Criteria For Transplantation Research Articles

Bendamustine Lymphodepletion (LD) Prior to Idecabtagene Vicleucel (Ide-cel) Is Associated with Inferior Outcomes in Relapsed Refractory Multiple Myeloma (RRMM)

Background Chimeric antigen receptor therapy (CART) has revolutionized the management of RRMM. LD prior to CART cells modulates the immune environment creating optimal conditions for T cell expansion and subsequent efficacy. Fludarabine/cyclophosphamide (FLU/CY) is an effective LD regimen, and its use has been adopted widely prior to CART cells for all indications. Since the safety of FLU/CY is not established in patients with substantial renal impairment and given recent nationwide fludarabine shortage, alternative lymphodepletion strategies have been explored. Bendamustine (BENDA) has been shown to be a safe alternative with equivalent efficacy and reduced toxicity in non-Hodgkin's lymphoma (NHL). While its use has been extrapolated to RRMM, efficacy and long-term outcomes have not been examined. Methods We retrieved and analyzed data on sequential patients (pts) with RRMM treated with commercial Ide-cel at a single institution from its approval in 3/2021 until 5/2023. We captured baseline patient, disease and treatment characteristics. We used IgG (with monoclonal component deducted) and uninvolved FLC as indirect surrogate of CAR-T expansion and on target, off tumor killing of non-malignant plasma cells. We assessed cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity (ICANS) based on the American Society for Transplantation and Cellular Therapy criteria and disease responses using the International Myeloma Working Group response criteria. We graded hematologic toxicity using the Common Terminology Criteria for Adverse Events version 5.0. We compared efficacy between the cohorts using overall response rate (ORR) and progression-free survival (PFS), since overall survival is expected to be affected by choice of subsequent, often experimental therapies. Results We identified 28 pts with RRMM who met the inclusion criteria. Nine pts received alternative LD with BENDA (2 pts - renal dysfunction with creatinine clearance <30ml/min; 7 - fludarabine shortage) and 19 received FLU/CY as LD. Baseline characteristics are summarized in Table. Prior autologous stem cell transplant (ASCT) and prior B cell maturation antigen (BCMA) targeting therapy were more frequent in the FLU/CY cohort. Median absolute lymphocyte count (measured in 10^3/ cmm) prior to LD chemotherapy was similar in both cohorts (0.85 in BENDA vs 0.80 in FLU/CY). Median duration of absolute neutrophil count <1,000/μL was shorter in the BENDA cohort. The incidence of any grade CRS (56% vs. 90%, p=0.06) and tocilizumab use (56% vs. 84%, p=0.16) was lower with BENDA compared to FLU/CY. In the absence of ide-cel expansion data, we used nadir polyclonal IgG and uninvolved free light chain (uFLC) in the initial 90 days post CART cell infusion as surrogate of non-malignant plasma burden and therefore ide-cel expansion. We noted lower median uFLC and median IgG with FLU/CY vs. BENDA. The overall response rate was lower with BENDA (22%) vs. FLU/CY (79%, p=0.01). With median follow up of 4.8 mo., all pts in the BENDA cohort progressed with median PFS of 1.6 months vs 7.8 months for FLU/CY (p<0.001, Figure). The median OS for both cohorts is not yet reached. Conclusion: BENDA LD prior to ide-cel infusion results in suboptimal lymphodepletion and subsequent inferior outcomes including low rate of objective responses and decreased progression free survival. The inferior efficacy of BENDA as LD likely results from inferior ide-cel expansion and persistence resulting in less frequent and severe CRS and cytopenias and less suppression of unaffected immunoglobulins. Future efforts to study alternative lymphodepletion approaches is essential given inability to use fludarabine in patients with severe renal dysfunction and periods of critical drug shortages. While there is a need to develop alternatives for LD prior to ide-cel, BENDA is an inadequate substitute of FLU/CY.

Glofitamab Monotherapy in Relapsed or Refractory Large B-Cell Lymphoma: Extended Follow-Up from a Pivotal Phase II Study and Subgroup Analyses in Patients with Prior Chimeric Antigen Receptor T-Cell Therapy and by Baseline Total Metabolic Tumor Volume

