Lisocabtagene Maraleucel Research Articles

CAR-T Cell Therapy Vs. Standard of Care for B-Cell Lymphoma: A Systematic Review and Meta- Analysis of Updated Results of Clinical Trials

Background: For many years, platinum based immunochemotherapy followed by high dose chemotherapy and stem cell transplantation remained standard of care for relapsed/refractory large B-cell lymphoma. About half of the patients do not undergo transplantation due to disease insensitivity to 2 nd line therapy and cured in <30%. In recent years, feasibility of chimeric antigen receptor (CAR) t-cell therapies is tested as 2 nd line of treatment. In this meta-analysis, we will assess the efficacy and safety of CAR-T cell therapy as 2 nd line therapy as compared to standard therapy in large B cell lymphoma based on updated clinical trial results. Methods: A literature search was performed on PubMed and Embase with keywords for “CAR-T cell therapy” and “B-cell lymphoma” from the inception of data till 07/01/2023. PRISMA guidelines were followed while conducting this meta-analysis. A total of 3091 articles were screened and 3 randomized clinical trials (RCTs, N=865) were included based on inclusion criteria. “R” software was used to conduct this meta-analysis. Results: In 3 RCTs (N=865), 180 patients were treated with axicabtagene ciloleucel, 92 patients with lisocabtagene maraleucel, 162 patients with tisagenlecleucel, and 431 patients with standard therapy. Based on updated results of 2 trials (N=543), pooled hazard ratios (HRs) of progression free survival (PFS) was 0.47 (95% CI= 0.37-0.60, I 2=0), overall survival (OS) was 0.73 (95% CI=0.56-0.94, I 2=0), and event free survival (EFS) was 0.4 (95% CI=0.32-0.49, I 2=0) in favor of CAR-T cell therapy as compared to standard therapy. Pooled relative risk (RR) of complete response (CR) and overall response (ORR) were 1.88 (95% CI=1.57-2.25, I 2=2%), and 1.69 (95% CI=1.48-1.92, I 2=0%), respectively, in favor of CAR-T cell therapy. The Belinda RCT on tisagenlecleucel by Bishop et al. was the outlier. HR of EFS, RR of CR, and RR of ORR were 1.07 (95% CI= 0.82-1.4), 1.03 (0.73-1.47), and 1.09 (95% CI= 0.85-1.39), respectively, similar in the two groups. In 3 RCTs, RR of ≥ grade 3 any adverse effects were 1.02 (95% CI=0.92-1.12, I 2=72%), neurotoxicity was 7.35 (95% CI=0.97-55, I 2=64%), and neutropenia was 1.41 (95% CI=1.04-1.91, I 2=78%). Pooled incidence of ≥ grade cytokine release syndrome (CRS) was 5% (CI=0.03-0.08) and was 0 with standard therapy. Fig 1. Conclusion: Based on updated results, CAR-T cell therapies, axicabtagene ciloleucel and lisocabtagene maraleucel, were significantly more effective in terms of response and survival rates. ≥Grade 3 side effects were similar with CAR-T cell and standard therapy. CRS, neurotoxicity, and hematological side effects were higher with CAR-T cells. Tisagenlecleucel was found as an outlier and the efficacy was similar to standard care. More randomized double-blind large-scale phase III clinical trials are needed to confirm these results.

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS): A Review of Pharmacovigilance

Background: CAR-T cell therapies have revolutionized cancer therapeutics with durable responses in hematologic malignancies. However, toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are well-established off-target effects of CAR-T therapy. Immune effector cell (IEC) therapy can result in hemophagocytic lymphohistiocytosis (HLH)-like events, which are now understood as separate entities. Rare and fatal, HLH is characterized by abnormal activation of natural killer (NK) cells, macrophages, and cytotoxic T-lymphocytes; this leads to supraphysiologic production of cytokines and immune-mediated organ system damage. Expert consensus review defines IEC-HS as the development of pathologic features of HLH/macrophage activation independent from CRS and ICANS attributed to IEC therapy, including new onset or worsening cytopenia, hyperferritinemia (>2 times the upper limit of normal), coagulopathy with hypofibrinogenemia, and elevated transaminases. Few clinical studies have shown IEC-HS in Acute Lymphocytic Leukemia (ALL), especially in the pediatric and adolescent populations. However, the incidence and risk of IEC-HS exposure to CD19 and BCMA CAR-T are yet to be determined in B-cell lymphomas and Myelomas. The FDA Adverse Event Reporting System (FAERS) contains circumstantial case reports and serious post-CAR-T therapy IEC-HS. This retrospective analysis from the FAERS aims to address these questions and estimate the risk of IEC-HS with CAR-T cell therapies. Methods: FAERS is a publicly accessible database of adverse event reports associated with various therapies, including CAR-T cell therapies. To estimate the risk of HLH-like syndrome associated with CAR-T treatment, we analyzed the reporting of four CD19 CAR-T therapies (Axicabtagene Ciloleucel, Brexucabtagene Autoleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel) and BCMA CAR-T (Idecabtagene Vicleucel) from the database between 2016 and 2023. Statistical analysis involved a disproportionality analysis using a reported odds ratio (ROR). OpenVigil, a software package used to analyze pharmacovigilance data, enabled the calculation of the ROR with a 95% confidence interval (CI). ROR greater than one, p<0.05, and a confidence interval not including one was considered significant. Results: Between 2016 and April 2023, the FAERS database recorded 8,302 CD19 CAR-T therapies (axicabtagene ciloleucel, n = 4,496; brexucabtagene autoleucel, n = 713; tisagenlecleucel n = 27,51; lisocabtagene maraleucel; n = 342) and 472 BCMA CAR-T therapies, Idecabtagene Vicleucel. We identified 177 reported HLH events as the primary events in patients receiving CAR-T therapies (CD19 CAR-T n = 165; BCMA n = 12). Thirty-six (20.3%) were reported as single IEC-HS, 96 (54.2%) as combined IEC-HS and CRS, 9 (5.1%) as combined IEC-HS and ICANS, and 36 (20.3%) as having all three IEC-related toxicities. The median age was 57 (4-89) years, and males > females at a ratio of 2:1. The study's limitation is that medical personnel reported most of the adverse events (n = 166 of 177 [94%]), and it is unclear if the diagnosis of IEC-HS followed current diagnostic criteria. The CD19 CAR-T was primarily associated with B-cell lymphomas (n = 104, 60.0%), followed by R/R ALL (n= 39, 22.0%) and Chronic Lymphocytic Leukemia, CLL (n = 3, 1.7%). Their combined elevated risk for IEC-HS was greater than that of patients in the database who had not been exposed [ROR, 63.6; 95% CI 54.7-74.1] [p<0.001]. In addition, we conducted a stratified analysis for each drug. Tisagenlecleucel had the highest risk for IEC-HS among the CD19 CAR-T drugs [ROR, 82.3; 95% CI 65.5-104.0] [p<0.001]. The risk was also significant with Idecabtagene Vicleucel [ROR, 73.5; 95% CI 41.4-130.5]. Overall, the results of the study indicate a strong association between CAR-T cell therapy exposure and IEC-HS. Conclusion: CAR-T cell therapy poses a risk for rare IEC-HS, CRS, and ICANS, necessitating early detection to minimize morbidity and mortality. The study's results will be compared to the institutional patient cohort for annual meeting. Understanding factors contributing to this rare complication is crucial for optimizing patient outcomes and ensuring safe CAR T cell therapy use.

Evaluation of the Impact of Tocilizumab Use in Recipients of CAR T Cells for Non-Hodgkin Lymphoma

Introduction: CAR T has revolutionized the treatment of patients with relapsed or refractory (R/R) Non-Hodgkin lymphoma (NHL). Treatment of the major toxicity of cytokine release syndrome (CRS) is tocilizumab (toci) and corticosteroids based on the ASTCT grade. Real-world experiences in the United States and Europe have reported a higher rate of tocilizumab use than in pivotal trials; however, the impact of single or multiple administrations on clinical outcomes is not clear. Methods: Patients diagnosed with diffuse (DLBCL), high grade (HGBCL) and primary mediastinal B cell lymphoma (PMBL) treated at our institution with commercial CAR T were retrospectively identified. The association between the number of doses received with best overall response by day 100, PFS, and OS was investigated through a Cox regression model using a 14-day landmark analysis. Late neutropenia was defined as an ANC <1000/mmc for two consecutive counts beyond day 30 post CAR-T infusion and a 30-day landmark analysis was performed in this case. Results: 230 patients with R/R DLBCL (80%), HGBCL (17%) and PMBL (3%) were included in the analysis. Axicabtagene ciloleucel (Axi-cel), tisagenlecleucel (Tisa-cel), and lisocabtagene maraleucel (Liso-cel) were administered in 62%, 29% and 9% of cases, respectively. Median age at time of CAR-T infusion was 65 years (range 20-86), with a male predominance (63%). The median number of prior treatment lines was 3 (range 1-12), and 21% underwent a prior autologous hematopoietic cell transplant. Disease burden prior to CAR-T infusion can be inferred by the following: bridging therapy was deemed necessary in 77% of patients, pre-lymphodepletion LDH was elevated in 40%, and bulky disease with largest mass diameter was > 10 cm in 10%. CRS and ICANS were grade 2 in 107 patients (46%) and 46 patients (20%), respectively. Median time to first administration of toci was 4 days (range 1-16) with patients receiving 0 (51%), 1 (27%), 2 (14%), or 3-4 (8%) doses. Best response by day 100 for the whole cohort was CR in 138 (60%) and PR in 36 (16%) patients. In univariable analysis, factors associated with a lower likelihood of response were the administration of Tisa-cel (p=0.014), bulky disease (p<0.001), administration of bridging therapy (p=0.009), and being refractory to the last treatment line (p=0.006). Number of doses of tocilizumab did not impact the likelihood of response (p=0.72). In a Cox regression model for survival, number of doses of tocilizumab was not associated with worse PFS (p=0.38, Figure 1) or OS (p=0.64), while other known negative predictors of response had impact on survival, such as bulky and refractory disease. By univariable analysis, tocilizumab administration was significantly associated with prolonged neutropenia (p<0.001). The likelihood to observe an ANC<1000/mmc beyond day 30 increased accordingly to the number of doses received (Figure 2). Other factors associated with late neutropenia were bulky disease (P=0.013), need of bridging therapy (p=0.004), and corticosteroids administration (p<0.001). Conclusion: The number of tocilizumab infusions did not impact CAR T efficacy in terms of overall response and long-term survival, a finding that is concordant with other real-world experiences. The cumulative incidence of late neutropenia events was impacted by the number of doses received. We speculate that a severe CRS driven systemic inflammatory response, requiring several tocilizumab and corticosteroids administrations, may hinder the bone marrow function and recovery.

