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.

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 Long-Term Follow-Up of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy

2020 ◽  
Vol 38 (32) ◽  
pp. 3805-3815
Author(s):  
Kathryn M. Cappell ◽  
Richard M. Sherry ◽  
James C. Yang ◽  
Stephanie L. Goff ◽  
Danielle A. Vanasse ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T

PURPOSE Anti-CD19 chimeric antigen receptors (CARs) are artificial fusion proteins that cause CD19-specific T-cell activation. Durability of remissions and incidence of long-term adverse events are critical factors determining the utility of anti-CD19 CAR T-cell therapy, but long-term follow-up of patients treated with anti-CD19 CAR T cells is limited. This work provides the longest follow-up of patients in remission after anti-CD19 CAR T-cell therapy. METHODS Between 2009 and 2015, we administered 46 CAR T-cell treatments to 43 patients (ClinicalTrials.gov identifier: NCT00924326 ). Patients had relapsed B-cell malignancies of the following types: diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma (DLBCL/PMBCL; n = 28), low-grade B-cell lymphoma (n = 8), or chronic lymphocytic leukemia (CLL; n = 7). This report focuses on long-term outcomes of these patients. The CAR used was FMC63-28Z; axicabtagene ciloleucel uses the same CAR. Cyclophosphamide plus fludarabine conditioning chemotherapy was administered before CAR T cells. RESULTS The percentages of CAR T-cell treatments resulting in a > 3-year duration of response (DOR) were 51% (95% CI, 35% to 67%) for all evaluable treatments, 48% (95% CI, 28% to 69%) for DLBCL/PMBCL, 63% (95% CI, 25% to 92%) for low-grade lymphoma, and 50% (95% CI, 16% to 84%) for CLL. The median event-free survival of all 45 evaluable treatments was 55 months. Long-term adverse effects were rare, except for B-cell depletion and hypogammaglobulinemia. Median peak blood CAR-positive cell levels were higher among patients with a DOR of > 3 years (98/µL; range, 9-1,217/µL) than among patients with a DOR of < 3 years (18/µL; range, 0-308/μL, P = .0051). CONCLUSION Complete remissions of a variety of B-cell malignancies lasting ≥ 3 years occurred after 51% of evaluable anti-CD19 CAR T-cell treatments. Remissions of up to 9 years are ongoing. Late adverse events were rare.

CD22-Directed CAR T-Cell Therapy Induces Complete Remissions in CD19-Directed CAR-Refractory Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Author(s):  
John H Baird ◽  
Matthew Joshua Frank ◽  
Juliana Craig ◽  
Shabnum Patel ◽  
Jay Y Spiegel ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dose Escalation Study ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T ◽  
Large B Cell

The prognosis for patients with large B-cell lymphoma (LBCL) progressing after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first three consecutive patients with autologous CAR19-refractory LBCL treated with a single infusion of autologous 1×106 CAR+ T-cells/kg targeting CD22 (CAR22) as part of a phase I dose escalation study. CAR22 therapy was relatively well tolerated, without any observed non-hematologic adverse events higher than grade 2. Following infusion, all three patients achieved complete remission, with all responses ongoing at the time of last follow up (mean 7.8 months, range 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range 85.4-350 cells/µL), and persisted beyond three months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA (ctDNA) beyond six months post-infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients who have failed prior CAR T-cell therapies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT04088890)

scholarly journals Fatal late-onset CAR T-cell–mediated encephalitis after axicabtagene-ciloleucel in a patient with large B-cell lymphoma

2021 ◽  
Vol 5 (19) ◽  
pp. 3789-3793
Author(s):  
Susanne Jung ◽  
Jochen Greiner ◽  
Stephanie von Harsdorf ◽  
Pavle Popovic ◽  
Roland Moll ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Abstract Treatment with CD19-directed (CAR) T cells has evolved as a standard of care for multiply relapsed or refractory large B-cell lymphoma (r/r LBCL). A common side effect of this treatment is the immune effector cell–associated neurotoxicity syndrome (ICANS). Severe ICANS can occur in up to 30% to 40% of patients treated with axicabtagene-ciloleucel (axi-cel), usually within the first 4 weeks after administration of the dose and usually responding well to steroids. We describe a case of progressive central neurotoxicity occurring 9 months after axi-cel infusion in a patient with r/r LBCL who had undergone a prior allogeneic hematopoietic cell transplant. Despite extensive systemic and intrathecal immunosuppression, neurological deterioration was inexorable and eventually fatal within 5 months. High CAR T-cell DNA copy numbers and elevated levels of interleukin-1 (IL-1) and IL-6 were found in the cerebral spinal fluid as clinical symptoms emerged, and CAR T-cell brain infiltration was observed on autopsy, suggesting that CAR T cells played a major pathogenetic role. This case of unexpected, devastating, late neurotoxicity warrants intensified investigation of neurological off-target effects of CD19-directed CAR T cells and highlights the need for continuous monitoring for late toxicities in this vulnerable patient population.

scholarly journals Liposomal Vincristine as a Bridge Therapy Prior to CAR-T Therapy in Relapsed and Refractory Diffuse Large B-Cell Lymphoma?

2019 ◽  
Author(s):  
Juskaran Chadha ◽  
Shafinaz Hussein ◽  
Yougen Zhan ◽  
Jonah Shulman ◽  
Joshua Brody ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Bridge Therapy ◽  
Line Chemotherapy ◽  
Large B Cell

We report a case of a 76-year-old male with a history of relapsed and refractory diffuse large B-cell lymphoma (DLBCL).Our patient was initially treated with front line chemotherapy along with central nervous system (CNS) prophylaxis with complete response. He subsequently relapsed, was sensitive to second-line chemotherapy, and underwent autologous stem cell transplantation achieving a complete remission. Only a few months after transplant, the patient suffered his second relapse and was deemed a candidate for Chimeric Antigen Receptor T-Cell Therapy (CAR-T). Given his aggressive disease, combined with the time needed to generate CAR-T cells, a multidisciplinary team recommended to treat our patient with liposomal vincristine in combination with rituximab as a bridge therapy. Durable responses have been seen using liposomal vincristine based on results from a recent phase II trial in heavily pretreated patients with DLBCL1. This therapy was effective in stabilizing and reducing active disease in our patient. This case looks to illustrate the use of liposomal vincristine in combination with immunotherapy in a novel setting bridging highly selected patients with active and refractory lymphoma prior to CAR-T. Moreover, we expanded an additional therapeutic point, highlighting the importance of optimal disease control prior to CAR-T cell harvesting, as recent literature has shown that residual malignant cells in the pheresis product may be inadvertently be transfected with the CAR gene, resulting in resistance and further relapse2.

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