Background: Glofitamab is a CD20xCD3 bispecific antibody with a 2:1 (CD20:CD3) format that engages and redirects T cells to eliminate B cells. In a pivotal Phase II study (NCT03075696), fixed-duration glofitamab monotherapy induced high complete response (CR) rates and had a manageable safety profile in patients with relapsed and/or refractory (R/R) large B-cell lymphoma (LBCL; Dickinson et al. N Engl J Med 2022). Here, we present an extended follow up, as well as subgroup analyses in patients with prior chimeric antigen receptor (CAR) T-cell therapy and by baseline total metabolic tumor volume (TMTV). Methods: Patients with LBCL and ≥2 prior therapies received obinutuzumab pretreatment (1000mg) on Day (D) 1 of Cycle (C) 1. Intravenous glofitamab was then given as step-up doses during C1 (2.5mg on D8; 10mg on D15), followed by the target dose (30mg) on D1 of C2-12 (21-day cycles; total of 8.3 months). The primary endpoint was independent review committee (IRC)-assessed CR rate using Lugano criteria (Cheson et al. J Clin Oncol 2014). Cytokine release syndrome (CRS) events were assessed using American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019). Exploratory analyses were performed to investigate the association between TMTV at baseline and progression-free survival (PFS) and CRS. As there is currently no consensus on the method for standardized uptake value (SUV) thresholding in non-Hodgkin's lymphoma, a variety of methods are used in clinical studies (Keijzer et al. Comput Struct Biotechnol J 2023). Here, we used IRC-assessed TMTV derived from baseline positron emission tomography images using a semi-automatic method with a threshold for TMTV of 2x the SUV mean of the liver. Results: As of May 1, 2023, 155 patients were enrolled; 154 patients had received ≥1 dose of study treatment. Baseline characteristics were as previously presented (Dickinson et al. N Engl J Med 2022): median prior therapies received was 3 (range: 2-7); 33% of patients had received prior CAR T-cell therapy, and 85% were refractory to their most recent regimen. Median time on study was 25.8 months (range: 0-35). The IRC-assessed overall response and CR rates were 52% and 40%, respectively. The majority of CRs (40/62; 65%) were ongoing at data cut-off. Median duration of CR (DoCR) was 26.9 months (95% confidence interval [CI]: 18.4-not evaluable [NE]); an estimated 67% of patients with a CR at any time remained in remission at 18 months. PFS and overall survival rates at 12 months in patients with a CR at end of treatment (EOT) were 80% and 90%, respectively. In patients with prior CAR T-cell therapy (n=52), CR rates were consistent with the overall population (N=155; 37% vs 40%, respectively) and median DoCR was 22.0 months (95% CI: 6.7-NE). The safety profile of glofitamab was consistent with what has been described previously, with no new safety signals observed. Baseline TMTV was available for 144 patients and the median was 128.7mL (range: 0-3820; data cut-off: January 16, 2023). Higher TMTV was associated with an increased risk of experiencing a Grade ≥2 CRS event. The proportion of patients with Grade ≥2 CRS events in the first, second, third, and fourth TMTV quartiles was 2.8%, 11.1%, 16.7%, and 38.9%, respectively (Chi-square=16.273; degrees of freedom=1; p<0.0001). Patients with a baseline TMTV above or equal to the median (n=72) had a 12-month PFS rate of 16.8% (95% CI: 9.7-29.1), compared with 50.1% (95% CI: 39.5- 63.7) amongst patients with a baseline TMTV below the median (n=72; hazard ratio: 2.6, 95% CI: 1.7-3.9; Figure). Conclusions: Glofitamab continued to demonstrate durable responses in patients with R/R LBCL, with most patients with CR at EOT still in remission, and no new safety signals observed. These data indicate that there may be potential for favorable long-term outcomes with fixed-duration glofitamab for R/R LBCL. CR rates in patients with prior CAR T-cell therapy were durable and consistent with the overall population. Data from the subgroup analyses showed that higher baseline TMTV was associated with an increased risk of Grade ≥2 CRS and suggested that baseline TMTV may be prognostic for PFS. Updated analyses, with a follow-up of approximately 24 months post EOT, and further TMTV exploratory analyses will be presented.

Multicenter, Real-World Study in Patients with R/R Large B-Cell Lymphoma (LBCL) Who Received Lisocabtagene Maraleucel (liso-cel) in the United States (US)

Background: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells that has demonstrated efficacy and favorable safety based on clinical studies. Liso-cel is approved in the US for the treatment of adults with R/R LBCL after 1 or more lines of systemic therapy, but data describing outcomes in patients treated with liso-cel in the real-world setting are limited. We report real-world clinical effectiveness and safety of commercial liso-cel in patients with R/R LBCL based on a postmarketing study using data collected at the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods: This is a noninterventional, observational, multicenter study of US patients who were followed in the CIBMTR Cellular Therapy Registry between February 2021 and November 2022 after infusion with commercial liso-cel (conforming product only) for the treatment of R/R LBCL. Patients who received nonconforming product are being followed in a separate postmarketing study. The primary objective was to evaluate the real-world clinical effectiveness and safety outcomes of patients with R/R LBCL receiving liso-cel, including ORR, CR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results were analyzed and reported descriptively. Results: At data cutoff (May 4, 2023), 323 patients who received commercial liso-cel across > 50 treatment sites were included in the analysis. The median vein-to-vein time (from leukapheresis to liso-cel infusion) was 36 days (IQR, 34‒42), which is consistent with clinical studies of liso-cel. The median age was 70 years (range, 24‒91). Patients included those with high-risk disease (Table). Most patients had DLBCL not otherwise specified (NOS; 81%), 27% had disease transformed from indolent lymphoma, 12% had high-grade B-cell lymphoma (HGBCL), 37% had International Prognostic Index (IPI) ≥ 3, 6% had active CNS involvement, and 15% had prior transplant. The median number of prior lines of systemic therapy was 3 (range, 0‒11), with 25% of patients having received ≥ 4 lines. The median time from diagnosis to liso-cel infusion was 1.4 years (range, 0.2‒29.7). At a median follow-up of 7.4 months, ORR was 79%, with a 65% CR rate. Median time to response was 1.2 months (IQR, 1.0‒3.1). The median DOR has not been reached; DOR rate at 6 months was 73% (95% CI, 66%‒79%). The median PFS and median OS had not been reached at the time of data cutoff. Estimated 6-month PFS and OS rates were 64% and 82%, respectively. Most events of CRS and ICANS were of low grade, with no CRS and ICANS reported in 48% and 70% of patients, respectively. Overall, 52% of patients had CRS and 3% had grade ≥ 3 events. There was a high concordance on CRS grading per Lee 2014 and American Society for Transplantation and Cellular Therapy criteria. The most common treatments for CRS were tocilizumab (20%) and corticosteroids/tocilizumab (12%). ICANS was seen in 30% of patients, with grade ≥ 3 events in 11%. ICANS was mostly treated with corticosteroids (12%) and corticosteroids/antiepileptics (5%). Based on the attributed cause of death, grade 5 CRS or ICANS were observed in 3 and 3 patients, respectively, and all but 2 patients had concomitant causes of death, including disease progression (n = 3) and hemophagocytic lymphohistiocytosis (n = 2). Prolonged cytopenia (grade 4 thrombocytopenia and/or neutropenia persistent at 30 days postinfusion) occurred in 10% of patients. Conclusions: This is the first large, multicenter, real-world study of patients with R/R LBCL who received commercial liso-cel in the US. Baseline characteristics of patients treated in the real-world setting were consistent with or worse than the liso-cel registrational study experience, including the percentage of patients who had received ≥ 4 lines of prior systemic therapy (25% vs 26% in TRANSCEND). One-time infusion of liso-cel demonstrated deep and durable responses in patients with R/R LBCL across a broad age range, including those with high-risk features characteristic of poor prognosis. The incidence of severe (grade ≥ 3) CRS and ICANS was low. These results further support liso-cel as a therapeutic option with a favorable benefit/risk profile for a broad, real-world population of patients with R/R LBCL.

