 11/57 (19) | ||
| Hypertensive nephropathy | 26/143 (18) | 8/57 (14) | ||
| Other (%) | 32/143 (22) | 7/57 (12) | ||
| Cystic kidney disease (%) | 20/143 (14) | 10/57 (18) | ||
| Reflux nephropathy (%) | 8/143 (6) | 6/57 (11) | ||
| Unknown a (%) | 7/143 (5) | 11/57 (19) | ||
Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; IQR, interquartile range; rATG, rabbit anti‐thymocyte globulin; SMD, standardized mean difference.
Statistically significant result. p values: sex, 0.03; diabetic nephropathy, 0.01; unknown primary disease, <0.01.
TABLE 2.
Transplant characteristics.
| Patient group | ||||
|---|---|---|---|---|
|
Alemtuzumab (n = 143) |
rATG (n = 57) |
SMD | ||
| Recipient age at transplantation | Median (IQR) | 57 (44−64) | 54 (34−63) | 0.18 |
| Number of transplantations | 1/2/3 or more (%) | 127/14/2 (89/10/1) | 47/10/0 (82/18/0) | 0.28 |
| Preemptive kidney transplantation | No/Yes (%) |
100/43 (70/30) |
42/15 (74/26) |
0.08 |
| PRA peak percentage class | 0−10/10−50/50−100 (%) | 116/8/19 (81/6/13) |
48/2/7 (84/4/12) |
0.11 |
| CMV status recipient | Negative/Positive (%) |
50/93 (35/65) |
22/35 (39/61) |
0.08 |
| EBV status recipient | Negative/Positive (%) |
8/135 (6/94) |
2/53 (4/96) |
0.09 |
| Unknown (%) | 0 | 2 (4) | ||
| Donor age | Median (IQR) | 57 (48−65) | 58 (49−63) | 0.02 |
| Donor type | DCD a (%) | 30/143 (21) | 22/57 (39) | 0.44 |
| DBD (%) | 17/143 (12) | 8/57 (14) | ||
| Living a (%) | 96/143 (67) | 27/57 (47) | ||
| ECD b | No/Yes (%) | 23/22 (51/49) | 16/14 (53/47) | 0.04 |
| Unknown (%) | 2 (4) | 0 | ||
| Donor creatinine b | Median (IQR) | 59 (46−77) | 68 (51−85) | 0.07 |
| First WIT (min) c | Median (IQR) | 17 (14−19) | 14 (12−19) | 0.30 |
| CIT (min) a , b | Median (IQR) | 692 (516−799) | 773 (638−896) | 0.46 |
| CMV status donor | Negative/Positive (%) |
57/86 (40/60) |
20/37 (35/65) |
0.10 |
| EBV status donor | Negative/Positive (%) |
6/83 (7/93) |
3/39 (7/93) |
0.02 |
| Unknown (%) | 54 (38) | 15 (26) | ||
| HLA mismatch | Median (IQR) | 4.00 (3−5) | 3.00 (2−4) | 0.15 |
| HLA A mismatch | 0/1/2 (%) | 34/69/40 (24/48/28) | 12/32/12 (21/57/21) | 0.19 |
| Unknown (%) | 0 | 1 (2) | ||
| HLA B mismatch | 0/1/2 | 16/59/68 (11/41/48) |
9/27/20 (16/48/36) |
0.25 |
| Unknown (%) | 0 | 1 (2) | ||
| HLA DR mismatch | 0/1/2 (%) | 21/75/47 (15/52/33) | 11/26/20 (19/46/35) | 0.15 |
| ABOi transplantation | No/Yes (%) |
135/8 (94/6) |
51/6 (89/11) |
0.18 |
| DGF | No/Yes (%) |
95/48 (66/34) |
34/23 (60/40) |
0.14 |
Abbreviations: ABOi, blood group incompatible; CIT, cold ischemia time; CMV, cytomegalovirus; DBD, donation after brain death; DCD, donation after circulatory death; DGF, delayed graft function; EBV, Epstein–Barr virus; ECD, expanded criteria donor; HLA, human leukocyte antigen; IQR, interquartile range; PRA, panel reactive antibody; rATG, rabbit anti‐thymocyte globulin; SMD, standardized mean difference; WIT, warm ischemia time.
Statistically significant result. p values: DCD donor type, 0.01; living donor type, 0.02; CIT, 0.03.
