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Bortezomib in Highly Sensitized Patients Awaiting Heart Transplantation - A Potentially Sensitive ID Issue?


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Stephanie Pouch
The Ohio State University
Columbus, OH, USA
Stephanie.Pouch@osumc.edu



Sensitization to human leukocyte antigens, which occurs through blood transfusions, previous organ transplantation, pregnancy, prior cardiac surgery with homografts, and the presence of ventricular assist devices, has historically limited access to heart transplantation [1]. However, the percentage of patients with high panel reactive antibody (PRA) listed for heart transplantation has increased over the past decade [2], and intravenous immunoglobulin, plasmapheresis, and rituximab have been shown to decrease allosensitization by reducing circulating antibodies. More recently, bortezomib has shown promise as a novel treatment strategy for antibody-mediated rejection as well as pre-transplant desensitization [1, 3].

Bortezomib, the first-in-class 26S proteasome inhibitor, is currently FDA approved for the treatment of multiple myeloma and relapsed mantle cell lymphoma. Proteasome inhibition reduces nuclear factor-kappa B activity and down-regulates peptide loading in class I major histocompatibility complex molecules, though its major effect is cell cycle arrest, resulting in plasma cell apoptosis and decreased antibody production [4-5]. As bortezomib continues to be evaluated further as a treatment strategy for highly sensitized patients awaiting heart transplantation, the question of the transplant ID provider is how this immunomodulation will impact the patient's risk for infection.

Earlier work evaluating the efficacy of bortezomib in patients with relapsed multiple myeloma showed a 13% incidence of herpes zoster (HZ) among those treated with bortezomib compared to a 5% HZ incidence in those treated with dexamethasone (p<0.001) [6]. Subsequent studies have reported an incidence of HZ ranging from 10-22% among patients with multiple myeloma receiving bortezomib, and antiviral prophylaxis is recommended in this population [7-8]. Whether this translates to highly sensitized patients awaiting heart transplantation remains uncertain; the two patient populations certainly differ in terms of underlying immunodysregulation, and bortezomib is typically provided in ongoing 3-week cycles for multiple myeloma. In a study of 7 patients with elevated anti-HLA antibodies awaiting heart transplantation, desensitization with bortezomib and plasmapheresis resulted in decreased cPRA, but appears to have been associated with an increased risk for infection following therapy. Two of 7 patients in the cohort died of sepsis, one while awaiting transplant and another in the context of post-transplant graft failure requiring augmented immunosuppression. Four line infections, 3 urinary tract infections, and a case of C difficile colitis also occurred among the patients in this cohort, but there were no reported episodes of viral infection [1]. Infectious complications of bortezomib use in pediatric cardiac transplant recipients with antibody-mediated rejection have included cellulitis and Klebsiella pneumoniae bacteremia [9].

Large multicenter studies assessing the role of bortezomib in highly sensitized patients awaiting heart transplantation are required to better evaluate the potential infectious risks associated with its use. While small reports do suggest an increased risk of infection, particularly of bacterial etiology, a causative relationship has yet to be described, and it is unclear whether the infections reported to date were related to low immunoglobulin levels, intercurrent illness, or other host factors. As with many issues in clinical transplantation, we are left with more questions than answers. One thing is clear, though - as we work to develop new strategies aimed at improving patient outcomes, we're all in it together. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


References:

  1. Patel J, Everly M, Chang D, et al. Reduction of alloantibodies via proteosome inhibition in cardiac transplantation. J Heart Lung Transplant 2011; 30: 1320-6.
  2. Lund LH, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-first official adult heart transplant report - 2014; focus theme: retransplantation. J Heart Lung Transplant 2014; 33: 996-1008.
  3. Everly MJ. A summary of bortezomib use in transplantation across 29 centers. Clin Transpl 2009: 323-37.
  4. Everly MJ, Everly JJ, Terasaki PI. Role of proteasome inhibition in sensitized transplant candidates. Chin Med J 2011; 124(5): 771-4.
  5. Perry DK, Burns JM, Pollinger HS, et al. Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am J Transplant 2009; 9: 201-9.
  6. Richardson PG, Sonneveid P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352(24): 2487-98.
  7. Yi Y, Chung J, Song M, et al. The risk factors for herpes zoster in bortezomib treatment in patients with multiple myeloma. Korean J Hematol 2010; 45(3): 188-92.
  8. Nucci N, Anaissie E. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis 2009; 49(8): 1211-25.
  9. Zinn MD, L'Ecuyer TJ, Fagoaga OR, et al. Bortezomib use in a pediatric cardiac transplant center. Pediatr Transplantation 2014; 18: 469-76.




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