Chimeric Antigen Receptor T-Cell Therapy in Elderly Patients with Relapsed or Refractory Large B-Cell Lymphoma: A Multicenter Study

Background: Anti-CD19 chimeric antigen receptor T-cell (CART) therapy is a standard of care in patients (pts) with relapsed or refractory (RR) large B-cell lymphoma (LBCL). However, it remains underutilized in elderly pts due to limited efficacy and safety data. We therefore evaluated real world outcomes of CART in such pts. Methods: Seven academic centers participated in this retrospective study. Pts aged ≥65 years with RR LBCL who received a commercial CART product were included. Baseline characteristics, treatment data, CART toxicity, and clinical outcomes were collected. Progression-free survival (PFS; time from infusion to disease progression or death) and overall survival (OS; time from infusion to death from any cause) were analyzed using Kaplan-Meier method. Cumulative incidences of non-relapse mortality (NRM) and disease relapse/progression were estimated accounting for competing risks. Statistical analyses were performed in JMP v15 and XLSTAT v2022.1.2. Results: 209 pts were identified. Baseline characteristics and treatment pattern are shown in Table. Median age at infusion was 71 years (range 65-89), and 25 (12%) were ≥80 years. 131 (63%) were male, 188 (90%) were white, and 27 (13%) had ECOG PS of ≥2. The median HCT-CI was 1 (range 0-6), and 39 (22%) pts had a score of ≥3. 165 (84%) had stage III-IV disease, 131 (70%) had extranodal involvement, 24 (18%) had bulky disease, and 24 (11%) had high grade B-cell lymphoma (HGBL; double- or triple-hit lymphoma, n=15; HGBL, NOS, n=9). The median number of prior lines of therapy was 2 (range 1-8), and 99 (48%) pts had ≥3 prior lines of therapy, 45 (22%) had prior bendamustine, and 44 (21%) had prior stem cell transplant (SCT; auto-SCT, n=41; allo-SCT, n=2; both auto- and allo-SCT, n=1). Bridging therapy was given to 100 (52%) pts; among those, 57 had chemotherapy, 20 had radiotherapy, 6 had both chemotherapy and radiotherapy, 10 had lenalidomide-based regimen, and 7 had CD20 antibody and/or corticosteroids. Axicabtagene ciloleucel (axi-cel) was most frequently used (63%, n=131), followed by lisocabtagene maraleucel (liso-cel) (24%, n=49) and tisagenlecleucel (tisa-cel) (13%, n=27). Cytokine release syndrome (CRS) occurred in 75% of pts, and a minority (6%) had grade ≥3. Immune effector cell associated neurotoxicity syndrome (ICANS) occurred in 55%, and 29% had grade ≥3. The management of CRS and ICANS included corticosteroids in 101 (49%) pts, tocilizumab in 116 (56%) pts, and other biologic agents (anakinra, siltuximab, basiliximab) in 8 (4%) pts. Day 30 response was evaluable in 195 pts with an objective response rate (ORR) of 84%, and a complete response rate (CR) of 52%. 82% of the responders continued to have a response at 3 month follow up. The ORR/CR rates were 86%/53% for axi-cel, 64%/44% for tisa-cel, and 89%/52% for liso-cel, respectively. At a median follow up of 19.1 months (95% CI 16.1-23.6) after infusion, the median PFS was 6.7 months (95% CI 5.1-11.5), with 6- and 12-month PFS rates of 54% (95% CI 47-61) and 43% (95% CI 35-50), respectively. The median OS was 16.5 months (95% CI 13.2-26.7), and the 6-and 12-month OS rates were 70% (95% CI 64-77) and 61% (95% CI 54-68), respectively. The NRM rate was 17% (95% CI 11-24) at 1 year, primarily due to infections including 5 COVID-19 related deaths. In univariate analysis, ECOG PS ≥2, bulky disease, elevated LDH, and the need for bridging therapy were associated with inferior PFS and OS. No significant difference in PFS and OS was seen based on age at infusion with a median PFS of 6.4 vs 9.6 vs 6.4 vs 6.0 months ( P=0.93) (Figure) and OS of 16.4 vs 19.2 vs 28.5 vs 12.7 months ( P=0.85) in age groups ≥65-69 vs ≥70-74 vs ≥75-79 vs ≥80-89. In addition, there was no statistically significant difference in PFS and OS based on type of CART with a median PFS of 6.4 vs 5.6 vs 12.7 months ( P=0.16) and OS of 15.1 vs vs 16.1 vs NR months ( P=0.24) in pts treated with axi-cel vs tisa-cel vs liso-cel. Conclusions: In this large multicenter study of elderly pts with RR LBCL, CART therapy demonstrated favorable efficacy and safety profile comparable to that in pivotal registration trials. Survival outcomes appeared similar regardless of patient age, including those aged ≥80 years, and type of CART product used. Similar to younger pts, high tumor burden and poor performance status at CART infusion were associated with inferior survival. This analysis confirms that older pts should not be excluded from receiving CART therapy solely due to chronological age.

Real-World Outcomes in Patients with Transformed Follicular Lymphoma Treated with CD19-Targeting CAR-T Therapy

INTRODUCTION. CD19-targeting CAR-T cell therapy has changed the treatment landscape of refractory/relapsed large B cell lymphoma, including transformed from FL (tFL). Axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel) are now FDA-approved for the treatment of tFL, but limited data are available on their clinical activity in patients (pts) with tFL since outcomes in those pts were not separately reported in registrational studies. Here, we report a single center's experience with CD19-directed CAR-T cell therapy in pts with tFL. METHODS. We performed a retrospective analysis of 54 pts with tFL treated with CAR-T cell therapy from January 2018 to December 2022. Pathological evidence of histologic transformation (HT) was confirmed. The main clinical-biological characteristics of the pts were extracted from the electronic medical records. Cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT guidelines. Progression-free (PFS) and overall survival (OS) were measured from the time of CAR-T cell infusion; PFS events were death, relapse, and disease progression. RESULTS. Within our cohort of patients with tFL, the median age was 67 years (range 42-81), 65% were male and 77% had stage III-IV disease. Eight of the pts (15%) had an ECOG Performance Status (ECOG-PS) ≥2. Median time to transformation was 27 months from original FL diagnosis (range 0 to 223), including 6 cases with composite lymphoma (FL + aggressive histology) and 4 with synchronous transformation. Twenty percent presented with high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements. Using Hans' algorithm, 85% (44/52) were identified as a germinal center B-cell origin (GCB). In 22 cases, targeted sequencing using the MSK-IMPACT panel was performed at the time of HT or prior to CAR-T. TP53 mutation/deletion was present in 50% of the cases (Figure 1). Pts received a median of 3 (range 1-9) prior lines of therapy including those for FL, and 9 pts (17%) had undergone prior autologous stem cell transplantation (SCT). Thirty-four pts (63%) were refractory to the last therapy, including 29 pts (53.7%) with primary refractory disease after HT. Forty-one pts (76%) received bridging therapy. Seventy-two percent of pts received axi-cel, 19% tisa-cel, and 9% liso-cel. CRS of any grade was seen in 43 (80%) pts with grade >3 in 3 (6%). Neurologic toxicity of any grade was observed in 20 (37%) pts with grade >3 in 7 (13%). The median duration of follow-up was 26.2 months. The overall response rate was 87%, including 67% complete response (CR). The median response duration (DOR) was 11 months, with a 2-year DOR of 42% (95% CI: 28-61%). Objective responses were achieved in pts with high-risk features such as HGBCL, TP53 mutation, and chemotherapy-refractory disease. Twenty-nine pts experienced relapse/progression during follow-up, with a median PFS for the entire cohort of 9.8 months and a 2-year PFS of 40% (95% CI: 28.3-56.3%) (Figure 2). Refractory disease after HT and high LDH serum levels were associated with a significantly lower PFS (median PFS not reached vs. 6.4 months, P=0.031; 24.4 vs. 3.2 months, P=0.003 respectively). Notably, all pts who achieved PR eventually progressed. In 23 pts with relapse, a biopsy was obtained, showing DLBCL or HGBCL morphology in all instances. Interestingly, all relapses occurred during the first 24 months. Twenty-six pts received salvage therapy after CAR-T progression, with a median of 1 line (range 1-7). Out of these, eight (31%) pts achieved a CR and went to allogenic SCT as a consolidative strategy. Twenty-two pts died during follow-up, 19 due to progression and 3 of non-lymphoma causes, including 2 of COVID-19 infection. The median OS was 31 months, and the 2-year OS rate was 57% (95% CI: 44.3-73.8%) (Figure 2). Median OS was not reached among the 36 pts who achieved a complete response. CONCLUSIONS. CD19-targeting CAR-T cell therapy is effective for pts with relapsed/refractory tFL, including patients with characteristics of poor prognosis, with efficacy and toxicity profiles comparable to that observed in previous DLBCL studies. Unfortunately, pts who relapse post-CAR-T therapy have limited effective therapeutic options available, and this currently remains an unmet medical need within the field.

