Author + information
- Chetan B. Patel, MD∗ ( and )
- Christopher L. Holley, MD, PhD
- Cardiac Transplant Program, Division of Cardiology, Duke University Medical Center, Durham, North CarolinaCardiac Transplant Program, Division of Cardiology, Duke University Medical Center, Durham, North Carolina
- ↵∗Address for correspondence:
Dr. Chetan B. Patel, DUMC 3034, Durham North Carolina 27710.
Although the median survival after heart transplantation is now >13 years, one of the limiting factors to even longer survival is progressive luminal narrowing of the allograft’s coronary arteries. This disease, known as cardiac allograft vasculopathy (CAV), remains a vexing problem in cardiac transplantation and a major cause of mortality 3 to 10 years after transplantation (1). Mechanisms implicated in this progressive disease include alloimmunity, with evidence of increased risk for CAV in transplantation recipients who develop antibodies against donor human leucocyte antigen (HLAs). Similarly, episodes of antibody-mediated rejection (AMR), which are often mediated through anti-HLA antibodies, appear to increase the incidence of CAV (1). Other risk factors for the development of CAV include acute cellular rejection episodes and the development of transplant-associated viral illnesses. In total, these observations suggest that strategies to mitigate CAV might include additional immune modulation, especially targeting B cells to prevent alloantibody production (2).
In this issue of the Journal, the CTOT-11 (Clinical Trials in Organ Transplantation-11) investigators (3) present the results of a multicenter, randomized, placebo-controlled trial of early B-cell depletion therapy to test whether this strategy would attenuate the development of CAV. The primary strategy for B-cell depletion in this study was the use of rituximab, a well-established antibody therapy against CD-20+ B cells. In total, 163 heart transplantation recipients were randomized to rituximab 1,000 mg intravenously or placebo on days 0 and 12 post-transplantation as a modified induction strategy to replace other agents such as basiliximab (an interleukin-2 receptor inhibitor) or anti-thymocyte globulin. Primary outcome was change in the percent atheroma volume (PAV) from baseline to 1 year as measured by intravascular ultrasound, a common method to assess subclinical CAV. Secondary outcomes included treated episodes of acute rejection, development of de novo anti-HLA antibodies (including donor specific antibodies), and phenotypic differentiation of B cells. Using this strategy, the mean change in PAV at 12 months was +6.8 ± 8.2% rituximab versus +1.9 ± 4.4% placebo (p = 0.0019), which suggested that this approach did not reduce CAV progression but instead accelerated the process.
One premise for using rituximab as an atypical induction therapy in heart transplantation was based on a primate model that showed that rituximab induction therapy reduced coronary atheroma volume at 90-days post-transplantation. However, in this short-term animal model, a full regimen of standard immunosuppression therapies for human heart transplantation were not used, with the only maintenance immunosuppression being the calcineurin inhibitor cyclosporine. In modern human heart transplantation, combination therapy with a calcineurin inhibitor, an antimetabolite (typically mycophenolate), and glucocorticoids is used throughout most of the first year post-transplantation. Because the primate model was effectively a comparison of calcineurin inhibitor monotherapy versus calcineurin inhibitor plus rituximab induction, the observed reduction in rejection, improved survival, and CAV with the addition of a second agent should therefore be an expected finding. In contrast, standard human immunosuppression already inhibits multiple areas of T-cell activation and subsequent interleukin production (which can promote B-cell proliferation), such that the addition of rituximab induction should not be expected to have the same impact.
Overall, the complexity of the human immune system is illuminated by this ambitious trial. Not only do the results demonstrate the interplay between cell- and antibody-mediated rejection in human transplantation, there are signals that show the importance of B-cell regulation in the development of tolerance. The increase in CD 19− cells by 12 months and the persistently higher CD19-IgD+CD38+ cells throughout the treatment course may provide surrogate markers for B-cell dysregulation created by the early CD20+ B cell depletion. Other unmeasured effector cells may have also proliferated, leading to early CAV, a process not typically seen within 1 year of transplantation. Because there was limited evidence of increased rejection or development of donor-specific antibodies (other biomarkers for CAV), we can surmise that other immune mechanisms were also involved.
Because rituximab induction therapy seems to accelerate CAV, a better strategy moving forward might be to focus on long-term immune suppression. For example, long-term treatment with rituximab, perhaps after steroid weaning, may have resulted in a different result with chronic B-cell suppression and attenuation of CAV. Other studies with newer immunosuppressants are also underway, including a protocol that adds anti−interleukin-6 therapy (tocilizumab) to standard immunosuppression. In this protocol, tocilizumab will be delivered as an infusion every 4 weeks, for a total of 20 months, to limit inflammation, and CAV will be measured as a secondary endpoint.
In summary, the CTOT-11 study clearly demonstrates that rituximab should not be considered effective induction therapy in heart transplantation and is not an adequate means of CAV prevention. Rituximab continues to have a role in desensitization protocols to reduce pre-transplantation anti-HLA antibodies and in the treatment of AMR to reduce post-transplantation donor-specific antibodies. The CTOT-11 study highlights our rudimentary understanding of the immune response to a transplanted organ, and raises even more questions about when and how to prevent CAV. The investigators should be commended for reporting these important negative results as the transplantation community continues its charge to understand and combat this important adversary that limits even better outcomes with heart transplantation.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2019 American College of Cardiology Foundation
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- for the CTOT-11 Study Investigators