Author + information
- Received December 26, 2018
- Revision received April 9, 2019
- Accepted April 11, 2019
- Published online July 1, 2019.
- Randall C. Starling, MD, MPHa@rcstarling,
- Brian Armstrong, MPHb,
- Nancy D. Bridges, MDc,
- Howard Eisen, MDd,
- Michael M. Givertz, MDe,
- Abdallah G. Kfoury, MDf,
- Jon Kobashigawa, MDg,
- David Ikle, PhDb,
- Yvonne Morrison, MSc,
- Sean Pinney, MDh,
- Josef Stehlik, MD, MPHi,
- Sudipta Tripathi, PhDe,
- Mohamed H. Sayegh, MDe,∗,
- Anil Chandraker, MDe,∗∗ (, )
- for the CTOT-11 Study Investigators
- aDepartment of Medicine, Cleveland Clinic Foundation, Cleveland, OhioDepartment of Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
- bRho Federal Systems Division, Chapel Hill, North CarolinaRho Federal Systems Division, Chapel Hill, North Carolina
- cNational Institute of Allergy and Infectious Diseases, Bethesda, MarylandNational Institute of Allergy and Infectious Diseases, Bethesda, Maryland
- dDepartment of Medicine, Drexel University College of Medicine, Philadelphia, PennsylvaniaDepartment of Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania
- eTransplantation Research Center, Renal Division, Brigham and Women’s Hospital, Boston, MassachusettsTransplantation Research Center, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts
- fDepartment of Medicine, Intermountain Medical Center, Murray, UtahDepartment of Medicine, Intermountain Medical Center, Murray, Utah
- gDepartment of Medicine, Cedars Sinai Medical Center, Los Angeles, CaliforniaDepartment of Medicine, Cedars Sinai Medical Center, Los Angeles, California
- hDepartment of Medicine, Mount Sinai School of Medicine, New York, New YorkDepartment of Medicine, Mount Sinai School of Medicine, New York, New York
- iDepartment of Medicine, University of Utah, Salt Lake City, UtahDepartment of Medicine, University of Utah, Salt Lake City, Utah
- ↵∗Address for correspondence:
Dr. Anil Chandraker, Transplantation Research Center, Renal Division, 221 Longwood Avenue, Brigham and Women’s Hospital, Boston, Massachusetts 02115.
Background The CTOT-11 (Prevention of Cardiac Allograft Vasculopathy Using Rituximab Therapy in Cardiac Transplantation [Clinical Trials in Organ Transplantation-11]) study was a randomized, placebo-controlled, multicenter, double-blinded clinical trial in nonsensitized primary heart transplant (HTX) recipients.
Objectives The study sought to determine whether B cell depletion therapy would attenuate the development of cardiac allograft vasculopathy.
Methods A total of 163 HTX recipients were randomized to rituximab 1,000 mg intravenous or placebo on days 0 and 12 post-transplant. Primary outcome was change in percent atheroma volume (PAV) from baseline to 1 year measured by intravascular ultrasound. Secondary outcomes included treated episodes of acute rejection, de novo anti-HLA antibodies (including donor-specific antibodies), and phenotypic differentiation of B cells.
Results There were no significant differences at study entry between the rituximab and placebo groups. Paired intravascular ultrasound measures were available at baseline and 1 year in 86 subjects (49 rituximab, 37 placebo). The mean ± SD change in PAV at 12 months was +6.8 ± 8.2% rituximab versus +1.9 ± 4.4% placebo (p = 0.0019). Mortality at 12 months was 3.4% rituximab versus 6.8% placebo (p = 0.47); there were no retransplants or post-transplant lymphoproliferative disorder. The rate of treated rejection was 24.7% rituximab versus 32.4% placebo (p = 0.28). Rituximab therapy effectively eliminated CD20+/CD19+ B cells followed by a gradual expansion of a CD19– cell population in the rituximab-treated group.
Conclusions A marked, unexpected increase in coronary artery PAV with rituximab was observed during the first year in HTX recipients. One-year mortality was not impacted; however, longer-term follow-up and mechanistic explanations are required. (Prevention of Cardiac Allograft Vasculopathy Using Rituximab [Rituxan] Therapy in Cardiac Transplantation; NCT01278745)
Cardiac allograft vasculopathy (CAV) is a serious limitation for heart transplant recipients; it is the second leading cause of death (after malignancy) at 3 years and beyond after a heart transplant (1). Unfortunately, CAV is resistant to traditional treatment modalities for coronary artery disease, leaving retransplantation as the only definitive treatment.
