Outcome Of Large B-cell Lymphoma Research Articles

CAR T access and outcomes in large B-cell lymphoma according to ethnicity and socioeconomic deprivation in the UK.

Data on the impact of ethnic and socioeconomic factors on Chimeric antigen receptor (CAR) T-cell therapy (access and outcomes are limited, but key to understand whether results from the registration trials are generalizable to real-world patient populations. Here, we analysed ethnicity, socioeconomic deprivation and referral patterns in a cohort of 314 large B-cell lymphoma patients approved for third-line CD19 CAR-T across three large UK CAR-T centres. Patients from deprived areas had a lower infusion rate compared to low deprivation areas (73% vs. 86%, p = 0.04). CAR-T response rates, toxicities, progression-free survival or non-relapse mortality were similar with respect to ethnicity or deprivation. We did not find evidence of referral barriers according to ethnicity, but potential regional barriers for socioeconomically deprived patients in two of three centres. Intention-to-treat overall survival was significantly inferior in patients from deprived areas (1-year OS 44.5% vs. 58% for high vs. low deprivation; p = 0.02), likely reflecting general health disparities and higher drop-out rates in this group. Our data suggest similar outcomes of CD19 CAR-T-treated patients across a socioeconomically and ethnically heterogeneous real-world population. Results demonstrate broad access to CAR-T within the UK national delivery system, but the high drop-out rate and potential regional referral barriers for deprived communities should be further investigated.

Metabolic Tumor Volume Response after Bridging Therapy Determines Chimeric Antigen Receptor T-Cell Outcomes in Large B-Cell Lymphoma.

Greater disease burden is a well-established predictor of poorer outcomes following chimeric antigen receptor T-cell (CAR T) therapy. Although bridging therapy (BT) is widely used between leukapheresis and CAR T infusion, limited data have evaluated the impact of BT on CAR T outcomes. In this study, we hypothesized that the quantitative dynamics of radiomic cytoreduction during bridging are prognostic. Patients with large B-cell lymphoma treated with CD19-CAR T from 2016 to 2022 were included in the study. Metabolic tumor volume (MTV) was determined for all patients on pre-leukapheresis PET and on post-BT/pre-infusion PET in those who received BT. Patients were stratified into "High" and "Low" disease burden using an MTV cutpoint of 65.4cc established by maximally selected log-rank statistic for progression-free survival (PFS). Of 191 patients treated with CAR T, 144 (75%) received BT. In the BT cohort, 56% had a reduction in MTV post-BT. On multivariate analysis, the MTV trajectory across the bridging period remained significantly associated with PFS (P < 0.001); however, notably, patients with improved MTV (High->Low) had equivalent PFS compared with those with initially and persistently low MTV (Low->Low; HR for High->Low MTV: 2.74; 95% confidence interval, 0.82-9.18). There was a reduction in any grade immune effector cell-associated neurotoxicity syndrome in the High->Low MTV cohort as compared with the High->High MTV cohort (13% vs. 41%; P = 0.05). This is the first study to use radiomics to quantify disease burden pre- and post-BT in a large real-world large B-cell lymphoma cohort. We demonstrate that effective BT can enable initially high-disease burden patients to achieve post-CAR T outcomes comparable with low-disease burden patients.

Rolling the DICEP on lymphoma salvage treatments? Choose wisely.

Although immunotherapy is rapidly changing the treatment approach to r/r diffuse large B cell lymphoma, there is still a place for autologous stem cell transplantation in some patients. The report by Stewart etal. focuses on induction therapy and the importance of the pretransplantation phase. Commentary on: Stewart etal. Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-Outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP. Br J Haematol 2024; 205:881-890.

Metabolic pathway-based subtyping reveals distinct microenvironmental states associated with diffuse large B-cell lymphoma outcomes.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease that requires personalized clinical treatment. Assigning patients to different risk categories and cytogenetic abnormality and genetic mutation groups has been widely applied for prognostic stratification of DLBCL. Increasing evidence has demonstrated that dysregulated metabolic processes contribute to the initiation and progression of DLBCL. Metabolic competition within the tumor microenvironment is also known to influence immune cell metabolism. However, metabolism- and immune-related stratification has not been established. Here, 1660 genes involved in 84 metabolic pathways were selected and tested to establish metabolic clusters (MECs) of DLBCL. MECs established based on independent lymphoma datasets distinguished different survival outcomes. The CIBERSORT algorithm and EcoTyper were applied to quantify the relative abundance of immune cell types and identify variation in cell states for 13 lineages comprising the tumor micro environment among different MECs, respectively. Functional characterization showed that MECs were an indicator of the immune microenvironment and correlated with distinctive mutational characteristics and oncogenic signaling pathways. The novel immune-related MECs exhibited promising clinical prognostic value and potential for informing DLBCL treatment decisions.

Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP.

The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.

Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity

AbstractAxicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell–associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.

The impact of race and ethnicity on diffuse large B-cell lymphoma outcomes within the veterans health administration (VHA)

We performed a retrospective chart review of 6266 randomly selected DLBCL patients treated in the VHA nationwide between 1/1/2011 and 12/31/2021. The 3178 patients who met inclusion criteria were predominantly male (97%) and white (75%). Median age of diagnosis for Black patients was 63 years vs 69 years for the entire cohort (p < 0.001). However, patients in each race/ethnicity subgroup presented with similar rates of stage I/II and III/IV disease, IPI score, cell of origin and HIT status. Outcomes analysis revealed similar treatment, response rates, median overall survival, and 1-, 3-, and 5-year survival across all subgroups. Hispanic patients had a 21% lower risk of death (HR = 0.79) than white patients, and Black patients had no significant difference in survival (HR = 0.98). This large retrospective study shows that when standard of care therapy is given within an equal access system, short-term treatment and survival outcomes are the same for all races.

CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity

AbstractChimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas (BCLs). CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell lymphoma (MCL), follicular lymphoma, and large BCL (LBCL) over the course of 5 years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL than other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required fourfold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and the requirement for granulocyte colony-stimulating factor 14 days after infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.

Impact of Obesity on Efficacy, Safety, and Expansion Kinetics of Chimeric Antigen Receptor-T (CAR T) Therapy in Patients with Relapsed or Refractory Large B Cell Lymphoma (LBCL)

Introduction: Obesity causes low-grade inflammation and immune escape, where T-cells lose their ability to infiltrate tumors. However, such T-cell exhaustion, characterized by increased expression of inhibitory checkpoint receptors, has led to better responses to immune checkpoint blockade therapy in patients with higher body mass index (BMI) (Wang Nature Medicine 2019). Previous studies have shown no significant association of obesity with safety or efficacy of Chimeric Antigen Receptor T-cell (CAR T) therapy in hematologic malignancies (Faruqi Blood Advances 2022). However, data on the impact of BMI on outcomes in LBCL and CAR T expansion kinetics is limited. We conducted a single-site study to investigate the effect of obesity on efficacy and safety outcomes, healthcare utilization, and CAR T expansion in patients with relapsed/refractory LBCL treated with Axicabtagene Ciloleucel(axi-cel). Methods: 189 patients with relapsed/refractory LBCL who were consecutively treated with axi-cel from 12/2017 to 5/2022 were included in the study. BMI was calculated on the day of apheresis. Patients were then divided into three BMI categories based on CDC guidelines: underweight/normal (≤24.99kg/m 2), overweight (&amp;gt;25kg/m 2 and ≤29.99kg/m 2), and obese (&amp;gt;30kg/m 2). Response was assessed using the Lugano 2014 criteria, and toxicities via the CTCAE version 5.0 and ASTCT grading. CAR T expansion was measured by real-time flow cytometry with anti-idiotype-FMC63 conjugated to Dylight 650. Areas under the curve (AUCs) were calculated for CAR T expansion in the 28 days following infusion using the linear trapezoidal method on raw values, and results were transformed using a base-10 logarithm. Continuous outcomes were compared using a Kruskal-Wallis test, categorical outcomes using Chi-square tests, and time-to-event outcomes using the Kaplan-Meier estimator and the log-rank test. Statistical significance was determined at p &amp;lt; 0.05. All analyses were conducted in R 4.3.0. Results: Out of 189 patients, 46% (n=87) were in the underweight/normal group, 29% (n=56) in the overweight, and 24% (n=46) were obese. Baseline demographics and clinical characteristics between groups were similar except for gender ( p=0.009). Complete response (CR) and overall response (ORR) including partial response (PR) and CR were compared among these cohorts. Neither complete response nor overall response was found to be significantly different amongst the BMI categories for their best response within 12 months of CAR T infusion ( p=0.9886 and 0.802, respectively). Median progression-free survival (PFS) was 14.6 months (IQR 4.93, 44.81) for the underweight/normal weight cohort, 14.89 months (IQR 5.82, 40.07) for the overweight cohort, and 28.37 months (IQR 3.88, NA) for obese; but was not statistically significant ( p=0.8004) [Figure 1]. Median overall survival (OS) was 44.81 months (IQR 18.18, NA) for the underweight/normal weight cohort and 40.07 months (IQR 23.18, NA) for the overweight category. This was not achieved for the obese category, and no statistical difference was found ( p=0.3478). When cytokine release syndrome (CRS) or immune cell-associated neurologic toxicity syndrome (ICANS) events were compared among these groups, there was no significant difference in either overall incidence or when graded as severe (›3), based on BMI category. Similarly, no significant differences were found in healthcare utilization variables, including length of hospital stay, ICU admissions, tocilizumab, anakinra or steroid use. Differences in day 7 and day 14 CAR T expansion were not statistically significant ( p=0.754 and 0.355, respectively). For AUC calculations, there was no statistically significant difference amongst the BMI categories (CD4: p=0.8284, CD8: p=0.8695, CD4 + CD8: p=0.8820) [Figure 2]. Conclusion: Contrary to the effect of obesity on response to therapies like checkpoint inhibitors we demonstrate that BMI does not significantly impact patients treated with CAR T. Weight has been central to chemotherapy dosing for lymphoma, but despite weight-based dosing for axi-cel, correlative studies on CAR T expansion kinetics did not indicate any significant difference. These findings suggest that obesity may not substantially influence the outcomes or dosing considerations of CAR T therapy, supporting the use of CAR T therapy as an effective treatment option for lymphoma patients, regardless of their BMI.

