Abstract
Transplant patients are at risk for post-transplant lymphoproliferative disease (PTLD), a virally driven malignancy. Induction with the depleting antibody preparations Thymoglobulin and OKT3 is associated with PTLD, suggesting that T cell depletion increases PTLD risk. We therefore studied 59,560 kidney recipients from the OPTN/UNOS database for a relationship between induction agent use and PTLD. Two agents with comparable depletional effects, alemtuzumab and Thymoglobulin, were compared to non-depletional induction agents or no induction. Univariate and multivariate Cox regression analyses were performed to examine the association between induction regimen and PTLD. The overall incidence of PTLD was 0.42% and differed significantly by induction strategy (p<0.01): without induction (0.43%), basiliximab (0.38%), daclizumab (0.33%), Thymoglobulin (0.67%), and alemtuzumab (0.37%). Thymoglobulin was associated with a significantly increased risk of PTLD (p=0.0025), but alemtuzumab (p=0.74), basiliximab (p=0.33), and daclizumab, which trended toward a protective effect (p=0.06), were not. Alemtuzumab and Thymoglobulin treated patients did not differ in any established parameter affecting PTLD risk. Interestingly, maintenance therapy with an mTOR inhibitor was strongly associated with PTLD (0.71%, p<0.0001). Thus, depletional induction is not an independent risk factor for PTLD. Rather, aggregate chronic immunosuppression or maintenance drug selection may be a more relevant determinant of PTLD risk.
Introduction
OPTN/UNOS data show that the use of antibody induction therapies at the time of kidney transplantation has increased substantially from 39% in 1998 to 70% in 2005. Indeed, the use of induction antibodies is growing in all organ categories in the United States and approximates or exceeds 50% of patients for all organs except the liver [1, 2]. Although antibody induction has been shown to reduce significantly the risk of early acute kidney rejection [3, 4], depletional antibody induction, specifically treatment with polyclonal anti-T cell preparations or OKT3, has also been associated with an increased risk of post transplant lymphoproliferative disease (PTLD) [5], a potentially fatal, malignant transformation of B cells (most commonly), driven by activation of latent or newly acquired Epstein Barr Virus (EBV) [reviewed in 6]. This association has led to the common perception that T cell depletion specifically predisposes one to PTLD. An alternative hypothesis, however, is that aggressive immunosuppression of any sort increases ones risk of PTLD by inhibiting protective immunity against EBV, and that depletion is typically deployed in concert with other aggressive immunosuppressive strategies. In this view, T cell depletion would be associated with PTLD only to the extent that it was part of a vigorous immunosuppressive regimen, or specifically targeted T cells involved in EBV immunity.
Alemtuzumab, a humanized CD52-specific antibody, has been shown to achieve rapid and thorough depletion of peripheral and secondary lymphoid T cells in kidney transplant recipients comparable to other clinically available depletional induction agents, and has been used with increasing frequency as a depletional induction agent [7–16]. While alemtuzumab is an effective T cell depleting agent, it is unique in that it also depletes B cells. This could be a significant distinction, as B cell depletion is a known therapeutic maneuver used to treat PTLD [17]. Additionally, many centers have combined alemtuzumab with maintenance regimens that are less vigorous than these that have been historically used with depletional induction [7–16]. Furthermore, alemtuzumab has recently been demonstrated to deplete naïve T cells more efficiently than memory T cells potentially sparing T cells involved in established protective EBV immunity [18]. Given these characteristics of alemtuzumab, and its rapidly increasing use in kidney transplantation, we sought to determine whether alemtuzumab predisposes patients to PTLD, particularly compared to Thymoglobulin, another depletional induction agent, or non-depletional strategies. We find that despite alemtuzumab’s clear therapeutic depletional effect, as currently used, it is not associated with an increased incidence of PTLD.