Lisocabtagene Maraleucel Versus Axicabtagene Ciloleucel: Efficacy and Toxicity in a Real-World Setting

CD19 CAR-T therapy has revolutionized the management of high-risk and relapsed/refractory (R/R) large B-cell lymphoma (LBCL) but remains limited by significant toxicities leading to morbidity/mortality and high resource utilization. Single-arm studies have suggested differences in efficacy and toxicity across FDA-approved CD19 CAR-T products. A matching-adjusted indirect treatment comparison showed comparable efficacy and more favorable safety with lisocabtagene maraleucel (liso-cel) compared to axicabtagene ciloleucel (axi-cel), but was limited to clinical trial patients (pts) and suffered from an absence of patient-level data (Maloney, J Hematol Oncol, 2021). In the absence of randomized clinical trial data, adjusted comparative analyses using pt-level data are critically needed to guide product choice. Therefore, we retrospectively evaluated the impact of CAR-T product type on the outcomes of 129 LBCL pts receiving liso-cel or axi-cel per standard of care. All LBCL pts treated at our center with liso-cel or axi-cel outside of a clinical trial between 1/2018 and 5/2023 were included. Best response was determined within 3 months of CAR-T infusion by PET-CT imaging per Lugano 2014 criteria. Cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS) were graded using ASTCT criteria. Of 129 total pts, 37% (n=48) and 63% (n=81) received liso-cel and axi-cel, respectively. Seven pts received out-of-specification liso-cel on an expanded access protocol. Pts who received liso-cel were older (median 67 vs 62 years, p=.003). Other baseline characteristics, including male sex (liso-cel vs axi-cel: 63% vs 69%, p=.4), HCT-CI score (1.0 vs 1.0, p=.6), pre-lymphodepletion (LD) LDH (178 vs 214 U/L, p=.14) and ALC (0.65 vs 0.60 x 10³/µL, p=.3), largest lesion diameter (3.1 vs 3.0 cm, p=.4), and extranodal disease (56% vs 56%, p>.9) were similar. The vein-to-vein time (time from leukapheresis to CAR-T infusion) was longer for liso-cel: median, 35 vs 27 days (p<.001). After liso-cel, the total inpt duration was shorter (median, 5 vs 14 days, p<.001) and fewer pts had ≥2 admissions (8.3% vs 22%, p=0.043). In pts with measurable disease prior to LD (n=113), we observed comparable efficacy with liso-cel vs axi-cel: ORR, 82% vs 77% (p=.5); CR, 56% vs 51% (p=.8). After a median follow-up of 17.7 months, we observed comparable 1-year outcomes with liso-cel vs axi-cel: duration of response (DOR), 56% vs 61% (p=.7); progression-free survival (PFS), 47% vs 47% (p=.99; Figure); and overall survival (OS), 69% vs 60% (p=.39). In pts evaluable for toxicity assessment (n=129), liso-cel was associated with lower rates of CRS and ICANS compared to axi-cel: any grade CRS, 62% vs 88% (p=.001); ICANS any grade, 32% vs 56% (p=.010); days with fever, median 2 vs 5 days (p<.001). Grade 3-4 CRS, 2.1% vs 9.9% (p=.2) or grade 3-4 ICANS, 23% vs 19% (p=0.5) were similar. We measured lower peak serum inflammatory markers after liso-cel: CRP, 58 vs 114 mg/L (p<.001); ferritin, 622 vs 1,315 ng/mL (p=0.007); IL-6, 55 vs 204 pg/mL (p=.010); and D-dimer, 1.4 vs 2.4 mg/L (p=.017). The incidence of infectious complications after liso-cel vs axi-cel was as follows: bacteremia: 6% vs 9% (p=.7); CMV viremia: 13% vs 6.2% (p=.3). Post-infusion median nadir cytopenias were less severe after liso-cel: ANC, 0.32 vs 0.04 x 10³/µL (p<.001); Plt, 69 vs 35 x 10³/µL (p=.003); and Hgb, 8.9 vs 8.2 g/dL (p<.001). Fewer pts developed severe neutropenia after liso-cel: 72% vs 93% (p=0.002). In multivariable analysis including pre-LD LDH and ALC, largest lesion diameter, age and HCT-CI score, we could not confirm an independent impact of the product type on CR, PFS, or OS ( Table). However, axi-cel remained independently associated with a higher odds of any grade CRS (adjusted OR [aOR] 4.56, 95% CI 1.65-13.5, p=.004) and any grade ICANS (aOR 3.44, 95% CI 1.42-8.85, p=.008). Our analysis of CD19 CAR-T therapy for R/R LBCL in the non-trial setting showed similar rates of durable responses following liso-cel and axi-cel. Pts who received liso-cel were older, with otherwise comparable baseline characteristics. Although liso-cel was associated with less toxicity, its vein-to-vein time was longer. In multivariable analyses, pre-LD LDH and largest lesion diameter were the only factors independently associated with response outcomes. We conclude that liso-cel is a robust alternative to other CD19 CAR-T products in older and frailer LBCL pts.

Efficacy of Lisocabtagene Maraleucel for Relapsed or Refractory Aggressive B Cell Lymphoma in Our Hospital

[Background] Although the standard treatment for relapsed or refractory large B-cell lymphoma (LBCL) is high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT), the prognosis of relapsed or refractory LBCL is poor. The chimeric antigen receptor (CAR) T-cell therapy showed efficacy against relapsed or refractory LBCL. However, little real-world data on lisocabtagene maraleucel (liso-cel) were reported. Therefore, we report our data on liso-cel for relapsed or refractory LBCL in our institution. [Methods] We retrospectively analyzed clinical characteristics of patients who underwent leukapheresis to manufacture liso-cel between August 2021 and March 2023 at Toranomon Hospital. Overall survival (OS), progression-free survival (PFS), and duration of response (DOR) were calculated using the Kaplan-Meier method. OS was defined as the time from infusion of liso-cel to the date of death or last follow-up. PFS was defined as the time from infusion of liso-cel to progression of disease or death. DOR was defined as the time from first complete response or partial response to disease progression or death. The Cox proportional hazards model was used to determine the significance of multiple variables. [Results] Leukapheresis for the manufacture of liso-cel was performed in 25 cases. Of these 25 cases, liso-cel could not be manufactured in only one patient, and the other 24 patients received liso-cel infusion. Of the 24 patients who received liso-cel, 14 were men and the median age was 64.5 years (range, 29-78). Twenty-one patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; the other 3 had a PS of 2. The other clinical characteristics were as follows: Stage III/IV in 21 (87.5%); Bulky mass in 6 (25%); extranodal involvement > 1 in 9 (38%); international prognostic index (IPI) > 2 in 13 (54%); and elevated LDH in 11 (46％). Histological diagnoses were diffuse large B-cell lymphoma (n=13), transformed follicular lymphoma (n=6), primary mediastinal large B-cell lymphoma (n=3), and high-grade B-cell lymphoma (n=2), respectively. Secondary central nervous system (CNS) involvement was detected in 4 cases. The number of patients with primary refractory disease or relapse within 12 months after first-line chemotherapy is 10 (42%) and 10 (42%), respectively. Since 10 patients with primary refractory disease required immediate chemotherapy until leukapheresis was performed, liso-cel was used as a third-line or later in all cases. Patients had received a median of 4 (range, 2-9) previous lines of chemotherapy. Six patients (25%) had received a previous autologous HSCT, and two (8%) had received a previous allogeneic HSCT, respectively. The median time from leukapheresis to liso-cel arrival at our institution was 42 (range, 37-45) days. Bridging chemotherapy after leukapheresis was performed in all cases, with polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) being the most common with 13 cases (54%). Eight cases (33%) had achieved complete response (CR), and 8 cases (33%) had achieved partial response (PR) before lymphodepleting chemotherapy. The median follow-up of survivors was 7.7 months (range, 2.5-14.5). The median OS, PFS, and DOR were 11.5 months (95% confidence interval [CI]: 8.9 to not applicable, NA), 8.5 months (95% CI: 2.1 to NA), and 8.9 months (95% CI: 3.3 to NA), respectively. The overall response rate was 71%, with 54% achieving CR. Cytokine release syndrome (CRS) and neurological events (NEs) occurred in 21 (88%) and 2 patients (8%); grade 3 or worse CRS and NEs occurred in 1 (4%) and 2 patients (8%). Grade 3 or worse neutropenia, anemia, and thrombocytopenia were occurred in 23 (96%), 14 (50%), and 17 cases (71%), respectively. Prolonged Grade 3 or worse neutropenia was seen in 12 cases (50%) at 28 days after liso-cel infusion. No treatment-related death was not observed. Six patients died, and the causes of death were LBCL (n=3), pneumonia (n=2), and COVID-19 (n=1). In the multivariate analysis, independent risk factors for PFS were PS of 2 (hazard ratio [HR], 56.39; 95% CI, 8.31 to 382.7; p<0.001) and disease status (stable disease/progressive disease) before lymphodepleting chemotherapy (HR, 6.14; 95% CI, 1.07 to 35.06; p=0.04). [Conclusion] In our cohort, liso-cel has shown high response in relapsed or refractory LBCL. Disease status before lymphodepleting chemotherapy is significant for better prognosis.

Introduction of Glofitamab for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) after ≥2 Lines of Systemic Therapy Results in Cost Savings to the Healthcare System Based on a United States Budget Impact Analysis

Background: Glofitamab is a humanized CD20xCD3 T-cell engaging bispecific immunoglobulin G1 antibody that was granted accelerated approval from the United States (US) Food and Drug Administration for adult patients with relapsed or refractory (R/R) DLBCL, not otherwise specified or large B-cell lymphoma arising from follicular lymphoma, after ≥2 lines of systemic therapy. We conducted a budget impact analysis to assess the effect of introducing glofitamab as a treatment option for R/R DLBCL after ≥2 lines of systemic therapy by estimating total costs to a US health plan, with and without glofitamab. Methods: A 3-year budget impact model was developed for a hypothetical cohort of 1 million patients enrolled in a mixed commercial/Medicare health plan. Comparators were axicabtagene ciloleucel (Axi-cel), lisocabtagene maraleucel (Liso-cel), tisagenlecleucel (Tisa-cel), loncastuximab tesirine (Lonca), polatuzumab vedotin + bendamustine + rituximab (Pola-BR), rituximab + gemcitabine + oxaliplatin (R-GemOx), tafasitamab + lenalidomide, and epcoritamab. Total costs included those of the drug (based on mean treatment duration observed in pivotal trials) and its administration, as well as those arising from managing adverse reactions (including cytokine release syndrome and hematology laboratory abnormalities) and routine care. Drug costs were estimated based on the average wholesale acquisition cost reported in AnalySource ® (2023) or the Average Sales Price in the Centers for Medicare Services Pricing File (2023). All other costs were based on several US published sources. Market shares were based on Genentech internal projections and expert opinions. All costs were inflated to 2023 US dollars, where applicable. Budget impact outcomes over 3 years were presented as total cumulative costs and average per-member per-month (PMPM) costs. In a scenario analysis, we examined the budget impact when maximum treatment duration per US prescribing information (USPI) was applied across treatments. The net budget impact was the difference in costs between the projected scenario with glofitamab and the current scenario without glofitamab. Results: Among 1 million patients,approximately nine patients were projected to be eligible for treatment of R/R DLBCL after ≥2 lines of therapy.The introduction of glofitamab as a treatment option resulted in an estimated cumulative total cost saving of $728,697 over 3 years; the average PMPM net budget impact was −$0.0202 ( Figure A). The introduction of glofitamab reduced costs across all categories ( Figure A). Among the newer therapies including chimeric antigen receptor T-cell therapy and bispecific antipbodies, the total cost per treated patient was lowest for glofitamab over the 3-year period: glofitamab = $226,658; Tisa-cel = $564,113; Axi-cel = $540,002; Liso-cel = $516,272; epcoritamab = $335,293 ( Figure B). In the scenario analysis where the full treatment duration per USPI was modeled, the introduction of glofitamab as a treatment option resulted in greater cost savings over 3 years, versus the current scenario without glofitamab (cumulative: −$921,407 and PMPM: −$0.0256). Conclusions: Over 3 years, the estimated cumulative per-patient cost of glofitamab is projected to be the lowest when compared with per-patient costs of other available T-cell engaging therapies, resulting in cost savings after its formulary adoption for the treatment of R/R DLBCL after ≥2 lines of therapy.

