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Benefits of Rituximab Combined With Intravenous Immunoglobulin for Desensitization in Kidney Transplant Recipients

Vo, Ashley A.1; Choi, Jua1; Cisneros, Kristen1; Reinsmoen, Nancy2; Haas, Mark3; Ge, Shili4; Toyoda, Mieko4; Kahwaji, Joseph1; Peng, Alice1; Villicana, Rafael1; Jordan, Stanley C.1,5

doi: 10.1097/TP.0000000000000064
Clinical and Translational Research
Free
SDC

Background Highly HLA-sensitized (HS) patients have difficulty accessing compatible donors, especially deceased donor (DD) transplants. Desensitization protocols (DES) have evolved, but rigorous evaluation is lacking. Here, we examined the efficacy of rituximab as a DES agent in a placebo-controlled trial.

Methods Candidates were randomized to IVIG+placebo versus IVIG+rituximab. End points included rates of transplantation, antibody-mediated rejection (ABMR), and renal function. Protocol biopsies were performed at 1 year and analysis of patient and graft survival and donor-specific HLA antibodies (DSA) were performed.

Results Initially, 15 HS DDs were randomized with 13 receiving transplants. However, we discontinued study entry after five serious adverse events were observed. The study was un-blinded and attribution of patients was noted (IVIG+placebo N=7, IVIG+rituximab N=6). No significant differences were seen in DSA levels at transplant. All ABMR episodes occurred in the IVIG+placebo arm and required intense therapy (P=0.06). The two graft losses were in the placebo group. DSA rebound associated with severe ABMR was seen in three patients in the IVIG+placebo group. No rebound was seen in the IVIG+rituximab group. Renal function at 6 and 12 months showed a significant benefit for IVIG+rituximab (P=0.04).

Conclusions Based on limited assessment with acknowledged limitations, both protocols appear effective in achieving levels of DSA allowable for transplantation. However, IVIG+rituximab appeared more effective in preventing DSA rebound and, more importantly, preventing ABMR and development of transplant glomerulopathy.

Supplemental digital content is available in the text.

1 Comprehensive Transplant Center, Transplant Immunotherapy Program, Cedars-Sinai Medical Center, Los Angeles, CA.

2 HLA Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA.

3 Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

4 Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA.

5 Address correspondence to: Stanley C. Jordan, M.D., David Geffen School of Medicine at UCLA and Kidney Transplant Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048.

This work was supported by a grant from Genentech-Roche Inc. (S.C.J., MD, Principal Investigator). S.C.J. also has grant support from CSL-Behring Inc.

The authors declare no conflicts of interest.

E-mail: sjordan@cshs.org

A.A.V. participated in designing and performing the research, analyzing the data, and writing the article. J.C. participated in performing the research and analyzing the data. K.C. participated in performing the research. N.R. participated in analyzing the data and writing the article. M.H. participated in analyzing the data. S.G. participated in designing and performing the research. M.T. participated in designing and performing the research. J.K. participated in performing the research and analyzing the data. A.P. participated in performing the research. R.V. participated in performing the research. S.C.J. participated in designing and performing the research, analyzing the data, and writing the article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Received 23 September 2013. Revision requested 14 October 2013.

Accepted 9 January 2014.

Renal transplantation is the treatment of choice for end-stage renal disease (ESRD), as it offers improved quality of life and survival (1–3). Currently, there are more than 96,538 ESRD patients on the deceased donor (DD) waiting list, and almost 30,000 new patients register annually, yet fewer than 16,680 kidney transplants were performed in 2011 (OPTN data as of March 2013) (3, 4). Unfortunately, the most rapidly growing aspect of kidney transplantation is the number of patients who need one, particularly for patients that are difficult to match because of broadly reactive HLA-specific alloantibodies (resulting from previous pregnancies, blood or blood product transfusions, and transplantation).

DD transplants are allocated based on the calculated panel reactive antibody (CPRA) and blood group compatibility. The CPRA has been implemented in the allocation algorithm for DD as a means of defining the level of sensitization to HLA and of optimizing the identification of a compatible donor (5). Currently, candidates with a CPRA of 80 or greater receive four allocation points. The assignment of antigens in the donor pool considered unacceptable for a given recipient is at the discretion of the individual transplant center because a positive crossmatch (+CMX) is associated with high risk for hyperacute rejection and graft loss (6–8). In addition, the development of de novo DSAs is associated with poor allograft outcomes long term (9–11).

