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Tisagenlecleucel demonstrated high response rates and a manageable safety profile in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. However, lack of response and chimeric antigen receptor (CAR) T-cell exhaustion were observed in patients with programmed cell death protein 1 (PD-1) overexpression. Hence, pembrolizumab, a PD-1 inhibitor, was hypothesized to improve efficacy and cellular expansion of CAR T-cells in vivo. Here, we report the final analysis of the PORTIA trial in adult patients with r/r DLBCL who had ≥2 prior lines of therapy and had an Eastern Cooperative Oncology Group performance status of ≤1. Patients received 1 tisagenlecleucel infusion on day 1. Pembrolizumab (200 mg) was given every 21 days, for up to 6 doses. Three cohorts initiated pembrolizumab on days 15 (n = 4), 8 (n = 4), or –1 (n = 4). Safety, efficacy, cellular kinetics, and biomarker analyses were included. Tisagenlecleucel plus pembrolizumab was feasible and showed a manageable safety profile, without dose-limiting toxicities. Emerging efficacy with tisagenlecleucel was observed when pembrolizumab was given the day before tisagenlecleucel; however, the limited patient sample and short follow-up do not allow for definitive conclusions. Adding pembrolizumab to tisagenlecleucel did not augment the cellular expansion of tisagenlecleucel but delayed peak expansion if given the day before tisagenlecleucel (NCT03630159).

PURPOSE Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

We systematically evaluated the primary and secondary endpoints used in acute myeloid leukemia (AML) phase III randomized controlled trials (RCTs). We included 238 phase III AML RCTs in the past 15 years that reported 279 primary endpoints and 657 secondary endpoints. Overall survival (OS), progression-free survival (PFS), event-free survival (EFS), and complete remission (CR) were primary endpoints in 120 (43%), 34 (12%), 30 (11%), and 41 (15%) studies, respectively. OS (12.5%), PFS (13.2%), CR (14%), safety (11%), and EFS (9%) were commonly reported secondary endpoints. Among primary endpoints, a higher use of OS (OR 2.03, 95%CI 1.10-3.75

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed chimeric antigen receptor (CAR) T cell therapies approved for the treatment of relapsed/refractory aggressive B cell lymphomas. We present a multicenter retrospective study among centers that prescribe either commercial product to evaluate usage patterns, safety and efficacy outcomes, and resource utilization. Data collection included all patients from 8 US centers who underwent apheresis between May 1, 2018, and July 31, 2019. Patient selection, toxicity management, and disease assessment followed institutional practices. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy consensus criteria, and tumor responses were assessed according to the Lugano 2014 classification scheme. A total of 260 patients underwent apheresis, including 168 (65%) for axi-cel and 92 (35%) for tisa-cel. Among the infused patients, the median age was 59 years for axi-cel recipients and 67 years for tisa-cel recipients (P.001). The median time from apheresis to infusion was 28 days for axi-cel recipients and 45 days for tisa-cel recipients (P.001). Sixty-one percent of the axi-cel recipients and 43% of the tisa-cel recipients would have been ineligible for the ZUMA-1 and JULIET trials, respectively. Grade ≥3 CRS occurred in 9% of axi-cel recipients and in 1% of tisa-cel recipients (P = .017), and grade ≥3 ICANS was seen in 38% of axi-cel recipients and 1% of tisa-cel recipients (P.001). Inpatient cell therapy infusion was common (92% in axi-cel recipients, 37% in tisa-cel recipients). The day 90 overall response rate was 52% in the axi-cel group and 41% in the tisa-cel group (P = .113), with complete response in 44% and 35%, respectively (P = .319). Twelve-month progression-free survival (42% versus 32%; P = .206) and overall survival (62% versus 59%; P = .909) rates were comparable in the axi-cel and tisa-cel groups. Baseline characteristics differed between the 2 groups, although response rates and survival outcomes were comparable, albeit lower than those in the pivotal trials. Safety and resource utilization appear to be key differentiators between axi-cel and tisa-cel.

Chimeric antigen receptor (CAR) T-cell therapy is an individualized immunotherapy that genetically reprograms a patient's T cells to target and eliminate cancer cells. Tisagenlecleucel is a US Food and Drug Administration-approved CD19-directed CAR T-cell therapy for patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia and r/r diffuse large B-cell lymphoma. Manufacturing CAR T cells is an intricate process that begins with leukapheresis to obtain T cells from the patient's peripheral blood. An optimal leukapheresis product is essential to the success of CAR T-cell therapy; therefore, understanding factors that may affect the quality or T-cell content is imperative. CAR T-cell therapy requires detailed organization throughout the entire multistep process, including appropriate training of a multidisciplinary team in leukapheresis collection, cell processing, timing and coordination with manufacturing and administration to achieve suitable patient care. Consideration of logistical parameters, including leukapheresis timing, location and patient availability, when clinically evaluating the patient and the trajectory of their disease progression must be reflected in the overall collection strategy. Challenges of obtaining optimal leukapheresis product for CAR T-cell manufacturing include vascular access for smaller patients, achieving sufficient T-cell yield, eliminating contaminating cell types in the leukapheresis product, determining appropriate washout periods for medication and managing adverse events at collection. In this review, the authors provide recommendations on navigating CAR T-cell therapy and leukapheresis based on experience and data from tisagenlecleucel manufacturing in clinical trials and the real-world setting.

