Does bortezomib influence pre-transplant desensitization therapy or benefit post-heart transplant outcomes for highly sensitized patients?

BACKGROUND: The use of bortezomib which is a proteasome inhibitor has been demonstrated to be efficacious in small number of patients as a desensitization strategy in heart transplant. We reviewed our single center's experience using Bortezomib along with plasmapheresis as desensitization therapy for highly sensitized patients to assess pre- and post-transplant outcomes. METHOD: We assessed 43 highly sensitized patients awaiting HTx (defined as cPRA > 50%) between 2010 and 2021 who underwent desensitization therapy with bortezomib. Only those patients who subsequently underwent HTx were included in this study. Enrolled patients received up to four doses of bortezomib (1.3 mg/m2 ) over 2 weeks in conjunction with plasmapheresis. The efficacy of PP/BTZ was assessed by comparing the calculated panel reactive antibodies to HLA class I or class II antigens. Post-transplant outcomes including overall survival and incidence of rejection were compared to those of non-sensitized patients (PRA < 10%, n = 649) from the same center. RESULTS: The average cPRA prior to PP/BTZ was 94.5%. Post-PP/BTZ there was no statistically significant decline in mean cPRA, class I cPRA, or class II cPRA, though the average percentage decrease in class I cPRA (8.7 ± 17.0%) was higher than the change in class II cPRA (4.4 ± 13.3%). Resulted were also replicated with C1q-binding antibodies showing more effect on I class compared to class II (15.0 ± 37.4% vs. 6.8 ± 33.6%) as well as with 1:8 dilutional assay (14.0 ± 23.0% vs. 9.1 ± 34.9%). Additionally, PP/BTZ treated patients and the control group of non-sensitized patients had similar overall 1 year survival (95.4 vs. 92.5%) but patients with PP/BTZ had increased incidence of AMR (79.1% vs. 97.1%, p = < .001), any treated rejection (62.8% vs. 86.7%, p = < .001) and de novo DSA development (81.4% vs. 92.5%, p = .007). Major side effects of PP/BTZ included thrombocytopenia (42%), infection requiring antibiotics (28%), and neuropathy (12%). CONCLUSION: The use of bortezomib in highly sensitized patients does not significantly lower circulating antibodies prior to heart transplantation. However, its use may improve the chances of obtaining an immuno-compatible donor heart and contribute to acceptable post-transplant outcomes.

Heart Transplant Immunosuppression Strategies at Cedars-Sinai Medical Center.

Heart transplant is the optimal treatment for selected patients with end-stage heart failure. Immunosuppression after heart transplantation has significantly reduced the incidence of rejection and improved patient outcomes with the routine use of calcineurin inhibitors. Antimetabolites and proliferation signal inhibitors add to the improvement in patient outcomes as well. The goal of induction therapy is to provide intense immunosuppression when the risk of allograft rejection is highest. Most maintenance immunosuppressive protocols employ a 3-drug regimen consisting of a calcineurin inhibitor, an antimetabolite agent and glucocorticoids. The management of rejection proceeds in a stepwise fashion based on the severity of rejection detected on biopsy and the patient's clinical presentation. This review will cover induction, maintenance, rejection therapy and some special considerations including sensitization, renal sparing protocol, and corticosteroid weaning. It will end in consideration of potential future directions in immunosuppressive strategies to promote patient and graft survival.

Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients.

