scholarly journals 675 Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A703-A703
Author(s):  
Michael Jain ◽  
Bachisio Ziccheddu ◽  
Caroline Coughlin ◽  
Rawan Faramand ◽  
Anthony Griswold ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genomic Alteration ◽  
Genomic Alterations ◽  
Poor Outcome ◽  
Genomic Complexity ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

BackgroundCD19-directed chimeric antigen receptor-reprogrammed autologous T cells are breakthrough immunotherapies for heavily pretreated patients with diffuse large B-cell lymphoma (DLBCL), but across CAR-19 products, ~60% of patients fail to respond or relapse. Inflammatory markers and clinical factors associate with impaired responses, but tumor-intrinsic resistance drivers are largely undefined.MethodsTo characterize the genomic mechanisms involved resistance to CAR-19, we interrogated whole genome sequencing (WGS) from 28 relapsed/refractory (r/r) aggressive lymphoma patients uniformly treated with axicabtagene ciloleucel (axi-cel).ResultsBecause prognostic factors defined in the frontline treatment setting are largely inapplicable to CAR-19, we leveraged the WGS data, including comparative analyses with untreated DLBCL cases in the Pan-Cancer Analysis of Whole Genomes (PCAWG) (figure 1). In analyses of individual mutated genes, TP53 was significantly enriched (p=0.002) in CAR-19 patients, but did not predict outcome. However, mutations in either NFKBIA or MYC associated with worse PFS after CAR-19 (p=0.04, p=0.025 respectively). We next identified 12 single base substitution (SBS) mutational signatures in our cohort and found presence of APOBEC (SBS2 and SBS13) signatures associated with worse PFS, with 4/5 patients progressing (p=0.03). Copy number analysis by GISTIC2.0 revealed focal deletions of RHOA and RB1 to be significantly enriched in our cohort and independently predicted poor outcome (p=0.0007, p=0.05 respectively). WGS identifies structural variants and complex events. We found chromothripsis, a catastrophic shattering and reassembly of chromosomes, in 39.3% of r/r DLBCL, which was strongly associated with poor CAR-19 outcome, with 9/11 affected cases progressing (p=0.041). Finally, reduced expression (n=3) or genomic alteration (n=3) of CD19 did not associate with poor outcome. One case with durable response contained a sub-clonal CD19 mutation (L174V) previously reported as associated with CAR-19 resistance. These findings demonstrate predominance of CD19-independent resistance and indicate antigen-mediated tumor killing is not the only mechanism of tumor eradication. Genomic complexity appears to promote an immunosuppressive tumor microenvironment (TME), limiting CAR-19 efficacy.ConclusionsLeveraging the resolution of WGS, we observed that markers of genomic complexity (chromothripsis and APOBEC) and specific genomic alterations (RHOA and RB1 deletions) associate with resistance to CAR-19 immunotherapy for aggressive B-cell lymphomas (figure 1). 93.8% of CAR-19 relapsed patients contained at least one or these genomic alterations. Recent patient data demonstrate that an immunosuppressed TME leads to CAR-19 failure. Combining these findings with our genomics findings, successful CAR-19 therapy must overcome the immune-exhausted TME to mobilize the host immune system and eliminate the tumor.Abstract 675 Figure 1Genomic alterations associated with disease progression. (a) The heatmap shows the significant genomic alteration present in at least 4 patients associated with progression after CD19 CAR-T cell therapy. (b) Kaplan-Meier curve of progression free survival with the combination of statistically significant genomic anomalies

REAL-WORLD RESULTS ON CD19 CAR T-CELL FOR 60 FRENCH PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA INCLUDED IN A TEMPORARY AUTHORIZATION FOR USE PROGRAM

2019 ◽  
Vol 37 ◽  
pp. 301-301 ◽  
Author(s):  
C. Thieblemont ◽  
S. Le Gouill ◽  
R. Di Blasi ◽  
G. Cartron ◽  
F. Morschhauser ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Real World ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

scholarly journals CD5 expression is potentially predictive of poor outcome among biomarkers in patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy

2008 ◽  
Vol 19 (11) ◽  
pp. 1921-1926 ◽  
Author(s):  
D. Ennishi ◽  
K. Takeuchi ◽  
M. Yokoyama ◽  
H. Asai ◽  
Y. Mishima ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Poor Outcome ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Chop Therapy

scholarly journals Systematic Literature Review of the Clinical Evidence in Relapsed/Refractory (R/R) Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5821-5821
Author(s):  
David G. Maloney ◽  
Fei Fei Liu ◽  
Lisette Nientker ◽  
Cathelijne Alleman ◽  
Brian Hutton ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Introduction: Large B-cell lymphoma (LBCL) is the most common subtype of non-Hodgkin lymphoma. Frontline treatment is curative in ~60% of patients (pts); however, ~30% of pts relapse and ~10% are refractory to frontline treatment. Treatment options for pts with relapsed/refractory (R/R) disease, especially in the third-line or greater (3L+) setting, have been primarily salvage chemotherapies (CTs). Recently, 2 CAR T cell products, axicabtagene ciloleucel (Yescarta®) and tisagenlecleucel (Kymriah®), and the antibody-drug conjugate, polatuzumab vedotin (Polivy®), were approved in the 3L setting. A systematic literature review (SLR) of R/R LBCL was conducted to identify relevant evidence on clinical outcomes in LBCL pts, including these new therapies, within the second-line and greater (2L+) or 3L+ setting, and to define the unmet medical need. Methods: This SLR was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and European Union Health Technology Assessment requirements. The review identified randomized and nonrandomized/observational studies within R/R LBCL, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma grade 3B (FL3B), primary mediastinal large B-cell lymphoma (PMBCL), DLBCL transformed from indolent lymphomas, and R/R DLBCL with secondary central nervous system (SCNS) involvement. Sources were EMBASE, MEDLINE, The Cochrane Library, and clinical conferences (ASCO, ESMO, EHA, ASH, ICML, AACR, and EORTC) from Jan 2000 to Apr 2019. Results : Following screening of 8683 database records and additional sources, 103 publications covering 78 unique studies were identified. Studies identified were characterized by line of treatment and R/R LBCL subtype (Figure). OS, PFS, DOR, OR, and safety observed from the identified studies were described. Disease subtypes, pt eligibility criteria, and length of follow-up varied notably across studies. In the 3L+ population, 11 salvage CT and 2 CAR T cell therapy studies reported survival outcomes. With salvage CT, the reported ORR across studies ranged from 0% to 54%, while CR ranged from 5.6%-31%. Median OS (mOS) ranged between 3-9 months, with one outlying study reporting mOS at 20 months. Median PFS (mPFS) reported within the salvage CT studies ranged from 2-6 months. Among CAR T cell therapies, pts treated with axicabtagene ciloleucel (n=101) reported a CR rate of 58% and median DOR (mDOR) was 11.1 months after a median follow-up of 27.1 months. mPFS was 5.9 months and mOS was not reached. At a median follow-up of 19.3 months, pts treated with tisagenlecleucel (n=115) had a CR of 40% but the mDOR was not reached. mOS was 11.1 months for all infused patients. In the 2L+ transplant-eligible population (36 studies), pts who received high-dose CT + HSCT achieved mOS between 9 months to 5 years. In the transplant noneligible population, 16 studies reported mOS between 3-20 months. Studies involving mixed transplant-eligible and noneligible populations (30 studies) reported mOS of 1-17 months. A few studies with limited sample sizes were found to report outcomes in LBCL subtypes (eg, PMBCL, SCNS lymphoma, DLBCL transformed from non-FL indolent lymphoma, FL3B). In the 3L+ setting, 1 study reported that mOS was not reached after a median of 6.6 months. In the 2L+ setting, 4 studies reported mPFS and mOS outcomes ranging between 2-9 months and 10-16 months, respectively. Among studies assessing safety of salvage CTs in R/R LBCL, neutropenia, leukocytopenia, thrombocytopenia, and infections were the most commonly reported adverse events (AEs), with neutropenia being the most reported. Among the 3 studies reporting safety outcomes of CAR T cell therapy, data suggest that hematologic AEs (possibly related to lymphodepleting CT), cytokine release syndrome, and neurotoxicity are the most reported. Conclusions : Despite the availability of new therapies for 2L+ and 3L + LBCL, examination of the current evidence has shown that there exists a high unmet need for additional therapeutic options that provide favorable benefit/risk and durable response for these patients. Furthermore, limited data are available for the rarer subtypes of LBCL. Both findings represent important treatment gaps for R/R LBCL that must be addressed in future research geared toward improvement of the current treatment landscape. Disclosures Maloney: Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . Liu:Celgene Corporation: Employment. Nientker:Celgene Corporation: Consultancy; Pharmerit Cöoperatief U.A.: Employment. Alleman:Pharmerit Cöoperatief U.A.: Employment; Celgene Corporation: Consultancy. Garcia:Celgene: Employment, Equity Ownership.

