Characterization of lymphopenia and correlating the risk of cytopenias with dose and BM volume irradiated in aggressive B-cell lymphoma patients bridged with radiation therapy for CAR-T cell therapy.

INTRODUCTION: The impact of bridging radiation therapy (bRT) for CAR T-cell therapy on absolute lymphocyte count (ALC) kinetics and treatment outcome is unknown. METHODS: We retrospectively reviewed adults with relapsed/refractory aggressive large B-cell lymphoma (LBCL) who received bRT prior to CD-19 CAR-T between 11/2017-4/2023. The change in ALC (ALC Δ RT) was computed by subtracting ALC pre- and post-bRT. Percent bone marrow (%BM) irradiated was calculated by estimating skeletal BM distribution. PFS, DSS, and OS were modeled via Kaplan-Meier. RESULTS: Fifty-one patients received bRT, of which 13 (25.5%) had bulky disease (≥7.5cm). The median bRT dose was 30Gy (range: 4-48Gy); 26 patients (51%) received ≥30Gy. Thirty-one patients (61%) received bRT comprehensively to all disease sites. The median cumulative %BM irradiated was 5.05% (range: 0-50%). At a median follow-up of 10.3 months (95% CI: 7.7-16.4), the 1-year OS, PFS, and DSS rates were 80% (95% CI: 66-99), 78% (64-87), and 82% (68-90), respectively. The incidence of ≥Grade 3 lymphopenia was 33% pre-RT and 68% post-RT, but recovered to 43% at the conditioning chemotherapy (CC) timepoint. There was no correlation between post-RT Grade ≥3 lymphopenia and the receipt of comprehensive bRT, combined modality bridging, ≥30Gy bRT, or bRT to ≥15% of BM (all p>0.2). Among patients with Grade 0-2 lymphopenia pre-RT, increased conversion to Grade ≥3 lymphopenia post-RT correlated with comprehensive or ≥30Gy bRT, but these factors did not impair ALC recovery at CC. There was no association between ALC Δ RT or post-RT ALC with 30 or 90 day response (p>0.25), DSS, PFS, or OS (p>0.3). CONCLUSIONS: Lymphocyte change during bRT is not associated with CAR-T outcomes. Persistent cytopenia risk following bRT is not associated with bRT to ≥30Gy, ≥15% of BM, or comprehensive coverage. While bRT can be delivered safely, we urge careful treatment planning when incorporating into pre-CAR-T regimens.

Outcomes and toxicities in patients with diffuse-large B cell lymphoma involving the gastrointestinal tract and digestive organs.

Background: Diffuse large B-cell lymphoma (DLBCL) involving the gastrointestinal (GI) organs is rare, and real-world outcomes after combined modality therapy (CMT) with systemic therapy (ST) and radiotherapy (RT) are not well-characterized, particularly in the contemporary era. We characterized outcomes in a large cohort of GI-DLBCL patients treated with ST alone or CMT. Methods: Patients with GI-DLBCL treated at a single institution were retrospectively reviewed. Kaplan-Meier and Cox regression models estimated survival. Multivariable analyses were conducted using the Cox proportional hazards model. Results: Of 204 patients, gastric involvement was most common (63%). Most presented with early-stage disease (61%). All patients received ST and 65 patients (32%) received RT, 88% as part of first-line CMT. Median dose was 36 Gy (IQR 30.6-39.6) in 18 fractions (IQR 17-22). Median follow-up was 46 months. Five-year overall survival (OS) and progression-free survival (PFS) was 88% and 84%, respectively; complete response (CR) rate was 82%. Improved OS associated with low IPI (p=0.001), fewer chemotherapy lines (p<0.001), early stage (p<0.006), and CR (p<0.001). Survival did not differ by RT receipt (p>0.25). Only early stage and CR correlated with improved OS on multivariable analysis. Stomach-directed RT vs. RT to other sites correlated with improved PFS and OS (p<0.04). Patients with early stage DLBCL treated with CMT in the post-rituximab era had equivalent OS vs. ST alone, even with fewer chemotherapy cycles (p<0.02; median of 4 with RT vs. 6 cycles without). Fifty patients had bulky disease (≥7.5 cm), of whom 18 (36%) had early stage disease. Among patients with bulky disease, 5 (10%) developed relapse at the initial site of disease bulk. Four of the 5 patients did not receive consolidative radiation. Among these 4 patients, 3 relapsed only in their initial site of bulky disease. Of 191 patients with luminal GI-DLBCL, n=4 (2.1%) developed perforation; only one received RT. Acute Grade 3 toxicities were reported in 41.2% of patients, and 12 (5.8%) patients had late Grade 3 toxicities, 99% attributed to chemotherapy. Conclusion: GI-DLBCL patients have favorable outcomes after CMT with minimal late toxicity. CMT may be offered with abridged systemic regimens with equivalent outcomes. Stomach directed-RT may mitigate relapse risk associated with incomplete disease response or bulky disease.