Long-Term Efficacy and Safety of Elranatamab Monotherapy in the Phase 2 Magnetismm-3 Trial in Relapsed or Refractory Multiple Myeloma (RRMM)

BACKGROUND Elranatamab is a humanized, bispecific antibody that targets B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, with the aim of inducing T-cell-mediated cytolysis of the myeloma cells. In the MagnetisMM-3 (NCT04649359) trial, an open-label, multicenter, non-randomized, phase 2 registrational study of elranatamab monotherapy, patients with RRMM who had not received prior BCMA-directed therapy (ie, BCMA-naïve patients; n=123) achieved objective responses with an overall response rate (ORR) of 61%. Here, we report the long-term efficacy and safety of elranatamab. METHODS Eligible patients had previously received at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Patients received step-up doses of 12 and 32 mg elranatamab subcutaneously on days 1 and 4 of cycle 1, respectively, followed by 76 mg elranatamab once-weekly (QW), starting on day 8 of the first 4-week cycle. Patients who received ≥6 months of QW dosing and achieved ≥ partial response lasting at least 2 months were transitioned to a once every 2 weeks (Q2W) dosing schedule and from Q2W to once every 4 weeks after at least 6 Q2W cycles. Treatment with elranatamab continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was ORR, assessed by blinded-central review per International Myeloma Working Group criteria. Minimal residual disease (MRD) status was assessed using next-generation sequencing, with MRD negativity defined as <1 myeloma cell in 10 5 nucleated cells. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) severity were graded by American Society for Transplantation and Cellular Therapy criteria. RESULTS After a median follow-up of 15.9 months (data cutoff, April 16, 2023), 32.5% of patients remained on treatment. The confirmed ORR was 61.0% (n=123; 95% CI, 51.8-69.6), with 35.8% of patients achieving complete responses (CR) or better. Among evaluable patients (those with ≥CR and evaluable for MRD, n=29), 89.7% achieved MRD negativity. Median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) have not been reached, and the probabilities of maintaining a response, being progression-free, and being alive at 15 months were 70.8% (95% CI, 58.2-80.2), 50.2% (95% CI, 40.2-59.3), and 56.3% (95% CI, 47.0-64.6), respectively. All participants (100%) had ≥1 any grade treatment-emergent adverse events (TEAEs), and 70.7% of patients had grade 3/4 TEAEs. The most common any grade (≥25%) and grade 3/4 (≥10%) adverse events (any grade, grade 3/4) were infections (69.9%, 40.7%), CRS (57.7%, 0%), anemia (48.8%, 37.4%), neutropenia (48.8%, 48.8%), diarrhea (41.5%, 1.6%) thrombocytopenia (31.7%, 23.6%), lymphopenia (26.8%, 25.2%), fatigue (36.6%, 4.1%), nausea (26.8%, 0%), injection site reaction (26.8%, 0%), hypokalemia (26.0%, 10.6%), cough (26.0%, 0%) pyrexia (30.9%, 4.1%), decreased appetite (33.3%, 0.8%), leukopenia (15.4%, 13.0%) and COVID-19 pneumonia (14.6%, 11.4%). CONCLUSIONS Extended follow-up from the ongoing phase 2 MagnetisMM-3 trial of elranatamab in heavily pretreated participants with RRMM demonstrated sustained clinical efficacy, with median DOR, PFS, and OS not reached, and no new safety signals.

Prophylactic Tocilizumab to Prevent Cytokine Release Syndrome (CRS) with Teclistamab Administration