An Economic Model to Estimate Costs of Cytokine Release Syndrome and Neurological Events Among Patients Treated with CAR T Cell Therapies for Relapsed or Refractory Follicular Lymphoma

Background: CAR T cell therapies have exhibited promising clinical responses in populations that are traditionally challenging to treat. Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are 2 CAR T cell therapies now available in the United States (US) for the treatment of R/R follicular lymphoma (FL) after 2 or more lines of systemic therapy. Lisocabtagene maraleucel (liso-cel) is currently being investigated in clinical trials for the treatment of patients with R/R second-line high-risk and third line or later FL. As observed in other approved indications, the improved response and survival rates from the introduction of CAR T cell therapies are typically accompanied by the potential for AEs, such as cytokine release syndrome (CRS) and neurological events (NEs). However, the rates and severity of these AEs tend to vary across CAR T cell therapies. Understanding the economic implications of these 3 CAR T cell therapies and their associated AEs is crucial for informed decision-making and to underscore key economic and safety differences across the 3 CAR T cell therapies. The primary objective of this analysis was to estimate the average per-patient weighted costs of CRS and NEs for a patient with R/R FL treated with a CAR T cell therapy (liso-cel, axi-cel, or tisa-cel) based on clinical trial rates. Secondary objectives included estimates for (1) the opportunity cost of treating with axi-cel or tisa-cel versus liso-cel and (2) the additional number of patients eligible for treatment with liso-cel based on a hypothetical sample of 100 treated patients. Methods: An economic model was developed using data from the TRANSCEND FL (NCT04245839; n = 130), ZUMA-5 (NCT03105336; n = 124), and ELARA (NCT03568461; n = 97) studies. CRS and NE rates reported in the FL studies were incorporated in a decision analytic economic model to estimate costs from a health care system perspective in 2023 US dollars. Microcosting analysis data from the TRANSCEND FL study were used as CRS and NE cost inputs; the model assumed that CRS and NE management costs across CAR T cell therapies would not differ. The analysis used a Monte Carlo simulation approach to address uncertainty surrounding the clinical and economic data. The model output was a weighted average that represented cost for the average treated patient, including those with and without CRS and/or NEs. The average per-patient total cost difference between CAR T cell therapies was used to estimate the number of additional patients who could be treated with liso-cel versus axi-cel or tisa-cel. Results: Rates of CRS grade 1‒2/≥ 3 were 56.9/0.8% for liso-cel, 71.8%/6.5% for axi-cel, and 48.5%/0.0% for tisa-cel. Rates of NE grade 1‒2/≥ 3 were 13.1%/2.3% for liso-cel, 41.1%/ 15.3% for axi-cel, and 34.0%/ 3.1% for tisa-cel. The overall per-patient weighted average costs for CRS and NEs were estimated to be $20,626 for liso-cel, $44,096 for axi-cel, and $26,460 for tisa-cel (Figure). The per-patient weighted average cost per CRS event was $14,631 for liso-cel, $21,299 for axi-cel, and $12,456 for tisa-cel. The per-patient weighted average cost per NE was $5994, $22,797, and $14,004 for liso-cel, axi-cel, and tisa-cel, respectively. Total per-patient cost differences for liso-cel compared with axi-cel and tisa-cel were −$23,470 and −$5835, respectively. The resulting opportunity costs from treating 100 patients with liso-cel instead of axi-cel and tisa-cel would allow for the treatment of an additional 5.2 and 1.3 patients, respectively. Conclusions: This economic analysis revealed lower overall per-patient weighted average costs associated with liso-cel compared with axi-cel and tisa-cel, primarily due to lower CRS and NE rates versus axi-cel and lower NE rates versus tisa-cel. In comparison with axi-cel and tisa-cel, liso-cel demonstrated robust economic and clinical value, with lower rates of CRS and/or NEs associated with substantial cost savings per AE event.

Pilot Study of Longitudinal Geriatric Assessment and Neurocognitive Evaluation in CAR T-Cell Therapy for Older Patients with Relapsed Refractory, Large B-Cell Lymphoma

Introduction: Chimeric antigen receptor T-cell (CAR T) therapy is increasingly utilized for older patients with relapsed refractory, large b-cell lymphoma (LBCL) with promising efficacy. However, the feasibility of conducting serial geriatric assessments with appropriate management has not been examined in this vulnerable population of patients. Moreover, the short-term and long-term impact of CAR T-cell therapy on the older patient's overall physical and neurocognitive functioning remains unknown. Methods: In this prospective pilot study (NCT04300998), we enrolled older patients with LBCL receiving commercial CAR T and conducted serial geriatric assessments (GA), formal neurocognitive testing in domains sensitive to cancer therapy side effects including attention, memory, and executive functions, and quality-of-life surveys prior to and following CAR T treatment at 3, 6, and 12 months among patients who remained in remission. CAR T manufacturing, treatment, and follow-ups followed national and institutional guidelines. Cytokine release syndrome (CRS) and Immune effector cell-associated neurologic syndromes (ICANS) were graded according to the ASTCT criteria. Standard statistical analysis was performed for CAR T treatment outcomes. GA impairment in each domain (binary outcome) was tabulated as percentages. For neurocognitive testing, means across timepoints were estimated for each test score using a linear mixed model predicting the score by timepoint. A random intercept was included to account for multiple assessments per patient. Results: Between April 2020 to March 2022, 18 patients were enrolled. The median age was 69.8 years (range 63.7 to 85.0) and 8 of 18 patients, 44%, were female. Eight patients received Axicabtagene ciloleucel while 6 and 4 patients received Tisagenlecleucel and Lisocabtagene maraleucel, respectively. Fourteen out of 18 patients, 78% (95% confidence interval [CI] 52 - 94), completed all required GA visits (baseline and all follow-up timepoints while in remission), meeting the prespecified feasibility endpoint of 75%. Geriatric vulnerabilities detected by GA were highly prevalent at the baseline including functional impairment by instrumental activities of daily living (44%), mobility impairment (24%), multimorbidity (61%), polypharmacy (44%), poor psychosocial support (39%), and depression (28%). Moreover, on a panel of 7 neurocognitive tests, 52.9% of patients had at least one and 29.4% had 2 or more impairments at baseline. With a median follow-up of 24 months (95% 23 - not reached), the 2-year overall and progression-free survival was 70% (95% CI 51 - 96) and 42% (95% CI 24 - 74), respectively. Ten patients had relapsed/progressed and among them 5 had died. Thirteen patients, 72%, experienced CRS with the majority grade 1-2 and only 2 patients (11%) had grade 3 CRS. Four patients, 22%, experienced ICANS (three grade 1 and one grade 2). The most common high-grade toxicities within 100 days of CAR T treatment were infections (n=4); cardiac complications (n=2); and thrombotic complications (n=2). There was no treatment-related death. Finally, longitudinal GA post-CAR T revealed the stability of geriatric impairment overtime among patients remaining in remission (Figure 1 left). Moreover, detailed neurocognitive testing revealed global stability of cognitive performance with improvements in 3 cognitive tests overtime, HVLT, ZBTA, and ZBF (Figure 1 right HVLT test). These findings support the notion among patients who achieve remission. Conclusions: In this prospective pilot study, we showed that longitudinal GA was feasible to perform in older, vulnerable lymphoma patients receiving CAR T therapy. Despite advanced age and high prevalence of baseline geriatric and cognitive deficits, CAR T treatment was well tolerated without excessive or unexpected toxicities. Stable GA deficits and improvement in some areas of cognitive performance were observed descriptively among patients in ongoing remission, supporting that CAR T treatment in older patients is safe without detrimental, long-term cognitive and functional impacts. Although the small sample size and incomplete data limited study interpretation and generalization, GA and geriatric management may provide valuable, actionable information to optimize older lymphoma patients for CAR T-cell therapy.