Although alloimmunity has been postulated to play a significant role in CAV, the pathogenesis is poorly understood. Animal models have demonstrated a link between circulating antibodies and chronic allograft rejection (2). Clinical research confirms the involvement of anti-HLA antibodies in accelerating CAV (3–5). A recent study by Loupy et al. (3) examined 40 explanted hearts and 402 endomyocardial biopsy samples from these hearts before graft loss. Their work demonstrated that 47.5% of explanted, failing allografts had undiagnosed antibody-mediated rejection and 40% unrecognized 4.5 ± 3.5 years earlier. Immune modulation targeting the humoral response might, therefore, play a role in preventing or slowing the progression of CAV.
Rituximab is a chimeric antibody against the B cell marker CD20. Kelishadi et al. (6) established a cynomolgus monkey model for heart transplantation; in that model, they demonstrated that rituximab was effective at depleting B cells, and that animals treated with rituximab had lower levels of anti-donor immunoglobulin G (IgG) antibodies and less severe CAV.
Currently, angiography is the recommended diagnostic test for detecting CAV in clinical practice (7). However, intravascular ultrasound (IVUS) of the coronary arteries has been shown to be more sensitive and more specific for diagnosing CAV (8). In a multisite study that analyzed heart transplant at post-transplant baseline and 5 years, subjects with IVUS-measured CAV progression during the first post-transplant year had a higher incidence of death, graft loss, and nonfatal major cardiac events over a 5-year period (9). The CTOT-05 (Clinical Trials in Organ Transplantation-5) study, an observational study of heart transplant, examined the usefulness of biomarkers in assessing post-transplant outcomes, including CAV, and demonstrated the feasibility of measuring PAV serially.
Therefore, we designed the CTOT-11 (Prevention of Cardiac Allograft Vasculopathy Using Rituximab Therapy in Cardiac Transplantation [Clinical Trials in Organ Transplantation-11]) study, hypothesizing that depletion of CD20-positive B cells at the time of transplantation would have a beneficial effect on the early development of CAV as assessed by IVUS.
Clinical trial design
The CTOT-11 study (NCT01278745) was a Phase II, prospective, multicenter, randomized, placebo-controlled clinical trial in which primary heart transplant recipients with a panel reactive antibody (PRA) <10% were randomized (1:1) to receive induction therapy with either anti-CD20 mAb (rituximab) or placebo, with both groups receiving conventional maintenance immunosuppression (tacrolimus or equivalent, mycophenolate mofetil or equivalent, and rapid steroid taper per local investigators’ discretion) (Table 1). The trial was approved by the Institutional Review Board at each study center, and the CTOT steering committee and the National Institute of Allergy and Infective Diseases/Division of Allergy, Immunology, and Transplantation clinical review committee reviewed and approved the trial. All subjects provided written informed consent.
Eligibility requirements included men and women at least 18 to 75 years of age who were candidates for a primary heart transplant (listed for heart transplant only), a PRA <10%, and a calculated glomerular filtration rate ≥40 ml/min using the Chronic Kidney Disease Epidemiology Collaboration equation. Other exclusion and inclusion criteria are listed in Table 2.
Study subjects were recruited while on the United Network of Organ Sharing waitlist from 23 participating centers. Randomization occurred early post-transplant once the recipient was considered hemodynamically stable.
Rituximab 1,000 mg (Genentech, Inc., South San Francisco, California) or placebo was administered in a double-blind fashion as a slow intravenous infusion through a dedicated line on day 0 (within 48 h post-transplant based on site investigator evaluation of subject hemodynamic stability) and day 12 (±2 days). Participants were premedicated using acetaminophen and loratadine or diphenhydramine. Methylprednisolone was administered on day 0 (per center pre-transplant standard of care) and day 12 (100 mg intravenous, or its equivalent). Rituximab or placebo infusion was discontinued for severe or life-threatening reactions, hypersensitivity reactions, or serious or life-threatening cardiac arrhythmias. Participants who prematurely discontinued treatment remained in the study unless they elected to withdraw consent were “lost to follow-up” or died.
