Clinical and Radiographic Predictors of Progression and Survival in Relapsed/Refractory Lymphoma Patients Receiving CAR-T Cell Therapy

Abstract Introduction: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of relapsed/refractory (R/R) B-cell lymphomas. Despite this improvement, a subset of patients do not respond to treatment or relapses afterwards. The purpose of this study is to determine patient clinical and radiographic variables that may be predictive of response to CAR-T therapy in order to improve patient selection for CAR-T therapy. Methods: We conducted a single-center retrospective review of all R/R B-cell non-Hodgkin lymphoma patients who received infusion of CAR T-cells from 2017-2020 and had one PET scan post-treatment for response evaluation. Clinicopathological and radiographic parameters were identified a-priori and collected through chart review. PET parameters included standardized uptake value (SUV), total metabolic tumor volume (TMTV), and total lesion glycolysis (TLG). For continuous parameters without established cutoffs, variables were dichotomized separately for time to progression and time to death using the Contal and O'Quigley method. Risk factors for progression free survival (PFS) and overall survival (OS) were identified by constructing a univariate Cox proportional hazards regression model. Variables meeting a p-value threshold of 0.10 for PFS or OS were included in stepwise selection to create a final multivariate model for PFS and OS at one year. Variables were retained with a p-value ≤0.05. The same process was also completed to create multivariate logistic regression models for progressive disease and death at one year. The final multivariate logistic regression models were used to estimate the area under the receiver operating curve (AUROC). Results: 64 patients with R/R lymphoma (87% DLBCL) were included in the study. At a median follow up of 23.7 months (95% CI: 16.8 months, 28.8 months), 37 patients (57.8%) progressed and 33 patients (51.6%) remain alive. Median progression free survival (PFS) at 1 year was 9.0 months (95% CI: 3.1 months, not reached) and median overall survival (OS) at 1 year was not reached, though the lower bound of its 95% CI is 11.4 months. Investigating progression at 1 year, the following variables met a p-value threshold of 0.10 in univariate Cox regression models and were therefore included in stepwise selection of the multivariate model for progression: stage (III/IV vs I/II) (odds ratio (OR) 3.132, p=0.0824), extranodal involvement (OR 2.117, p=0.0314), IPI score (OR 1.467, p=0.0125) and tocilizumab administration (OR 0.555, p=0.0932). The final multivariate model identified IPI (OR 1.972, p=0.0022) and tocilizumab administration (OR 0.277, p=0.0095) as predictive variables for PFS at 1 year. Investigating OS at 1 year, the following variables met a p-value threshold of 0.10 in univariate Cox regression models and were therefore included in stepwise selection of the multivariate model for survival: ECOG 2 (OR 4.677, p=0.0757), LDH high (OR 2.401, p=0.0453), CNS involvement (OR 5.030, p=0.0105), IPI (OR 1.720, p=0.0075), Ferritin pre CAR T (continuous) (OR 1.001, p=0.0041), CRS (OR 0.437, p=0.0658), tocilizumab administration (OR 0.363, p=0.0363), TMTV >89 (OR 2.479, p=0.0442), TLG >229 (OR 2.188, p=0.0918), and SUV >18 (OR 2.116, p=0.0906). The final multivariate model identified IPI (OR 1.973, p=0.0082), ferritin (OR 1.001, p=0.0101), and tocilizumab administration (OR 0.216, p=0.0046) as predictive variables for OS at 1 year. The multivariate logistic regression model identified stage IV disease (OR 23.952, p=0.0029) and BMI >24 (OR 0.225, p=0.0472) as predictors for progression at 1 year and IPI (OR 2.607, p=0.0071) and tocilizumab administration (OR 0.108, p=0.0068) as predictors for survival at 1 year. The AUROC for progression and death were 0.815 (p<0.0001) and 0.833 (p<0.0001), respectively. Conclusions: Both clinical and radiographic variables identify R/R lymphoma patients who are at low or high risk for progression and/or poor overall survival after CAR T-cell therapy. IPI, ferritin, BMI, advanced stage, and tocilizumab administration may be predictors of response. These results need validation in larger prospective trials. Figure 1 Figure 1. Disclosures Kamdar: Celgene (BMS): Consultancy; Adaptive Biotechnologies: Consultancy; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy; Genetech: Other; Kite: Consultancy; KaryoPharm: Consultancy; AbbVie: Consultancy; Genentech: Research Funding; TG Therapeutics: Research Funding; SeaGen: Speakers Bureau; Celgene: Other.