The scarcity of donor organs has contributed to the disenfranchisement of highly sensitized (HS) ESRD patients. Thus, in an effort to optimize the availability of compatible donors, several transplant centers have developed protocols to overcome HLA sensitization.

Two main desensitization regimens are currently utilized—low-dose intravenous immunoglobulin with plasma exchange (IVIG/PLEX) and high-dose IVIG (HD-IVIG). IVIG/PLEX has been used successfully in ABO-incompatible and +CMX renal transplantation (12, 13), whereas HD-IVIG has been used to desensitize both living-donor +CMX and HS-DD recipients on the waitlist (12, 14–19). HD-IVIG (2 g/kg) in multiple dosing regimens is considered a reasonable approach for desensitization (20). Rituximab has emerged as an agent used in desensitization protocols (13, 15–19). The B-cell depleting agent is often used in combination with HD-IVIG and IVIG/PLEX protocols. However, some investigators have questioned the benefit of rituximab as a desensitization agent (21–23).

To address this issue, we undertook a double-blinded, placebo-controlled trial aimed at assessing the usefulness of rituximab in desensitization. Here, we report on the initial analysis of data from this trial.

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RESULTS

Study Patient Characteristics

The initial study was designed to enter 90 HS patients awaiting DD transplantation at three U.S. transplant centers. The study was initiated at Cedars-Sinai. Between February 2011 and June 2012, 15 HS patients who met entry criteria were randomized in the study. The attribution of patients to study groups is shown in Figure 1. Thirteen patients received transplants (87%) (IVIG+placebo N=7 vs. IVIG+rituximab N=6). Two patients did not receive transplants (one per group). In addition, two patients (one per group) received transplants with negative CMXs and no DSAs at all time points. The demographic and baseline characteristics for both groups were similar including PRA and DSA levels at time of transplantation with the exception of more patients with previous transplants in the IVIG+placebo group (P=0.048) (Table 1 and Table 2).

FIGURE 1

FIGURE 1

TABLE 1

TABLE 1

TABLE 2

TABLE 2

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Assignment of Unacceptable Antigens

A critical component of transplanting HS patients after desensitization is development of an algorithm for defining acceptable antigens permissive for transplantation (19, 29, 30). Here, unacceptable antigens were assigned as those expected to produce a complement-dependent cytotoxicity crossmatch or result in C1q-positive binding in the Luminex-platform single antigen assay (LSA), or both. Also excluded are those antigens in the high binding LSA range greater than 10,000 MFI. In general, the titer of these antibodies is less than 1:16. These antigens were entered into UNet to optimize identification of a compatible deceased donor. Our previous reports indicate that DSA levels below these threshold criteria are known to minimize the risk for antibody-mediated rejection (ABMR) posttransplant (19, 29, 30). The class I and II antigen frequency PRAs, based on the frequency of these antigens in over 57,000 donor HLA typing results in the UNOS registry (Outland Enterprises), the CPRA in UNet, DSA binding strengths at transplant, and pretransplant crossmatch characteristics were similar between the two groups (Table 2).

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Assessment of End Points

The mean time to transplant was also similar, 7 months for IVIG+placebo versus 6 months for IVIG+rituximab (Fig. 1). Thus, the primary end point in this early and limited analysis was not met.

On July 19, 2012, study entry was halted and the study code was broken as per protocol because of three observed serious adverse events (SAEs) (ABMRs) in study patients. Evaluation of data showed that all ABMR episodes occurred in the IVIG+placebo group (N=3) (43%) versus IVIG+rituximab N=0 (0%) (P=0.06). There were also two graft losses in the IVIG+placebo group versus 0 in the IVIG+rituximab. One patient in the IVIG+rituximab group died at 1 year with functioning graft (Table 1). Although not significant and limited by the number of observations, these findings suggest a trend to poorer outcomes with the IVIG+placebo treatment. The course of the highest single DSA value of each patient entered in the study are shown in Figure 2A and B. ABMR episodes in the IVIG+placebo group were associated with a rapid rebound in DSA levels within 1 to 4 weeks posttransplant in two patients with severe features of ABMR (thrombotic microangiopathy [TMA] and intense C4d deposition) on renal biopsy. A third patient experienced severe TMA without DSA detection. All three required treatment with PLEX and Eculizumab (anti-complement, anti-C5; Alexion Inc., Cheshire, CT) (Fig. 2C). Two of three recovered, but with significant impairment of allograft function. The course of DSAs and allograft biopsy results are shown in Figure 2C and Table 3. In contrast, DSA patterns in patients treated with IVIG+rituximab tended downward posttransplant without evidence of rebound. There was minimal effect of desensitization on PRA values (non-DSAs) noted throughout the study for both groups (see Table 2 Figures S1A and S1B, SDC,http://links.lww.com/TP/A956).