Endomyocardial biopsies were performed routinely as per site-specific standard of care. The original hematoxylin and eosin stained slides from biopsies at week 2, week 4, month 3, month 6, and any treated rejection were submitted to a core laboratory for histologic interpretation. Details of the diagnosis and treatment of rejection are provided in Figure 1. IVUS imaging of the target coronary artery segment was performed at baseline (4 to 8 weeks post-transplant) and at month 12. Each site investigator determined the safety to perform IVUS based on renal function and suitability for heparin required for the IVUS procedure. IVUS images were reviewed by the core laboratory and the patient was only considered suitable for the primary endpoint analysis if both the baseline and 1 year follow-up image quality was suitable.
The primary endpoint was the nominal change from baseline to 1 year in percent atheroma volume (PAV) measured by IVUS in a target coronary artery segment. Secondary clinical endpoints assessed at 6 and 12 months included death, retransplantation or relisting for transplantation, incidence of biopsy-proven acute rejection including episodes of rejection associated with hemodynamic compromise, development of angiographically evident CAV at 1 year, serious infections requiring intravenous antimicrobial therapy, incidence of post-transplant lymphoproliferative disorder, and safety and tolerability of rituximab. Secondary mechanistic endpoints included the development of post-transplant anti-HLA antibodies, including donor-specific antibody (DSA) (Anti-HLA Ab; Luminex, Austin, Texas), complement binding antibody (Luminex), and B cell depletion and recovery profile (lineage-specific markers of peripheral B cells).
Immunophenotyping of B cell subsets was performed using a BD Canto II flow cytometer (BD Biosciences, San Jose, California) on a total of 21 subjects (9 placebo and 12 rituximab-treated patients) pre-treatment, 1 month post-treatment, and 12 months post-treatment.
Characterization of B cell phenotyping was performed by surface staining with anti-CD19-FITC, CD20-PE, CD38-PE/Cy7, CD27-APC, CD24-APC/Cy7, IgM-BV421, and IgD-BV510. Cell viability was determined using 7-aminoactinomycin D. Nonspecific binding was blocked using Human TruStain FcX (BioLegend, San Diego, California). All antibodies were purchased from BioLegend. All staining steps were performed in phosphate-buffered saline containing 2% fetal bovine serum at 4°C for 30 min. The cells were washed in phosphate-buffered saline + 2% fetal bovine serum after antibody labeling and acquired on a BD Canto II flow cytometer. Data analysis was performed using FlowJo software (Tree Star, Portland, Oregon).
The primary endpoint analysis was conducted on PAV measurements from subjects who received at least 1 rituximab or placebo infusion (intention-to-treat sample) and had evaluable, paired IVUS images. The 12-month change from baseline PAV of all allografts surviving to month 12 post-transplant with evaluable studies was analyzed in a linear model that included a dichotomous treatment term and a covariate representing the baseline PAV values. In a sensitivity analysis, any baseline clinical characteristics that were significantly different between the analysis groups were added to the linear model as covariates.
Analyses of secondary endpoints were conducted on nonmissing data from the intention-to-treat sample. One of the secondary objectives was to test for treatment differences in clinical endpoints that are either directly reflective of graft failure (e.g., death or acute rejection) or are reflective of underlying mechanistic processes (e.g., cellular rejection). Secondary categorical and continuous endpoints were compared between groups at 12 months using chi-square tests or t tests, respectively. Time-to-event endpoints were compared using Kaplan-Meier plots and log-rank tests. B cell fractions were compared between groups at baseline and 1 and 12 months post-randomization using a linear mixed model to account for repeated measures with p values from Tukey’s honestly significant difference test for multiple comparisons between means. Statistical analyses were performed using SAS software (SAS Institute, Cary, North Carolina) and GraphPad Prism (GraphPad Software, San Diego, California).
Sample size and power calculation
The original sample size requirement of 400 enrolled subjects was based on detection of a hypothesized absolute reduction of 1.5% in PAV in treated subjects compared with control with a standard deviation of 5%, which was derived from an unpublished pilot study. Subsequently, the completed CTOT-05 study, which was performed at many of the same clinical sites as the CTOT-11 study, found the standard deviation of PAV by IVUS at 12 months to be 4.3% (10). Based on this revised estimate, allowing for a 15% dropout rate, and keeping all other parameters of the sample size calculation the same (power 80%, difference 1.5%, 2-tailed test at the 0.05 level), the required sample size was estimated to be 150 transplanted subjects per treatment group with an enrollment period of 48 months.