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PCN6 EVALUATING THE QUALITY AND RISK OF BIAS IN OVERALL SURVIVAL OUTCOMES FROM NON-RANDOMISED CAR T-CELL THERAPY PIVOTAL TRIALS

Value in Health ◽

10.1016/j.jval.2019.09.203 ◽

2019 ◽

Vol 22 ◽

pp. S436

Author(s):

N. Carey ◽

L. McCullagh ◽

M. Barry

Keyword(s):

Overall Survival ◽

T Cell ◽

Cell Therapy ◽

Risk Of Bias ◽

Survival Outcomes ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

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NIMG-74. MULTIPARAMETER MRI INVESTIGATION OF HIGH-GRADE GLIOMA RESPONSE TO CAR T CELL IMMUNOTHERAPY

Neuro-Oncology ◽

10.1093/neuonc/noz175.743 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi178-vi178

Author(s):

Harshan Ravi ◽

Olya Stringfield ◽

Gustavo De Leon ◽

Sandra Johnston ◽

Russell Rockne ◽

...

Keyword(s):

Overall Survival ◽

T Cells ◽

T Cell ◽

High Grade Glioma ◽

High Grade ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract INTRODUCTION Immunotherapy with engineered CAR T cells is a promising new therapy for glioblastoma, for which predictive and prognostic biomarkers are needed to inform effective intervention. Recently, our group analyzed standard-of-care (SOC) MRI images of long-term and short-term glioblastoma survivors and identified six intratumoral “habitats” of which “Habitat 6” was correlated with survival at diagnosis in high-grade glioma. Based on the MRI characteristics of “Habitat 6”, viz. high enhancement and high edema, we hypothesized that it could be a marker of tumor immune infiltrates. We are studying longitudinal changes in tumor “habitat” composition on MRIs of subjects with recurrent high-grade glioma treated with CAR T cells engineered to target IL13Ra2. METHODS MRI scans of the brain were acquired in 6 subjects at 3.0 T at baseline and various times before and after initiation of CAR T cell therapy. FLAIR, T1W and T1W-CE MRI images were registered to T2W images and six intratumoral “habitats” were computed as per our recently published methodology. The six habitats generated at the end of the tumor segmentation process were: “Habitat 1” (low FLAIR, low enhancement), “Habitat 2” (high FLAIR, low enhancement), “Habitat 3” (low FLAIR, medium enhancement), “Habitat 4” (high FLAIR, medium enhancement), “Habitat 5” (low FLAIR, high enhancement), and “Habitat 6” (high FLAIR, high enhancement). RESULTS Analysis of temporal changes in the six “habitats” shows an initial increase in both “Habitat 4” and “Habitat 6” following CAR T cell therapy initiation. Subjects with higher absolute volumes of “Habitat 6” at the baseline (pre-treatment) showed longer overall survival. Overall survival is a function of absolute “Habitat 6” volume at baseline, its direction of change immediately post-therapy, the duration of any increase in “Habitat 6” post-treatment, and the “Habitat 6” to “Habitat 4” ratio. Additional subjects are being evaluated to further understand these preliminary observations.

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Complete Versus Incomplete Hematologic Recovery after CAR T Cell Therapy: Implications for Relapse Free Survival and Overall Survival in Pediatric and Young Adult Patients with Relapsed/Refractory B-ALL

Blood ◽

10.1182/blood-2021-151114 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1747-1747

Author(s):

Benjamin J Lerman ◽

Yimei Li ◽

Hongyan Liu ◽

Regina M. Myers ◽

Kaitlin Devine ◽

...

Keyword(s):