FIGURE 2

FIGURE 2

TABLE 3

TABLE 3

Protocol or for cause biopsies were performed in six of seven patients in IVIG+placebo and five of six in IVIG+rituximab, with no additional patients showing evidence for ABMR. One patient in the IVIG+placebo and one in the IVIG+rituximab group experienced Banff 1A cellular rejection at 1 year. An analysis of all biopsies performed in both groups is shown in Table 3. Of note, no TG was seen on protocol biopsies for the patients treated with IVIG+rituximab. Assessment of renal function in both groups showed mean serum creatinine levels of 1.7±0.5 mg/dL and 2.0±0.6 mg/dL for IVIG+placebo and 1.1±0.4 mg/dL and 1.1±0.4 mg/dL for IVIG+rituximab at 6 M (P=0.026) and 12 M (P=0.046), respectively. Thus, treatment with IVIG+rituximab was associated with significantly improved renal function posttransplant at 6 M and 12 M, likely a result of the impact of ABMR in the two IVIG+placebo patients with surviving allografts.

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Safety

Adverse events (AEs) were minimal, including minimal infusion-related reactions to IVIG+rituximab and IVIG alone that were similar to those previously described (12, 15, 16, 19). Six patients (86%) developed SAEs (eight episodes) in the IVIG+placebo group versus three patients (50%) in the IVIG+rituximab group (P=ns). Of note, one patient (IVIG+rituximab) died at 12 months from a Nocardia brain abscess. This was likely a complication of the immunosuppressive protocol. These are summarized in Table 1.

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DISCUSSION

Desensitization therapies have emerged as part of a multipronged effort to increase transplants among HS patients. Unfortunately, neither desensitization or paired exchange paradigms have increased the number of patients undergoing transplantation in the United States (UNOS/OPTN, 2013) (3, 4). Despite these discouraging observations, there is progress in both areas that will likely improve the numbers of transplants performed for sensitized patients. Toward this end, new UNOS allocation policies will give special advantage to HS patients awaiting DD transplantation (25). Thus, continued development of desensitization therapies is critical because HS patients remain on the UNOS wait list for years with increased morbidity and mortality compared to desensitized and transplant patients (14, 19). Our group has extensive experience with both HD IVIG alone (12) and IVIG+rituximab as desensitization agents for DD recipients (15, 16, 19).

This placebo-controlled trial was undertaken to determine the benefit of rituximab as a desensitization agent when used with IVIG. Unfortunately, the number of SAEs experienced prohibited the completion of this trial and limited the assessments that can be made from it. However, there are still important lessons learned. There was a trend toward increasing numbers and severity of early ABMR episodes within the first month posttransplant in patients desensitized in the IVIG+placebo group (3/7 placebo vs. 0/6 rituximab, P=0.06). We also noted a trend toward lower DSA levels posttransplant in the IVIG+rituximab group. This observation suggests that the effect of rituximab in desensitization is likely aimed at depletion of memory B cells that rapidly become activated and increase DSA production when the alloantigen stimulus of the allograft is seen. Data to support this contention have recently been presented by Zachary et al. (26) who detected alloreactive B cells in DSA-negative patients with a sensitization history. A similar group of patients who were treated with rituximab before transplantation showed no alloreactive B cells. Kohei et al. (27) also showed that treatment of ABOi transplant patients with rituximab resulted in long-term prevention of de novo DSA production and low levels of ABMR compared to a cohort of non-ABOi LD transplant recipients not receiving rituximab. They concluded that rituximab administration at the early phase could prevent chronic B-cell activation, de novo DSA production, and chronic ABMR. In addition, Lynch et al. (28) recently showed that non-sensitized living donor transplant recipients rapidly developed detectable alloreactive B cells secreting HLA class I specific DSAs within 1 month posttransplant. The authors conclude that cryptic B-cell responses to allografts are more common than previously thought.