Introduction: Teclistamab is a T-cell redirecting bispecific antibody that targets both CD3 on the T-cell surface and B-cell maturation antigen (BCMA) expressed on myeloma cells. Teclistamab gained accelerated approval for RRMM patients that had previously been treated with 4 prior lines of therapy including a PI, IMID and a CD38 monoclonal antibody. This approval was based on the results of the MajesTEC-1 study demonstrating an ORR of 63%. Cytokine release syndrome (CRS), a known complication of T-cell engaging therapies, occurred in 72% patients which required a REMS program to monitor the patients in hospital for 48 hours post both priming doses and the target dosing. Several approaches are in place to minimize the risk of CRS to allow for the administration of teclistamab safely as an outpatient. We have evaluated the role of administering tocilizumab prophylactically to mitigate the incidence and the severity of CRS. Methods: A total of 48 patients were admitted to the Emory University hospital from December 2022 until July 2023 as mandated by REMS program for teclistamab step-up dosing followed by the first full dose at least 48 hours apart (0.06, 0.3, and 1.5mg/kg) with premeds per institutional guidelines (Benadryl 50 PO, Tylenol 650 PO, and Dexamethasone 16mg PO 30 minutes prior to each dose). Upon evaluation of our first 15 patients, the median time to CRS from the administration of the first-priming dose was 48 hours. We subsequently administered tocilizumab 8mg/kg IV over an hour (max dose of 800 mg) prophylactically at 44 hours (4 hours prior to the second step-up dose level) for the next 33 patients. CRS was graded per the American Society for Transplantation and Cellular Therapy criteria and managed according to institutional guidelines. Results: The median age of the patients was 66 years (range, 44-82). All patients were IMID, PI and CD38 mab refractory. The rate of all grade CRS amongst the entire cohort was 21 of 48 patients (43.8%). CRS occurred in 10 of the 33 patients (30.3%) who received prophylactic tocilizumab, compared to 11 of 15 (73.3%) of patients that did not. The majority the events in the prophylactic tocilizumab group are grade 1 [8 (24.2%)]. 1 patient had grade 2 and another had grade 3 CRS (patient with an aggressive relapse at time of teclistamab administration, requiring 3 doses of tocilizumab every 8 hours). The median number of tocilizumab doses was 1 (range, 1-3). The median duration of CRS was 1 day (range, 1-3). 1 dose of steroids (outside of premeds) was administered in the 1 patient who experienced grade 3 CRS but in no additional patients treated with prophylactic tocilizumab. Concurrent immune effector cell neurotoxicity syndrome (ICANS) was also decreased with the incorporation of prophylactic tocilizumab (20% vs 6.1%, respectively). All ICANS in the prophylactic cohort were grade 1 and managed symptomatically. The median duration of ICANS was 1 day. The non-prophylactic cohort experienced 3 of 15 (20%) patients with readmissions, with 1 additional patient going to hospice. None of the patients in the prophylactic cohort were readmitted to the hospital within 14 days of discharge. Conclusion: Prophylactic tocilizumab prior to the second priming dose has decreased the incidence and severity of CRS in heavily refractory RRMM patients receiving teclistamab. These results are lower in absolute incidence and severity when compared to the MajesTEC-1 trial where CRS was seen in 72% of patients. Prophylactic tocilizumab prevented usage of steroids, prevented dose delays, prevented readmission to the hospital, and possibly reduced the occurrence of ICANS. These data make a case for early incorporation of prophylactic tocilizumab and support outpatient administration of teclistamab in most patients.

A Pro-Inflammatory State and Peak Cytokines Are Associated with Toxicity and Early Responses in Real-World Multiple Myeloma Patients Treated with Idecabtagene Vicleucel

Introduction. Idecabtagene vicleucel (ide-cel) is a chimeric antigen receptor T-cell therapy (CAR-T) approved for patients with triple-class exposed relapsed/refractory multiple myeloma (TCE RRMM) (Munshi NC, et al. N Engl J Med 2021;384:705-716). Treatment-related toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are prevalent and common to all CAR T-cell therapies. We examined the association of serum cytokines and pre-CAR-T bone marrow composition with toxicity and early response among patients with TCE RRMM treated with ide-cel. Methods. Patients treated with commercial ide-cel at H. Lee Moffitt Cancer Center between May 5 th, 2021 to May 18 th, 2023, and that consented to a biospecimen collection protocol, were included. Serum cytokine levels (GM-CSF, IL2, IL6, IL15, IFNγ, Angiopoietin 1&2 [ANG1, ANG2] and TNFα) were measured at apheresis, pre-lymphodepleting (LD) chemotherapy (day -6), infusion (D0) and at least weekly until day 28 using the Ella system (ProteinSimple). Inflammatory markers (C-reactive protein [CRP], ferritin, and albumin) at pre-LD were measured in the clinical laboratory. Marrow biopsy plasma cell burden (PCB) and marrow aspirate immune cell phenotyping of T cells, myeloid cells, and natural killer (NK) cells by flow cytometry were calculated prior to LD. High PCB was considered ≥50% CD138+ plasma cells. CRS and ICANS were graded per the American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria. Patient characteristics, cytokines, and other biomarkers were examined by any grade and ≥ grade 2 CRS and ICANS and day 90 (D90) response using Wilcoxon rank sum or chi-square tests. Results. 86 patients were included, and 30 (35%) were analyzed by flow cytometry. Patient characteristics included a median age of 66 years (range, 43-83), 30% high PCB, 33% high-risk cytogenetics, and a median of 6 prior lines of therapy (range 4-13). Any grade CRS occurred in 80% of the patients, ≥ grade 2 CRS in 19%, any grade ICANS in 14%, and ≥ grade 2 ICANS in 10%. Tocilizumab was administered to 65%, 29% received steroids, and 2% received anakinra. At D90, 52/78 (67%) had achieved ≥ partial response (PR) and 26/78 (33%) had either stable disease (SD), progressive disease (PD) or had died. Three deaths occurred by D90 and were attributed to complications of myeloma progression. Older patients (≥ 65 years) were more likely to develop any grade CRS (p=0.04) and ICANS (p=0.047), and those requiring bridging chemotherapy were more likely to develop ICANS (p=0.025). High PCB was not associated with CRS or ICANS, but was associated with T cell exhaustion and increased CD56 dim NK-cells (p<0.05, Figure A). At apheresis, patients with higher TNFα levels were more likely to develop ICANS (p=0.004), but no other cytokines were associated with toxicity at this timepoint, although patients with CRS and ICANS had numerically higher IL-6. At LD, elevated ratio of ANG2/ANG1 (p=0.029), IL-15 (p=0.019), and high CRP/low albumin ratio (p=0.007) were observed for patients that developed ICANS. Higher peak cytokines, ferritin, and CRP were associated with any grade CRS (p<0.05), and higher peak IL6 was associated with grade ≥ 2 CRS (p=0.03). Patients that developed any grade ICANS had higher peak IL6, IL15, ANG2 /ANG1 ratio, ferritin, and CRP (p<0.05), and these associations persisted for IL15, ANG2/ANG1 ratio, ferritin, and CRP for grade ≥ 2 ICANS (p<0.05). Achievement of ≥PR at D90 was associated with higher peak levels of GM-CSF, IL2, IFNγ, and TNFα (p<0.05, Figure B). Conclusion. In this analysis of real-world TCE RRMM patients treated with commercial ide-cel, inflammatory markers, pre-treatment marrow plasma cell burden, and immune cell subsets were associated with treatment-related toxicities and early responses. These findings provide insights into potential avenues for toxicity prevention and therapeutic optimization in high-risk patients. Additional studies in a larger patient cohort are warranted to understand the complex relationships between inflammation, immunity, toxicity, and efficacy among TCE RRMM patients treated with ide-cel.