Only included deceased donations.
Only included DCD donor type.
TABLE 3.
Immunosuppression and rejection characteristics.
| Patient group | ||||
|---|---|---|---|---|
|
Alemtuzumab (n = 143) |
rATG (n = 57) |
SMD | ||
| Induction therapy | Basiliximab (%) | 132/142 (93) | 57/57 (100) | 0.39 |
| Rituximab (%) | 8/142 (6) | 0 | ||
| None (%) | 2/142 (1) | 0 | ||
| Unknown (%) | 1 (1) | 0 | ||
| Maintenance immunosuppression | TAC/MMF/pred (%) a | 98/143 (69) | 52/57 (91) | 0.72 |
| TAC/MMF a | 26/143 (18) | 2/57 (4) | ||
| TAC + other a | 5/143 (3) | 2/57 (4) | ||
| MMF + other | 13/143 (9) | 0 | ||
| Other | 1/143 (1) | 1/57 (2) | ||
| MMF dose (mg) before therapy | Median (IQR) | 2000 (1000−2000) | 1500 (1000−1500) | 0.19 |
| TAC concentration (µg/L) before therapy | Median (IQR) | 7.8 (5.3−10.6) | 8.6 (6.7−10.7) | 0.17 |
| Methylprednisolone before/during therapy | No/Yes (%) |
7/136 (5/95) |
4/53 (7/93) |
0.09 |
| IVIG before/during therapy | No/Yes (%) a | 126/17 (88/12) |
57/0 (100/0) |
0.52 |
| Plasma exchange before/during therapy | No/Yes (%) a |
142/1 (99/1) |
50/7 (88/12) |
0.48 |
| Time since transplantation | Median (IQR) | 18 (6−266) | 17 (9−350) | 0.21 |
| Timing of the rejection | Early/Late b (%) |
87/56 (61/39) |
33/24 (58/42) |
0.06 |
| Anti‐HLA DSA at rejection | Negative/Positive (%) |
80/18 (82/18) |
45/9 (83/17) |
0.05 |
| Unknown (%) | 45 (31) | 3 (5) | ||
| Anti‐HLA class I DSA | Negative/Positive (%) |
93/5 (95/5) |
50/4 (93/7) |
0.10 |
| Unknown (%) | 45 (31) | 3 (5) | ||
| Anti‐HLA class II DSA | Negative/Positive |
82/16 (84/16) |
48/6 (89/11) |
0.15 |
| Unknown (%) | 45 (31) | 3 (5) | ||
| TCMR grade II or higher | No/Yes (%) |
35/108 (24/76) |
20/37 (35/65) |
0.23 |
| Dialysis dependence at therapy | No/Yes (%) |
105/38 (73/27) |
46/11 (81/19) |
0.17 |
Abbreviations: DSA, donor‐specific antibodies; HLA, human leukocyte antigen; IVIG, intravenous immunoglobulin; IQR, interquartile range; MMF, mycophenolate mofetil; TAC, tacrolimus; rATG, rabbit anti‐thymocyte globulin; SMD, standardized mean difference.
Statistically significant result. p values: TAC/MMF/prednisolone: <0.01, TAC/MMF: 0.01, MMF + other: 0.02, IVIG: <0.01, Antibody removal: <0.01. Dialysis dependence: <0.01.
Early rejection: within 3 months; Late rejection: after 3 months or more.
3.2. Graft Loss and Function
The cumulative incidence of graft loss is shown in Figure 2A. Graft loss did not differ over the entire follow‐up time between the two groups (p = 0.23), but the cumulative incidence of graft loss was consistently higher in the alemtuzumab cohort at all time points. This difference developed around 3 months after therapy and remained consistent during the remaining follow‐up. The 1‐, 3‐, and 5‐year cumulative incidences of graft loss were 23.1% (95% CI 16.0–30.2), 30.4% (95%‐CI 22.5–38.3), and 32.3% (95%‐CI 24.2–40.5), respectively, for alemtuzumab, versus 14.0% (95%‐CI 4.7–23.3, p = 0.14), 19.5% (95%‐CI 8.8‐30.2, p = 0.13), and 29.2% (95% CI 16.0–42.4, p = 0.41), respectively, for the rATG group. Multivariable Cox regression analysis also showed a lower, but non‐significant, association between the rATG group and the hazard of death‐censored graft loss (hazard ratio [HR] 0.56, 95%‐CI 0.30–1.04, p = 0.07; Table S1). A notable difference in the occurrence of primary non‐functioning grafts (PNF) was found, between the two cohorts: 10 cases of PNF occurred in the alemtuzumab cohort and none in the rATG cohort. All 10 cases were characterized by a complicated transplantation course on top of their TCMR, with either a complicated surgery, renal oxalosis, or recurring transplant infections, and often had a marginal donor. In two cases, TCMR was the sole problem, here, TCMR was severe with necrosis and infarction and grafts were lost shortly after initiation of alemtuzumab therapy. A sensitivity analysis was performed with exclusion of the patients with PNF. Without PNF cases, the incidence of graft loss over time was comparable between the two groups (Figure S1).