Predicting diffuse large B-cell lymphoma outcomes with lesion-to-liver maximum standardized uptake value for interim-treatment and end-of-treatment positron emission tomography-computed tomography.

18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) has been used in response evaluation systems for malignant lymphomas and is an important tool for determining efficacy and prognosis. The Deauville 5-point scale (D-5PS) is an 18F-FDG PET-CT image-interpretation protocol for patients with lymphoma. Nevertheless, a number of limitations in visual image interpretation, such as interobserver disagreement and the increase of false-positive results, suggests that new parameters are needed. In this study, we aimed to evaluate the prognostic values of interim-treatment (I-) and end-of-treatment (EOT) PET-CT by comparing D-5PS to the semiquantitative lesion-to-liver maximum standardized uptake value ratio (RLL). A total of 90 patients with diffuse large B-cell lymphoma (DLBCL) (45 I-PET and 45 EOT-PET) were analyzed, and the RLL was calculated. Patients were additionally evaluated using the D-5PS system. We determined the optimal cutoff value of RLL using receiver operating characteristic (ROC) analysis. Kaplan-Meier survival analysis was used to compare the outcome predictions, while multivariate Cox regression analysis was used to identify the predictive factors. Among the patients examined, 41 (20 I-PET and 21 EOT-PET) experienced progression, and 49 (25 I-PET, 24 EOT-PET) did not. The optimal cutoff values of the RLL for predicting disease progression were 1.37 for I-PET (sensitivity 75%, specificity 88%) and 2.03 for EOT-PET (sensitivity 45.5%, specificity 100%), while the cutoffs of the D-5PS were scores 4 for I-PET (sensitivity 80%, specificity 72%) and 5 for EOT-PET (sensitivity 40.9%, specificity 100%). The prognostic efficacy was higher for the RLL at interim than for the D-5PS [area under the curve (AUC) =0.848 vs. 0.741]. The EOT prognostic efficacy of both evaluation methods was essentially equivalent (AUC =0.785 vs. 0.725). Univariate and multivariate analyses showed that RLL and D-5PS were independent factors affecting DLBCL outcomes for both interim and EOT assessment. RLL and D-5PS have independent predictive values for the interim and EOT evaluation of outcomes in patients with DLBCL. The RLL has better interim predictive ability than does D-5PS and can optimize D-5PS interpretation, thus improving interim outcome prediction.

Effective bridging therapy can improve CD19 CAR-T outcomes while maintaining safety in patients with large B-cell lymphoma.