Evaluation of Circulating Endothelial Cells (CECs) As Marker of Endothelial Damage in Allo-Transplanted Patients at High Risk of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS): The Cecinvod Study

INTRODUCTION Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially fatal complication after allogeneic stem cell transplantation (alloSCT). Identifying a predictive biomarker for VOD has been challenging. Since endothelial injury is considered one of the main pathogenic factors for VOD onset, with the CECinVOD prospective study we aimed to evaluate Circulating Endothelial Cells (CEC) in allo-transplanted patients (pts) at higher risk to develop VOD. METHODS From October 2020 to November 2022, 150 pts have been enrolled in the CECinVOD study from 11 Italian Bone Marrow Transplantation Units. All pts must be older than 18 years and undergoing myeloablative alloSCT. CECs were detected using the CellSearch system, the FDA-approved immunomagnetic selection approach incorporating ferrofluid nanoparticles (anti CD146) and fluorophore-labelled antibodies (anti CD105, CD45 and DAPI). CEC were defined as CD146+, CD105+, DAPI+ and CD45-. CEC were collected at the following timepoints: before conditioning regimen (T0), at the end of conditioning regimen and before alloSCT (T1), at the time of neutrophils engraftment (T2), and 7-10 days after engraftment (T3). In pts who developed VOD, additional timepoints were collected as follows: at any time of suspected or proven VOD onset (T4), and then weekly during Defibrotide treatment (T5-T8). SOS/VOD was defined according to the 2016 European Group for Blood and Marrow Transplantation criteria. RESULTS Pts' main characteristics are summarized in Table 1. Six out of 150 pts (4%) developed VOD during the follow up (4 “severe”, and 2 “very severe”). All pts were treated with Defibrotide, obtaining a complete remission in 5 of them, while 1 pt died due to VOD complications. Pts receiving TBI-based regimen were more likely to develop VOD compared to those receiving Treosulfan (10 to 14 g/m2) or Busulfan ev (9.6 to 12.8 mg/kg) (p 0.08). Similarly, higher baseline levels of bilirubin were associated with a higher incidence of VOD (p 0.08). Considering the CECs analysis, 615 samples were evaluated. At the enrollment, CECs levels were not related with any of clinical characteristics analyzed, except for the number of previous treatments. Indeed, those pts with 2 or more previous lines of treatments had higher levels of CECs (OR=0.53; p<0.001). Considering the different timepoints, conditioning regimen and alloSCT result in higher levels of CECs. Thus, CEC were higher at T1 than at T0 (p 0.02), as well as they were even higher at T2 than at T1 (p<0.0001) (Fig.1). Conversely, no significant differences have been observed between T3 and T2. No other clinical characteristic was correlated with CEC counts at the different timepoints. Pts who developed VOD had higher median levels of CEC at all the timepoints analyzed, but this difference has not achieved statistical significance, probably due to the low number of pts in the VOD group. At VOD onset, the pts always had an increase in CEC levels compared with the previous timepoint. After defibrotide treatment, the CEC levels increased in the first week, while they progressively decreased during the VOD treatment (T6 and T7, -50,7% and -71,5%, respectively). Recently, another endothelial activation marker has been considered: the Easix score. We didn't find any relationship between the Easix score at transplant and the VOD onset, even if a trend may be observed. We also investigated whether the CEC levels may be related with Easix score, but we didn't find any relationship at each timepoint. Interestingly, in a subgroup of pts CECs have been observed as a cluster of multiple cells. This data is firstly described in allo-SCT. Its functional significate remains unclear, but we found a relationship between CECs cluster and the number of CECs (p < 0.001). CONCLUSIONS The incidence of VOD in our prospective study was low with respect to the one reported in the literature. This can be explained by the changes in alloSCT from the past (better selection of the pts, lower use of TBI, higher use of reduced intensity regimen) and the retrospective nature of most of the previous reports. We show that CECs can be considered reliable marker of endothelial damage in alloSCT pts, highlighting the impact of previous treatments, the conditioning regimen, and allo-SCT itself. Increased CEC level may be helpful to confirm VOD diagnosis, as well as their monitoring may be useful to evaluate the response to the treatment for VOD.

