Utility of a fusion protein T-cell co-stimulation blocker Belatacept in heart transplant recipients: Real world experience from a high volume center.

BACKGROUND: Belatacept (BTC), a fusion protein, selectively inhibits T-cell co-stimulation by binding to the CD80 and CD86 receptors on antigen-presenting cells (APCs) and has been used as immunosuppression in adult renal transplant recipients. However, data regarding its use in heart transplant (HT) recipients are limited. This retrospective cohort study aimed to delineate BTC's application in HT, focusing on efficacy, safety, and associated complications at a high-volume HT center. METHODS: A retrospective cohort study was conducted of patients who underwent HT between January 2017 and December 2021 and subsequently received BTC as part of their immunosuppressive regimen. Twenty-one HT recipients were identified. Baseline characteristics, history of rejection, and indication for BTC use were collected. Outcomes included renal function, graft function, allograft rejection and mortality. Follow-up data were collected through December 2023. RESULTS: Among 776 patients monitored from January 2017 to December 2021 21 (2.7%) received BTC treatment. Average age at transplantation was 53 years (± 12 years), and 38% were women. BTC administration began, on average, 689 [483, 1830] days post-HT. The primary indications for BTC were elevated pre-formed donor-specific antibodies in highly sensitized patients (66.6%) and renal sparing (23.8%), in conjunction with reduced calcineurin inhibitor dosage. Only one (4.8%) patient encountered rejection within a year of starting BTC. Graft function by echocardiography remained stable at 6 and 12 months posttreatment. An improvement was observed in serum creatinine levels (76.2% of patients), decreasing from a median of 1.58 to 1.45 (IQR [1.0-2.1] to [1.1-1.9]) over 12 months (p = .054). eGFR improved at 3 and 6 months compared with 3 months pre- BTC levels; however, this was not statistically significant (p = .24). Treatment discontinuation occurred in seven patients (33.3%) of whom four (19%) were switched back to full dose CNI. Infections occurred in 11 patients (52.4%), leading to BTC discontinuation in 4 patients (19%). CONCLUSION: In this cohort, BTC therapy was used as alternative immunosuppression for management of highly sensitized patients or for renal sparing. BTC therapy when combined with CNI dose reduction resulted in stabilization in renal function as measured through renal surrogate markers, which did not, however, reach statistical significance. Patients on BTC maintained a low rejection rate and preserved graft function. Infections were common during BTC therapy and were associated with medication pause/discontinuation in 19% of patients. Further randomized studies are needed to assess the efficacy and safety of BTC in HT recipients.

Bridging to transplant with HeartMate 3 left ventricular assist devices in the new heart organ allocation system: An individualized approach.

BACKGROUND: Following the MOMENTUM 3 trial and the discontinuation of the HeartWare HVAD, the HeartMate 3 LVAD (HM 3) has become the main durable device for bridging to transplantation; however, outcome of this strategy in the new heart allocation system is not well understood. METHODS: The United Network for Organ Sharing (UNOS) registry was queried to include adult patients (≥18 years old) listed for heart transplantation between 2010 and 2020. Trends in durable LVAD utilization and outcomes of patients with HM 3 LVAD were examined in the pre- vs post-heart allocation system. RESULTS: From 2017 to 2020, there was a 28.3% decline in the number of patients waitlisted with an FDA-approved durable LVAD. Overall, 449 patients were waitlisted with HM 3 in the pre-allocation era compared to 1094 patients in the post-allocation. Cumulative incidence of heart transplantation (53.4% vs 50.7%, p = 0.76) and death or delisting for worsening status (5.0%, vs 4.2%, p = 0.43) at 1-year after listing with HM 3 LVAD was comparable in the pre- vs post-allocation era. Old age (>50), ischemic HF, poor functional status, elevated creatinine (>1.3 mg/dL), pulmonary hypertension (>3 WU), and obesity (body mass index > 33 kg/m2) were predictors of post-transplant graft mortality after bridging with HM 3. CONCLUSIONS: While the utilization of durable devices as BTT have declined under the new heart allocation system, bridging with HM 3 LVAD remains a safe strategy in carefully selected patients. Bridging decision should be individualized based on patient risk factors.

Characterizing metastatic uveal melanoma patients who develop symptomatic brain metastases.

Metastatic uveal melanoma (mUM) is an advanced ocular malignancy characterized by a hepatotropic pattern of spread. As the incidence of brain metastases (BM) in mUM patients has been thought to be low, routine CNS surveillance has not been recommended. Notably, no formal assessment of BM incidence in mUM has to date been published to support this clinical practice. We aimed to determine the true rate of BM in mUM and to clarify the clinical and genomic risk factors associated with BM patients through a collaborative multicenter, retrospective research effort. Data collected from 1,845 mUM patients in databases across four NCI-designated comprehensive cancer centers from 2006-2021 were retrospectively analyzed to identify patients with BM. Brain imaging in most cases were performed due to onset of neurological symptoms and not for routine surveillance. An analysis of demographics, therapies, gene expression profile, tumor next generation sequencing (NGS) data, time to metastasis (brain or other), and survival in the BM cohort was completed. 116/1,845 (6.3%) mUM patients were identified with BM. The median age at time of UM diagnosis was 54 years old (range: 18-77). The median time to any metastasis was 4.2 years (range: 0-30.8). The most common initial metastatic site was the liver (75.9%). 15/116 (12.9%) BM patients presented with BM at the time of initial metastatic diagnosis. Median survival after a diagnosis of BM was 7.6 months (range: 0.4-73.9). The median number of organs involved at time of BM diagnosis was 3 (range: 1-9). DecisionDX-UM profiling was completed on 13 patients: 10-Class 2, 2-Class 1B, and 1-Class 1A. NGS and cytogenetic data were available for 34 and 21 patients, respectively. BM was identified in 6.3% of mUM cases and was associated with high disease burden and a median survival of under 8 months once diagnosed. Since most patients in this cohort were symptomatic, the incidence of asymptomatic BM remains unknown. These data suggest the use of routine brain imaging in all mUM patients at risk for developing BM for early detection.