Clinical Outcomes of Patients with Hematologic Malignancies Receiving Bendamustine Lymphodepletion Prior to CAR-T Cell Infusion

CAR-T cell therapy has revolutionized the treatment of adult patients with relapsed/refractory (r/r) non-Hodgkin lymphomas (NHL) and multiple myeloma (MM). While lymphodepletion (LD) with fludarabine/cyclophosphamide (flu/cy) has been the standard, the fludarabine drug shortage has caused a shift toward the use of bendamustine as an alternative. This study expands upon previous investigations evaluating bendamustine as a LD agent prior to CART therapy. We conducted a retrospective study of 48 patients with r/r NHL (marginal zone lymphoma (MZL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL)) and MM who received bendamustine LD prior to treatment with commercial CART products at the UPMC Shadyside Hospital between 07/2022-04/2023. Data were collected using chart review and analyzed by descriptive statistics. Responses for NHL and MM were assessed based on the Lugano 2014 criteria and the International Myeloma Working Group consensus criteria, respectively. Toxicities were evaluated based on the American Society for Transplantation and Cellular Therapy consensus grading and the Common Terminology Criteria for Adverse Events. 33 patients with NHL (24 with DLBCL, 2 with MZL, 2 with FL and 5 with MCL) and 15 with MM, were included with a mean age of 65.8 years. The median number of prior therapies was 2 [1 - 5] for NHL, and 5 [4 - 10] for MM. In the NHL cohort, 14/33 patients were treated in the second line. Among NHL patients, 5/33 patients received brexucabtagene autoleucel, 24/33 axicabtagene ciloleucel (axi-cel), and 4/33 lisocabtagene maraleucel (liso-cel). Among MM patients, 2/15 patients received idecabtagene vicleucel, and 13/15 ciltacabtagene autoleucel (cilta-cel). Grade (G) 1-2 CRS occurred in 23/33 of NHL and 14/15 of MM patients, without any reported G3 CRS. ICANS was reported in 9/33 (3 G3) of NHL and 7/15 (1 G3) of MM patients. The overall response rate (ORR) in MM patients was 12/15, with 6/12 achieving complete response (CR) or stringent CR (sCR) and 6/12 a very good partial response (VGPR), and only 1/12 progressing after a response. In the NHL cohort, we evaluated the ORR for every subtype. The ORR was 16/24 (11/16 CR and 5/16 PR) in DLBCL, 1/2 (CR) in MZL, 3/5 (all CR) in MCL, and 2/2 (all CR) in FL. Only 3 patients with DLBCL, 1 with MZL and 1 with MCL eventually progressed after a response. These response results are comparable with prior CART studies of flu/cy LD that have shown ORR range of 72-73% (CR 51-54%) for DLBCL ( Locke F, Lancet Oncol., 2019; Abramson JS, Lancet 2020), 91% (CR 60%) for FL ( Jacobsen CA, Lancel Oncol. 2022), and 98% (sCR 78%) for MM ( Berdeja JG, Lancet 2021). Next, we evaluated the change in hematologic parameters after LD. Absolute lymphocyte counts (ALC) showed mean decreases of 66.8% (± 28.4%) in NHL and 69.3% (± 16.4%) in MM from pre-LD to the day of CAR-T infusion (D CART), with median time-to-nadir (TTN) post-D CART of 1 [0-13] days in NHL and 1 [0-8] days in MM. We then compared the incidence of neutropenia in our cohort relative to historical controls treated with flu/cy LD. Neutropenia was seen in 80% of patients (G≥3, 68%) with axi-cel, 50% (G≥3, 50%) with liso-cel, and 100% (G≥3, 77%) with cilta-cel. This compares favorably to historical data with axi-cel, (86%; G≥3, 80%), liso-cel (63%; G≥3, 60%), and cilta-cel (96%; Gr≥3, 95%). Table 1 illustrates the grades of cytopenias and ANC nadir and TTN post-D CART in our study. Finally, we investigated the mean change in inflammatory markers as a surrogate of CAR-T activation and expansion. CRP showed a median increase of 2.8-fold [0 - 66.5] in a median of 5 [0-55] days in NHL, and a median increase of 4.6-fold [0.22 - 74.9] in a median of 8 [2-15] days in MM. Ferritin had a median increase of 1.2-fold [0- 50] in median of 9 [0-171] days in NHL, and median increase of 3.8-fold [0.63 - 59.4] in median 10 [0-148] days in MM. In conclusion, bendamustine is a successful LD agent prior to CAR-T infusion, yielding response rates comparable to historical controls in NHL and MM. Notably, our study reveals a favorable safety profile with a lower rate of high grade cytopenias than was seen in the pivotal trials using flu/cy LD. These findings are reassuring regarding the use of bendamustine as an alternative LD agent in the face of the ongoing fludarabine drug shortage. Further studies assessing CART copy numbers and persistence of CART are needed.

Lisocabtagene Maraleucel (liso-cel) in Patients (Pts) with R/R MCL: Subgroup Analyses in Pts with High-Risk Disease Features from the MCL Cohort of the TRANSCEND NHL 001 Study

Background: Pts with R/R MCL after ≥ 2 prior lines of therapy, including a Bruton tyrosine kinase inhibitor (BTKi), have poor prognosis. Among pts with R/R MCL, several high-risk disease features are associated with a worse prognosis, including TP53 mutation, high proliferation index (Ki-67 ≥ 30%), blastoid morphology, and secondary CNS involvement. 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. In the primary analysis of the MCL cohort from the phase 1, seamless design TRANSCEND NHL 001 study (NCT02631044), liso-cel treatment resulted in a rapid, high rate of durable CRs with a manageable safety profile in pts with heavily pretreated R/R MCL. Here we report the outcomes in pts with R/R MCL from prespecified subgroup analyses based on high-risk disease features. Methods: Eligible pts had PET-positive R/R MCL after ≥ 2 lines of prior therapy, including a BTKi, alkylating agent, and CD20-targeted agent. Pts received liso-cel at a target dose of 50 × 10 6 or 100 × 10 6 CAR + T cells after lymphodepleting chemotherapy. Bridging therapy was allowed. Primary endpoints were treatment-emergent AEs (TEAE) and ORR by independent review committee (IRC) per Lugano 2014 criteria; secondary endpoints included CR rate, duration of response (DOR), PFS, and OS. The liso-cel-treated set included all pts who received liso-cel. The efficacy analysis set included all pts in the liso-cel-treated set who had PET-positive disease per IRC at baseline. Results: Of 104 leukapheresed pts, 88 received liso-cel. Median on-study follow-up was 16.1 mo (range, 0.4-60.5). Median age was 68.5 y (range, 36-86) and median prior systemic lines of therapy was 3 (range, 1-11). Among liso-cel-treated pts, 66 (75%) had Ki-67 ≥ 30% and 15 (17%) had Ki-67 < 30% (Ki-67 was not reported in 7 [8%] pts); 20 (23%) had a TP53 mutation present and 34 (39%) did not ( TP53 mutation was indeterminate in 4 [5%] pts and not reported in 30 [34%] pts); and 27 (31%) had blastoid morphology and 48 (55%) did not (blastoid morphology was not reported in 13 [15%] pts). Most pts with these high-risk disease features also had disease that was refractory to last therapy, was refractory to prior BTKi, and had a complex karyotype. A total of 7 (8%) pts had secondary CNS lymphoma, of which 5 had refractory disease, 5 had Ki-67 ≥ 30%, and 1 each had TP53 mutation and blastoid morphology. Response rates, PFS, and OS across subgroups were consistent with the overall population, with high ORR and CR rate that was durable and high PFS and OS (Table 1). Although a limited number of pts had TP53 mutation assessed, pts with TP53 mutation had a numerically lower median DOR than the overall population, likely due to a higher proportion of objective responders achieving a PR than CR; however, pts with TP53 mutation who achieved CR had durable responses with 6 of 11 pts in an ongoing response at data cutoff. Among the 7 pts with secondary CNS lymphoma, response rates were high (ORR, 86% [n = 6]; CR rate, 71% [n = 5]), and 3 of 5 pts who achieved CR were in an ongoing response at data cutoff. Safety outcomes across subgroups were generally consistent with the overall population (Table 2). Most cytokine release syndrome (CRS) and neurological events (NE) were low grade in all subgroups, similar to the overall population (any-grade CRS, 61% [grade 3-4, 1%]; any-grade NEs, 31% [grade 3-4, 9%]; and no grade 5 CRS or NEs). Incidences of other TEAEs of special interest were also similar among subgroups. Of the 7 pts with secondary CNS lymphoma, 5 had low-grade CRS and 3 had low-grade NEs with no grade ≥ 3 CRS or NEs reported; 1 pt had a grade ≥ 3 infection. Cellular kinetics and B-cell aplasia by subgroup will be presented. Conclusions: In these subgroup analyses including pts with R/R MCL and high-risk disease features (Ki-67 proliferation index ≥ 30%, TP53 mutation, blastoid morphology, and secondary CNS lymphoma), liso-cel demonstrated clinically meaningful efficacy across subgroups with durable responses. Efficacy and safety outcomes were generally consistent with the overall study population. While some subgroups were limited by small numbers, these results suggest a favorable benefit/risk profile for liso-cel in pts with R/R MCL and high-risk disease features, a pt population for whom effective treatment options are rarely available.

Long-term Follow-up from Qualitative Interviews of Patients with Relapsed or Refractory Large B-Cell Lymphoma on Their Treatment Experience While Enrolled in a Lisocabtagene Maraleucel Study