Expanding the Criteria for Heart Transplantation Donors: A Review of DCD, Increased Ischemic Times, HCV, HIV, and Extended Criteria Donors.

With the demand for heart transplantation continuing to outpace the available donor organs, previously underutilized donors are now being reconsidered. We sought to describe the emerging techniques and outcomes of expanded criteria heart transplantation. A comprehensive review of the recent literature concerning expanded donor selection in heart transplantation was performed using the PubMed MEDLINE database. To characterize trends in transplant practice, the United Network for Organ Sharing (UNOS/OPTN) registry was queried for all adult isolated heart transplants since 2010, and data regarding transplant parameters was collected. Donation after cardiac death (DCD), DCD with normothermic regional perfusion, increased ischemic time, hepatitis C positive donor organs, HIV-positive donor organs, and extended criteria donors were identified as promising avenues currently being explored to expand the number of donor organs. The utilization of various expanded criteria for heart transplantation was summarized since 2010 and showed an increasing use of these donor organs, contributing to the overall increasing frequency of heart transplantation. Utilization of expanded criteria for donor selection in heart transplantation has the potential to increase the supply of donor organs with comparable outcomes in selected recipients.

Hepatocellular Carcinoma: The Role of Immunotherapy and Transplantation in the Era of Transplant Oncology.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths worldwide. As most patients present with advanced disease, curative therapy such as surgical resection and radiofrequency ablation are rarely utilized. With the advent of immunotherapy, historical treatment approaches such as liver transplantation are being challenged. In particular, the use of immune checkpoint inhibitors (ICIs) has emerged as a safe and useful option in the treatment of HCC. However, there is concern over adverse effects, such as graft rejection and graft loss. This updated review discusses the role of immunotherapy in the pre- and post-transplantation setting and provides insights into the potential of immunotherapy as an adjunct to liver transplantation. We deliberate on the use of ICI in the setting of the Milan criteria as well as the University of California San Francisco's expanded criteria for liver transplantation. Current data suggest that ICI has utility, especially in the pretransplantation setting. Nevertheless, larger, purposefully designed clinical trials are needed to clearly identify patients who will benefit most from ICI treatment in the transplant setting and determine parameters that will minimize the risk of graft rejection and maximize the benefits of this adjunct treatment.

Immunological Nuances and Complications of Pediatric Organ Transplant: A Narrative Review.

Organ transplantation is considered an exaggerated immune state in which the body reacts in an elaborate cascade of reactions against the lifesaving graft transplanted. Unrepairable organ damage is the main indication for a pediatric patient to undergo a transplant. The host and the donor must fulfill the criteria for a successful transplant to have as few side effects as possible. There has been much-needed research in the domain of surgery of organ transplantation, thereby extending into the pediatric age group. This article elaborates on the post-transplant management, the immuno-biochemistry aspect, and its post-surgery treatment. The post-surgery period requires great emphasis as morbidity and mortality are highest. There is much to understand about managing transplant patients to avoid complications such as infections, hypertension, or side effects of immunosuppressive drugs. The treating clinician faces the challenges of managing the dose and frequency of immuno-suppressive medicines to prevent complications in the patients. If the dose is inadequate, there are chances of graft rejection. If the immuno-suppression is prolonged, there may be chances of infections in the patient. This article aims to summarize the mechanism of graft rejection and put forth the need for further research about creating a universal protocol for managing a patient's immune system post-transplant. The authors hope this protocol will help the clinician better understand the patient's current state and help in appropriately using immuno-suppressive drugs. It calls upon the need for a reliable and easily repeatable battery of investigations that will help solve this dilemma.

European Society of Organ Transplantation (ESOT) Consensus Report on Downstaging, Bridging and Immunotherapy in Liver Transplantation for Hepatocellular Carcinoma.

Liver transplantation offers the best chance of cure for most patients with non-metastatic hepatocellular carcinoma (HCC). Although not all patients with HCC are eligible for liver transplantation at diagnosis, some can be downstaged using locoregional treatments such as ablation and transarterial chemoembolization. These aforementioned treatments are being applied as bridging therapies to keep patients within transplant criteria and to avoid them from dropping out of the waiting list while awaiting a liver transplant. Moreover, immunotherapy might have great potential to support downstaging and bridging therapies. To address the contemporary status of downstaging, bridging, and immunotherapy in liver transplantation for HCC, European Society of Organ Transplantation (ESOT) convened a dedicated working group comprised of experts in the treatment of HCC to review literature and to develop guidelines pertaining to this cause that were subsequently discussed and voted during the Transplant Learning Journey (TLJ) 3.0 Consensus Conference that took place in person in Prague. The findings and recommendations of the working group on Downstaging, Bridging and Immunotherapy in Liver Transplantation for Hepatocellular Carcinoma are presented in this article.

Controversies and prospects for surgical treatment of pancreatic neuroendocrine neoplasms with liver metastases

The incidence of pancreatic neuroendocrine neoplasm(pNEN) increased over the past two decades. Liver metastasis, the most common type of distal metastasis, is also one of the most important prognostic factors. Although several medical treatments, including biotherapy, chemotherapy, targeted therapy, peptide receptor radionuclide therapy and locoregional therapy, are available for pNEN with liver metastases, surgery is still the only possible treatment for cure. Currently, there are several controversies as regards surgical treatment for pNEN with liver metastases. These controversies include, but are not limited to, whether surgical resection is appropriate for pancreatic neuroendocrine tumor G3 with liver metastases, how to classify primary lesion and hepatic metastases comprehensively and accurately, what is the optimal surgical strategy for type Ⅱ liver metastases, who can benefit greatly from cytoreduction, and how to refine the Milan criteria for liver transplantation. This article aims to discuss those main controversies and provide prospects for future clinical trials.