The CTOT-11 study enrolled a total of 362 subjects at 23 participating centers between July 2011 and August 2014, of whom 241 had been transplanted at the time the study was halted for inability to accrue to target during the funding period despite extending the original accrual and funding periods by 12 months. Although enrollment of eligible transplant candidates proceeded as anticipated, the rate at which subjects were transplanted was much slower than anticipated during study planning. Of the 362 subjects enrolled, 241 underwent heart transplant and 163 completed randomization (Figure 2). The reasons for study discontinuation before transplant included: not transplanted before study conclusion (n = 62), became ineligible while on waitlist (n = 42), death pre-transplant (n = 7), withdrew consent (n = 5), and other (n = 5). The reasons for study discontinuation post-transplant but before randomization included failure to meet randomization eligibility criteria (n = 61), local investigator assessment that subjects were not acceptable candidates for randomization during the 48-h post-transplant window requirement (n = 9), and other (n = 8). Of the 163 randomized, 89 were randomized to rituximab and 74 to placebo, and 90% were administered the full dose of the investigational treatment or matching placebo. Baseline characteristics of all study subjects are summarized in Online Table 1. Table 3 contains baseline characteristics for study subjects included in the primary endpoint analysis rituximab (n = 49) and placebo (n = 37).
The primary outcome, change in PAV from baseline to 12 months measured by IVUS, was assessed in 86 subjects (49 who received rituximab and 37 who received placebo) who had evaluable, paired IVUS exams. The estimated mean treatment effect was a 4.79% increase (95% confidence interval: 1.83% to 7.75%) in PAV observed in the rituximab group compared with the placebo group (p = 0.0019), when adjusted for baseline PAV (Figure 3). The clinical characteristics described in Table 3 were compared between these 2 analysis groups and none were significantly different between the groups. The complete IVUS parameters analyzed are shown in Table 4. These additional IVUS analyses demonstrate trends similar to that of the primary endpoint reflecting more vascular wall remodeling with rituximab versus placebo.
Secondary outcomes are summarized in Table 5. None were significantly different between groups at the 0.05 level.
Mortality in the 2 study arms was similar, with 3 (3.4%) deaths in the rituximab arm and 5 (6.8%) deaths in the placebo arm at 12 months after transplant (p = 0.47) Survival curves through 450 days were similar between the groups (p = 0.35) (Figure 4A). Two subjects in the rituximab arm died of sepsis and 1 died of CAV, while 2 subjects in the placebo arm died of acute rejection, 1 of sudden cardiac death, 1 of multiorgan system failure, and 1 of cancer (adenocarcinoma). None of the subjects were retransplanted or relisted for transplantation in the 12 months after the index transplant.
Acute graft rejection
The rate of treated rejection within 12 months was 24.7% in the rituximab group and 32.4% in the placebo group (p = 0.28), with no detectable difference in freedom from treated rejection (p = 0.35) or in the number of treated rejections (Figure 4B). The rate of C4d positivity on locally read biopsies was similar between the groups (12.4% and 13.5%; p = 0.83). Acute cellular rejection determinations were made centrally by the pathology core lab; the rate of moderate or severe (International Society for Heart and Lung Transplantation grade ≥2R) rejection was 15.1% in the rituximab group and 21.4% in the control group within 12 months (p = 0.31), with freedom from International Society for Heart and Lung Transplantation grade ≥2R rejection similar between the 2 groups (p = 0.49) (Figure 4C).
Post-transplant anti-HLA antibodies
A similar proportion of subjects in the rituximab group and the placebo group had detectable anti-HLA antibodies at 12 months after transplant: 35% versus 28%, (p = 0.35) (Table 5). Compared with placebo-treated subjects, there was a trend for rituximab treated subjects to less likely develop Class I anti-HLA antibody (p = 0.07) and more likely develop Class II anti-HLA antibody (p = 0.10). DSAs were present in approximately 12% of subjects at 12 months. Approximately one-third of subjects who were allosensitized at 12 months had donor specific antibody, while the remaining two-thirds had alloantibody not directed against the HLA antigens of the donor. The Class I versus Class II DSA profile was similar to that of the larger allosensitized group.