Methods
Patients
The study included 59,560 primary kidney transplant recipients recorded in the OPTN/UNOS database from 2000–2004, with at least 8 days of survival, and who were reported to have one of the following induction therapies: alemtuzumab, Thymoglobulin, basiliximab, daclizumab, or no induction (Table 1). OKT3 is known to give a higher risk of PTLD [5]; however, this agent was not re-evaluated since it was used infrequently during the study period. Patients receiving two or more of the induction strategies (e.g. alemtuzumab and Thymoglobulin) were excluded from study. Dosages of induction and maintenance immunosuppressive drugs are not reported to the OPTN/UNOS database and therefore were not evaluated in this study.
Table 1.
Unadjusted Rate of PTLD within 730 Days of Transplant by Study Variable
| Variable | Group | No. of Patients | PTLD Rate (%) | Log-rank P-value |
|---|---|---|---|---|
| All Patients | 59,560 | 248 (0.46%) | ||
| Induction | Basilixumab | 14,182 | 50 (0.38%) | 0.0031 |
| Daclizumab | 7,511 | 23 (0.33%) | ||
| Thymoglobulin | 13,110 | 79 (0.67%) | ||
| Alemtuzumab | 1,691 | 6 (0.37%) | ||
| No Induction | 23,066 | 90 (0.43%) | ||
| TAC-based Discharge Regimen | No | 25,099 | 94 (0.41%) | 0.1699 |
| Yes | 34,461 | 154 (0.49%) | ||
| MMF-based Discharge Regimen | No | 13,632 | 70 (0.56%) | 0.0365 |
| Yes | 45,928 | 178 (0.43%) | ||
| TOR-i based Discharge Regimen | No | 50,807 | 186 (0.40%) | <0.0001 |
| Yes | 8,753 | 62 (0.76%) | ||
| Discharge Acute Rejection | No | 56,609 | 239 (0.46%) | 0.3811 |
| Yes | 2,951 | 9 (0.33%) | ||
| Recipient Race | Non-White | 25,372 | 63 (0.27%) | <0.0001 |
| White | 34,188 | 185 (0.59%) | ||
| Age Group | Pediatric (<18) | 3,105 | 64 (2.18%) | <0.0001 |
| Adult (18+) | 56,455 | 184 (0.36%) | ||
| EBV Serostatus | Negative | 5,414 | 97 (1.91%) | <0.0001 |
| Positive | 28,803 | 66 (0.26%) | ||
| Unknown | 25,343 | 85 (0.37%) | ||
| Donor to Recipient CMV Serostatus | Negative to Negative | 9,933 | 83 (0.88%) | <0.0001 |
| Negative to Positive | 13,414 | 37 (0.30%) | ||
| Positive to Negative | 10,632 | 64 (0.67%) | ||
| Positive to Positive | 25,581 | 64 (0.28%) | ||
| Living Donor | Deceased | 33,069 | 138 (0.47%) | 0.8034 |
| Living | 26,491 | 110 (0.44%) | ||
| Transplant Year | 2000 | 10,844 | 42 (0.41%) | 0.9314 |
| 2001 | 11,585 | 49 (0.44%) | ||
| 2002 | 11,924 | 55 (0.49%) | ||
| 2003 | 12,329 | 55 (0.48%) | ||
| 2004 | 12,878 | 47 (0.47%) |
Because the development of PTLD is time dependent, and alemtuzumab has only recently been introduced into clinical transplant practice, records with follow-up greater than 730 days were censored to ensure comparable follow-up among the induction groups. The time of 730 days was selected because it represented the median follow-up time for the induction group with the shortest follow-up. In addition to induction type, recipient characteristics that were evaluated included discharge maintenance regimen: tacrolimus (TAC) based, mycophenolate mofetil (MMF) based, target of rapamycin inhibitor(TOR-i) including sirolimus and everolimus; presence of early acute rejection at discharge; pediatric (<18) versus adult (18+) age group at transplant: white versus non-white race; EBV serological status at transplant; donor to recipient CMV status (as a surrogate for EBV positive to negative); living versus deceased donor; and transplant year. These factors have established relationships to the development of PTLD and were analyzed to insure that differential induction drug use in these populations did not skew the risk of PTLD.