FIGURE 2.
(A) Cumulative incidence function of graft loss by treatment group, (B) Kaplan–Meier estimate of the patient survival over time by treatment group. rATG, rabbit anti‐thymocyte globulin.
The kidney function was best described with a linear mixed effects model with subject‐specific intercept and slope and interaction between all the fixed covariates and time (Table S2). The treatment group was not significantly associated with the kidney function at 3 months after therapy or with the change in kidney function over time (Table S2). At all‐time points, the mean kidney function of functioning grafts ranged between 30 and 35 mL/min/1.72m2 for both groups and did not differ significantly between treatment groups (Figure S2). These findings were not altered with the sensitivity analysis of graft loss (results not shown).
3.3. Patient Survival
Patient survival was not different between the two groups (p = 0.55; Figure 2B). One‐, three‐, and five‐year survival rates were 95.8% (95%‐CI 92.5–99.1), 82.0% (95%‐CI 75.6–89.0), and 71.0% (95%‐CI 63.0–79.9), respectively, in the alemtuzumab group, and 100%, 90.1% (95%‐CI 82.2–98.8), and 70.7% (95%‐CI 58.3–85.7), respectively, in the rATG group. Multivariable analysis showed that the treatment group was not significantly associated with death (HR 1.05, 95%‐CI 0.60–1.85; p = 0.86, Table S3).
3.4. Serious Infections and Malignancies
In total, 329 serious infections were registered in the alemtuzumab group and 130 in the rATG group (Table 4). Over the entire follow‐up, the serious infection incidence rate was higher in the alemtuzumab group: 56.6 serious infections per hundred person‐years versus 47.0 serious infections per hundred person‐years in the rATG group, but this difference was not statistically significant (p = 0.08; Table 4). With correction for other variables, treatment group was also not significantly associated with the infection incidence rate (p = 0.39; Table S4). These results were confirmed by the repeated event analysis that is included in the Supporting Materials (Figure S3, Table S5).
TABLE 4.
Incidence rate of infections and malignancies, per hundred person‐years.
| Patient group | Statistic a | ||
|---|---|---|---|
| Serious infections |
Alemtuzumab n = 143 |
rATG n = 57 |
p value |
| Total serious infections (n) | 56.6 (329) | 47.5 (130) | 0.10 |
| Urogenital infections (n) | 24.9 (145) | 16.1 (44) | 0.01 |
| Respiratory infections (n) | 14.4 (84) | 9.5 (26) | 0.07 |
| Gastro‐intestinal infections (n) | 6.2 (36) | 9.5 (26) | 0.10 |
| Cutaneous infections (n) | 3.8 (22) | 3.7 (10) | 0.99 |
| Other (n) | 7.2 (42) | 8.8 (24) | 0.43 |
| Opportunistic infections | |||
| BKV viremia (n) | 5.0 (29) | 3.3 (9) | 0.30 |
| CMV viremia (n) | 6.9 (40) | 5.1 (14) | 0.38 |
| Malignancies | |||
| Total malignancies (n) | 3.1 (20) | 3.6 (10) | 0.69 |
| Solid malignancies (n) | 2. (14) | 2.2 (6) | 1.00 |
| Colon (n) | 0.3 (2) | 0.0 | — |
| Lung (n) | 0.7 (1) | 0.7 (2) | — |
| Mamma (n) | 0.3 (2) | 0.0 | — |
| Renal/Urogenital (n) | 0.5 (3) | 1.0 (3) | — |
| Other/unknown (n) | 0.3 (2) | 0.4 (1) | — |
| Metastatic, cutaneous SCC (n) | 0.3 (2) | 1.5 (4) | 0.07 |
| PTLD (n) | 0.6 (4) | 0.0 (0) | 0.32 |
Abbreviations: BKV, BK virus; CMV, cytomegalovirus; PTLD,post‐transplant lymphoproliferative disease; rATG, rabbit anti‐thymocyte globulin.