Owing to the observed relatively low MFI values, dilutional studies and C1q testing would provide minimal incremental information and these studies were not performed.
Nine of 80 rituximab subjects and 3 of 65 placebo subjects had Class II DSA.
The specificities identified for rituximab subjects were: DR4 (1 of 9), DR15 (2 of 9), DR51 (1 of 9), DR52 (2 of 9), DR53 (1 of 9), DQ4 (2 of 9), DQ6 (2 of 9), and DQ7 (1 of 9). One rituximab subject had 3 specificities identified (DR53, DQ6, and DQ7) and a different rituximab subject had 2 specificities identified (DR52 and DQ6). The specificities identified for the placebo subjects were: DR13 (1 of 3), DQ2 (1 of 3), and DQ8 (1 of 3).
A left ventricular assist device was present in 47.2% of the Rituximab group and 39.2% of the controls. Online Table 2 shows no difference in DSA development or change in PAV between subjects who were on an left ventricular assist device at transplant and those who were not.
Phenotypic differentiation of B cells
Multiple studies have demonstrated that treatment with rituximab effectively depletes circulating CD20+ and CD19+ cell populations temporarily, but less is known about how reconstitution of the B cells occurs following treatment (11). The percentage of circulating CD20+ B cells present pre-treatment was similar in both groups, but as expected these cells were selectively depleted 4 weeks post-treatment in the rituximab compared with the placebo group (p < 0.001) (Figure 5A). By 12 months post-treatment, the proportion of CD20- or CD19-expressing B cells in the rituximab treated group was again similar to the placebo group (Figure 5B).
Interestingly while the CD19– population was relatively flat in the placebo-treated group, the same population increased significantly at month 12 in the rituximab-treated group compared with baseline and month 1 (Figure 5C). However, we were unable to better characterize this increased CD19– population from surface staining for CD38, CD27, CD24, IgM, or IgD (Figure 6). In particular we did not see an increase in the CD19–IgD+CD38+ subset in the rituximab group from pretreatment to month 12 (Figure 5D).
Potential contributors to post-transplant vasculopathy
We collected immunosuppressive medications, antimicrobial medications, statins, and inotropic agents. Unfortunately, we do not have a reliable way to ascertain use of insulin or oral hypoglycemic agents. Lipid panels were collected at months 6 and 12. Blood pressure was collected at every scheduled visit during the first year. Per protocol we recommended the use of a statin drug in all patients. No differences in lipids or blood pressure values in the rituximab and placebo groups were observed.
All 163 randomized subjects received calcineurin inhibitor therapy. Eight subjects (5 rituximab, 3 placebo) received a mammalian target of rapamycin (mTOR) inhibitor (sirolimus or everolimus); all 8 of these subjects received their mTOR inhibitor subsequently after having received calcineurin inhibitor. As only 8 patients were converted to mTOR inhibitor we are unable to perform further statistical analysis. Eight subjects were treated for a cytomegalovirus infection: 4 of 89 (4.5%) in the rituximab group and 4 of 74 (5.4%) in the placebo group; cytomegalovirus was hence evenly distributed in both groups.
Online Table 3 contains final crossmatch results. No differences between the 2 treatment groups was observed. Many centers utilize “virtual crossmatches”; hence, we did not have complete prospective crossmatch information. However, as noted a minority of subjects developed DSA.
Antibody mediated rejection may occur in the absence of complement on biopsy and with non-HLA antibody; hence negative DSA. We did not observe a preponderance of graft failure and or graft dysfunction in either group. We captured ejection fraction data serially which was similar in both groups. Hemodynamic data (mean right atrial, right ventricle, pulmonary artery, mean pulmonary capillary wedge pressure) and cardiac output or index was collected serially. No differences between rituximab and placebo group were observed.
We analyzed the IVUS primary endpoint for the entire cohort based upon presence or absence of Class I and Class II DSA. No association was observed with any DSA (n = 10: PAV 1.90 ± 5.91) versus no DSA (n = 71: 5.20 ± 7.52) (p = 0.184 adjusted for baseline PAV via linear model).