Background: Patients(pts) with R/R large B-cell lymphoma (LBCL) have rapid and durable responses when treated with lisocabtagene maraleucel (liso-cel), a CD19-directed CAR T cell therapy. The safety profile is manageable with low rates of grade ≥ 3 cytokine release syndrome, neurological events, and infections and no new safety signals after long-term follow-up (Abramson JS, et al. Blood 2021). Qualitative pt interviews can generate meaningful data to gain deeper understanding of the treatment (tx) experience and benefit from the pt perspective, help interpret pt-reported outcome (PRO) scores, and help identify what is most important to pts. Previous qualitative pt interviews within the context of a clinical trial showed positive pt experience in the first 3 months after liso-cel infusion (Siddiqi T, et al. Blood 2021). This analysis assessed pt perceptions of liso-cel tx 6‒24 months after infusion. Methods: Pts with R/R LBCL treated with liso-cel in a single-arm phase 2 study (TRANSCEND WORLD [NCT03484702]) had an option to participate in a series of semistructured guided interviews that included 5 close-ended questions. Interviews were conducted by trained researchers independent of the trial and were audio recorded and transcribed. Analyses included thematic analysis, quantitative descriptive analysis of close-ended items, and qualitative longitudinal analysis. Interviews were conducted at baseline (before leukapheresis), after leukapheresis and before infusion; in the 3 days after infusion; and at 1, 2, 3, 6, 9, 12, 18, and 24 months after infusion. Results from Months 6‒24 are presented. Results: Overall, 48 interviews were analyzed across 21 unique pts (8 from Spain; 4 from France; 3 from Austria; 2 from Finland; and 1 each from Germany, Italy, Japan, and the Netherlands). Mean age was 62 years, and the sample was 62% male. Most interviews were conducted in the first year: 12 at Month 6, 18 at Month 9, 10 at Month 12, 4 at Month 18, and 4 at Month 24. Whereas all pts (n = 21, 100%) reported ≥ 1 tx-related advantage between Months 6 and 24, 71% (n = 15) reported ≥ 1 tx-related disadvantage. The most common advantages included benefits regarding the lack of side effects (SEs) or the minor nature of SEs (n = 19, 90%) and efficacy (n = 18, 86%) associated with liso-cel. Fewer pts mentioned SEs associated with liso-cel (n = 10, 48%) and lack of efficacy (n = 7, 33%) as disadvantages. When specifically compared with other txs received (eg, transplant, radiation, chemotherapy, and unspecified txs), liso-cel was most often considered more advantageous in terms of favorable efficacy and SEs. The majority of pts (n = 15, 71%) described ≥ 1 advantage related to trial conduct (eg, quality of site staff), short time needed for infusion, or frequent medical care from follow-ups. Most pts (n = 15, 71%) also described ≥ 1 trial-related disadvantage, including the burden of safety monitoring and uncertainty about long-term outcomes. Between baseline and each time point, pts who received liso-cel as their only tx while enrolled in the trial either improved more often than they worsened or maintained stability in health and well-being areas of “physical capacity and day-to-day life” and “future outlook” (n = 14, 67%). Pts most frequently maintained stability over the course of the trial in areas of “feelings and mood,” “family, friends, and leisure,” “work and career,” and “income and expenses.” There were no clear trends in change over time for the area of “physical health.” In 2 separate interview questions, pts were asked to rate the benefits and negatives of liso-cel tx on a 0‒10 scale (0 = none; 10 = tremendous). Mean benefits score ranged from 7.28 at Month 12 to 9.25 at Month 24. Negative ratings were at the low end of the scale; mean score ranged from 1.33 at Month 6 to 3.17 at Month 18. At each time point, most pts (58%‒78%) reported that benefits outweighed negatives, and ≥ 75% reported that they would make the same decision to receive liso-cel. Between 50% and 100% of pts also stated they would recommend the trial to a friend. Conclusions: This study provides unique insights into the pt experience during the 2-year follow-up after liso-cel infusion that complement PRO data and provide a qualitative assessment of change over time. Pts generally reported positive tx experiences, improvements or stability in quality of life, and that they would repeat their decision to receive liso-cel.

Real-World Outcomes of CD19CAR T Cell Therapy in Adult Patients with Relapsed Refractory Transformed Indolent Lymphoma

Introduction Transformation of indolent lymphomas to diffuse large B-cell lymphoma (DLBCL) is associated with poor outcomes, particularly for patients (pts) with relapsed or refractory (r/r) disease. While chimeric antigen receptor (CAR) T cell therapy has revolutionized the management of r/r DLBCL and is approved for transformed indolent lymphoma (TIL), patients with TIL were largely underrepresented in the pivotal trials leading to the approval of CD19CAR T. In this study, we evaluate the safety and efficacy of standard of care (SOC) CD19CAR T in TIL relative to de novo DLBCL (dDLBCL). Methods We performed a multi-center retrospective study to evaluate safety and efficacy of SOC CD19CAR T in adults with r/r TIL and dDLBCL treated at 5 centers. Eligibility criteria included age ≥ 18 years old, diagnosis of DLBCL (de novo or transformed), r/r disease, and receipt of SOC CD19CAR T. Pts who received CAR T on clinical trials were excluded. We defined TIL as DLBCL transformed from follicular lymphoma (FL), marginal zone lymphoma (MZL), or Waldenstrom's macroglobulinemia (WM). Pts with Richter's syndrome were excluded. Safety endpoints: incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. Response was assessed using 2014 Lugano Criteria. Efficacy endpoints include best overall response rate (ORR) (proportion of patients achieving a complete or partial response), complete response (CR) rate, progression/relapse-free survival (PFS) and overall survival (OS). Results A total of 788 pts were included (212 (27%) TIL, 576 (73%) dDLBCL) with the CAR T infusion date ranging from 12/2017 to 03/2023. In the TIL cohort, 192 (91%) pts transformed from FL, 14 (7%) MZL, 5 (2%) WM, and 1 indolent lymphoma NOS. In TIL and dDLBCL cohorts, respectively, the median age at infusion was 64 (range 33-85)/64 (21-85) yrs, 37%/36% were female, pts received a median of 3 (range: 1-11)/ 3 (1-13) prior lines of therapy, and 11%/13% had ECOG ≥2 at time of lymphodepletion. In TIL cohort, 44 (21%) pts received prior stem cell transplantation (41 autologous, 3 allogeneic, and none both), while in dDLBCL cohort, 135 (23%) received prior SCT (122 autologous, 9 allogeneic, and 4 both). In TIL and dDLBCL cohorts, 76%/73% received axicabtagene ciloleucel, 17%/18% tisagenlecleucel, and 7%/10% lisocabtagene maraleucel, respectively. Similar toxicities were observed in both cohorts. Any grade CRS/grade ≥ 3 CRS were observed in 76% (95% CI: 70-82%)/ 5% (3-9%) of TIL pts and 81% (78-84%)/ 6% (4-8%) of dDLBCL pts, respectively. Any grade ICANS/grade ≥ 3 ICANS rate were observed in 37% (95%CI: 31-44%)/ 16% (11-21%) of TIL pts and 49% (45-53%)/ 23% (20-27%) of dDLBCL pts, respectively. In TIL and dDLBCL cohorts, respectively, 49%/59% of pts received tocilizumab for CRS and 41%/51% received steroids for CRS or ICANS. Efficacy outcomes were comparable. The best ORR/ CR rate were 78% (95%CI: 72-83%)/ 63% (56-70%) in the TIL cohort and 77% (73-80%)/ 55% (51-59%) in the dDLBCL cohort. Among responders, the median time from infusion to best response was 33 days (IQR: 29-69) and 34 days (IQR: 29-85), respectively. With a median overall follow-up of 13.4 (0.03-63.1) months (mons), the median PFS was 11.2 mons (95%CI: 6.3-20.8) in the TIL and 7.9 mons (95%CI: 6.1-12.2) in the dDLBCL cohort, with a 24-month PFS of 39.4% (95%CI: 32.2-46.5%) and 39.7% (95%CI: 35.5-44.0%) respectively (logrank p=0.45). Median OS was 41.7 mons (95%CI: 24.9-not reached) and 29.7 mons (95%CI: 22.1-not reached) with a 24-month OS of 57.8% (95%CI: 50.1-64.7%) and 53.2% (95%CI: 48.4-57.7%) in TIL and dDLBCL cohorts, respectively (logrank p=0.49). There was no statistically significant difference between the survival outcomes of the TIL and dDLBCL cohorts. 41% (86/212) and 42% (241/576) pts died in the TIL and dDLBCL cohorts respectively, with similar rates of CAR T cell related deaths (9.3% vs 7.1%). Conclusion This study represents the largest evaluation to date of outcomes of CD19CAR T in TIL. The results indicate that CD19CAR T is tolerable and active in pts with r/r TIL with safety and efficacy outcomes similar to that observed in pts with dDLBCL. Our findings suggest CD19CAR T cell therapy may be able to overcome the historically poor prognosis associated with r/r TIL.

Are Pivotal CART Trials Representative of Population at Risk?

Introduction Since 2017, 6 chimeric antigen receptor T-cell (CAR-T) therapies have been approved for Acute Lymphoblastic Leukemia (ALL), Mantle Cell Lymphoma (MCL), Diffuse Large B-cell Lymphoma (DLBL), Follicular Lymphoma (FL), and Multiple Myeloma (MM) and have changed the treatment landscape immensely. There is significant demographic and geographic under-representation in pivotal clinical trials leading to drug approvals for leukemias, lymphomas and MM compared with the population affected. We investigated whether similar disparities exist in pivotal CAR-T trials. Method Clinical Trials leading to CAR-T approval were identified from the US Food and Drug Administration databases. Demographic data was collected from clinicaltrials.gov and primary manuscripts. Standard descriptive statistics were used to analyze the data with stratification by race, ethnicity, sex, and malignancy subtypes. Total incidence of respective malignancies and the demographic representation was obtained from SEER data. Results A total of 10 out of 11 (90.91%) clinical trials leading to CAR-T approval reported data on race and 8 (72.72%) on ethnicity. These trials led to approvals for MM, non-Hodgkin lymphoma (DLBCL, FL and MCL), and ALL. These trials included 1441 patients of which 1155 (80.15%) were reported as White. NCT02445248, for Tisagenlecleucel (tisa-cel) lacked racial data and was excluded from analysis. Data are summarized in Table 1. For MM, 2 CARTs have been approved, Idecabtagene vicleucel and Ciltacabtagene autoleucel (cilta-cel). African American (AA) representation in these pivotal trials, NCT03361748 and NCT03548207 (CARTITUDE-1), respectively was 4.7 % and 17.5 %. In contrast, SEER data shows that AA population represent 21% of the incident MM cases over the last 5 years (2016-2021). In ALL, 2 CARTs, tisa-cel and Brexucabtagene Autoleucel (brexu-cel) have been approved. AAs had 0.55% of representation in the CAR-T ALL clinical trials, whereas they represent 7.5% of all ALL cases in the past 5 years. For follicular lymphoma, Tisa-cel and Axicabtagene ciloleucel (Axi-cel) have been approved as third line treatment. For DLBCL, lisocabtagene maraleucel (liso-cel), tisa-cel and axi-cel have been approved as third line with liso-cel and axi-cel also having second line DLBCL indication. Brexu-cel has been approved for third line MCL. Under-representation of AAs with respect to disease distribution was noted in all these trials. Female patients were also disproportionately under-represented in lymphoma trials overall. Ethnicity was reported less frequently in aforementioned studies but available data suggests Hispanic groups being underrepresented in these trials. Conclusion There are significant demographic under-representations and imbalances in pivotal clinical trials leading to CART approval compared with the population affected. Efforts need to be directed at ensuring racial and ethnic inclusivity and equity in trials for better applicability to the “real world”. Trials should also consistently report demographic data, especially ethnic and racial, for better transparency and accurate analysis of presented data.