In order to validate the PTLD cases in alemtuzumab treated patients and guard against an under-reporting bias, data regarding the incidence of PTLD was collected from the six US centers with the most prevalent use of alemtuzumab and aggregately matched with the OPTN/UNOS data. In all cases, data from the six centers were identical with OPTN/UNOS reported data, indicating that reporting of PTLD (a relatively uncommon complication) to the OPTN/UNOS database was not missed in alemtuzumab treated patients.
Statistics
Chi-square test was used to compare study characteristics among the induction groups. The unadjusted rates of PTLD within 730 days in different groups of patients were calculated using the Kaplan-Meier method and compared using the log-rank test. Because this was not a controlled randomized study (therefore, the study characteristics may not be comparable among the induction groups), multivariate Cox regression models were used to determine the impact of the induction therapies on the risk of PTLD in the presence of the other characteristics. For variables with missing data, the median or most frequent category was used. The results of the Cox regression are presented as relative risks (RR), their 95% confidence limits, and two tailed p-values. All statistical analyses were performed using SAS Version 9.1 (SAS Institute, Inc., Cary, NC).
Results
Table 1 summarizes the unadjusted incidence of PTLD within 730 days of transplant in different patient groups. The utilization of each type of antibody induction in different patient groups is summarized in Table 2, and the results of the multivariate Cox analysis presented as the adjusted relative risk of developing PTLD for variables included in the study are listed in Table 3.
Table 2.
Utilization of Antibody Induction by Study Variable
| ANTIBODY INDUCTION THERAPY |
Total | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Basilixumab (N=14,182) |
Daclizumab (N=7,511) |
Thymoglobulin (N=13,110) |
Alemtuzumab (N=1,691) |
No Induction (N=23,066) |
||||||||
| N | % | N | % | N | % | N | % | N | % | N | % | |
| TAC-BASED DISCHARGE REGIMEN | ||||||||||||
| No | 6858 | 48.36 | 3455 | 46.00 | 4122 | 31.44 | 580 | 34.30 | 10084 | 43.72 | 25099 | 42.14 |
| Yes | 7324 | 51.64 | 4056 | 54.00 | 8988 | 68.56 | 1111 | 65.70 | 12982 | 56.28 | 34461 | 57.86 |
| MMF-BASED DISCHARGE REGIMEN | ||||||||||||
| No | 2950 | 20.80 | 832 | 11.08 | 3023 | 23.06 | 455 | 26.91 | 6372 | 27.63 | 13632 | 22.89 |
| Yes | 11232 | 79.20 | 6679 | 88.92 | 10087 | 76.94 | 1236 | 73.09 | 16694 | 72.37 | 45928 | 77.11 |