The impact of bridging therapy (BT) on CD19-directed chimeric antigen receptor T-cell (CD19CAR-T) outcomes in large B-cell lymphoma (LBCL) is poorly characterized. Current practice is guided through physician preference rather than established evidence. Identification of effective BT modalities and factors predictive of response could improve both CAR-T intention to treat and clinical outcomes. We assessed BT modality and response in 375 adult patients with LBCL in relation to outcomes after axicabtagene ciloleucel (Axi-cel) or tisagenlecleucel (Tisa-cel) administration. The majority of patients received BT with chemotherapy (57%) or radiotherapy (17%). We observed that BT was safe for patients, with minimal morbidity or mortality. We showed that complete or partial response to BT conferred a 42% reduction in disease progression and death after CD19CAR-T therapy. Multivariate analysis identified several factors associated with likelihood of response to BT, including response to last line therapy, the absence of bulky disease, and the use of polatuzumab-containing chemotherapy regimens. Our data suggested that complete or partial response to BT may be more important for Tisa-cel than for Axi-cel, because all patients receiving Tisa-cel with less than partial response to BT experienced frank relapse within 12months of CD19CAR-T infusion. In summary, BT in LBCL should be carefully planned toward optimal response and disease debulking, to improve patient outcomes associated with CD19CAR-T. Polatuzumab-containing regimens should be strongly considered for all suitable patients, and failure to achieve complete orpartial response to BT before Tisa-cel administration may prompt consideration of further lines of BT where possible.

Circulating tumor DNA (ctDNA) by clonoSEQ to monitor residual disease after axicabtagene ciloleucel (axi-cel) in large B-cell lymphoma (LBCL).

7547 Background: Most patients (pts) with LBCL respond to axi-cel, but many will eventually experience disease progression (Jacobson et al. JCO. 2020). Monitoring of ctDNA from blood, a minimally invasive diagnostic tool, has been used to assess measurable residual disease (MRD) with prognostic value, including in pts with diffuse LBCL treated with axi-cel in the third line of therapy (3L; Frank et al. JCO. 2019). Here, we explored the value of ctDNA to predict outcomes in LBCL after axi-cel across lines of treatment. Methods: Pts with LBCL from ZUMA-12 (Phase 2 axi-cel in 1L), ZUMA-7 (Phase 3 axi-cel or standard of care [SOC] in 2L), and ZUMA-14 (Phase 2 axi-cel + rituximab in 3L) were included. All studies included initial MRD testing ≈30 days post axi-cel infusion. ClonoSEQ MRD assay (limit of detection≈0.0001%-0.00001%) was used to define the lymphoma B-cell clonotype in formalin-fixed, paraffin-embedded (FFPE) biopsy tissue prior to axi-cel infusion and to track ctDNA in blood after treatment. Positive predictive value (PPV; MRD+ pts who relapsed or were nonresponders/total MRD+ pts ×100) and negative predictive value (NPV; MRD- pts in ongoing response/total MRD- pts ×100) were assessed at Day 28, Month (Mo) 3, and Mo 5 for 3L; Days 50, 100, 150, Mo 9,and Mo 24 for 2L; and Day 28, Mo 3, and Mo 6 for 1L. Results: In 3L, the PPV at Day 28 was 88% (7/8) and NPV was 83% (10/12). NPV remained 83% at Mo 3 (10/12) and increased to 100% (8/8) at Mo 5. Overall, 83% (5/6) of relapsed pts had MRD detected at any time; of those 5, 100% (5/5) had MRD detected at any time prior to or at progression with a median detection of 43 days prior to progression. In 2L, the MRD+ detection rate among evaluable pre-infusion samples was only 69% (11/16). At Day 50, PPV was 100% (7/7) in the SOC arm, whereas it was only 57% (4/7) in the axi-cel arm. PPV increased over time in the axi-cel arm, reaching 100% by Mo 9 (2/2). At Day 50, NPV was 53% (8/15) in the axi-cel arm and 38% (5/13) in the SOC arm. Overall, 47% (9/19) of relapsed pts on the axi-cel arm had MRD detected at any time; of those 9, 78% (7/9) had MRD detected prior to or at progression with a median of 35 days prior to progression. In 1L, most pts (11/14) remained in ongoing response by data cut off. The PPV at Day 28 was 50% (1/2): of the two pts who had detectable MRD at Day 28, one subsequently became MRD negative at Mo 3 yet relapsed just after Mo 3, while the second became negative by Mo 3 and had ongoing response up to Mo 24. The NPV at Day 28 was 88% (7/8). Conclusions: The prognostic value of MRD assessment by clonoSEQ varied across lines of therapy in pts with LBCL treated with axi-cel. A relatively high rate of undetectable MRD at baseline in the 2L setting and prior to relapse in the 2L and 1L settings warrants exploration of more sensitive ctDNA monitoring methods. Clinical trial information: NCT03391466 NCT03761056 NCT04002401 .