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of aggressive B-cell lymphoma patients following CAR T-cell therapy failure. To more definitively define CPI therapy efficacy in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 U.S. academic centers. Most patients (53%) had DLBCL, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 versus 51 days) and OS (387 versus 131 days) were significantly longer in patients with late (>180 days) versus early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of CPI-treated patients. Most patients (83%) died, commonly due to progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of aggressive B-cell lymphoma patients treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes.

Background: Infection with SARS-CoV-2 has led to a global pandemic and has significantly impacted the care of cancer patients. Breast cancer patients receiving active systemic therapy need protection against COVID19 but the efficacy of vaccines in this population is unknown. Although specific biomarkers associated with protection from SARS-CoV-2 infection have yet to be identified, measurement of serum antibody activity is generally accepted as a surrogate of in vivo humoral response to vaccine. This study evaluates the efficiency and durability of binding antibodies to SARS-CoV-2 spike (S) protein in response to COVID19 vaccine in breast cancer patients receiving systemic treatment. Methods: Breast cancer patients, who were unvaccinated, partially or fully vaccinated with Pfizer-BioNTech BNT162b2 (PF), Moderna mRNA-1273 (Mod) or Johnson & Johnson AD26.COV2.S (J&J) were enrolled in this prospective longitudinal study. Eligible patients were on systemic treatment with cytotoxic chemotherapy, chemotherapy plus a checkpoint inhibitor (CPI), CPI alone or a CDK 4/6 inhibitor. Longitudinal blood samples are being collected at baseline, prior to vaccination in unvaccinated patients (T0), 2 weeks after the first vaccine dose and before the second dose for the mRNA vaccines (T1), 1 month (T2), 3 months (T3), 6 months (T4) and 12 month post vaccination. For J&J, there was no T1 timepoint. Roche Elecsys® Anti-SARS-CoV-2 S receptor binding domain (RBD) antibody immunoassay was used to measure antibody titers (range 0.4 to 250 U/mL). Cut points of N% Seropositive (>0.8 U/mL)Mean Antibody Levels (U/mL)T0T1T2T3T0T1T2T3All subjects7510789810012.6102.3204.4214.6Chemotherapy50577961003.3105.6200.0250CDK 4/6 inhibitors15257510010013.786.8234.7205.8CPI + Chemotherapy82583100NA*62.8121.4177.5NA*CPI therapy20100100NA*0.46.82250NA*CPI=Checkpoint Inhibitors; *Timepoint for longitudinal samples not reached Citation Format: Cory Bivona, Kevin Li, Priyanka Sharma, Jianghua He, Grace Martin, Andrew K Godwin, Anthony Rooney, Stephen Williamson, Gary Doolittle, Weijing Sun, Bruce F Kimler, Anne P O'Dea, Lauren E Nye, Joseph P McGuirk, Ziyan Pessetto, Lisa Haney, Nicole Balmaceda, Laura Mitchell, Karissa Finke, Maggie Nelson, Dinesh Pal Mudaranthakam, Natalie Streeter, Stephanie Lafaver, Jaimie Heldstab, Qamar J Khan. Immunogenicity of SARS-CoV-2 vaccination in subjects on active treatment for breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-03.

Chimeric antigen receptor (CAR) T-cell therapy revolutionized treatment for many patients with aggressive relapsed or refractory large B-cell lymphoma (LBCL) Treatment can be complicated by clinically evident cytokine release syndrome (CRS), which is characterized by the development of fevers, hypoxia, and hypotension and can be life-threatening. Most patients treated with CAR T cells develop CRS, which is thought to represent an immune phenomenon. It was previously unknown if patients who do not develop CRS have reduced CAR T-cell activity and therefore are likely to have worse outcomes. We conducted a multicenter retrospective analysis that included 352 adult patients treated at eight academic medical centers within the United States who received axicabtagene ciloleucel or tisagenlecleucel for treatment of LBCL. Outcomes of interest included progression free survival, overall survival, complete response rate, and overall response rate. Of the included patients, 262 (74.4%) developed CRS. There was no significant difference in progression free (p=0.99) or overall survival (p=0.16) between patients who developed CRS and those who did not. Peak ferritin during treatment >5000 and lactate dehydrogenase greater than the institutional upper limit of normal prior to lymphodepleting chemotherapy were associated in multivariate analysis with significantly worse progression free and overall survival. There was no significant difference in complete response or overall response rate between patients who did and did not develop CRS. In this retrospective analysis, we report that patients who develop CRS have similar clinical outcomes compared to patients without CRS treated with commercial anti-CD19 CAR T cells.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined. METHODS We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration. RESULTS The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm ( P = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; P = .003). The survival benefit was seen across all subgroups examined. CONCLUSION We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS.