| TOR-i BASED DISCHARGE REGIMEN | ||||||||||||
| No | 11923 | 84.07 | 6867 | 91.43 | 10661 | 81.32 | 1573 | 93.02 | 19783 | 85.77 | 50807 | 85.30 |
| Yes | 2259 | 15.93 | 644 | 8.57 | 2449 | 18.68 | 118 | 6.98 | 3283 | 14.23 | 8753 | 14.70 |
| TREATMENT FOR EARLY ACUTE REJECTION | ||||||||||||
| No | 13507 | 95.24 | 7195 | 95.79 | 12722 | 97.04 | 1655 | 97.87 | 21530 | 93.34 | 56609 | 95.05 |
| Yes | 675 | 4.76 | 316 | 4.21 | 388 | 2.96 | 36 | 2.13 | 1536 | 6.66 | 2951 | 4.95 |
| RECIPIENT AGE GROUP | ||||||||||||
| Pediatric (<18) | 764 | 5.39 | 741 | 9.87 | 537 | 4.10 | 25 | 1.48 | 1038 | 4.50 | 3105 | 5.21 |
| Adult (18+) | 13418 | 94.61 | 6770 | 90.13 | 12573 | 95.90 | 1666 | 98.52 | 22028 | 95.50 | 56455 | 94.79 |
| RECIPIENT WHITE | ||||||||||||
| No | 5747 | 40.52 | 3448 | 45.91 | 5658 | 43.16 | 590 | 34.89 | 9929 | 43.05 | 25372 | 42.60 |
| Yes | 8435 | 59.48 | 4063 | 54.09 | 7452 | 56.84 | 1101 | 65.11 | 13137 | 56.95 | 34188 | 57.40 |
| RECIPIENT EBV STATUS AT TRANSPLANT | ||||||||||||
| Negative | 1374 | 9.69 | 861 | 11.46 | 900 | 6.86 | 164 | 9.70 | 2115 | 9.17 | 5414 | 9.09 |
| Positive | 7780 | 54.86 | 3499 | 46.59 | 6798 | 51.85 | 1265 | 74.81 | 9461 | 41.02 | 28803 | 48.36 |
| Unknown | 5028 | 35.45 | 3151 | 41.95 | 5412 | 41.28 | 262 | 15.49 | 11490 | 49.81 | 25343 | 42.55 |
| DONOR TO RECIPIENT CMV STATUS | ||||||||||||
| CMV − to CMV − | 2333 | 16.45 | 1212 | 16.14 | 2132 | 16.26 | 348 | 20.58 | 3908 | 16.94 | 9933 | 16.68 |
| CMV − to CMV + | 3278 | 23.11 | 1501 | 19.98 | 3075 | 23.46 | 396 | 23.42 | 5164 | 22.39 | 13414 | 22.52 |
| CMV + to CMV − | 2577 | 18.17 | 1376 | 18.32 | 2262 | 17.25 | 312 | 18.45 | 4105 | 17.80 | 10632 | 17.85 |
| CMV + to CMV + | 5994 | 42.26 | 3422 | 45.56 | 5641 | 43.03 | 635 | 37.55 | 9889 | 42.87 | 25581 | 42.95 |
| DONOR TYPE | ||||||||||||
| Deceased | 8176 | 57.65 | 3875 | 51.59 | 8090 | 61.71 | 815 | 48.20 | 12113 | 52.51 | 33069 | 55.52 |
| Living | 6006 | 42.35 | 3636 | 48.41 | 5020 | 38.29 | 876 | 51.80 | 10953 | 47.49 | 26491 | 44.48 |
| TRANSPLANT YEAR | ||||||||||||
| 2000 | 2867 | 20.22 | 1406 | 18.72 | 821 | 6.26 | 11 | 0.65 | 5739 | 24.88 | 10844 | 18.21 |
| 2001 | 2977 | 20.99 | 1674 | 22.29 | 1662 | 12.68 | 39 | 2.31 | 5233 | 22.69 | 11585 | 19.45 |
| 2002 | 3220 | 22.70 | 1547 | 20.60 | 2631 | 20.07 | 200 | 11.83 | 4326 | 18.75 | 11924 | 20.02 |
| 2003 | 2657 | 18.74 | 1535 | 20.44 | 3729 | 28.44 | 572 | 33.83 | 3836 | 16.63 | 12329 | 20.70 |
| 2004 | 2461 | 17.35 | 1349 | 17.96 | 4267 | 32.55 | 869 | 51.39 | 3932 | 17.05 | 12878 | 21.62 |
Table 3.