MO-0960 Evaluating semi-automated 18F-FDG PET segmentation methods to predict Large B-cell lymphoma outcomes

MO-0960 Evaluating semi-automated 18F-FDG PET segmentation methods to predict Large B-cell lymphoma outcomes

Impact of TP53 Genomic Alterations in Large B-Cell Lymphoma Treated With CD19-Chimeric Antigen Receptor T-Cell Therapy.

Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T. Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre-CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status. We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type (P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration. TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.

Response to Bridging Therapy As a Predictor of Outcomes for Chimeric Antigen Receptor Therapy in Large B-Cell Lymphoma

Background: Bridging therapy (BT) was not allowed in the ZUMA-1 pivotal trial for axicabtagene ciloleucel (axi-cel) chimeric antigen receptor T-cell therapy (CAR-T) . Since then, several real-world studies have shown the use of bridging therapy to be associated with worse overall survival, duration of response, and complete remission rates. In addition, patients requiring BT during CAR-T manufacturing have a more aggressive and higher tumor burden of disease, also factors associated with poor outcomes. Therefore, factors that can predict outcomes in this high-risk patient cohort are required. We herein examine the impact of response to BT on CAR-T outcomes in large B-cell lymphoma (LBCL).Methods: A retrospective review of patients who received axi-cel for NHL from June 2016 - July 2020 at Mayo Clinic, Rochester, was performed. BT was defined as any lymphoma-directed therapy given between leukapheresis and CAR-T infusion. Patients received BT if there were concerns for symptomatic progression of disease during CAR-T manufacturing, reducing the likelihood of eligibility to receive CAR-T. The decision and choice of BT were at the discretion of the treating physician. Response to all lymphoma-directed therapy was evaluated using the 2014 Lugano criteria. Response to BT included patients with a partial response (PR) or stable disease (SD) on PET-CT before initiating lymphodepletion chemotherapy. Event-free survival (EFS) was defined as the time from axi-cel infusion to progression, next treatment, or death. Overall survival (OS) was defined as the time from axi-cel infusion to death. Survival curves were calculated using Kaplan-Meier estimates and were compared between subgroups using the log-rank test. Cox regression was used for univariate and multivariate analysis (MVA).Results: A total of 73 patients underwent car T therapy during this period. Of these, 67% (49/73) received BT therapy. Table 1 shows baseline characteristics of the total BT cohort (n = 49). The median age at CAR-T infusion was 59 years (IQR 46-64); 57% were males and comprised of 47% (23/49) DLBCL followed by 31% (15/49) high-grade B-cell lymphoma types. Based on the Lugano criteria on PET-CT, 22/49 (45%) patients responded to BT. The baseline characteristics were comparable between the responders and non-responders to BT except for a higher proportion (73%) of patients receiving systemic chemotherapy as BT in the responders (Table 1). At a median follow-up of 24 months, 75% had either progressed, died, or started the next treatment (event), and 59% (29/49) had died. The median EFS was significantly longer in the responders as compared to the non-responders to BT, figure 1 (13.04 months (95%CI, 3.54-not reached [NR]) vs. 2.56 months (95%CI, 1.18-3.02), p = 0.002). The OS also trended in favor of the responders (median OS 18.4 months (95% CI, 13.44-NR) vs. 11.84 months (95% CI, 5.05-NR), p = 0.092). The responder group also had a higher 6-month CR rate of 50% than 11.1% in the non-responder group (p = 0.004). There were no differences in any grade or grade ≥ 3 cytokine release syndrome and neurotoxicity rates in the two groups. On univariate analysis within the bridging group (n = 49), type of bridge (non-chemo) and response to bridge (PR+SD) were associated with a better EFS. In the MVA, only response to BT maintained significance for EFS (HR 0.34, p = 0.025).Conclusions: Having some control of lymphoma after BT was associated with better EFS and 6-month CR rate. Future studies need to prospectively evaluate the type and response to BT as a prognostic factor for improving outcomes in patients receiving CAR-T. [Display omitted] DisclosuresWang: InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genentech: Research Funding; MorphoSys: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend: Consultancy; Sorrento: Consultancy; Gamida Cell: Consultancy; Vineti: Consultancy; Merck: Research Funding; Takeda: Research Funding.