Overall Survival ◽

T Cell ◽

Complete Remission ◽

Cell Therapy ◽

Research Funding ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

First Relapse

Abstract Background: Anti-CD19 Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a mainstay in the treatment of patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). While trials have shown encouraging survival rates, up to 50% of patients receiving CART eventually relapse. Identification of risk factors for subsequent relapse is crucial, as this could allow tailored surveillance and treatment approaches for high-risk patients, potentially leading to improved morbidity and mortality. Complete remission with incomplete hematologic recovery (CRi) has been associated with decreased remission duration and overall survival in acute leukemias. As count suppression following CAR T cell therapy is frequently seen, this study evaluated CRi as a prognostic marker for worse relapse-free (RFS) and overall survival (OS) after CAR T cell therapy in comparison to complete remission with hematologic recovery (CR). Methods: Patients with r/r ALL who achieved a complete morphologic remission after receiving anti-CD19 CAR T cell treatment with the 4-1BB-containing products CTL019 or humanized CART19 in the context of a clinical trial (NCT01626495, NCT02374333, NCT02228096, NCT02435849, NCT02906371) or commercial product (tisagenlecleucel) at Children's Hospital of Philadelphia from 4/2012-4/2019 were identified. Patients who received prior CAR therapy, and those with Trisomy 21 were excluded. Demographic, disease and treatment characteristics, and outcome data were abstracted from the medical record or clinical trial datasets. CR was defined as achieving a morphologic remission with both an absolute neutrophil count (ANC) ≥1,000/µL and a transfusion-independent platelet count ≥100,000/µL at any time between 27-33 days after CAR T cell infusion, whereas those achieving a morphologic remission without complete hematologic recovery were defined as CRi. RFS and OS were described for each cohort. Exposure-outcome association was assessed via the log-rank test and multivariable Cox proportional hazard regression. Results: Of the 206 patients included in the analysis, 104 (51%) achieved CR, 102 (49%) CRi. Forty patients (39%) met criteria for CRi with both ANC <1000/µL and platelets <100,000/µL, 40 (39%) for isolated thrombocytopenia, and 20 (20%) for neutropenia alone. Median age at leukemia diagnosis was 7 years (range 0.2-24), and at CAR T cell infusion was 12 years (range 1-29), with 48% undergoing a prior allogeneic stem cell transplant (HSCT), 32% with high risk cytogenetics, and 10% with prior blinatumomab treatment, none of which differed between the CR and CRi groups (Table 1). The number of relapses prior to CAR T cell referral was different between the groups (p=0.003), with more CR patients having been referred for primary refractory disease (25% vs 9.8%), and more CRi patients for first relapse (34% vs 18%). More CRi patients had >25% bone marrow blasts (43% vs 19%) at infusion, whereas more CR patients were MRD-negative (50% vs 30%) at infusion (p=0.002). CRi patients were also more likely to have Grade 3/4 CRS (38% vs 6.7%). Median length of follow-up for patients with CR was 39 months (range 7-89), which was not statistically significantly different than for those patients with CRi (41 months, 11-98, p=0.875). There was no difference in RFS when stratified by hematologic recovery (Figure 1, p=0.2165), with RFS at 36 months for CR of 57% (47-69) and CRi of 46% (36-59). OS was significantly lower (Figure 2, p=0.0081) for those with CRi, with 36-month OS for CR of 81% (74-89), and for CRi of 63% (54-73). In multivariable analysis adjusting for sex, prior blinatumomab, relapse number, disease burden at infusion, and maximum CRS grade, CR was not associated with either RFS (HR 0.76 [95%CI 0.50-1.17] p=0.2182) or OS (HR 0.74 [95%CI 0.43-1.29] p=0.2908), in comparison to CRi, Table 2. Discussion: Complete remission with incomplete hematologic recovery, manifesting as neutropenia and/or thrombocytopenia, at the first disease assessment following CAR T cell infusion should not be regarded as a harbinger of relapse and demonstrates that patients with CRi have similar probability of durable remission without further therapy. Anticipatory guidance should be provided to patients, and their families, that CRi is more frequently seen in patients who experience high grade CRS, who have high disease burden at infusion, and who are treated in first relapse. Figure 1 Figure 1. Disclosures Callahan: Novartis: Speakers Bureau. Rheingold: Optinose: Other: Spouse's current employment; Pfizer: Research Funding. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Novartis, Kite, Vertex, and Servier: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding. Maude: Wugen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding.