Risk Factors of PTLD within 730 Days of Transplants Presented as Adjusted Relative Risk (RR), 95% CL of RR and P-value
| Risk Factor | RR [95% CL] | P-value |
|---|---|---|
| Induction: Alemtuzumab vs. No Induction | 1.154 [0.495, 2.693] | 0.7396 |
| Induction: Thymoglobulin vs. No Induction | 1.630 [1.188, 2.235] | 0.0025 |
| Induction: Basiliximab vs. No Induction | 0.841 [0.592, 1.195] | 0.3331 |
| Induction: Daclizumab vs. No Induction | 0.644 [0.404, 1.026] | 0.0641 |
| TOR-i Discharge Regimen: Yes vs. No | 2.047 [1.444, 2.901] | <0.0001 |
| TAC-Based Discharge Regimen: Yes vs. No | 1.167 [0.896, 1.521] | 0.2528 |
| MMF-Based Discharge Regimen: Yes vs. No | 1.132 [0.808, 1.585] | 0.4714 |
| Early Acute Rejection: Yes vs. No | 0.823 [0.422, 1.606] | 0.5686 |
| Pediatric vs. Adult Recipient | 3.672 [2.658, 5.074] | <0.0001 |
| Recipient White vs. non-White | 1.957 [1.452, 2.637] | <0.0001 |
| Recipient EBV Status at TX: Negative vs. Positive | 5.255 [3.754, 7.357] | <0.0001 |
| Recipient EBV Status at TX: Unknown vs. Positive | 1.694 [1.222, 2.349] | 0.0016 |
| Donor to Recipient CMV: Neg to Neg vs. Pos to Pos | 2.036 [1.444, 2.871] | <0.0001 |
| Donor to Recipient CMV: Neg to Pos vs. Pos to Pos | 1.043 [0.695, 1.565] | 0.8390 |
| Donor to Recipient CMV: Pos to Neg vs. Pos to Pos | 1.489 [1.040, 2.130] | 0.0297 |
| Living vs. Deceased Donor TX | 0.714 [0.549, 0.928] | 0.0118 |
| Transplant Year: 2001 vs. 2000 | 0.980 [0.647, 1.484] | 0.9227 |
| Transplant Year: 2002 vs. 2000 | 1.039 [0.688, 1.568] | 0.8557 |
| Transplant Year: 2003 vs. 2000 | 0.988 [0.650, 1.502] | 0.9545 |
| Transplant Year: 2004 vs. 2000 | 0.924 [0.596, 1.432] | 0.7241 |
Notes: RR for each risk factor was computed where the other risk factors are at baseline values.
Baseline recipient had the following characteristics: adult, non-White, with no induction, not on TOR-i, not on TAC, not on MMF, no acute rejection at discharge, EBV positive, CMV positive with CMV positive donor, and received a deceased donor transplant in 2000.
Alemtuzumab was used in 1,691 (3%) of the recipients transplanted during the study period; Thymoglobulin was used in 13,110 (22%) of recipients, basiliximab in 14,182 (24%), and daclizumab in 7,511 (13%). No antibody induction was used in 23,066 (39%) recipients (Table 1). A total of 248 cases of PTLD were reported within 730 days of transplant in the study population for an overall incidence of 0.42% (Table 3). This is consistent with prior analyses of PTLD risk from patients from an earlier era [5]. As has been previously observed, the induction strategies used were significantly associated with the risk of PTLD (p=0.0031). The unadjusted actual incidence of PTLD within 730 days of transplant was 0.37% (6 cases) in alemtuzumab treated patients, 0.67% (79 cases) in Thymoglobulin treated patients, 0.38% (50 cases) with basiliximab, 0.33% (23 cases) with daclizumab and 0.43% (90 cases) in patients receiving no antibody induction (Table 2).
Multivariate Cox analysis indicated that, compared to no induction, alemtuzumab was not associated with an increased risk of PTLD (p=0.74, RR=1.15) (Table 3). The anti-IL-2 approaches using daclizumab and basiliximab were also not associated with increased PTLD risk (p=0.06, RR=0.64 and p=0.33, RR=0.84, respectively), with daclizumab trending toward a protective association. Conversely, as has been reported in the analysis of an earlier experience [5], Thymoglobulin was associated with an increased risk of PTLD (p<0.01, RR=1.63). Thus, the use a depletional agent was not independently associated with an increased risk of PTLD. Rather, the risk stratified with a particular depletion agent, or associated aspects of the regimen.