Tumor Inflammation and Myeloid Derived Suppressor Cells Reduce the Efficacy of CD19 CAR T Cell Therapy in Lymphoma

Introduction: Approximately 60% of Large B cell Lymphoma (LBCL) patients that receive CD19 CAR T cell therapy with axicabtagene ciloleucel (axi-cel) experience lymphoma progression (Locke et al. Lancet Oncol. 2019) and the likelihood of response to subsequent therapy is low (Spiegel, Dahiya et al. ASCO 2019). Target loss of CD19 is observed in less than a third of patients experiencing relapse. Alternative mechanisms of resistance to axi-cel are poorly understood. Lymphoma patients with elevated serum markers of systemic inflammation, such as ferritin and IL-6, have worse outcomes following axi-cel (Locke, Neelapu et al. Mol.Ther.2017; Faramand et al. ASH 2018). We hypothesized that suppressive monocytic myeloid derived suppressor cells (M-MDSCs), which are associated with worse chemotherapy outcomes in LBCL (Azzaoui et al. Blood 2016), and tumor driven inflammation may be present and responsible for decreased efficacy of axi-cel in LBCL. Methods: LBCL patients undergoing axi-cel treatment were enrolled onto prospective sample collection protocols. Patients were stratified for analysis into ongoing responders (complete response or partial response) or relapsed (progressive disease) after a minimum of 3 months follow-up (range 3 - 15 months). M-MDSCs, defined as a Lin-, CD11b+, CD33+, CD15-, CD14+, HLA-DRlow population, were sorted from leftover apheresis material after collection for axi-cel manufacture. M-MDSC ability to suppress proliferation of autologous T cells stimulated with CD3/CD28 coated beads was measured by 3H thymidine incorporation. Circulating peripheral blood M-MDSCs, quantified by % of live cells by flow cytometry, were measured at the time of apheresis and serially after axi-cel infusion until day 30. In vitro mouse experiments utilized a CD19-CD28 CAR and cytokine-induced bone marrow MDSCs (Thevenot et al. Immunity 2014). Cytokines were measured by ELISA and cytotoxicity against CD19 bearing cell lines used xCELLigence real-time cell analysis, as we have done previously (Li et al. JCI Insight 2018).Tumor biopsies were taken within 1 month prior to infusion of axi-cel. Limited gene expression profiling of tumor microenvironment (TME) genes used the Nanostring IO360 panel (770 genes). Analysis used nSolver to identify cell types, GSEA and differential gene expression between groups. Results: First, we demonstrated that M-MDSCs sorted from patient apheresis material suppressed the proliferation of autologous T cells (n=6). We next enumerated M-MDSCs in the peripheral blood (n = 32). M-MDSC numbers initially decreased after lymphodepleting chemotherapy but recovered to baseline levels by day +10. The level of M-MDSCs following CAR T cell therapy strongly correlated with pre-CAR T baseline levels (R = 0.871, p &lt;0.0001), suggesting that the number of M-MDSCs present during CAR T cell expansion is dependent on factors already present before therapy began. M-MDSC levels were significantly higher in patients who subsequently relapsed, both at baseline (p= 0.01) and after axi-cel (p=0.04), as compared to patients with durable response. Mouse MDSCs were able to suppress CAR T cell IFN-gamma excretion (p&lt;0.0001) and cytotoxicity (p&lt;0.0001) in vitro. To evaluate the role of the TME we interrogated limited set gene expression profiling on patient (n=27) pre-axi-cel tumor biopsies. By cell type scoring, the macrophage gene score was significantly higher in patients who relapsed after CAR T therapy (p &lt;0.001). By differential gene expression and gene set enrichment, patients who relapsed had a significantly higher expression (p &lt;0.01) of multiple genes indicative of chronic interferon (IFN) signaling including higher levels of OAS2, OAS3, IFI6 and IFIT1, as well as the IFN-stimulated macrophage gene SIGLEC-1/CD169. Conclusions: Systemic inflammatory myeloid cytokines, circulating M-MDSCs in the blood and chronic IFN in the TME all associate with LBCL relapse after axi-cel CAR T cell therapy. Our observations support that CAR T cells can be suppressed by baseline patient and tumor-related factors and strategies to overcome these factors should be targeted to improve patient outcomes. MDJ and HZ contributed equally. Disclosures Jain: Kite/Gilead: Consultancy. Bachmeier:Kite/Gilead: Speakers Bureau. Chavez:Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau. Shah:Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria. Mullinax:Iovance: Research Funding. Davila:Celgene: Research Funding; GlaxoSmithKline: Consultancy; Precision Biosciences: Consultancy; Novartis: Research Funding; Atara: Research Funding; Bellicum: Consultancy; Adaptive: Consultancy; Anixa: Consultancy. Locke:Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy.