Allosensitization represents a major barrier to heart transplantation (HTx). We assessed the efficacy and safety of complement inhibition at transplant in highly sensitized heart transplant recipients. We performed a single-center, single-arm, open-label trial (NCT02013037). Patients with panel reactive antibodies (PRA) ≥70% and pre-formed donor-specific antibodies (DSA) were eligible. In addition to standard of care, patients received nine infusions of eculizumab during the first 2 months posttransplant. The primary composite endpoint was antibody-mediated rejection (AMR) ≥pAMR2 and/or left ventricular dysfunction during the first year. Secondary endpoints included hemodynamic compromise, allograft rejection, and patient survival. Twenty patients were included. Median cPRA and mean fluorescence intensity of immunodominant DSA were 95% (90%-97%) and 6250 (5000-10 000), respectively. Retrospective B cell and T cell flow crossmatches were positive in 14 and 11 patients, respectively. The primary endpoint occurred in four patients (20%). Survival at 1 year was 90% with no deaths resulting from AMR. In a prespecified analysis comparing treated patients to matched control patients, we observed a dramatic reduction in the risk of biopsy-proven AMR in patients treated with eculizumab (HR = 0.36, 95% CI = 0.14-0.95, p = .032). Our findings support the prophylactic use of complement inhibition for heart transplantation at high immunological risk. ClinincalTrials.gov, NCT02013037.

Extracorporeal Membrane Oxygenation in a 29-Year-Old Man with Pneumocystis jirovecii Respiratory Failure and AIDS.

The use of extracorporeal membrane oxygenation (ECMO) in patients who have acute respiratory distress syndrome has been generally beneficial. However, because of various concerns, ECMO has rarely been used in patients who have human immunodeficiency virus infection with or without acquired immune deficiency syndrome. We report our successful use of venovenous ECMO in a 29-year-old man who presented with severe respiratory distress secondary to Pneumocystis jirovecii pneumonia associated with undiagnosed infection with the human immunodeficiency virus and acquired immune deficiency syndrome. After highly active antiretroviral therapy was begun, acute immune reconstitution inflammatory syndrome developed. The patient's respiratory condition deteriorated rapidly; he was placed on venovenous ECMO for 19 days and remained intubated thereafter. After a 65-day hospital stay and inpatient pulmonary rehabilitation, he recovered fully. In addition to presenting this case, we review the few previous reports and note the multidisciplinary medical and surgical support necessary to treat similar patients.

Successful Orthotopic Heart Transplantation and Immunosuppressive Management in 2 Human Immunodeficiency Virus-Seropositive Patients.

Few orthotopic heart transplantations have been performed in patients infected with the human immunodeficiency virus since the first such case was reported in 2001. Since that time, advances in highly active antiretroviral therapy have resulted in potent and durable suppression of the causative human immunodeficiency virus-accompanied by robust immune reconstitution, reversal of previous immunodeficiency, a marked decrease in opportunistic and other infections, and near-normal long-term survival. Although human immunodeficiency virus infection is not an absolute contraindication, few centers in the United States and Canada have performed heart transplantations in this patient population; these patients have been de facto excluded from this procedure in North America. Re-evaluation of the reasons for excluding these patients from cardiac transplantation is warranted in light of such significant advances in antiretroviral therapy. This case report documents successful orthotopic heart transplantation in 2 patients infected with human immunodeficiency virus, and we describe their antiretroviral therapy and immunosuppressive management challenges. Both patients were doing well without sequelae 43 and 38 months after transplantation.

Testosterone therapy: treatment of metabolic disturbances in heart failure.

Heart failure (HF) is a complex progressive multisystem disease state with significant morbidity and mortality, which is not solely defined by pathology of the cardiovascular system but also is influenced by neurohormonal regulatory adjustments, peripheral cytokines, as well as hormonal and musculoskeletal dysfunction. Recent attention to the catabolic state found in patients with chronic heart failure has sparked interest in new potential targets for medical therapy. In particular, as many as 26% to 37% of men affected with HF have been found to be testosterone deficient. The severity of androgen deficiency has been shown to correlate with symptoms, functional class, and prognosis in patients with heart failure. Testosterone supplementation has been an accepted therapy in hypogonadal men with fatigue, muscle wasting, and sexual dysfunction for some time. Patients with severe HF show a similar constellation of symptoms and hypothetically would benefit from androgen replacement. Recent clinical studies have confirmed that functional, biochemical, and cardiopulmonary status in patients with HF have significant improvements when treated with testosterone supplementation. Symptomatic improvements may be obtainable in hypogonadal patients with HF who receive supplemental testosterone. This review seeks to outline the cardiovascular and peripheral effects of testosterone supplementation in patients with chronic HF.