Interestingly, the use of TAC-based or MMF-based discharge maintenance immunosuppressive regimen was not statistically related to PTLD risk (p-values of 0.25 and 0.47, respectively) (Table 3), although TOR-based discharge maintenance was strongly and unexpectedly associated with an increased risk of PTLD (p<0.0001, RR=2.05). Maintenance drug use varied significantly with induction drug choice (Table 2). Tacrolimus based maintenance regimens were used in the majority (58%) of patients. However, tacrolimus was used more frequently in patients treated with Thymoglobulin and alemtuzumab (69 and 66%, respectively) than compared to the IL2R based strategies daclizumab (54%) and basiliximab (52%), or no induction (56%) (p<0.001). The use of MMF was also significantly different by induction regimen (p<0.001) with a majority (77%) of patients taking MMF, but more patients treated with daclizumab (89%) and basiliximab (79%) using MMF, compared to Thymoglobulin (77%), and alemtuzumab (73%) and no induction (72%). TOR-i use was also significantly (p<0.001) skewed by induction group with significantly more use in association with Thymoglobulin (19%), basiliximab (16%), and no induction (14%) compared to daclizumab (9%) and alemtuzumab (7%).
As previously reported, there was no statistical difference in the risk of PTLD between tacrolimus and cyclosporine based discharge regimens (p=0.25; RR=1.17) (Table 3). The association between MMF and a reduced risk of PTLD was not seen in this study (p=0.47; RR=1.13), unlike similar analyses from earlier years [5]. Strikingly, TOR-i was associated with a significantly increased risk of PTLD (p<0.001, RR=2.05) that has not previously been reported.
Early acute rejection rates (rejection prior to initial discharge) for recipients treated with Thymoglobulin and alemtuzumab were similarly low (3% and 2% respectively) (Table 2), and significantly lower (p<0.001) than those for patients treated with daclizumab (4%), basiliximab (5%) and no induction (7%). Neither depletional agent was commonly used in children, who have a known predilection for PTLD. Only 4% of patients receiving Thymoglobulin and 2% of patients receiving alemtuzumab were pediatrics (age <18), compared to 10% of pediatric patients receiving daclizumab and 5% receiving either basiliximab or no induction (p<0.001). Seronegativity for EBV was clearly a dominant risk factor for PTLD (p<0.001, RR=5.26) (Table 3), but was actually less common in Thymoglobulin (7%) and alemtuzumab treated patients (10%) compared with daclizumab (12%) and basilixumab (10%) (Table 2). Similarly, CMV seronegative recipients of kidneys from CMV seropositive donors had an increased risk for PTLD (p=0.03, RR=1.49) (Table 3) but this status was not different between Thymoglobulin (17%) and alemtuzumab (18%) treated patients (Table 2).
To address the risk of PTLD in high risk patient population (i.e., pediatrics with EBV seronegative), the adjusted relative risks of PTLD for pediatric patients with EBV seronegative were computed for different induction strategies and are shown in Table 4. EBV seronegative pediatric patients not on induction were about 5 times more likely to develop PTLD as compared with EBV seropositive pediatric patients with no induction (p<0.0001, RR=5.26), whereas those on Thymoglobulin were almost 9 times more likely to develop PTLD (p<0.0001, RR=8.56).
Table 4.