Outcomes in large B-cell lymphoma progressing after axicabtagene ciloleucel (Axi-cel): Results from the U.S. Lymphoma CAR-T Consortium.

7517 Background: Axi-cel, an anti-CD19 CART cell therapy, achieved 83% ORR, 58% CR rate, with 39% PFS at 2 years in patients (pts) with relapsed refractory large B-cell lymphoma (LBCL) on the ZUMA-1 study (Locke, Lancet Oncology 2018). Data from a 17-center consortium showed response rates were similar in 274 pts treated with commercial axi-cel (Nastoupil, ASH 2018). Here, we performed retrospective analysis of outcomes in pts with progressive disease (PD) after axi-cel. Methods: Response status was determined by Cheson 2014 and reported as date of radiologic relapse. 274 pts were infused by December 26, 2018 with maximum follow-up of 14 months; 116 pts had PD as of Feb 1, 2019. Twelve sites provided additional data, detailing 85% of PD pts (n=99) with a median time to relapse of 54 days (IQR 16-120). Results: Pre axi-cel pt characteristics: median lines of therapy were 4 (range 2-11), 86% were Stage III/IV and 22% were ECOG &gt;1. Following relapse, 60% (n=61) were biopsied and 70% (43/61) had CD19 expression measured. Thirty percent (13/43) were CD19 negative by: IHC (3/13), flow (2/13) or both (8/13). Seventy percent (n=71) received salvage therapy for PD. Median lines of salvage therapy was 1 (range 0-4). The most common therapies were Lenalidomide-based (30%), checkpoint inhibitors (30%), chemotherapy (20%) and radiation (10%). First salvage therapy ORR by regimen: checkpoint inhibitors = 24%, lenalidomide regimens = 20% and chemotherapy = 11%. One patient received allogeneic transplant. Twelve pts enrolled on clinical trial, with one receiving 2nd CAR-T. Median OS following relapse was 108 days (95% LCL 71). Nineteen pts relapsed &lt;3 months after axi-cel and did not receive therapy with median OS 17 days (95% CI 7-49); 33 pts relapsed &lt;3 months and received therapy with 114 day median OS (95% LCL 82). In contrast, 30 pts who relapsed &gt;3 months post axi-cel and received therapy had estimated median OS &gt;220 days (95% LCL 81). Conclusions: Patients with LBCL relapsing less than 3 months following axi-cel have extremely poor outcomes supporting the development of novel therapies. Therapy for relapse &gt;3 months appears promising. JYS and SD contributed equally; APR, DBM and BTH contributed equally.

Skeletal muscle density is an independent predictor of diffuse large B-cell lymphoma outcomes treated with rituximab-based chemoimmunotherapy.

BackgroundWhile much cancer research focuses on tumours and their microenvironment, malignancies cause widespread physiologic changes. Cancer and treatment‐related sarcopenia, measured with quantitative imaging or as a decrease in overall body mass, are indicative of poor prognosis in elderly diffuse large B‐cell lymphoma (DLBCL) patients, skeletal muscle radiodensity (SMD) may be a better prognostic marker. SMD, a measure of muscle radiation attenuation on CT imaging, is more prognostic than sarcopenia or International Prognostic Index (IPI) scores in follicular lymphoma and multiple solid organ malignancies. Low SMD appears to correlate with fat accumulation in muscle and is associated with inflammation. This study set out to examine SMD's prognostic ability in DLBCL.MethodsAll DLBCL patients treated with rituximab‐containing therapy between 2004 and 2009 were compared to determine SMD's prognostic ability in this single centre, retrospective study. Pre‐treatment CT scans were used to measure SMD and muscle cross‐sectional area. Primary endpoints included progression free (PFS) and overall survival (OS) while objective response rates (ORR) were secondary.ResultsOf 224 evaluable patients, 116 were identified as having low SMD. Low SMD predicted poorer 5 year PFS, 60 vs. 81% (p = 0.001) and OS, 58 vs. 86% (p < 0.0001). SMD's prognostic ability retained significance in multivariate analysis taking into consideration the Revised International Prognostic Index (R‐IPI) and sex. Although high SMD was not predictive of ORR (95.4 vs. 91.4%, p = 0.17), it was strongly associated with radiographic complete response (85 vs. 66%, p = 0.0007). Contrary to previous findings, sarcopenia did not predict for poorer OS but suggested improved OS in elderly DLBCL patients (HR 0.38, p = 0.01).ConclusionsSMD is a novel prognostic (and potentially treatment predictive) marker independent of R‐IPI in DLBCL. It presents an inexpensive yet complementary assessment to R‐IPI for prognosticating DLBCL outcomes.

