Citations

Abstract During the manufacturing period of autologous chimeric antigen receptor (CAR) T-cell therapy, patients may experience a decline in their condition due to cancer progression. In this study, we investigated the impact of bridging therapy (BT) on the outcome of patients with relapsed/refractory large B-cell lymphoma who received antilymphoma treatment between leukapheresis and axicabtagene ciloleucel (axi-cel) infusion. We conducted our analysis using data from the multicenter US Lymphoma CAR-T Consortium, with a median follow-up of 33 months (range, 4.3-42.1). Out of the 298 patients who underwent leukapheresis, 275 patients received axi-cel. A total 52% of patients (n = 143) who received BT had a higher baseline risk profile than patients who did not receive BT, and these patients, as a group, had inferior outcomes compared with those who did not receive BT. However, after propensity score matching between the 2 groups, there were no statistically significant differences in overall response rate (77% vs 87%; P = .13), complete response rate (58% vs 70%; P = .1), progression-free survival (hazard ratio [HR], 1.25; P = .23), and overall survival (HR, 1.39; P=.09) between the BT group and the no-BT group, respectively. Analyzing the effects of BT in the whole cohort that underwent leukapheresis regardless of receiving axi-cel (intention-to-treat analysis) showed similar results. Radiation BT resulted in outcomes similar to those observed with nonradiation BT. Our findings suggest that BT may be safe without a significant impact on long-term survival for patients who require disease stabilization during the manufacturing period. Moreover, our results suggest that there is no clear advantage to using radiation-based BT over nonradiation-based BT.

Abstract Aims An elevated risk of adverse events persists for years in cardiogenic shock (CS) survivors with high mortality rate and physical/mental disability. This study aims to link clinical CS-survivor phenotypes with distinct late host-response patterns at intensive care unit (ICU) discharge and long-term outcomes using model-based clustering. Methods and results In the original prospective, observational, international French and European Outcome Registry in Intensive Care Units (FROG-ICU) study, ICU patients with CS on admission were identified (N = 228). Among them, 173 were discharged alive from the ICU and included in the current study. Latent class analysis was applied to identify distinct CS-survivor phenotypes at ICU discharge using 15 readily available clinical and laboratory variables. The primary endpoint was 1 year of mortality after ICU discharge. Secondary endpoints were readmission and physical/mental disability [short form-36 questionnaire (SF-36) score] within 1 year after ICU discharge. Two distinct phenotypes at ICU discharge were identified (A and B). Patients in Phenotype B (38%) were more anaemic and had higher circulating levels of lactate, sustained kidney injury, and persistent elevation in plasma markers of inflammation, myocardial fibrosis, and endothelial dysfunction compared with Phenotype A. They had also a higher rate of non-ischaemic origin of CS and right ventricular dysfunction on admission. CS survivors in Phenotype B had higher 1 year of mortality compared with Phenotype A (P = 0.045, Kaplan–Meier analysis). When adjusted for traditional risk factors (i.e. age, severity of illness, and duration of ICU stay), Phenotype B was independently associated with 1 year of mortality [adjusted hazard ratio = 2.83 (95% confidence interval 1.21–6.60); P = 0.016]. There was a significantly lower physical quality of life in Phenotype B patients at 3 months (i.e. SF-36 physical component score). Conclusions A phenotype with sustained inflammation, myocardial fibrosis, and endothelial dysfunction at ICU discharge was identified from readily available data and was independently associated with poor long-term outcomes in CS survivors.

AbstractPancreas transplantation alone (PTA) is a β cell replacement option for selected patients with type 1 diabetes mellitus; concerns have been raised regarding deterioration in kidney function (KF) after PTA. This retrospective multicenter study assessed actual impact of transplantation and immunosuppression on KF in PTA recipients at three Transplant Centers. The primary composite endpoint 10 years after PTA was >50% eGFR decline, eGFR < 30 mL/min/1.73 m2, and/or receiving a kidney transplant (KT). Overall, 822 PTA recipients met eligibility. Median baseline and 10‐year eGFR (mL/min/1.73 m2) were 76.3 (58.1–100.8) and 51.3 (35.3–65.9), respectively. Primary composite endpoint occurred in 98 patients (53.5%) with 45 experiencing a >50% decrease in eGFR by 10 years post‐transplant, 38 eGFR < 30 mL/min/1.73 m2 and 49 requiring KT. KF declined most significantly within 6 months post‐PTA, more often in females and patients with better preserved GFR up to 5 years with 11.6% kidney failure at 10 years. Patient survival and death‐censored graft survival were both 68% at 10 years with overall graft thrombosis rate 8%. KF declined initially after PTA but stabilized with further slow progression. In conclusion, prospective intervention studies are needed to test renal sparing interventions while gathering more granular data.