Safety and activity of lenalidomide in combination with obinutuzumab in patients with relapsed indolent non-Hodgkin lymphoma: a single group, open-label, phase 1/2 trial.

Background: Rituximab and lenalidomide is a preferred option for relapsed indolent B cell non-Hodgkin lymphoma. Obinutuzumab may be a superior combination partner with lenalidomide given enhanced antibody dependent cellular cytotoxicity and phagocytosis compared to rituximab. Our aim was to determine the recommended phase 2 dose, safety, and activity of lenalidomide in combination with fixed dose of obinutuzumab in relapsed and refractory indolent B cell non-Hodgkin lymphoma. Methods: In this single-arm, open-label, phase 1/2 trial, we enrolled patients with relapsed or refractory WHO Grade 1-3A follicular lymphoma, marginal zone lymphoma and small lymphocytic lymphoma and adequate performance status (ECOG 0-2) at the MD Anderson Cancer Center. We excluded patients with evidence of ongoing transformation to aggressive lymphoma. During phase 1, 1000 mg intravenous obinutuzumab was administered with three predefined levels of oral lenalidomide in a 3 + 3 dose escalation design to establish lenalidomide 20 mg as the recommended phase 2 dose. During phase 2, patients received induction therapy with six 28-day cycles of lenalidomide 20 mg with intravenous obinutuzumab 1000 mg. In accordance with our prior experience with lenalidomide plus rituximab, patients who were responding to the combination could receive up to 6 additional cycles (up to 12 cycles in total) of combination therapy. Dosing of obinutuzumab was continued in all responding patients after cycle 6 every 2 months for a total of 30 months from the start of therapy. The decision of number of cycles of combination therapy beyond 6 was at discretion of the investigator and was included to allow individualisation of therapy to maximise response while minimising exposure. The co-primary objectives were to evaluate the safety and overall response, defined as the proportion of patients who achieved a complete or partial response in relapsed and refractory indolent non-Hodgkin lymphoma at the end of induction therapy, according to Cheson and colleagues (2007 criteria). The secondary endpoints were complete response after induction therapy and time to event endpoints including time to progression, progression free survival, and overall survival. Analyses were intent to treat in the efficacy cohort and per-treated in the safety population in all patients who received at least one dose of either investigational agent. This trial is registered with ClinicalTrials.gov, NCT01995669. Findings: Between June 03, 2014, and 07 March 2019, we completed planned enrolment, and 66 patients started therapy including 9 patients in phase 1 and 57 patients in phase 2. All patients were evaluated for safety and the 60 patients treated at the recommended phase 2 dose of lenalidomide 20 mg were evaluable for activity. Grade 3-4 haematological toxicities included neutropenia 21% (14/66) and thrombocytopenia 11% (7/66) with no cases of febrile neutropenia. Grade 3-4 non-haematological toxicities included lung infection 8% (5/66), fatigue 8% (5/66) and rash 6% (4/66). By Cheson 2007 criteria, 90% (54/60, 95% CI: 79-96) achieved an overall response at the end of induction meeting the prespecified activity endpoint. Complete responses were seen in 33% (20/60, 95% CI: 22-47) at the end of induction. Median progression free survival, time to progression and overall survival have not been reached after median follow-up of 41.7 months. Estimated 4-year progression free survival rates were 55% (95% CI: 42-73), time to progression of 56% (95% CI: 43-74) and overall survival of 84% (95% CI: 74-95). Interpretation: Our findings suggest that oral lenalidomide with obinutuzumab is safe and highly active in patients with relapsed and refractory indolent B cell non-Hodgkin lymphoma and is associated with prolonged remission duration. The study is limited by the lack of a control arm leading to cross-trial comparisons to evaluate activity. Future randomised trials comparing this regime to rituximab and lenalidomide are warranted. Funding: Genentech and an MD Anderson Core grant.