FCGR3A/2A polymorphisms and diffuse large B-cell lymphoma outcome treated with immunochemotherapy: a meta-analysis on 1134 patients from two prospective cohorts.

Single nucleotide polymorphisms (SNPs) in FCγ-receptor genes FCGR3A (rs396991) and FCGR2A (rs1801274) influence the affinity of the Fc portion of anti-CD20 immunoglobulin G1 monoclonal antibody. Their roles in diffuse large B-cell lymphoma (DLBCL) treated with rituximab in combination with anthracycline-based chemotherapy remain controversial. To address this question, we genotyped FCGR2A and FCGR3A SNPs in two prospective DLBCL cohorts from Lymphoma Study Association trials (N = 554) and Iowa/Mayo Specialized Program Of Research Excellence (N = 580). Correlations with treatment response and hematological toxicity were assessed in Lymphoma Study Association. Correlation with event-free survival (EFS) and overall survival (OS) was performed in both cohorts, followed by a meta-analysis to increase power. Our study shows the absence of correlation between these SNPs and treatment response. Grades 3 and 4 febrile neutropenia during treatment was more frequently observed in FCGR3A VV (39%) than VF (29%) and FF (32%) carriers (p = 0.04). Our analysis for EFS and OS shows that FCGR3A was not associated with outcome. In a meta-analysis using an ordinal model, FCGR2A (per R allele) was associated with a better EFS (hazard ratio = 0.87; 95%CI, 0.76-0.99; p = 0.04) and OS (hazard ratio = 0.86; 95%CI, 0.73-1.00; p = 0.05) which was not altered after adjustment for the International Prognostic Index. Overall, our data demonstrate that patients with DLBCL with the low-affinity FCγRIIA RR had an unexpectedly better outcome than FCγRIIA H carriers. Whether rituximab efficacy is improved in FCγRIIA RR patients due a clearance reduction or other functions of FCγRIIA in DLBCL should be investigated (clinicaltrials.gov identifiers: NCT00135499, NTC00135499 NCT00140595, NCT00144807, NCT00144755, NCT01087424, and NCT00301821). Copyright © 2016 John Wiley & Sons, Ltd.

Low expression of microRNA-146b-5p and microRNA-320d predicts poor outcome of large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone.

Although diffuse large B-cell lymphoma (DLBCL) encompasses a biologically and clinically diverse set of diseases, increasing evidence has pointed to an important role of microRNAs (miRs) in the pathogenesis of DLBCL. We report here that low expression of miR-146b-5p and miR-320d is associated with poor prognosis of DLBCL patients treated with the standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen and that this is related to the inhibitory effect of these miRs on DLBCL cell proliferation. Analysis of a retrospective cohort of 106 primary nodal DLBCL samples from patients who were treated with CHOP showed that, when the median survival period (40.8 months) was used as the cutoff point, miR-146b-5p and miR-320d were expressed at lower levels in DLBCLs with poor prognosis. Indeed, whereas low expression of miR-146b-5p was correlated with reduced progression-free survival, low expression of miR-320d was associated with decreases in both progression-free survival and overall survival. Moreover, miR-146b-5p and miR-320d were expressed at significantly lower levels in DLBCLs with the MYC t(8;14) translocation. Functional studies demonstrated that overexpression of miR-146b-5p or miR-320d inhibited DLBCL cell proliferation, wheareas knockdown of miR-146b-5p or miR-320d promoted proliferation of DLBCL cells. Taken together, these results suggest that low expression of miR-146b-5p and miR-320d may be predictive of compromised responses of a subset of DLBCL patients to treatment with the CHOP regimen and that restoration of these miRs may be useful to improve the therapeutic efficacy of CHOP.