AbstractIntroductionThe infusion of autograft Natural Killer Cells (NKC)/CD14+HLA‐DRDIM ratio is a predictor of survival in lymphoma patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). This study evaluated if the Day 100 NKC/CD14+HLA‐DRDIM ratio still functions as a prognostic immune‐biomarker.MethodsThis was a retrospective, single‐institution, cohort analysis including 107 patients in this study that had clinical assessment at Day 100 post‐APBHSCT from our prior phase III trial. We evaluated the prognostic ability of the Day 100 NKC/CD14+HLA‐DRDIM ratio to predict overall survival (OS) and progression‐free survival (PFS) using Cox regression model for outcome analysis and survival by Kaplan–Meier method.ResultsThe median follow‐up from day 100 was 94.7 months (range 4.83–158.1 months) for the entire cohort. Patients with a Day 100 NKC/CD14+HLA‐DRDIM ratio ≥1.67 experienced better OS and PFS versus those with a Day 100 NKC/CD14+HLA‐DRDIM ratio <1.67: median OS was not reached versus 49.7 months, the 5‐year OS rates were 91% (95% CI, 81%–96%) versus 40% (95% CI, 27%–55%), p < .0001, respectively; and median PFS was not reached versus 23.5 months, the 5‐year PFS rates were 66% (95% CI, 55%–81%) versus 21% (95% CI, 15%–40%), p < .0001, respectively. Day 100 NKC/CD14+HLA‐DRDIM ratio was an independent predictor for OS and PFS in the multivariate analysis.ConclusionsDay 100 NKC/CD14+HLA‐DRDIM ratio is a prognostic immune‐biomarker in lymphoma patients post‐ APBHSCT.

Background: GLUT4 inhibition via the use of a protease inhibitor, such as nelfinavir (NEL), is an attractive therapeutic option in multiple myeloma (MM), given the dependence of MM cells on glucose. Furthermore, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor, such as metformin (MET), may counter the possibility of therapeutic resistance to GLUT4 inhibition in MM cells, showing synergistic promise (Dalva-Aydemir et al., Clin Can Res 2015). In addition to GLUT4 inhibition, NEL also lowers the cytotoxicity resistance of MM cells against proteasome inhibitors such as bortezomib (BOR) (Driessen et al., Blood 2018). Thus, this study evaluated the safety and tolerability of repurposing MET and NEL, in combination with BOR for the treatment of relapsed/refractory MM (RRMM) that had progressed on all standard of care (SOC) therapies. Methods: This trial utilized a 3+3 dose escalation design with 3 dose levels planned for up to a maximum of six (21-day) cycles. MET was administered for 14/21 days and started at a dose of 500 mg BID with plans to be investigated at a maximum dose of 1000 mg BID. NEL was administered for 14/21 days and started at a dose of 1250 mg BID with plans to be investigated to a maximum dose of 2500 mg BID. SubQ BOR was administered on days 1, 8, and 15 of a 21-day cycle at a dose of 1.3 mg/m 2 to a portion of patients. Patients with RRMM were required to have had 2 prior lines of therapy and prior exposure to proteasome inhibitors (PIs), immunomodulators (IMiDs), and Anti-CD38 monoclonal antibodies. The primary objective was to determine the maximal tolerated dose (MTD) of this combination. The secondary objective was to evaluate the safety as well as the overall response rate (ORR) of this combination. This trial was funded by the Helen Diller Family Foundation. Results: From 4/2019 until 9/2022, nine patients were accrued with a median age of 65 (range: 42-81) that received a median of 7 prior lines of therapy (Range: 6-13). All but one patient had a prior autologous stem cell transplant. Only one patient was not triple-class refractory, and 2/3 rd (n = 6) also had prior anti-BCMA therapy. The first three patients received only MET (500 mg BID) and NEL (1250 mg BID) at the first dose level for up to one cycle before experiencing progressive disease and coming off the study. Given the limited activity of MET and NEL in the initial treatment of these three patients, two subsequent amendments to the protocol allowed for the upfront addition of BOR 1.3 mg/m2 to the original combination, as well as shortened the DLT evaluation period from two cycles to just one. Thus, the following six patients received MET (500 mg BID) and NEL (1250 mg BID) at the first dose level in addition to weekly BOR at 1.3 mg/m2. Four (44%) patients experienced grade 3+ hematological AEs and six (67%) experienced grade 3+ non-hematological AEs. The most common hematologic grade 3+ AE observed was anemia (44%). The nonhematologic grade 3+ AEs observed were dyspnea, fatigue, nausea, and vomiting (11% each). None of the AEs were possibly related to treatment, suggesting good overall safety of the combination. While eight of nine patients have since died of progressive disease, no deaths were attributable to the treatment. All six patients who received BOR upfront with MET and NEL were previously refractory to BOR in prior lines of therapy; however, none had received BOR as their last line of therapy prior to accrual to this study. Four of these six patients had progressive disease after one cycle of therapy and went off study. However, the remaining two were able to receive 2 or more cycles of therapy, with one experiencing an unconfirmed minor response (MR) in the first cycle and the other experiencing stable disease (SD) for all six cycles. The patient who experienced SD was safely able to transition to a subsequent clinical trial utilizing an anti-BCMA bispecific antibody therapy and remains alive at the time of this analysis. The study was closed before accrual to the next dose level was started. Conclusions: This is the first study to evaluate the safety and efficacy of this repurposed drug combination in this very difficult-to-treat population of RRMM. While no ORR was observed, identification of biomarkers used for selection of patients with no other SOC options who could experience at least SD responses may be beneficial in allowing this combination to slow or stabilize the disease progression until other novel therapies or clinical trials are available.