We have reported on the criteria used for acceptance of LD and DD transplants using the IVIG+rituximab protocol (19, 29, 30). Our experience indicates these ranges do not engender a high risk for rebound DSA development, ABMR, or graft loss from ABMR in IVIG+rituximab-treated patients. Since implementation of this protocol in 2005, we have consistently seen posttransplant ABMR rates at 24%. Here, it appears that IVIG+placebo was not sufficient to sustain low levels of DSA, ABMR, and graft loss when compared to IVIG+rituximab despite having a similar “acceptable” DSA and crossmatch starting point. DSA levels rapidly rebounded in two of three patients in the IVIG+placebo group who experienced ABMR, but declined over time in the IVIG+rituximab group (Fig. 2A and B). The risk for ABMR was also likely greater in the IVIG+placebo group because of higher numbers with previous transplants. Kannibhiran et al. (11) recently reported a similar finding in a survey of 487 patients. One hundred forty-three (29%) were DSA positive at transplant. The described features associated with ABMR included previous transplants (P<0.003) and the sum of all DSA scores (P<0.0001). Van Der Hooge et al. (31) reported on a placebo-controlled trial of rituximab as an induction agent for kidney transplant recipients. Two hundred eighty patients were examined (138 randomized to rituximab and 142 placebo). Overall, there was no difference in the graft rejection rates. However, when data for high-risk patients (repeat transplants and HLA sensitized) were analyzed, there was a significant reduction in rejection episodes for those who received rituximab (17.9% vs. 41.1%, P=0.039). The authors conclude that a single dose of rituximab given as an induction agent at transplant significantly reduces rejection rates in sensitized patients.

Alloreactive B cells can rapidly emerge in DSA-negative patients posttransplant (26, 28). Detecting these cells is an especially difficult problem as traditional markers for sensitization are not present (DSA) and assays for alloreactive B cells are just emerging (26, 28). However, rituximab can deplete these memory B cells with consistent prevention of ABMR episodes. Rituximab can also alter T-cell responses by reducing the antigen-presenting cell and cytokine production capabilities of B cells (32, 33).

Data from this abbreviated trial do have significant limitations in terms of making relevant conclusions. These include a possibility of type 1 statistical errors because of the low numbers of entered patients and random distribution of more patients with previous transplants to the IVIG+placebo group. However, clinically important trends were observed, most importantly, the prevention of ABMR episodes, TMA, and transplant glomerulopathy in the IVIG+rituximab group. In addition to assessment of DSA levels and crossmatch results at transplant, one should also assess sensitization history (especially repeat transplants) as risk for clandestinely sensitized B cells potentially mediating ABMR. One patient death from a Nocardia brain abscess is sobering, but unusual as rituximab is not associated with significant increased risk for infection or malignancy in sensitized transplant patients (34). Finally, this work is supportive of a role for rituximab as a desensitization agent because it appears to engender long-term effects on alloimmunity and alloreactive B cells that are likely beneficial to the allograft, and may be independent of effects on PRA levels.