Cardiopulmonary Exercise Testing in the Age of New Heart Failure Therapies: Still a Powerful Tool?

New therapies with prognostic benefits have been recently introduced in heart failure with reduced ejection fraction (HFrEF) management. The aim of this study was to evaluate the prognostic power of current listing criteria for heart transplantation (HT) in an HFrEF cohort submitted to cardiopulmonary exercise testing (CPET) between 2009 and 2014 (group A) and between 2015 and 2018 (group B). Consecutive patients with HFrEF who underwent CPET were followed-up for cardiac death and urgent HT. CPET was performed in 487 patients. The composite endpoint occurred in 19.4% of group A vs. 7.4% of group B in a 36-month follow-up. Peak VO2 (pVO2) and VE/VCO2 slope were the strongest independent predictors of mortality. International Society for Heart and Lung Transplantation (ISHLT) thresholds of pVO2 ≤ 12 mL/kg/min (≤14 if intolerant to β-blockers) and VE/VCO2 slope > 35 presented a similar and lower Youden index, respectively, in group B compared to group A, and a lower positive predictive value. pVO2 ≤ 10 mL/kg/min and VE/VCO2 slope > 40 outperformed the traditional cut-offs. An ischemic etiology subanalysis showed similar results. ISHLT thresholds showed a lower overall prognostic effectiveness in a contemporary HFrEF population. Novel parameters may be needed to improve risk stratification.

Hepatorenal syndrome: Updates.

Hepatorenal syndrome: Updates.

Proton beam radiotherapy versus transarterial chemoembolization for hepatocellular carcinoma: Results of a randomized clinical trial.

This study compares survival rates, recurrence patterns, toxicity, and treatment cost in patients with hepatocellular carcinoma (HCC) treated with either transarterial chemoembolization (TACE) or proton beam radiotherapy (PBT). Subjects with untreated HCC meeting Milan or San Francisco transplant criteria were recruited. Subjects were randomized to receive PBT (n=36) or TACE (n=40). Proton therapy was administered in 15 fractions over 3 weeks to a total dose of 70.2Gy. TACE was repeated until complete or maximal response. The primary outcome measure was overall survival (OS). Secondary end points were progression-free survival (PFS), local control (LC), toxicity, and cost. Of the 76 randomized patients, 74 were assessed for outcome measures. The 2-year OS for PBT versus TACE was similar at 68%, 95% confidence interval (CI), 0.54-0.86, and 65%, 95% CI, 0.52-0.83 (p=.80), however, median PFS was improved for PBT versus TACE (not reached vs. 12months, p=.002). LC was improved with PBT versus TACE (hazard ratio, 5.64; 95% CI, 1.78-17.9, p=.003). Days of posttreatment hospitalization were 24 for PBT and 166 for TACE (p<.001). Total mean cost per patient for treatment and posttreatment care revealed a 28% cost savings for PBT. PBT and TACE yielded similar OS for treatment of HCC, but PFS and LC were improved with PBT compared to TACE. Patients treated with PBT required fewer courses of treatment, fewer posttreatment hospitalization days, and reduced cost of treatment compared to TACE. These data support the use of PBT as a viable treatment alternative to TACE for patients with HCC within transplant criteria.

Investigation of the Effectiveness of Oleuropein in a Three-Dimensional In Vitro Hepatocellular Tumor Sphere Model.

This study was conducted to examine the dose-related effects over time of oleuropein on the proliferation and area of tumor spheroids in hepatocellular carcinoma cells. We examined the possible effects of 100 to 500 μM dose concentrations of oleuropein on HepG2 cell proliferation using a real-time cell analyzer. A 3-dimensional hepatocellular carcinoma tumor spheroid model was established by seeding HepG2 cells at a density of 160 cells/well in custom 96-well microplates with low attachment surfaces and culturing for 3 days. Tumor spheres were treated with increasing oleuropein doses for 72 hours, and images were captured every 24 hours. The dose-dependent effects of oleuropein on tumor sphere size were analyzed by measuring the area of tumor spheres with ImageJ software. We conducted oleuropein viability and cytotoxicity analyses using calcein acetoxymethyl ester-based and propidium iodide-based staining in the tumor model. Oleuropein inhibited cell proliferation; as the dose concentration of oleuropein increased, so did its capacity to inhibit cell proliferation (P < .001). The size of untreated tumor spheres increased at 72 hours (P < .001). However, treatment with 100 to 500 μM oleuropein reduced tumor size by 63.56% to 88.06% compared with untreated cells at the end of 72 hours (P < .001). With increasing concentrations, oleuropein inhibited the viability of tumor spheres, eliminating necrotic death caused by tumor hypoxia. Overall, oleuropein reduced the size of tumors by inhibiting tumor proliferation and viability. In this context, oleuropein could be a candidate molecule for further extensive studies to reduce hepatocellular carcinoma tumors to meet Milan criteria for liver transplant.