scholarly journals Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Multiply Relapsed or Refractory Adult Large B-Cell Lymphoma

2019 ◽  
Vol 37 (24) ◽  
pp. 2105-2119 ◽  
Author(s):  
John K. Lin ◽  
Lori S. Muffly ◽  
Michael A. Spinner ◽  
James I. Barnes ◽  
Douglas K. Owens ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Life Expectancy ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Uncertainty Interval ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

PURPOSE Two anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies are approved for diffuse large B-cell lymphoma, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel; each costs $373,000. We evaluated their cost effectiveness. METHODS We used a decision analytic Markov model informed by recent multicenter, single-arm trials to evaluate axi-cel and tisagenlecleucel in multiply relapsed/refractory, adult, diffuse large B-cell lymphoma from a US health payer perspective over a lifetime horizon. Under a range of plausible long-term effectiveness assumptions, each therapy was compared with salvage chemoimmunotherapy regimens and stem-cell transplantation. Main outcomes were undiscounted life years, discounted lifetime costs, discounted quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (3% annual discount rate). Sensitivity analyses explored uncertainty. RESULTS In an optimistic scenario, assuming a 40% 5-year progression-free survival (PFS), axi-cel increased life expectancy by 8.2 years at $129,000/QALY gained (95% uncertainty interval, $90,000 to $219,000). At a 30% 5-year PFS, improvements in life expectancy were more modest (6.4 years) and expensive ($159,000/QALY gained [95% uncertainty interval, $105,000 to $284,000]). In an optimistic scenario, assuming a 35% 5-year PFS, tisagenlecleucel increased life expectancy by 4.6 years at $168,000/QALY gained (95% uncertainty interval, $105,000 to $414,000/QALY). At a 25% 5-year PFS, improvements in life expectancy were smaller (3.4 years) and more expensive ($223,000/QALY gained [95% uncertainty interval, $123,000 to $1,170,000/QALY]). Administering CAR-T to all indicated patients would increase US health care costs by approximately $10 billion over 5 years. Price reductions to $250,000 and $200,000, respectively, or payment only for initial complete response (at current prices) would allow axi-cel and tisagenlecleucel to cost less than $150,000/QALY, even at 25% PFS. CONCLUSION At 2018 prices, it is possible that both CAR-T therapies meet a less than $150,000/QALY threshold. This depends on long-term outcomes compared with chemoimmunotherapy and stem-cell transplantation, which are uncertain. Widespread adoption would substantially increase non-Hodgkin lymphoma health care costs. Price reductions or payment for initial response would improve cost effectiveness, even with modest long-term outcomes.

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