Baseline IVUS was not performed in 19 subjects: 6 clinical decision based on renal function, 8 clinical decision nonrenal, 3 patient refusal, and 2 equipment malfunction.
We hypothesized that rituximab would reduce the development of CAV. Surprisingly, rituximab administration at the time of transplant was associated with a striking increase in CAV at 1 year after transplant (Central Illustration).
We chose an IVUS measure of CAV because it is a sensitive and reproducible modality to assay subtle changes in the vascular wall. The observed magnitude of change in PAV over 1 year far exceeds what is reported in nontransplant populations (12). This observation suggests that a robust immune mechanism plays an important role in the early development of CAV.
Rituximab has been used in cardiac transplant for desensitization, treatment of antibody-mediated rejection, and as induction therapy in subjects with elevated PRAs. We tested the use of rituximab in a population without sensitization to determine if the protective effect observed in nonhuman primates would be reproduced in humans. The impact in human heart transplant recipients was unanticipated, suggesting that abrogation of intact B cell function by a CD20 receptor antagonist may be harmful.
While at first surprising, especially given the previous primate studies, a previous study in kidney transplant recipients using rituximab as induction therapy was prematurely halted due to a high rate of acute rejection in rituximab treated recipients (13). It has also become increasingly apparent that some B cells may have a regulatory function with spontaneously tolerant transplant recipients being characterized by a specific B cell population (14). Other studies have found that a CD19+CD24hiCD38+ transitional B cell phenotype has regulatory properties and that its elimination precipitates rejection, even in the absence of a detectable increase in alloantibodies (15,16).
In this study, following rituximab treatment, there is effective depletion of circulating CD20+ B cells and possibly antibody secreting CD19– transitional B cells from the bone marrow fill the void before the repopulation of naïve B cells (17–19).
Recent studies have shown that CD19– B cells appear to be resistant to depletion with anti CD20 and demonstrated expansion of bone marrow CD19– populations after treatment with rituximab (20).
While expression of IgD+CD38+ correlates with transitional B cell development, which occurs before differentiation into mature circulating naïve B cells, we did not see an expansion of a population of antibody secreting CD19–IgD+CD38+ cells that might be associated with a more detrimental effect of the progression of CAV in cardiac transplant recipients (21–23).
Our results differ markedly compared with what was observed in primates (6). The report by Kelishadi et al. (6) examined preemptive CD20+ B cell depletion in cyclosporine-treated monkeys sacrificed at day 90 revealing an attenuation in graft coronary disease. Extrapolation from the primate to humans should be viewed with caution. Rituximab is used for the treatment of antibody mediated rejection and post-transplant lymphoproliferative disorders in heart transplant recipients. Based on our findings we would not discourage the use of rituximab for these indications. Our findings apply to a very specific subset of de novo transplant recipients that are not pre-sensitized and received rituximab as “induction” therapy with the goal to reduce coronary artery vasculopathy. There was no evidence of an increased risk of rejection, infection, or death (Table 5, Online Table 4).
In summary, the results of the CTOT-11 study indicate that rituximab use as an induction agent should be avoided in nonsensitized heart transplant recipients. The safety and efficacy of rituximab in other subject populations has not been analyzed carefully in randomized controlled clinical trials. The CTOT-11 study investigators are currently completing an National Institutes of Health–funded analysis of 4-year follow-up in this study population (CTOT-23 study), focusing on major adverse cardiac events, to determine the clinical impact of the striking increase in CAV observed 1 year after the administration of rituximab.
Despite the fact that the CTOT-11 study failed to reach target enrollment, sensitivity analyses confirm that the intention-to-treat and as-treated populations are similar. The large difference in treatment effect on the primary endpoint is highly significant (p = 0.0019). IVUS is a challenging endpoint based on the technical rigor required. Although 53% (86 of 163) had evaluable IVUS for the primary endpoint in the CTOT-11 study, historically in multicenter heart transplant clinical trials the percent of patients evaluable has been as low as 26% to 33%. The clinical significance of the coronary artery intimal hyperplastic response is unknown and mechanistically the explanation remains speculative. Although logically it is prudent to avoid use of rituximab as induction in nonsensitized cardiac transplant recipients, the implications of this observation in other settings and in noncardiac organ transplant recipients is unknown.