Early optical coherence tomography evaluation of donor-transmitted atherosclerosis and cardiac allograft vasculopathy: insights from a prospective, single-center study

The impact of donor transmitted atherosclerosis as assessed by intravascular ultrasound on development and progression of cardiac allograft vasculopathy (CAV) after heart transplantation (HT) remains poorly defined in contemporary practice. In this exploratory analysis, we sought to assess the prognostic role of early qualitative assessment of donor artery morphology using optical coherence tomography (OCT) as a more sensitive imaging modality. HT recipients were prospectively enrolled for baseline OCT imaging of the left anterior descending coronary artery. OCT findings were classified as normal, homogeneous intimal thickening, and advanced plaque characteristics. The endpoint was a composite of cardiac death, myocardial infarction, or new angiographically detectable CAV stratified by the International Society of Heart and Lung Transplantation criteria up to 4 years of follow-up. A total of 35 patients underwent baseline OCT of whom 51.4% had normal OCT, 14.3% had homogenous plaque, and 34.3% had advanced characteristics. There were no significant differences in baseline demographics between patients with and without normal morphology. During a mean follow-up of 3.3±0.4 years, the endpoint occurred in 11 patients including 1 death, 7 CAV1, 3 CAV2, and 1 CAV3. Kaplan-Meier analysis revealed a significantly higher event rate in patients with advanced characteristics (log-rank p=0.010). In multivariate analysis, OCT-based plaque morphology was an independent predictor of clinical events (adjusted hazard ratio 4.57, 95% confidence interval 1.50-13.92, p=0.008) while maximal intimal thickness ≥0.5mm was not. Early qualitative OCT assessment of donor coronary artery morphology appears to be a reliable marker for predicting future cardiovascular events in HT recipients. Our findings warrant more careful study in a larger cohort.

Evolving Landscape in Liver Transplantation for Hepatocellular Carcinoma: From Stage Migration to Immunotherapy Revolution.

Liver transplantation (LT) represents the primary curative option for HCC. Despite the extension of transplantation criteria and conversion with down-staging loco-regional treatments, transplantation is not always possible. The introduction of new standards of care in advanced HCC including a combination of immune checkpoint inhibitor-based therapies led to an improvement in response rates and could represent a promising strategy for down-staging the tumor burden. In this review, we identify reports and series, comprising a total of 43 patients who received immune checkpoint inhibitors as bridging or down-staging therapies prior to LT. Overall, treated patients registered an objective response rate of 21%, and 14 patients were reduced within the Milan criteria. Graft rejection was reported in seven patients, resulting in the death of four patients; in the remaining cases, LT was performed safely after immunotherapy. Further investigations are required to define the duration of immune checkpoint inhibitors, their minimum washout period and the LT long-term safety of this strategy. Some randomized clinical trials including immunotherapy combinations, loco-regional treatment and/or tyrosine kinase inhibitors are ongoing and will likely determine the appropriateness of immune checkpoint inhibitors' administration before LT.

Deceased donor availability for uterus transplantation in Australia.

Uterus transplantation is an emerging treatment option for uterine factor infertility. Most uterus transplantation research programs use living donors, although this comes with considerable surgical and psychological risks and not all women desiring uterus transplantation will have an available living donor. A deceased donor program eliminates donor risks; however, the availability of deceased uterus donors is currently unknown in Australia. To establish the feasibility of a deceased donor uterus transplantation program in Australia and consider expanded inclusion criteria for this model. A retrospective review of the New South Wales (NSW) Organ and Tissue Donation Service database was undertaken to identify potential deceased uterus donors, with comparison to the broad deceased donor inclusion criteria from three international uterus transplantation trials including female, brain-dead, multi-organ donation, no major abdominal surgery, and <60 years of age. Between January 1, 2018, and December 31, 2022, 648 deceased donors were available in NSW. Of these, 43% (279/648) were female and 67% of the women (187/279) were also multi-organ donors. When the brain-dead donor-only and age criteria (<60 years) were applied, a total of 107 deceased donors met the available criteria for uterus transplantation, with an average of 21 deceased donors per year in NSW. There appears to be adequate deceased donor organ availability to establish a deceased uterus transplantation program in NSW, Australia. Should interest in uterus transplantation increase, including criteria such as older and nulliparous donors could increase organ availability for a uterus transplantation program.

One size does not fit all: Differential benefits of simultaneous liver-kidney transplantation by eligibility criteria.

Standard eligibility criteria for simultaneous liver-kidney transplantation (SLK) are in place in the United States. We hypothesize that the benefit associated with SLK over liver transplant alone differs by patient, depending on the specific SLK criteria met. We analyzed a retrospective US cohort of 5446 adult liver transplant or SLK recipients between January 1, 2015, and December 31, 2018, who are potentially qualified for SLK. Exposure was a receipt of SLK. We tested effect modification by the specific SLK eligibility criteria met (end-stage kidney disease, acute kidney injury, chronic kidney disease, or unknown). The primary outcome was death within 1 year of a liver transplant. We used a modified Cox regression analysis containing an interaction term of SLK * time from transplant. Two hundred ten (9%) SLK recipients and 351 (11%) liver-alone recipients died in 1 year. In the overall population, SLK was associated with a mortality benefit over liver transplant on the day of the transplant, without adjustment [HR: 0.59 (95% CI, 0.46-0.76)] and with adjustment [aHR: 0.50 (95% CI, 0.35-0.71)]. However, when SLK eligibility criteria were included, only in patients with end-stage kidney disease was SLK associated with a sustained survival benefit at day 0 [HR: 0.17 (0.08-0.35)] up to 288 (95% CI, 120-649) days post-transplant. Benefit within the first year post-transplant associated with SLK over liver-alone transplantation was only pronounced in patients with end-stage kidney disease but not present in patients meeting other criteria for SLK. A "strict SLK liberal Safety Net" strategy may warrant consideration at the national policy level.