Poisson test statistic for rate parameter.
The overall malignancy incidence rate per hundred person‐years was comparable between the two cohorts: 3.1 in the alemtuzumab group and 3.6 in the rATG group (p = 0.69; Table 4).
4. Discussion
In this retrospective study, the efficacy and safety of both alemtuzumab and rATG therapy for TCMR were described and compared. Although the toxicity of both therapies was similar, a notable, albeit not statistically significant, difference of the death‐censored cumulative incidence of graft loss was observed.
The higher incidence of graft loss in the alemtuzumab group was explained by the surplus of patients with grafts with PNF in this group, as was demonstrated by the sensitivity analysis. The question remains if alemtuzumab is a less effective anti‐rejection therapy for these cases of early TCMR, or if the difference resulted from selection bias. However, the analysis of PNF cases suggests that other factors than TCMR probably played an important role in the eventual failure of these grafts.
Selection bias based on the expected graft function early after transplantation is difficult to prove; it depends on the clinical judgment of a transplant nephrologist and the risk of early graft loss is multifactorial [15, 16]. A notable difference between the centers that could indicate the presence of selection bias regarding graft quality, was the higher proportion of patients on dialysis before treatment with alemtuzumab, which is closely related to later PNF. Selection bias could have arisen from differences between centers in the decision to (not) treat a patient with a T‐cell depleting agent, as the indication for treatment is at the discretion of the nephrologist and not defined in (inter)national protocols. Furthermore, differences in criteria for accepting or declining a donor organ could have contributed to differences in graft quality between the two centers.
There were more cases of alemtuzumab‐treated TCMR than r‐ATG‐treated TCMR, which was not entirely explained by a higher number of transplantations during the study period. Differences in local practices could have contributed to this finding too. For instance, the early withdrawal of steroids at the EMC could have resulted in more severe rejections, since early steroid withdrawal is associated with a higher risk of acute rejection [17]. To what extent this practice has resulted in an excess of graft loss after rejection therapy is uncertain, but higher incidences of graft loss have been described after early steroid withdrawal [18]. However, considering that steroid tapering at both centers was equivalent during the first 3 months after transplantation, it seems unlikely that the different steroid withdrawal protocols contributed to a higher number of early graft loss after alemtuzumab therapy. In the present study, other differences in center‐specific practices and rejection classification could have influenced the results of the comparison of alemtuzumab and rATG efficacy, as well. However, these limitations are inevitable, as this study concerned the real‐world clinical experience regarding the treatment of severe TCMR in both transplant centers.
Some studies have reported a higher risk of donor‐specific antibody (DSA) formation and antibody‐mediated rejection after alemtuzumab versus rATG induction therapy [19, 20]. Unfortunately, in both centers, there was no protocolized screening of DSA or antibody‐mediated rejection during follow‐up. Therefore, no meaningful comparisons could be made on this topic. However, the findings that graft loss and graft function during later follow‐up were not significantly different, were reassuring.
Survival rates in this cohort were lower compared to the general survival rates after kidney transplantation [21]. For alemtuzumab, it was previously shown that after therapy, patient survival was lower, but the question remained if patient survival would also be worse in comparison to rATG [6]. This study demonstrated that the patient survival rates did not differ between alemtuzumab and rATG, which was in line with the findings of van der Zwan et al. [9].
The overall number of infections and the risk of recurrent serious infections was not different between the two cohorts, contrary to the findings of van der Zwan et al., who performed a single‐center comparison where the rATG group predated the alemtuzumab group. They found that the infection‐free survival was lower after rATG and suggested that this originated from the need to admit patients for several days for rATG administration and the use of central venous catheters [9]. Indeed, in the present study, hospital‐acquired infections were significantly more common during the first 2 months after rATG therapy (data not shown). However, the difference between groups disappeared within 2 years after therapy. It is possible that the lower infection‐free survival after rATG found by van der Zwan et al. was caused by differences in clinical care between the two eras of the two treatment groups that were compared. On the other hand, a potential effect of transplant center‐specific confounders cannot be ruled out in the present study.