Introduction: In Cohorts 1+2 of the ZUMA-1 Phase 1/2 study of axi-cel in R/R LBCL, 11% and 31% of patients (pts) experienced Grade ≥3 cytokine release syndrome (CRS) or neurologic evenets), respectively. To minimize the toxicities seen with axi-cel, a safety management cohort, Cohort 6 (N=40), was added to evaluate whether prophylactic (ppx) corticosteroids (CS) could decrease grade ≥ 3 CRS or ICANS. The 2-year update of ZUMA-1 Cohort 6 showed no grade ≥3 CRS and 15% grade ≥3 ICANS without any difference in objective response rate (ORR) or complete response rate (CR) when compared to cohorts 1+2 (Oluwole Blood 2022). The FDA had previously approved an update to the prescribing information for axi-cel to include use of ppx CS across all approved indications in January 2022. However, ppx CS is not a mandatory standard treatment and we sought to establish the clinical outcomes in the real-world practice. Methods: To assess the clinical outcomes of pts receiving ppx CS, we conducted a multicenter retrospective analysis of pts with R/R LBCL who were treated with axi-cel since the FDA approval of ppx CS in January 2022. Baseline characteristics, toxicities, and efficacy were compared between the no ppx and ppx CS groups. CRS and ICANS were graded based on ASTCT 2019 guidelines. Event-free survival (EFS) was defined as time from axi-cel infusion to progression, re-treatment, or death. Overall survival (OS) was defined as time from axi-cel infusion to death due to any cause. Results: A total of 66 pts at 5 centers received axi-cel between Jan 31, 2022, and June 20, 2023. Thirty-five (52%) pts received ppx CS, with a median age of 63 years (26-85 years). By histology, 75% (n=50) of the pts had DLBCL, 13.6% (n=9) had high grade B-cell lymphoma (HGBL), 9.1% (n=6) had transformed follicular lymphoma (TFL) and 1.5% (n=1) primary mediastinal LBCL (PMBCL). 59% of the pts (n=37) had IPI &gt;2 and 66% (n=43) had stage III/IV disease. The baseline characteristics at the time of apheresis are shown in Table 1 and were comparable between the 2 groups, except for more HGBL, fewer prior lines of therapy and longer median time from apheresis to axi-cel infusion in the ppx CS group. Among the entire cohort, only 37% (n=25) met ZUMA-1 eligibility criteria at the time of lymphodepletion, and 67% (n=44) needed bridging therapy. Any grade CRS occurred in 88% (n=58) of the pts, with grade ≥2 CRS in 38% (n=25). Any grade ICANS occurred in 55% (n=37) of the pts, with grade ≥2 ICANS in 41% (n=27). Any grade ICANS was significantly lower in the ppx CS group than the no ppx group (45.7% vs 65.5%). The rates of any grade CRS, grade ≥2 CRS, grade ≥2 ICANS, the median time to CRS onset, ICANS onset, CRS duration, and ICANS duration were comparable between the 2 groups. Tocilizumab and steroids use was similar between two groups with a trend towards less ICU admission in patients in the ppx CS group. Overall, 14 (21%) pts developed infectious complications within 30 days of axi-cel infusion. The day 30 ORR was 84% and was comparable between the 2 groups (77% in the ppx group vs 93% in the no ppx group). The CR was 45.7% in ppx CS group compared to 65.5% in no ppx group. At a median follow up of 219 days (27-1178), 37 (56.1%) pts had progressed and 25 (37.9%) pts had died. The number of days to progress was significantly lower in the ppx CS arm. The median EFS and OS were not significant between the 2 groups. Conclusions: This multicenter retrospective study showed that the efficacy of treatment with axi-cel in R/R LBCL did not decrease with the use of ppx CS. No significant differences in efficacy or CAR-T-associated toxicities were noted in the 2 groups, potentially due to selective use with patients at presumed higher risk of severe CRS and ICANS. A larger dataset and longer follow-up is needed for risk-stratified analysis and the study is ongoing.