CNS Radiotherapy As Bridging Prior to CAR T-Cell Therapy for Non-Hodgkin B-Cell Lymphoma

Introduction: Up to 80% of patients who receive CAR T-cell therapy (CAR T) for central nervous system lymphoma (CNSL) require bridging therapy, yet optimal regimens remain undefined. Radiotherapy is an established strategy for extracranial lymphoma that provides beneficial cytoreduction. However, CNS bridging radiotherapy (CNS-BRT) prior to CAR T is controversial due to concerns of potential enhanced neurotoxicity. We explored the safety and response profiles in patients treated with CNS-BRT prior to CAR T. Methods: We identified patients with non-hodgkin B-cell lymphoma who received CNS-BRT at our institution prior to commercial CAR T infusion. CNS-BRT was defined as treatment delivered between apheresis and CAR T infusion or within 30 days prior to apheresis, targeting the CNS parenchyma, leptomeninges, or epidural spine. Patients with epidural spine disease were included since the adjacent spinal cord is part of the treatment field. Safety was evaluated by rate of cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) after CAR T. Best CNS response post CAR T was evaluated using the International Primary CNS Lymphoma Collaborative Group (IPCG) or Response Assessment in Neuro-Oncology (RANO) for parenchymal or leptomeningeal lesions, respectively. Cytoreduction from CNS-BRT was estimated by calculating the change in lesion size (sum of product diameter) from before and after CNS-BRT, but before CAR T infusion. Risk of any CNS relapse after CAR T was estimated using the Gray's method with death as a competing risk. Patients with epidural spine disease were not evaluate for CNS response or relapse. Results: 12 patients received CNS-BRT with median follow up of 8.5 months (range: 3.2 - 30.2), median age of 60 (30-76), median Karnofsky Performance Status (KPS) of 80 (range: 50 - 90). Histologies included diffuse large B cell (DLBCL) (n = 9), mantle cell (n = 2), and Burkitt lymphoma (n = 1), with disease localizing to the brain parenchyma (n = 6), leptomeninges (n = 4), and epidural spine (n = 2). 9 patients had secondary CNSL and 1 patient had primary CNSL. Prior to CNS-BRT, 11/12 patients had progressive disease. 5/12 patients had disease outside of the CNS. 5/12 patients received prior autologous hematopoietic stem cell transplantation. 9/12 patients received prior high dose methotrexate with median 46-day interval to CNS-BRT (range: 0 - 393). RT targets included whole brain (n = 3), involved site (partial) brain (n = 4), involved site spine (n = 4), and orbits (n = 1) with median dose 24 Gy (range: 15 - 33). CAR T products included Tisagenlecleucel (n = 4), Lisocabtagene maraleucel (n = 7), and Axicabtagene ciloleucel (n = 1). Among 10 patients with available toxicity grading, 6/10 experienced CRS (n = 1 grade (G) 1, n = 4 G2, and n = 1 G3), and 3/10 experienced ICANS (n = 1 G1, n = 1 G3, n = 1 G4). 6/10 patients required tocilizumab and/or steroids. CNS-BRT achieved a 74.4% (95% CI, 62.9 - 85.9) mean reduction in lesion size prior to CAR T infusion. Best CNS response after CAR T infusion included 3 complete responses (CR), 6 partial responses (PR), and 1 progressive disease (PD). The patients who achieved PR remained in PR at last follow up. The 12-month estimated risk of CNS progression after CNS-BRT and CAR T infusion was 20.0% (95% CI, 3- 49). CNS progression was not observed in patients who received involved site brain RT. Conclusion: Preliminary data suggest CNS-BRT achieves rapid cytoreduction prior to CAR T therapy and is associated with a favorable CNS response profile. While overall numbers are limited to date, the rate of severe CRS and ICANS is similar to that of historical series of CNSL patients treated with CAR T. However, a larger cohort will be required to determine the safety of CNS-BRT. These data support further study of RT, and exploration of involved site brain RT, as an effective bridging modality for CAR T-cell therapy in CNSL.

A Systematic Literature Review (SLR) and Meta-Analysis of Clinical Evidence of Second Line or Later (2L+) Treatments for Follicular Lymphoma (FL) in Adult Patients

Background:First-line (1L)standard of care (SOC) options for patients with FL include an anti-CD20 monoclonal antibody with or without chemotherapy, and second-line (2L) therapeutic options are similar to 1L. There is no defined SOC for patients who require treatment in third, fourth, and later lines of therapy (LOT). Additionally, patients with high-risk FL who relapse ≤ 24 months after frontline treatment (POD24) have limited treatment options that can provide a durable response. Recently, novel treatments such as CAR T cell therapies and T cell engager regimens have been shown to improve efficacy outcomes in third line or later (3L+) and POD24 populations. We conducted an SLR of all relevant clinical evidence to evaluate the efficacy and safety of available therapies used in the treatment of adult patients with R/R FL in 3L+, fourth line or later (4L+), and 2L+ POD24 settings. We also aimed to conduct meta-analyses to derive pooled effect estimates for response and survival outcomes in these settings. Methods: Publications from 01/01/1998 to 09/17/2022 were identified using Ovid MEDLINE ®, Embase, and Cochrane Central Register of Controlled Trials, with supplemental hand searches of key conferences and bibliographies of recent relevant SLRs. Study eligibility was assessed according to prespecified population, intervention, comparator, outcome, and study design criteria. Studies were eligible if they were in English and enrolled patients with R/R FL (grade 1‒3A) in 3L+, 4L+, and POD24 settings. Eligible treatments included CAR T cell therapies (axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel), T cell engagers (mosunetuzumab, glofitamab, epcoritamab, odronextamab), phosphatidylinositol 3-kinase (PI3K) inhibitors (copanlisib, duvelisib, idelalisib), HSCT, yttrium-90 (90Y) ibritumomab tiuxetan, tazemetostat, and conventional therapies (immunochemotherapies, single- or multiagent chemo- or immunotherapies, and alkylating agents). Outcomes of interest were OS, PFS, ORR, CR rate, PR, duration of response, and time to next treatment. Independent review committee (IRC) data were extracted when both IRC- and investigator-assessed data were reported. Pooled estimates for ORR, CR rate, OS, and PFS across all treatments were calculated among 3L+, 4L+, and POD24 patient populations. For POD24 studies, we combined POD24 definitions (ie, definitions with respect to POD24 from frontline therapy or baseline) and POD24 patients across LOTs (ie, presenting in 2L+). For each outcome in 3L+, 4L+, and POD24 settings, ≥ 4 sufficiently similar studies were required for a meta-analysis to be deemed feasible. Results: Of 5250 records screened, 112 were included, representing 60 unique studies. Of 60 studies, 33 (55%) were retrospective or prospective observational, while 27 (45%) were clinical trials (randomized, nonrandomized, and single arm). There was significant heterogeneity in patient populations and baseline characteristics across studies. Most studies (n = 48; 80%) reported findings for 3L+ FL, with limited evidence for 4L+ and POD24 patients. Results for ORR, CR rate, PFS, and OS by treatment type across 3L+, 4L+, and POD24 patients are presented in Table 1. ORR and CR rate data were highly variable depending on treatment used and length of follow-up period in the study. Across 3L+, 4L+, and POD24 patients, the highest ORR and CR rate ranges were observed for CAR T cell therapies, T cell engagers, and HSCT. Median PFS was highest for HSCT, T cell engagers, and CAR T cell therapy in the 3L+ setting and was not reported or not reached for HSCT and T cell engagers in 4L+ and POD24 settings. Median OS was not reached for patients receiving T cell engagers in the 3L+ setting or those receiving CAR T cell therapy in the 3L+, 4L+, and POD24 settings. Various meta-analyses including all treatments were considered feasible for 3L+, 4L+, and POD24 populations (Table 2). For ORR and CR rate in the 3L+ population, sensitivity analyses excluding CAR T cell therapies, T cell engager regimens, and HSCT were feasible and showed lower ORR and CR rate when these therapies were removed. Conclusions: This SLR demonstrated an evolving FL treatment landscape, with new agents such as CAR T cell therapies and T cell engagers exhibiting potential for improving effectiveness of treatment for patients in 3L+, 4L+, and 2L+ POD24 populations.

Development of Cytokine Release Syndrome Is Associated with Superior Progression-Free Survival in DLBCL Patients Receiving Axi-Cel or Liso-Cel