Five-Year Follow-Up of Standard-of-Care Axicabtagene Ciloleucel for Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium.

PURPOSE: Axicabtagene ciloleucel (axi-cel) is an autologous CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for the treatment of relapsed or refractory large B-cell lymphoma. Little is known about the long-term survivorship after CAR T-cell therapy. METHODS: We previously reported the results of 298 patients who were leukapheresed with the intent to receive standard-of-care axi-cel (n = 275 infused) after two or more previous lines of therapy at a median follow-up of 12.9 months. Here, we report extended follow-up of this cohort to a median of 58 months, with a focus on late survivorship events. RESULTS: Among axi-cel-infused patients, progression-free survival at 5 years was 29% and overall survival (OS) at 5 years was 40%. The 5-year lymphoma-specific survival was 53% with infrequent late relapses. However, the 5-year nonrelapse mortality (NRM) was 16.2%, with over half of NRM events occurring beyond 2 years. Patients who were 60 years and older had a lower risk of relapse (P = .02), but a higher risk of NRM compared with patients younger than 60 years (NRM odds ratio, 4.5 [95% CI, 2.1 to 10.8]; P < .001). Late NRM was mainly due to infections and subsequent malignant neoplasms (SMNs). In total, SMNs occurred in 24 patients (9%), including therapy-related myeloid neoplasms (n = 15), solid tumors (n = 7), and unrelated lymphoid malignancies (n = 2). CONCLUSION: In the standard-of-care setting, axi-cel exhibits outcomes consistent with those reported in clinical trials, with sustained, durable responses observed at the 5-year time point. However, late infections and the development of SMN are key survivorship issues that reduce long-term survival after CAR T-cell therapy, particularly in the elderly.

Tocilizumab Prophylaxis Following Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma.

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Most patients treated with axi-cel experience cytokine release syndrome (CRS) and/or adverse neurologic events (NEs). To explore potential approaches for reducing CAR T-cell-related toxicities with axi-cel, several safety expansion cohorts were added to the pivotal ZUMA-1 trial. ZUMA-1 Cohort 3 was an exploratory safety cohort that investigated the use of the IL-6 receptor blocking antibody tocilizumab and anticonvulsant levetiracetam as prophylaxis against CRS and NEs in patients treated with axi-cel. Patients with R/R LBCL were enrolled in Cohort 3 and received conditioning chemotherapy on d- 5 through -3 followed by a single infusion of axi-cel (2 × 106 cells/kg) on d 0. Prophylactic tocilizumab (8 mg/kg) was administered 48 h after axi-cel infusion. Primary endpoints were incidence and severity of CRS and NEs. Key secondary endpoints included the incidence of adverse events, objective response rate (ORR), duration of response, progression-free survival, overall survival (OS), and biomarker analyses (eg, circulating CAR T cells, cytokines, chemokines). Forty-two patients were enrolled in Cohort 3, 38 of whom received axi-cel. In the 24-month analysis, any-grade CRS and NEs occurred in 92% and 87% of patients, and Grade ≥3 CRS and NEs occurred in 3% and 42% of patients, respectively. One Grade 5 NE (cerebral edema) occurred. With 24-mo minimum follow-up, the ORR was 63%, and 39.5% of patients had ongoing response. With 48-month follow-up, median OS was 34.8 mo (95% CI, 5.4-not estimable). CAR T-cell expansion in ZUMA-1 Cohort 3 was comparable with pivotal Cohorts 1 and 2. Consistent with tocilizumab-mediated inhibition of IL-6R, serum IL-6 levels were increased relative to Cohorts 1 and 2. Grade ≥3 NEs were associated with elevated IL-6 levels, proinflammatory cytokines, and myeloid cells in the cerebrospinal fluid. Based on these findings, prophylactic tocilizumab is not recommended to prevent CAR T-cell-related adverse events, and beneficial effects of prophylactic levetiracetam remain uncertain in patients with R/R LBCL.

Response-adapted ultra-low-dose 4 Gy radiation as definitive therapy of gastric MALT lymphoma: a single-centre, pilot trial.