Background Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of non-Hodgkin lymphoma. Clinicopathologic features are distinct from diffuse large B cell lymphoma, but it shares some clinical and biologic features with Nodular sclerosis classic Hodgkin lymphoma. Central nervous system (CNS) relapse appears to be rare in patients with PMBCL, with limited literature reporting a rate of approximately 1.5% to 4%. We examined the incidence of CNS relapse, treatment approaches and survival outcomes in patients with PMBCL. Methods Patients with newly diagnosed PMBCL seen at Mayo Clinic between 2002 and 2022 were identified using the prospective Mayo Clinic Lymphoma Database. Clinical features, treatment details and outcomes were abstracted from the medical record. Cumulative incidence of CNS relapse was analyzed with death as a competing risk. The association of CNS-IPI, systemic treatment, and CNS prophylaxis approach with CNS relapse rate was analyzed using competing risk models and descriptively. Event-free survival (EFS) for the cohort was defined as time from PMBCL diagnosis to first recorded CNS and/or systemic relapse or death from any cause. Overall survival (OS) was defined as time from PMBCL diagnosis (or CNS relapse) to death from any cause. Survival analysis was performed using the Kaplan-Meier method. Results A total of 124 PMBCL cases were identified. The median age at diagnosis was 37 years and 61% were female. The distribution of CNS-IPI was low-risk in 67 (61%), intermediate-risk in 41 (37%), and high-risk in 2 (2%). 64 patients (52%) received R-CHOP and 54 patients (44%) received R-DA-EPOCH as frontline therapy. High-dose methotrexate (HD-MTX) for CNS prophylaxis was administered to 6 patients (5%), 5 with R-CHOP and 1 with R-DA-EPOCH. 16 patients received intrathecal (IT) chemotherapy (methotrexate and/or cytarabine) for CNS prophylaxis, 3 with R-CHOP and 13 with R-DA-EPOCH. The median follow-up was 56.0 months. The 5-year EFS rate was 75.1% and the 5-year OS rate was 90.7% for the entire cohort. 20 patients had systemic relapse only and 3 had CNS relapse. The cumulative incidence of CNS relapse was 1.84% (95% CI 0.46%-7.17%) at 2 years and 2.92% (95% CI 0.50%-8.84%) at 5 years (Figure 1). No statistically significant association of CNS-IPI, systemic therapy or CNS prophylaxis regimen with CNS relapse rate was found in competing risk models; however, this analysis was limited by a small event number (n=3). Among the 3 patients with CNS relapse, 1 had high-risk CNS-IPI and 2 had intermediate risk. All 3 patients were treated initially with R-CHOP. Two patients did not receive any CNS prophylaxis and 1 patient received IT CNS prophylaxis. All three patients who had CNS relapse were female. Patient #1 was diagnosed at age 48 and had simultaneous CNS and systemic relapse 6 months later. The patient was treated with HD-MTX, temozolomide and rituximab for CNS relapse, and subsequently received multiple therapies for systemic disease including R-DHAP, R-ICE, and died 17 months after CNS relapse. Patient #2 was diagnosed at age 22 and had CNS relapse after 8.7 months, followed by systemic relapse 2 months later. The patient received HD-MTX, temozolomide and rituximab for CNS relapse, followed by systemic and whole-brain radiation therapy (RT) for both systemic and CNS relapse. Subsequently the patient received salvage chemotherapy, autologous and allogeneic stem cell transplant for systemic relapse. The patient died 26.8 months after CNS relapse. Patient #3 was diagnosed at age 24 and had systemic relapse after 20.7 months, followed by CNS relapse 5.4 months later. The patient received methotrexate and whole-brain RT following CNS relapse and died 1.2 months after CNS relapse. Besides these 3 patients, we identified 6 PMBCL patients with CNS relapse who were diagnosed at other medical centers and subsequently referred to our institution for management of refractory disease. The survival after CNS relapse was poor, with a median OS of 10.4 months (95% CI 5.6-15.2). Conclusion Our study showed that the CNS relapse rate (1.84% at 2 years and 2.92% at 5 years) was overall low in patients with PMBCL, consistent with previous reports. CNS relapse was associated with poor survival despite aggressive treatment approaches. Novel approaches utilizing biological risk factors for CNS relapse, such as circulating tumor DNA, are needed to identify patients with CNS relapse.