Although the treatment group was not associated with the infection incidence rate, infections were frequent complications after both therapies. Prolonged T lymphocyte depletion is associated with morbidity and high infection rates after kidney transplantation [22]. Therefore, reducing the duration of lymphocyte depletion might decrease the number of infections after both therapies. Unfortunately, it was not possible to assess the effect and therapy‐related differences of the duration of lymphocyte depletion, because lymphocytes were not measured routinely after rATG treatment. The absence of data on T cell depletion after rATG is therefore a limitation of the current study, and we advocate standard lymphocyte monitoring after the use of both alemtuzumab and rATG in clinical practice.
Other studies showed that lymphocyte recovery after rATG was dose‐dependent [23], and both low‐dose rATG and alemtuzumab were effective and safe as induction therapy [24– 27]. Pharmacokinetic simulations have shown that rATG dose reduction will lead to faster lymphocyte recovery and that the current dose of alemtuzumab causes prolonged exposure to lymphocytic drug levels [28, 29]. These findings provide the rationale that dose reductions may lead to reduced treatment‐related toxicity without reducing effectivity.
The 5‐year malignancy cumulative incidence reported here is somewhat higher compared to the short‐term incidences reported after kidney transplantation in other studies [30, 31], and after rATG induction therapy in particular [32]. This could indicate that on the short‐term, both anti‐rejection therapies have an additive risk for malignancies, which would partly explain the finding that a kidney rejection episode is a risk factor for post‐transplant malignancies [33]. Nevertheless, the observation that the malignancy risk was not different between rATG and alemtuzumab is reassuring, although longer follow‐up is needed.
Although the efficacy and toxicity of both therapies are comparable according to this real‐world clinical data, there are secondary characteristics to consider when comparing both therapies. Alemtuzumab has some advantages over r‐ATG. Most importantly, it has fewer infusion‐related side effects and an easier mode of administration [4]. In terms of medication costs, considering patients with a weight of 70 kg and a therapy duration of 7 days, r‐ATG will cost around 9500 euros. In comparison, 30 mg of alemtuzumab will cost around 20,000 euros [34, 35]. Importantly, these costs do not consider the cost difference that results from differences in hospital admission days with the two therapies and the possibility for alemtuzumab to be administered in a day‐care setting.
In conclusion, the majority of severe, TCMRs respond favorably to either alemtuzumab or rATG therapy in terms of long‐term graft survival and function, and no significant differences between the two therapies were found in this comparison of real‐world clinical data. Patient survival and the incidence of infections and malignancies also did not differ between both therapies. Alemtuzumab is an effective alternative to rATG for the treatment of severe TCMR.
Author Contributions
Lukas K. van Vugt co‐designed the study, collected and processed the data, performed the analysis, and wrote the initial manuscript; Erzsi Tegzess collected the data, was involved in the study design, and reviewed the manuscript; Marieke van der Zwan was involved in data collection and reviewed the manuscript; Marian C. Clahsen‐van Groningen provided histology data and consultation and reviewed the manuscript; Brenda C. M. de Winter was project supervisor and reviewed the manuscript; Priya Vart provided statistical consultation and reviewed the manuscript; Marlies E. J. Reinders was project supervisor and reviewed the manuscript; Jan Stephan F. Sanders was involved in study design and reviewed the manuscript; Stefan P. Berger was involved in study design and reviewed the manuscript; Dennis A. Hesselink co‐designed the study, was project supervisor, and reviewed the manuscript.
Disclosure
The authors of this manuscript have conflicts of interest to disclose. Dennis A. Hesselink received lecture and consulting fees from Astellas Pharma, Astra Zeneca, Chiesi Pharma, Medincell, Novartis Pharma, Sangamo Therapeutics, and Vifor Pharma. He received grant support from Astellas Pharma, Bristol‐Myers Squibb, and Chiesi Pharma (paid to his institution). He does not have employment or stock ownership at any of these companies, nor does he have patents or patent applications. Marian C. Clahsen‐van Groningen received consulting honoraria from Sangamo Therapeutics and project support from Astellas Pharma (paid to her institution). The remaining authors of this manuscript have no conflicts of interest to disclose.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Supporting Information
Acknowledgments
The authors would like to thank Judith A. Kal‐van Gestel for her contribution to this work.
Funding: The authors received no specific funding for this work.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.