We tested the use of rituximab at the time of transplantation in a population without allosensitization to determine if the protective effect observed in nonhuman primates would be reproduced in humans. Unexpected, the impact in human heart transplant recipients appears to accelerate vascular wall pathologic changes, suggesting mechanistically that abrogation of intact B cell function by a CD20 receptor antagonist is deleterious.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: When administered for induction immunosuppression, rituximab is associated with accelerated coronary vasculopathy during the first year after cardiac transplantation but does not increase rejection, infection, or mortality.
TRANSLATIONAL OUTLOOK: Future studies should investigate the mechanisms by which rituximab accelerates coronary vasculopathy after cardiac transplantation and assess whether clinical adverse events are more frequent among patients treated with rituximab.
The authors acknowledge the kind support of Genentech (a member of the Roche Group) in providing (Rituxan) for these studies. The authors wish to thank the investigators, study coordinators, research pharmacists, and laboratory technicians of CTOT-11; Cleveland Clinic: Barbara Gus, Karen Keslar, Bill Magyar, John Petrich, Randall C. Starling, W. H. Wilson Tang; Brigham and Women’s Hospital: Kimberly Brooks, Michael Givertz, Charles Kelly, Katie Klein; Massachusetts General Hospital: Kerry Crisalli, Sandra DeBronkart, Joren Madsen, Marc Semigran, John Vetrano; University of California San Francisco: Teresa DeMarco, Scott Fields, Carol Maguire; Northwestern University: Robert Gordon, Allen Anderson, Jane Regalado, Anna Warzecha; University of Pennsylvania: Lee Goldberg, Caroline Olt, Kenneth Rockwell; University of Wisconsin: Ashley Harris, Maryl Johnson, Susan Johnston, Chris Roginski; Mount Sinai School of Medicine: Rashid Ahmed, Ivy Cohen, Denise Peace, Sean Pinney, Tina Yao; The Methodist Hospital: Gloria Araujo, Arvind Bhimaraj, Eunice Karanga, Varsha Patel; University of California Los Angeles: Julie Chait, Mario Deng, Gregg Fonarow, Christina Shin; Medical City Dallas Hospital: Charles Gibbs, Judson Hunt, Melissa Johnson, Tina Worley; University of Utah: Jeff Gibbs, John Kirk, Winter Redd, Josef Stehlik; Intermountain Medical Center: Julia Bryan, Anna French, A.G. Kfoury, Kristin Konery; University of Maryland: Erika Feller, Myounghee Lee, Richard Pierson, Cindi Young; Medical University of South Carolina: Theodora Hollifield, Kimberley Porter, Mariann Schulz, Adrian VanBakel; Stanford University: Kiran Khush, Helen Luikart, Son Nguyen, Michael Pham; Tufts Medical Center: David DeNofrio, Ryan O’Kelly; Cedars Sinai Medical Center: Lucilla Garcia, Jon Kobashigawa, Sean Sana, Brandy Starks, Maria Thottam, Annie Yi; Minneapolis Heart Institute: Barry Cabuay, Rachel Olson, Larry Tucker, Laura Uppgaard; Drexel University College of Medicine: Howard Eisen, Denise Lai, Colleen Poisker; University of Minnesota: Klaudija Dragicevic, Harrison Kelner, Darlette Luke, Jennifer Nelson, Ganesh Raveendran; Allegheny General Hospital: Nick Kleissas, Srinivas Murali, Kenneth Rayl, Sarah Sherry. Rho: Michele Cosgrove (data manager).
↵∗ Drs. Sayegh and Chandraker contributed equally to this paper.
This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number U01-AI063623. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Pinney has received consulting fees from Abbott, CareDx and Medtronic; has received speaking fees from CareDx; and has served on the Medical Advisory Board for and received consultation fees from Procyrion. Dr Stehlik has served as a consultant to Medtronic and Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Kelly H. Schlendorf, MD, MHS, served as Guest Associate Editor for this paper.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Abbreviations and Acronyms
- cardiac allograft vasculopathy
- donor-specific antibody
- intravascular ultrasound
- mammalian target of rapamycin
- percent atheroma volume
- panel reactive antibody
- Received December 26, 2018.
- Revision received April 9, 2019.
- Accepted April 11, 2019.
- 2019 American College of Cardiology Foundation
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