BACKGROUND: Given the favourable prognosis of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, treatment-related toxicity should be minimised. We aimed to evaluate the efficacy of 4 Gy radiotherapy given in a response-adapted approach. METHODS: We conducted a single-centre, single-arm, prospective trial at MD Anderson Cancer Center (Houston, TX, USA) of response-adapted ultra-low-dose radiotherapy. Eligible patients were 18 years or older and had newly diagnosed or relapsed Helicobacter pylori-negative gastric MALT lymphoma, with stage I-IV disease. Given the expected low toxicity profile of treatment, performance status was not an exclusion criterion. Patients received external beam photon-based radiotherapy for a total dose of 4 Gy in two fractions. Patients with a complete response to 4 Gy via endoscopy and imaging at 3-4 months were observed; patients with a partial response were re-evaluated in 6-9 months. Residual disease at 9-13 months or stable or progressive disease at any time required additional treatment with 20 Gy. The primary endpoint was gastric complete response at 1 year (second evaluation timepoint) after 4 Gy treatment. All analyses were performed as intention to treat. This trial is registered at ClinicalTrials.gov (NCT03680586) and is complete and closed to enrolment. FINDINGS: Between March 27, 2019, and Oct 12, 2021, we enrolled 24 eligible patients. The median age of participants was 67 years (IQR 58-74; range 40-85); 15 (63%) were female and nine (37%) male; 18 (75%) were White, four (17%) Asian, and two (8%) Hispanic; 20 (83%) had stage I disease, one (4%) stage II, and three (13%) stage IV. Median follow-up time was 36 months (IQR 26-42). 20 patients (83%) had a complete response to 4 Gy (16 at 3-4 months, four at 9-13 months); two patients received 20 Gy for symptomatic stable disease at 3-4 months and two for residual disease at 9-13 months; all had a complete response. The 3-year local control rate was 96% (95% CI 88-100), with one local relapse at 14 months after 4 Gy radiotherapy salvaged successfully with 20 Gy. One patient with stage IV disease had a distant relapse. The most common adverse events were grade 1 nausea (nine [38%] of 24 patients who received 4 Gy and two [50%] of four patients who received 20 Gy) and grade 1 abdominal pain (five [21%] of 24 and zero of four, respectively). No grade 3 or worse adverse events were noted, including no treatment-related deaths. INTERPRETATION: Most patients had a complete response after 4 Gy radiotherapy; all who required an additional 20 Gy had a complete response within 12 months. This response-adapted strategy could be used to select patients who would benefit from additional radiotherapy and spare others potential associated toxicity. FUNDING: National Cancer Institute.

Network meta-analysis of CAR T-Cell therapy for the treatment of 3L+ R/R LBCL after using published comparative studies.

INTRODUCTION: Studies have compared chimeric antigen receptor (CAR) T-cell therapies and salvage chemotherapy in relapsed/refractory large B-cell lymphoma (LBCL) patients, but further evidence of their relative effectiveness is warranted. METHODS: Our systematic review identified studies comparing efficacy and safety outcomes of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel) and tisagenlecleucel (tisa-cel) trials to salvage chemotherapy cohorts in LBCL patients with ≥2 prior lines of treatment; and an extended evidence network included indirect comparisons comparing CAR T-cell therapies. We conducted network meta-analyzes using Bayesian hierarchical modeling. RESULTS: Three studies comparing ZUMA-1 (axi-cel), TRANSCEND (liso-cel) and JULIET (tisa-cel) trials to salvage chemotherapy within the SCHOLAR-1 cohort were identified. Axi-cel (odds ratio [OR]:5.63; 95% credible interval [CrI]:2.66-12.42) and liso-cel (OR:4.26; 95%CrI:2.33-7.93) showed a significant increased overall response rate compared to tisa-cel, but not to one-another. Axi-cel demonstrated significant improvements in overall survival relative to liso-cel (hazard ratio [HR]:0.54; 95%CrI:0.37-0.79) and tisa-cel (HR:0.47; 95%CrI:0.26-0.88). Higher rates of grade ≥3 neurological events were observed with axi-cel than with tisa-cel and liso-cel. CONCLUSIONS: We highlight important differences in clinical outcomes between CAR T-cell therapies. Axi-cel demonstrated improved overall survival compared to tisa-cel and liso-cel, and both axi-cel and liso-cel showed higher response rates compared to tisa-cel.