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Long Term Follow-up after SCRI-CAR19v1 Reveals Late Recurrences As Well As a Survival Advantage to Consolidation with HCT after CAR T Cell Induced Remission

Blood ◽

10.1182/blood-2018-99-115599 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 967-967 ◽

Cited By ~ 18

Author(s):

Corinne Summers ◽

Colleen Annesley ◽

Marie Bleakley ◽

Ann Dahlberg ◽

Michael C. Jensen ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

P Value ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

History Of ◽

Risk Of Relapse

Abstract Background: CD19 chimeric antigen receptor (CAR) T cell therapy has demonstrated robust responses in refractory/relapsed subjects with CD19+ acute lymphoblastic leukemia (ALL). Our Phase 1 clinical trial demonstrated a minimal residual disease (MRD) negative complete remission (CR) rate of 93% at 21 days following SCRI-CAR19v1 (a CD19 specific CAR T cell product) infusion (PMID: 29171004). Though remission is frequently attained, approximately half of patients recur. Controversy exists regarding the benefit of hematopoietic cell transplant (HCT) following CD19 CAR T cell therapy. Although not mandated by the study, our current institutional recommendation for relapsed/refractory patients without a history of allogeneic HCT is to undergo a HCT once in remission following SCRI-CAR19v1. Additionally, we have recommended HCT to those who have a short duration of persistence of SCRI-CAR19v1 in vivo regardless of prior HCT status. We report here the leukemia free survival (LFS) of subjects who proceeded to HCT following remission after SCRI-CAR19v1 infusion. Methods/Results: We analyzed the first 64 subjects on our Phase 1/2 trial, PLAT-02 (NCT02028455), with follow-up of ≥1 year to evaluate the potential benefit of consolidative HCT. We excluded subjects that did not respond (n=5) or relapsed prior to day 63 (n=9). Thirty-two of the evaluated subjects were treated on the Phase I dose finding portion of the study and 18 were treated on the Phase 2 portion at dose level of 1x106cells/kg. Of the 50 evaluable subjects, 33 had a history of at least one prior HCT, whereas 17 had no history of HCT. Figure A demonstrates the LFS for patients that did and did not undergo HCT following SCRI-CAR19v1. There is a trend towards improved LFS (p-value 0.057; Figure B) in patients who underwent first HCT following SCRI-CAR19v1. Of the 17 patients without a history of HCT, 3 did not pursue HCT following CAR therapy. Of those 3 subjects, only 1 remains in remission at 28 months. The other 2 subjects relapsed at 6 and 7 months with CD19+ and CD19- disease, respectively. Of the 14 patients that underwent first HCT after SCRI-CAR19v1, 2 relapsed following HCT. One had evidence of MRD by flow at the time of HCT and the other subject relapsed with CD19- disease. The role of second HCT following CAR therapy remains unclear. Of the 33 subjects with a history of HCT, 10 underwent a second HCT following SCRI-CAR19v1 infusion, and 5 are alive and remain in remission. The recurrences included 2 lineage switches and 2 CD19+ (1 was MRD positive by deep sequence prior to HCT), and one transplant related mortality (TRM). Of the 23 subjects that did not undergo a second HCT, 8 remain in remission (p-value not significant (NS); Figure C). We previously reported that subjects with a short duration of B cell aplasia (BCA) ≤63 days following SCRI-CAR19v1 have an increased risk of relapse. Here we show that subjects with short BCA who attained a CR and did not relapse prior to day 63 demonstrate a clear benefit of consolidative HCT (p-value 0.007; Figure D). Of the 15 subjects with short BCA (regardless of HCT history), 6 did not pursue HCT and all recurred (5 CD19+, 1 CD19-). Of the short BCA subjects that underwent HCT, 1 subject died of TRM (2ndHCT for this subject) and 2 subjects relapsed following HCT (1 was MRD positive prior to HCT). All events in the consolidative HCT group have occurred by 20 months following SCRI-CAR19v1. However, we continue to see late relapses following CAR T cell therapy in the group who did not proceed with HCT. Three subjects have relapsed beyond 2 years: 1 with CD19+ disease at 27months, 1 with CD19- disease at 41 months, and 1 patient with lineage switch AML at 38 months. Further analysis is needed to understand the continued long-term risk of relapse following CD19 CAR T cell therapy and the potential role and timing for consolidative HCT in patients with a previous HCT. Conclusions: We demonstrate a trend towards improved LFS for subjects without a history of HCT who undergo a consolidative HCT following CD19 CAR T cell therapy on PLAT-02. In addition, HCT appears to benefit subjects who attain a CR but are at increased risk of relapse with short-term BCA. Currently, the benefit of second HCT following CD19 CAR T cell therapy is unclear and may be restricted to those that have short functional persistence of SCRI-CAR19v1. Late relapses after SCRI-CAR19v1 have only occurred in those without consolidative HCT, but longer follow up is needed to confirm these findings. Figure Figure. Disclosures Jensen: Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.

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