Summary Background In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort. Methods In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0–1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov , NCT02445248 , and is ongoing. Findings Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8–43·8), the overall response rate was 53·0% (95% CI 43·5–62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3–4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported. Interpretation Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk–benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). Funding Novartis Pharmaceuticals.

Extramedullary disease (EMD) is an aggressive form of multiple myeloma (MM). Confirming the presence of plasma cells outside the bone marrow makes the diagnosis of EMD. There is no clear consensus on the management of EMD in MM, and this entity continues to remain an unmet need. Rapidly controlling EMD to prevent end-organ damage is a priority. Retrospectively, we reviewed our database for patients with EMD that received treatment with bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide (VDPACE) plus an immune modulator (IMiD) regimen. We identified 21 patients with a median age of 61 years. Ten patients received a VDPACE based regimen as a bridge to autologus stem cell transplant (ASCT). After a median follow-up of 51.4 months, the median overall survival (OS) and progression-free survival were 14.9 months (95% CI: 7.8-NA) and 5.5 months (95% CI: 3.9-NA), respectively. The overall response rate was 76%, with a manageable safety profile. Interestingly, these results were similar regardless of the presence of high-risk cytogenetics. The safety profile was acceptable. In conclusion, a salvage VDPACE-based regimen plus an IMiD remains an effective and safe bridging therapy to future ASCT and immunotherapy in relapsed/refractory multiple myeloma patients with EMD.

CD19 chimeric antigen receptor (CAR) T-cell therapy represents a breakthrough for patients with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) inducing sustained remissions in these patients. However, CAR T-cells can result in significant toxicities. Pre-infusion disease burden is associated with toxicities and outcomes after CAR T-cell therapy. We identified 33 patients with R/R DLBCL treated at 8 academic centers who had no detectable disease at the time of CAR T-cell therapy. The median time from leukapheresis to CAR T-cell infusion was 48 (19-193) days. Nine patients received axicabtagene ciloleucel and 24 received tisagenlecleucel. There was no severe (grade≥3) cytokine release syndrome and only 1 patient developed severe neurotoxicity (grade 4). After a median follow-up of 16 months, 13 patients relapsed (39.4%) and 6 died (18.1%). One-year event-free survival and overall survival were 59.6% and 81.3%, respectively. Our findings suggest that, in patients with R/R DLBCL who have an indication for CAR T-cell therapy, treating patients in complete remission at time of infusion is feasible, safe, and associated with favorable disease control. Further exploration in a larger clinical trial setting is warranted.

We conducted a systematic review and meta-analysis to evaluate outcomes after allogeneic hematopoietic stem cell transplantation (HSCT) in TP53-mutated acute myeloid leukemia (AML). We performed a literature search on PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. After screening 592 manuscripts, eight studies were included. Data were extracted following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CIs) were computed. We analyzed 297 patients. The median follow-up was 45 (0.9-407.3) months. The pooled 2-year overall survival was 29.7% (95% CI 0.17-0.43

Background Multiple myeloma (MM) is an incurable hematologic malignancy, and outcomes remain poor for patients with triple-class relapsed/refractory MM (RRMM). Descriptive analyses were performed on available data for patient characteristics, disease course, and outcomes of the KCd on triple-class RRMM patients at our institution. Patients and methods Twenty-three patients with triple-class RRMM treated with KCd between June 2017 and October 2020 were included in our analysis. The regimen KCd consisted of 28 days cycles of carfilzomib 20/36 mg/m2 IV on days 1, 2, 8, 9, 15, and 16, cyclophosphamide 300 mg/m2 IV weekly, and dexamethasone (20-40) mg orally weekly. Results Patients received a median of 6 (3-10) prior regimens. The median number of cycles administered was 4 (1-11) cycles. Overall response rate was 52%, 6 patients (26%) achieved very good partial response (VGPR), 6 patients (26%) achieved partial response (PR), and 5 patients (22%) achieved stable disease (SD). Progression-free survival (PFS) and Overall-survival (OS) were 4 and 11.9 months, respectively. There was no reported treatment-related mortality. The most common grade ≥3 adverse events were neutropenia (26%), thrombocytopenia (56.5%), and anemia (56.5%). Conclusions KCd showed clinically meaningful efficacy and manageable safety profile in patients with triple-class RRMM in real-world.