Introduction: Chimeric antigen receptor T-cell therapy (CAR-T) targeting CD19 is a new standard of care for diffuse large B-cell lymphoma (DLBCL) patients with primary refractory disease, early relapse after chemoimmunotherapy, or multiply relapsed disease. Three CD19-directed CAR-T products, axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), are FDA approved for relapsed/refractory (R/R) DLBCL and may cure approximately 30-40% of patients. Cytokine release syndrome (CRS), a systemic inflammatory response associated with CAR-T expansion, is a common early toxicity occurring in 42-93% of DLBCL patients in the pivotal phase 2 trials. We hypothesized that development of CRS may be associated with post-CAR-T efficacy outcomes. Methods: We retrospectively evaluated post-CAR-T outcomes for 57 consecutive patients with R/R DLBCL who received axi-cel or liso-cel infusion at the University of California San Francisco between June 2018 and December 2022. Early post-CAR-T toxicities including CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were recorded using ASTCT consensus grading. Post-CAR-T efficacy endpoints including overall response rate (ORR), complete remission (CR) rate (best response), progression-free survival (PFS), and overall survival (OS) were evaluated for the entire cohort and compared between patients who developed any grade CRS or no CRS after CAR-T infusion. Of note, patients with high-grade B-cell lymphoma or who received tisa-cel were excluded from this study to eliminate potential confounding given poorer outcomes in these subgroups and imbalance in their relative proportions between the CRS and no CRS cohorts. Results: For the entire cohort, the median age was 63 (range 26-81) and 59% of patients were male. Diagnoses included de novo DLBCL (65%), transformed follicular lymphoma (30%), and primary mediastinal B-cell lymphoma (5%). Patients had a median of 2.5 systemic therapies (range 1-8) prior to CAR-T infusion. CAR-T products included axi-cel (70%) or liso-cel (30%). 82% of patients received fludarabine and cyclophosphamide lymphodepletion, and the remaining 18% received bendamustine (during the national fludarabine shortage). Forty-one patients (72%) experienced CRS (grade 1: 35%, grade 2: 37%), and 16 patients (28%) never developed CRS. Seventeen patients (30%) developed ICANS (grade 2: 12%, grade 3: 16%, grade 4: 2%), which occurred exclusively among patients in the CRS cohort. 93% of patients in the CRS cohort received at least one dose of tocilizumab. Baseline characteristics were well balanced between the CRS and no CRS groups with no significant differences in age, sex, performance status, DLBCL subtype, number of prior therapies, CAR-T product administered, lymphodepletion administered, or lactate dehydrogenase at the time of infusion. For the entire cohort, the ORR and CR rate were 86% and 70%, respectively. With a median follow-up of 1.1 years (range 0.2-4.5 years), the 1-year PFS and OS estimates were 61% and 91%, respectively. Median PFS was 1.7 years and median OS was not reached. Outcomes were similar for patients receiving axi-cel and liso-cel (1-year PFS 62% vs 60%, p=0.94). For patients in the CRS cohort vs no CRS cohort, the ORR was 90% vs 75% (p=0.14) and CR rate was 73% vs 63%, respectively (p=0.44). Patients in the CRS cohort had superior PFS compared to patients with no CRS (1-year PFS 70% vs 38%, HR 0.36, 95% CI 0.14-0.98, logrank p=0.011), but there was no significant difference in OS ( Figure 1). There was no significant difference in PFS between patients with grade 1 vs grade 2 CRS (1-year PFS 64% vs 75%, p=0.46). Conclusions: Although limited in sample size, our study suggests that development of CRS may be associated with more favorable post-CAR-T efficacy including superior PFS compared to patients with no CRS after axi-cel or liso-cel infusion. The more favorable outcomes in patients experiencing CRS may reflect better CAR-T proliferation and cytotoxicity compared to patients with no CRS. These findings suggest a relationship between early post-CAR-T toxicity and efficacy outcomes but require validation in larger datasets.

Patient-Reported Outcomes from the MCL Cohort of the Phase 1, Seamless Design TRANSCEND NHL 001 Study of Lisocabtagene Maraleucel in Patients with R/R B-Cell NHL

Background: MCL is an aggressive form of NHL. Despite high initial response rates to currently available frontline therapies for newly diagnosed MCL, patients will inevitably experience relapse. Survival outcomes are poor for patients with R/R MCL. Lisocabtagene maraleucel (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. In the primary analysis of the MCL cohort from the phase 1, seamless design TRANSCEND NHL 001 study (NCT02631044), liso-cel treatment resulted in a rapid, high ORR and high rate of durable CR with low incidences of grade ≥ 3 cytokine release syndrome, neurological events, and infections in heavily pretreated patients with high-risk, aggressive R/R MCL (Wang M, et al. Hematol Oncol 2023). Here, we present patient-reported outcomes (PRO) results from the MCL cohort of TRANSCEND NHL 001. Methods: Patients had R/R MCL after ≥ 2 lines of prior therapy, including a Bruton tyrosine kinase inhibitor, alkylating agent, and CD20-targeted agent. After leukapheresis and lymphodepleting chemotherapy (LDC), patients received liso-cel. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30 items (EORTC QLQ-C30) and EQ-5D-5L utility index ≤ 7 days before LDC; before infusion on the day of liso-cel infusion (Day 1; baseline); then on Days 29, 60, 90, 180, 270, 365, 545, and 730 posttreatment; and at disease progression/relapse. Based on clinical relevance to MCL, the prespecified primary domains of interest were EORTC QLQ-C30 global health status/quality of life (QOL), physical functioning, fatigue, and pain. PRO analyses were conducted in all MCL patients treated with liso-cel who had an evaluable measure at baseline and at ≥ 1 postbaseline visit. The least squares (LS) mean change from baseline was estimated from a linear mixed-effects model for repeated measures at each time point above. Published minimally important difference thresholds (Cocks K, et al. Eur J Cancer 2012; Pickard AS, et al. Health Qual Life Outcomes 2007) were used to interpret whether LS mean changes from baseline were clinically meaningful. Proportions of patients with clinically meaningful change were calculated using published responder definitions of 5-30 points for EORTC QLQ-C30 domains (Cocks K, et al. Qual Life Res 2023), 0.08 for EQ-5D-5L utility index (Hernández-Alava M, et al. Pharmacoeconomics 2023), and 7 for EQ-5D-5L visual analog scale (EQ-VAS) (Pickard AS, et al. Health Qual Life Outcomes 2007). Results: Of 88 patients who received liso-cel, 66 were included in the PRO analyses (median age, 68.5 years [range, 36-86]; 76% male; 89% White; 94% not Hispanic or Latino). Baseline and clinical characteristics were comparable with those of the total liso-cel-treated population, including baseline ECOG PS scores and best response to any prior therapy. Baseline PRO scores for most primary domains were comparable with scores from a US general population norm; other domains fluctuated. Questionnaire completion rates ranged from 55% to 76% from Day 29 to Day 365 postinfusion. Overall LS mean changes from baseline showed significant and meaningful improvements for all primary domains except for pain, as well as for most other PRO domains. Although not showing meaningful improvement, pain scores remained largely unchanged through last assessment (Table 1). Across visits, most patients (60%-100%) experienced meaningful improvement or no meaningful change for all domains (primary domains shown in Table 2). More than 50% of patients achieved meaningful improvement in global health status/QOL, fatigue, social functioning, and EQ-VAS across visits after Day 29. In analyses evaluating the subset of patients in the MCL cohort with secondary CNS lymphoma (n = 5), improvements from baseline exceeded those of the non-secondary CNS population. Conclusions: Patients with R/R MCL who were treated with liso-cel in the MCL cohort of TRANSCEND NHL 001 showed meaningful improvements across relevant aspects of health-related QOL, including symptoms and functioning. Clinically meaningful improvements were observed for all primary domains except for pain, and for many of the other PRO domains. These findings complement the clinical efficacy and safety data from the primary analysis of the MCL cohort of TRANSCEND NHL 001, further supporting the benefit of liso-cel in patients with R/R MCL.

Second-Line Chimeric Antigen Receptor T Cell Therapy (CAR-T) As Standard of Care for Relapsed-Refractory Large B-Cell Lymphoma (LBCL)

Introduction: The randomized registrational ZUMA-7 (Locke, NEJM 2022) and TRANSFORM (Kamdar, Lancet 2022) trials in second line (2L) LBCL showed superiority of CAR T when compared to standard of care (SOC) chemotherapy-based regimens with a goal of consolidative autologous stem cell transplant. These results led to the FDA approval of axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) in 2L for LBCL with refractory disease or relapse within 1 year of completing induction chemotherapy. Significant differences exist between the registrational trial patient population and the real-world commercial CAR-T recipients in 3L+ setting (Nastoupil, JCO 2020, Jacobson, JCO 2020). Herein, we describe the outcomes of patients with LBCL treated with 2L commercial CAR T therapy. Methods: Five US academic institutions contributed data to this retrospective study. CAR T associated toxicities were graded by ASTCT consensus grading criteria (Lee, TCT 2019) and investigator assessed responses were reported per Lugano 2014 criteria. Patients who received CAR T therapy in 2L after the histologic diagnosis of LBCL were included, with leukapheresis between SOC approval on 4/1/2022, and 4/25/23. Patients were included if they received intermediary therapies before CAR T-cell infusion. These intermediary therapies included disease-holding therapy, defined as therapy given between relapse and the time of leukapheresis, given with the intent to “hold” patients' disease under control until CAR T-cell therapy was arranged (Bucklein, Hemasphere 2023). Patients who received therapy after relapse with the intent of restaging to decide on subsequent CAR T-cell therapy were excluded. Patients who received bridging therapy, defined as therapy given between leukapheresis and the start of lymphodepleting (LD) chemotherapy were also included. Kaplan-Meier analysis was used to calculate median progression-free survival (PFS) and overall-survival (OS). Results: 112 patients were leukapheresed with intention to receive commercial CAR T as 2L (103 axi-cel, 9 liso-cel). All but two patients received CAR T infusion (one manufacturing failure and one delayed due to infection). The median follow-up of the cohort was 6.2 months (95%CI 4.32 - 7.61). Median age of the cohort was 66.5 yrs (range 23-83) with male predominance (66%). The median international prognostic index (IPI) score was 3 (range 0-5) and 72% of the patients had stage III/IV disease. Fifty-nine percent of the patients had primary refractory disease. The median time between documentation of progression after 1L therapy and patient evaluation for 2L CAR T was 22 days (IQR 15-32). The median time from patient evaluation to CAR T infusion was 47.5 days (IQR 36.25 - 67). Forty-two patients (37.5%) received disease-holding therapy and 77 (69%) received bridging therapy. Twenty-nine patients (26%), received both disease-holding therapy and bridging therapy. Receipt of these therapies was associated with longer CAR T evaluation-to-infusion times, with a median time of 61 days for patients who received both disease-holding therapy and bridging therapy, as opposed to 38 days for patients who didn't receive either therapy. This is presumably related to washout requirements and the time needed to allow for count recovery prior to either leukapheresis or LD therapy. Among 110 CAR T infused patients, cytokine release syndrome(CRS) occurred in 88% (n=97) of the patients with grade 3 or 4 in 6.3% (n=7). Immune effector cell associated neurologic syndrome (ICANS) occurred in 59% (n= 65) with grade 3 or 4 in 30% (n= 33). No deaths from CRS or ICANS were observed. Overall response rate (ORR) was 82.7% and complete remission rate was 61.8%. Median PFS and OS were not reached. Point estimates of PFS and OS at six months were 64.1% (95% CI: 52.8 - 73.4), and 84.4% (95% CI: 73.8 - 90.9), respectively ( Figure 1). Conclusions: This multicenter retrospective study provides insights into practice and outcomes of SOC CAR T therapy for 2L relapsed-refractory LBCL. In clinical practice, patients commonly receive “disease-holding therapy” to control disease while organizing CAR T-cell consultation and leukapheresis. Despite the relatively short follow-up duration, the best response and toxicity profiles were comparable to those observed in the pivotal clinical trials. Updated follow-up and subgroup analysis will be presented at the meeting. SD and JYS contributed equally.