Letermovir for cytomegalovirus prophylaxis in high-risk heart transplant recipients.

Letermovir is a novel agent for the prevention of cytomegalovirus (CMV) infection and disease that, unlike traditional CMV DNA polymerase inhibitors, does not carry the risk of myelosuppression. The purpose of this study was to evaluate the safety, efficacy, and clinical application of letermovir for CMV prophylaxis in heart transplant (HT) recipients. Between November 1, 2019, and October 1, 2021, at a single, tertiary care hospital, 17 HT recipients were initiated on letermovir due to leukopenia while on valganciclovir. Fifteen (88%) had high-risk mismatch (CMV D+/R-). Median time on letermovir was 5 months (interquartile range, 2-8 months.) At the end of the study period, nine of 17 patients (52.9%) were still on letermovir and four of the 17 (23.5%) had successfully completed the prophylaxis window on letermovir and been switched to the pre-emptive strategy. One patient developed clinically significant CMV viremia in the setting of being unable to obtain medication due to insurance barriers but was later successfully restarted on letermovir. One patient was unable to tolerate letermovir due to symptoms of headache and myalgias. Two patients developed low-level non-clinically significant CMV viremia and were switched back to valacyclovir. All patients had tacrolimus dosages reduced at time of letermovir initiation to minimize the risk of supratherapeutic tacrolimus concentration. One patient required hospitalization due to symptomatic tacrolimus toxicity. For HT recipients who cannot tolerate valganciclovir, letermovir presents an alternative for CMV prophylaxis. Close monitoring for breakthrough CMV and calcineurin inhibitor levels is necessary. Larger studies are required to further delineate its use and help provide further evidence of its safety and efficacy.

The role of temporary mechanical circulatory support as a bridge to advanced heart failure therapies or recovery.

PURPOSE OF REVIEW: Temporary mechanical circulatory support (tMCS) has become central in the treatment of refractory cardiogenic shock and can be used to bridge patients to durable MCS, heart transplant or recovery. This review will discuss contemporary data regarding bridging strategies utilizing tMCS. RECENT FINDINGS: There has been significant growth in tMCS use recently, driven by increased familiarity with tMCS devices, and increased experience with both implantation and management. Identifying goals of therapy at the time of therapy initiation can facilitate better outcomes. The three primary goals are bridge to recovery, bridge to heart transplantation or bridge to durable left ventricular assist device. Bridging to recovery requires adequate treatment of underlying conditions and optimization of haemodynamics. Bridging to heart transplantation has become more frequent following changes to the heart allocation policy. Despite early concerns, patients bridge with tMCS, including ventricular-arterial extracorporeal membrane oxygenation, do not appear to have worse posttransplant outcomes. When bridging to durable mechanical circulatory support, tMCS can be used to enhance end-organ dysfunction and improve perioperative outcomes. In situations in which none of these goals are attainable, palliative care plays a critical role to identify patient wishes and assist with withdrawal of care when necessary. SUMMARY: The use of tMCS, as a bridge to recovery or heart replacement therapy in patients with refractory cardiogenic shock has grown significantly over the past decade. Multiple device choices are available and must be chosen appropriately to address the specific situation and the goals of therapy.

Incidence and Clinical Significance of Hyperkalemia Following Heart Transplantation.

BACKGROUND: Hyperkalemia (HK) is a life-threatening complication following solid organ transplantation, and patients often need potassium-chelating agents and deviations from standard posttransplant protocols. This is the first study to report the incidence and clinical impact of hyperkalemia following heart transplantation. METHODS: We retrospectively included patients who underwent heart transplantation at our institution between April 2014 and December 2018. Patients with multiorgan transplantation were excluded. Clinical outcomes of patients who had serum potassium >5.5 mEq/L in the first year posttransplant (HK group) were compared to patients who did not have serum potassium >5.5 mEq/L in the first year posttransplant (non-HK group). RESULTS: A total of 143 patients were included in this study. During the first year posttransplant, cumulative incidence of serum potassium >5.0, >5.5, and >6.0 mEq/L was 96%, 63%, and 24%, respectively. Fifty-five percent of patients required treatment with potassium-chelating agents. Sulfamethoxazole-trimethoprim was discontinued because of HK in 39% of patients. Overall survival of patients in the HK group (n = 89) was comparable to that of patients in the non-HK group (n = 54, 91% vs 98% at 1 year, P = .19), whereas infection-free survival was significantly lower in the HK group (34% vs 53% at 1 year, P = .010). Multivariate analysis revealed pretransplant renal dysfunction (odds ratio = 2.62; 95% confidence interval, 1.18-5.80; P = .018) and use of mechanical circulatory support (odds ratio = 2.90; 95% confidence interval, 1.08-7.76; P = .035) as significant predictors of posttransplant hyperkalemia. CONCLUSIONS: The incidence of HK following heart transplantation was high, with more than half of patients requiring any therapeutic interventions, and HK was related to an increase in infection events.