Benefit of axicabtagene ciloleucel versus chemoimmunotherapy in older patients and/or patients with poor ECOG performance status with relapsed or refractory large B-cell lymphoma after 2 or more lines of prior therapy.

Axicabtagene ciloleucel (axi-cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real-world effectiveness of axi-cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi-cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients treated with CIT for R/R LBCL after ≥2 lines of prior therapy were included from SCHOLAR-1 (an international, multicohort, retrospective study). After propensity score matching, at a median follow-up of 24 months for patients receiving axi-cel and 60 months for patients receiving CIT, 12-month overall survival rates were 62% and 28%, respectively (hazard ratio, 0.30 [95% CI, 0.24-0.37]). Objective response rate (ORR) was 76% (complete response [CR] rate 58%) in patients receiving axi-cel versus 28% (CR rate 16%) for those receiving CIT. A 57% difference in ORR (55% difference in CR rate) favoring axi-cel over CIT was observed among patients aged ≥65 years. Increased magnitude of benefit in response rates for axi-cel versus CIT was also observed among patients with ECOG PS = 2. These findings further support the broader use of axi-cel in older patients and patients with ECOG PS = 2 with R/R LBCL.

A Comparison of 3-Year Follow-up of ZUMA-5 (Axicabtagene Ciloleucel) With SCHOLAR-5 in Relapsed/Refractory Follicular Lymphoma.

In the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory follicular lymphoma patients. SCHOLAR-5 is an external control cohort designed to act as a comparator to ZUMA-5. Here, we present an updated comparative analysis of ZUMA-5 and SCHOLAR-5, using the 36-month follow-up data and the intent-to-treat population of ZUMA-5. Using propensity-score methods, 127 patients in ZUMA-5 were compared to 129 patients in SCHOLAR-5. At this extended follow-up, axi-cel continues to demonstrate clinically meaningful benefits in survival compared to historically available treatments in this population.

Bridging therapy with axicabtagene ciloleucel for large B-cell lymphoma: results from the US Lymphoma CAR-T Consortium.

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

Three-year follow-up analysis of axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5).

ABSTRACT: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel for patients with R/R indolent non-Hodgkin lymphoma (iNHL; N = 104), including FL and marginal zone lymphoma (MZL). In the primary analysis (median follow-up, 17.5 months), the overall response rate (ORR) was 92% (complete response rate, 74%). Here, we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after ≥2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2 × 106 CAR T cells per kg). The primary end point was ORR, assessed in this analysis by investigators in all enrolled patients (intent-to-treat). After median follow-up of 41.7 months in FL (n = 127) and 31.8 months in MZL (n = 31), ORR was comparable with that of the primary analysis (FL, 94%; MZL, 77%). Median progression-free survival was 40.2 months in FL and not reached in MZL. Medians of overall survival were not reached in either disease type. Grade ≥3 adverse events of interest that occurred after the prior analyses were largely in recently treated patients. Clinical and pharmacokinetic outcomes correlated negatively with recent exposure to bendamustine and high metabolic tumor volume. After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses, with very few relapses beyond 2 years, and manageable safety in patients with R/R iNHL. The ZUMA-5 study was registered at www.clinicaltrials.gov as #NCT03105336.

Safety and efficacy of ibrutinib in combination with rituximab and lenalidomide in previously untreated follicular and marginal zone lymphoma: An open label, phase 2 study.

BACKGROUND: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non-Hodgkin lymphomas (iNHL). Median survival for iNHL is approximately 20 years. Because standard treatments are not curative, patients often receive multiple lines of therapy with associated toxicity-rationally designed, combination therapies with curative potential are needed. The immunomodulatory drug lenalidomide was evaluated in combination with rituximab for the frontline treatment of FL in the phase 3 RELEVANCE study. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, is active in NHL and was evaluated in combination with lenalidomide, rituximab, and ibrutinib (IRR) in a phase 1 study. METHODS: The authors conducted an open-label, phase 2 clinical trial of IRR for previously untreated FL and MZL. The primary end point was progression-free survival (PFS) at 24 months. RESULTS: This study included 48 participants with previously untreated FL grade 1-3a (N = 38), or MZL (N = 10). Participants received 12, 28-day cycles of lenalidomide (15 mg, days 1-21 cycle 1; 20 mg, cycles 2-12), rituximab (375 mg/m2 weekly in cycle 1; day 1 cycles 2-12), and ibrutinib 560 mg daily. With a median follow-up of 65.3 months, the estimated PFS at 24 months was 78.8% (95% confidence interval [CI], 68.0%-91.4%) and 60-month PFS was 59.7% (95% CI, 46.6%-76.4%). One death occurred unrelated to disease progression. Grade 3-4 adverse events were observed in 64.6%, including 50% with grade 3-4 rash. CONCLUSIONS: IRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3-4 toxicity, particularly rash. The study was registered with ClinicalTrials.gov (NCT02532257).