Risk Factors of PTLD within 730 Days of Transplants by Induction Strategy Presented as Adjusted Relative Risk (RR) For Pediatric Patients with EBV Negative Serostatus at Transplant
| Group | No. of Patients | RR | P-value1 | P-value2 |
|---|---|---|---|---|
| EBV Negative | ||||
| - No Induction | 337 | 5.26 | <0.0001 | - |
| - Alemtuzumab | 12 | 6.07 | <0.0001 | 0.74 |
| - Thymoglobulin | 202 | 8.56 | <0.0001 | 0.0025 |
| - Basiliximab | 269 | 4.42 | <0.0001 | 0.33 |
| - Daclizumab | 254 | 3.38 | <0.0001 | 0.06 |
Notes: P-value for comparing each group with EBV seropositive pediatric patients receiving no induction..
P-value for comparing each induction group with no induction.
Discussion
The substantial benefit of kidney transplantation is partially offset by the risks associated with immunosuppressive drug use. It is thus important to understand objectively these risks and adjust therapeutic strategies accordingly. This understanding is confounded by the common use of multiple agents in combination, all of which have some immunosuppressive property and side effect potential, making it difficult to assign risk to particular, as opposed to general, approaches.
In this study, we have specifically asked if depletional induction is uniquely associated with PTLD compared to other induction strategies: PTLD being a specific, reportable, side effect that, given its causal relationship to EBV infection, is clearly immune-based. The concern regarding T cell depletion arises from previously reported associations between PTLD and the use of the depletional agents Thymoglobulin and OKT3 [5]. Concern is also raised by the marked increase in the use of depletional induction in recent years [1, 2]. We find that alemtuzumab, an induction agent with similar T cell depleting properties as Thymoglobulin, does not increase the risk of PTLD. We also find no increase in the risk of PTLD in recent years compared to earlier studies [5]. These findings indicate that T cell depletion may not have an independent association with PTLD per se. The dissociation of alemtuzumab’s depletional effects from the risk of PTLD is not explained by differences in known primary risk factors for PTLD such as EBV or CMV serotype, pediatric status, or early rejection.
There are many unique aspects of alemtuzumab that could differentiate it from Thymoglobulin or OKT3 with regard to PTLD risk. Alemtuzumab’s effects on B cells may certainly impact the development of a B cell proliferative disease with the risk of PTLD possibly being an aggregate of the immunosuppressive effects of T cell depletion combined with control of the EBV reservoir. Additionally, Thymoglobulin has a more varied set of target antigens (although this is not the case for OKT3) that could substantially broaden its immunosuppressive properties. However, another important difference is the tendency for alemtuzumab to be used in investigational maintenance minimization regimens that emphasize low dose maintenance regimens following depletional induction [7–16]. This later point suggests that the associated maintenance regimen is at least as relevant for the assessment of PTLD risk as is the induction approach used. Indeed, in this study we found significant variation in maintenance drug choice segregated by induction type.
One interesting and unexpected finding from this study is that the use of mTOR inhibitor-based maintenance regimens is associated with the highest rate of PTLD (0.76%) of any agent (maintenance or induction) evaluated in this study. While low in absolute terms, this association deserves further evaluation. Given their antiproliferative and anti-angiogenic effects, mTOR inhibitors have previously been thought to have antineoplastic properties [19]. However, with regard to this specific virally-driven hematogenous malignancy, there is clearly no protective effect of mTOR inhibitors. The clear association of this particular maintenance drug with PTLD risk again suggests that the intensity of a patient’s chronic maintenance regimen may be more closely associated with risk than any individual induction strategy.
These data support an approach toward immunosuppression that is more cognizant of total chronic immunosuppressive burden than the acute use of a particular drug. To the extent that this burden can be reduced, it is likely that risks such as PTLD can be minimized. Additional study into the association between mTOR inhibitors and PTLD is warranted.
Acknowledgments
This work was sponsored in part (ADK, MR) by the Division of Intramural Research, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, and in part by the UNOS private fund. The authors gratefully acknowledge Sheila P. Fedorek, RN, CCRC, for her help with data gathering, Yulin Cheng, for putting together the OPTN/UNOS analysis dataset, and Melissa Connell, for her help with the manuscript preparation.
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