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MATERIALS AND METHODS

Patients and Study Design

The study was designed as a multiple-center, phase I and II, exploratory study that used a blinded, placebo-controlled format. The study aimed to examine the safety and efficacy of human polyclonal IVIG 10%, when given at (2.0 g/kg [maximum 140 g/dose]×2) on days 1 and 30, +placebo (0.9% normal saline) (×1) versus IVIG (2.0 g/kg [maximum 140 g/dose]×2) on days 1 and 30, and +rituximab (1 g×1) administered on day 15 to reduce DSA to a level that was permissive for DD transplantation. Patients were randomized 1:1 by computer. The investigators were blinded to randomization and treatments. The study entered subjects actively listed on the UNOS list (18–65 years) who were (HS) defined as panel reactive HLA antibody (PRA) positive at greater than 50% with assessment of DSA and CMX values at time of transplant (19). Rates of transplantation were compared between the two groups as the primary end point. If acceptable crossmatches and DSA levels were seen, the patients proceeded to DD transplantation. An acceptable CMX in the context of desensitization is defined as a negative complement-dependent cytotoxicity, at least at a 1:2 dilution of sera. A negative flow cytometry crossmatch against donor T and B cells (FCMX) OR a positive T- and B-cell FCMX∼250 channel shifts (CS) or less (deemed an “acceptable” crossmatch) for T and B cells (negative: <100 mean channel shifts [MCS] for B cell and <50 MCS for T cell) (15, 16, 19). Transplant patients received an additional dose of IVIG at transplantation (within 10 days) and an additional dose of rituximab (1 g) or placebo at 6 months posttransplant. Patients who were desensitized and did not undergo transplantation within 6 months after desensitization completed the study. Criteria for acceptance of DD offers after desensitization and decision to proceed with transplantation as well as details of immunosuppression and posttransplantation management were previously described (15, 16, 19). Campath-1H was used as the induction agent in all study patients (24). All patients received immunosuppression with tacrolimus, mycophenolic acid, and prednisone, and all patients were monitored and prophylaxed for infectious complications as previously described (19, 23). Patients who experienced ABMR or AR were managed per center protocol as previously described (19). The study design is shown in Figure 1A.

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Study Assessments

Entered subjects were followed to determine the proportion who received a transplant within 6 months of study completion. This was the primary end point. We hypothesized that addition of rituximab to the IVIG desensitization protocol would increase rates of transplantation by exerting an additive effect on IVIG induced reduction in DSA levels. In addition, we examined multiple parameters including risk for ABMR, graft and patient survival, allograft function, infectious complications, and DSA levels at specific time points posttransplant. Implantation biopsies were performed in all transplant patients. In those who sustained a viable and functioning kidney allograft for 12 months, repeat study biopsies were performed. All subjects were evaluated on an intent-to-treat basis.

Assessments during therapy include routine laboratory tests; measurement of PRA, DSA, and DSA-relative intensity scale (RIS) levels; vital signs assessments with each infusion; electrocardiograms; and collection of data related to AE and SAE. All AEs and SAEs were recorded, graded, and reported to the Cedars-Sinai Medical Center Institutional Review Board (IRB), the study sponsor (Roche-Genentech), and FDA Medwatch. Safety stopping rules included assessment of infusion-related SAEs and occurrence of ABMR posttransplant in three or more transplant subjects.

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Study Oversight

This study was approved by the IRB at Cedars-Sinai Medical Center. The study was conducted in accordance with the Declaration of Helsinki, with the ethical guideline based on federal regulations and the common rule. Cedars-Sinai Medical Center also has a Federal Wide Assurance. The study was an investigator-initiated trial (NCT01178216, FDA IND#: 109067, S.C.J., MD, Principal Investigator). The study was designed, conducted, and evaluated solely by the investigators after approval and funding by Genentech-Roche Inc. The study was a phase I and II randomized double-blinded placebo controlled format with all investigators blinded to study drug administration. Data was maintained in a confidential manner until the study was terminated. In accordance with the study protocol, a data safety monitoring board was established to review safety concerns and report on any AEs or SAEs quarterly. In addition, safety-stopping points were included in the protocol. The study protocol and supporting documentation is available in the supplemental digital content submitted with the article. The data analysis and manuscript preparation was completed entirely by the investigators.

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Statistical Analysis

Statistical analysis was performed using the paired Student t test. Different parameters, including rates of transplantation by treatment group, patient and graft survival, mean serum creatinines (SCrs), primary or multiple transplants, acute rejection and ABMR episodes, and transplant by DSA status, were analyzed. Differences were considered significant at the two-sided 0.05 level. The relationship between DSA levels, DSA-RIS scores, graft loss, and patient and graft survival between the treatment groups were analyzed using chi-square methods.

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ACKNOWLEDGEMENTS

The authors thank the members of the Kidney Transplant and Transplant Immunotherapy Program, the Transplant Immunology Laboratory, the Renal Pathology Group, and HLA Laboratory at Cedars-Sinai Medical Center for their hard work and dedication to our patients.

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Keywords:

IVIG; Rituximab; Desensitization; Donor-specific HLA antibodies

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© 2014 by Lippincott Williams & Wilkins