Chimeric antigen receptor T cells to target CD79b in B-cell lymphomas.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent and durable effects in B-cell malignancies. However, antigen loss or downregulation is a frequent cause of resistance. Here, we report development of a novel CAR T-cell therapy product to target CD79b, a pan B-cell antigen, widely expressed in most B-cell lymphomas. METHODS: We generated a novel anti-CD79b monoclonal antibody by hybridoma method. The specificity of the antibody was determined by testing against isogenic cell lines with human CD79b knock-in or knock-out. A single-chain variable fragment derived from the monoclonal antibody was used to make a panel of CD79b-targeting CAR molecules containing various hinge, transmembrane, and co-stimulatory domains. These were lentivirally transduced into primary T cells and tested for antitumor activity in in vitro and in vivo B-cell lymphoma models. RESULTS: We found that the novel anti-CD79b monoclonal antibody was highly specific and bound only to human CD79b and no other cell surface protein. In testing the various CD79b-targeting CAR molecules, superior antitumor efficacy in vitro and in vivo was found for a CAR consisting CD8α hinge and transmembrane domains, an OX40 co-stimulatory domain, and a CD3ζ signaling domain. This CD79b CAR specifically recognized human CD79b-expressing lymphoma cell lines but not CD79b knock-out cell lines. CD79b CAR T cells, generated from T cells from either healthy donors or patients with lymphoma, proliferated, produced cytokines, degranulated, and exhibited robust cytotoxic activity in vitro against CD19+ and CD19- lymphoma cell lines and patient-derived lymphoma tumors relapsing after prior CD19 CAR T-cell therapy. Furthermore, CD79b CAR T cells were highly efficient at eradicating pre-established lymphoma tumors in vivo in three aggressive lymphoma xenograft models, including two cell line-derived xenografts and one patient-derived xenograft. Notably, these CAR T cells did not demonstrate any significant tonic signaling activity or markers of exhaustion. CONCLUSION: Our results indicated that this novel CD79b CAR T-cell therapy product has robust antitumor activity against B-cell lymphomas. These results supported initiation of a phase 1 clinical trial to evaluate this product in patients with relapsed or refractory B-cell lymphomas.

Effect of delayed cell infusion in patients with large B-cell lymphoma treated with chimeric antigen receptor T-cell therapy.

Complications occurring after lymphodepleting chemotherapy (LDC) may delay chimeric antigen receptor (CAR) T-cell infusion. The effect of these delays on clinical outcomes is unclear. We performed a retrospective analysis of 240 patients with relapsed/refractory large B-cell lymphoma treated with standard-of-care axicabtagene ciloleucel (axi-cel) and identified 40 patients (16.7%) who had delay in axi-cel infusion. Of these, 85% had delay due to infection. At time of LDC initiation, patients with delayed infusion had lower absolute neutrophil count (p=0.006), lower platelets (p=0.004), lower hemoglobin (p5 days (4.6 vs. 8.2 months; p=0.036), but not 1 day (5.7 vs. 8.2 months; p=0.238). Following propensity score matching, patients with delayed infusion continued to have shorter median PFS (3.5 vs. 6.0 months; p=0.015). Levels of proinflammatory cytokines on day of infusion were significantly higher in patients with delayed infusion. Together, these findings suggest that delays in CAR T-cell administration after initiation of LDC are associated with inferior outcomes. Further studies are needed to guide strategies to improve efficacy in such patients.

A single-cell atlas of CD19 chimeric antigen receptor T cells.

Li et al. present a resource of single-cell RNA sequencing (scRNA-seq) data from the infusion products of relapsed or refractory large B cell lymphoma (rrLBCL) patients treated with standard-of-care axicabtagene ciloleucel and identify features that are significantly different between products from responders and non-responders at 3-month followup by PET/CT, an important landmark for long-term outcomes.