Single-Center Experience with Axicabtagene-Ciloleucel (Axi-cel) and Tisagenlecleucel (Tisa-cel) for Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Comparable Response Rates and Manageable Toxicity

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Veit Buecklein ◽  
Viktoria Blumenberg ◽  
Josephine Ackermann ◽  
Christian Schmidt ◽  
Kai Rejeski ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Time Interval ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Single Center Experience ◽  
Car T Cell Therapy ◽  
Car T

The CD19 CAR T-cell products Axi-cel and Tisa-cel induce complete responses (CR) in 40-58% of patients (pts) with relapsed/refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL). However, treatment can be associated with significant toxicity, with Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) as the most prominent and specific adverse events of CAR T-cell therapy. Toxicity profiles differ between both commercially available products, mainly due to their divergent co-stimulatory domain (4-1BB in Tisa-cel vs. CD28 in Axi-cel). Here, we report our single-center experience of DLBCL patients treated with Axi-cel or Tisa-cel at the LMU Munich University Hospital between January 2019 and June 2020. Toxicities, response rates and survival of DLBCL patients were retrospectively assessed. As of June 2020, 48 patients were enrolled for CD19-CAR T-cell therapies at our centre, and 37 DLBCL patients (pts) were apheresed. Median time interval between apheresis and CAR T-cell treatment was 39 days. So far, 31 DLBCL pts were transfused (Axi-cel: 18, Tisa-cel: 13). Median age of transfused pts was 60 years (range 19-74, Axi-cel: 60 years, Tisa-cel: 60 years). ECOG was 0-1 in 19 and 2-3 in 12 pts at time of CAR T-cell transfusion (Axi-cel: 0-1 in 13 and 2-3 in 5 pts, Tisa-cel: 0-1 in 6 and 2-3 in 7 pts). 13 pts had undergone prior stem cell transplant (9 autologous, 3 allogeneic, Axi-cel: 4 auto, 2 allo; Tisa-cel: 5 auto, 1 allo). Median number of prior DLBCL therapy lines was four (range 2-9, Axi-cel: 4, Tisa-cel: 4). Only 9/31 pts (29%) met the inclusion criteria of the pivotal clinical trials (due to e.g. infection, CNS disease, thrombocytopenia) at time of enrolment into our CAR T-cell treatment program. 23 pts (74%) received bridging chemotherapy (Axi-cel: 13/18 pts [72%]; Tisa-cel: 10/13 [77%]). Further details on radiographic response and the incidence of toxicities for all treated pts are summarized in the accompanying table. Response assessment after three months using PET/CT was available for 28 pts. Objective response rate (ORR) was 46%, with CR in eight (28%) and partial remission (PR) in five pts (18%). CRS occurred in 29/31 pts (84% CRS °1-2, 10% °3). Tocilizumab was applied in all CRS pts, with a median of four total infusions (range 1-4). 16 pts (52%) developed ICANS (33% °1-2, 16% °3-4, and 3% °5), which was managed with steroids in 9/16 pts. With a median follow-up of seven months, median progression-free survival (PFS) was 2.4 months for all pts. PFS was significantly longer for pts with normal vs. elevated LDH at time of apheresis (not reached vs. 1.5 mo, p=0.031). PFS of patients with two prior lines of therapy (n=7) was comparable with pts with three (n=5) or more (n=15) lines (2 lines: 3.1 mo, ≥3 lines: 1.9 mo, p=0.520). The time interval of ≤ 12 months (n=8 pts) from initial diagnosis of DLBCL to CAR T-cell transfusion was not prognostic and did not identify patients with worse PFS (≤12 mo: 1.7 months, >12 mo: 2.8 mo, p=0.569). In summary, in our cohort of heavily pretreated patients with a median of four prior DLBCL therapy lines, we observed an ORR of 46% (28% CR) at 3 months after CAR T-cell therapy, with no significant differences between patients treated with Axi-cel and Tisa-cel. In line with results of the pivotal clinical trials, treatment with Axi-cel was associated with a moderately higher incidence of ICANS. Overall, CAR T-cell toxicities were well manageable. Normal LDH levels at time of apheresis identified patients with high probability of sustained remission. In contrast, the number of prior therapy lines or the time interval from initial diagnosis of DLBCL to CAR T-cell transfusion had no impact on PFS. These hypothesis-generating findings might be helpful for future clinical decision-making, but need to be confirmed in a larger cohort. Therefore, we have set up a comprehensive patient monitoring program to identify predictive clinical and immunological markers of response and survival in CAR T-cell treated DLBCL patients. We will present updated results with longer follow-up at the annual meeting. Figure Disclosures Buecklein: Celgene: Research Funding; Pfizer: Consultancy; Gilead: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Consultancy. Blumenberg:Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding. Subklewe:Seattle Genetics: Research Funding; Morphosys: Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding; AMGEN: Consultancy, Honoraria, Research Funding.

scholarly journals Highly Favorable Outcomes with Salvage Radiation Therapy Followed By Autologous Transplant in Relapsed and Refractory DLBCL Patients with Minimal or No Response to Salvage Chemotherapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4137-4137
Author(s):  
Joanna C Yang ◽  
Karen Chau ◽  
Michael Scordo ◽  
Craig S. Sauter ◽  
Joachim Yahalom
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
Refractory Disease ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Introduction: For patients with relapsed or primary refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who respond to salvage chemotherapy, high-dose chemotherapy and autologous hematopoietic cell transplantation (HDT-AHCT) is considered standard of care. Patients with refractory disease to salvage chemotherapy, defined as stable disease (SD) or progressive disease (PD), by functional imaging are ineligible for HDT-AHCT, and have a poor prognosis. In practice, we have attempted to salvage these patients with radiation therapy (RT) to residual sites of active disease prior to consolidative HDT-AHCT. The outcome of this unique combined modality salvage paradigm has not been previously reported. Methods: We retrospectively reviewed all patients with rel/ref DLBCL who received salvage chemotherapy followed by salvage RT and HDT-AHCT between the years of 2000 and 2017 at a single center. Only patients with SD or PD as defined on the 5-point Deauville scale after salvage chemotherapy and who had at least 1 year of follow-up were included in this analysis. The second-line age-adjusted International Prognostic Index (sAAIPI) was determined at the time of initiation of salvage chemotherapy.Survival functions were estimated by the Kaplan-Meier method and compared using a log-rank test. Results: Thirty-six patients, 12 with relapsed and 24 with primary refractory disease, with a median age of 44 years (range: 19-68 years) were analyzed. Twenty-three patients had DLBCL while 13 had primary mediastinal B-cell lymphoma (PMBCL). The majority of patients had KPS 80-100 (n=32, 89%), 0-1 extranodal sites (n=30, 83%), and normal LDH (n=21, 58%). The sAAIPI scores for this cohort were as follows: 0 (n=10), 1 (n=21), 2 (n=4), and 3 (n=1). All patients received salvage chemotherapy with subsequent functional imaging showing SD (n=32) and PD (n=4) and then went on to receive salvage RT to the sites of active disease. Median RT dose was 39.6Gy (range: 30-54Gy). Six patients also received TBI as part of their conditioning regimen prior to HDT-AHCT. With median follow up of 4.0 years (range: 1.0-12.3 years) for survivors, 4-year relapse-free survival (RFS) was 75.6% and 4-year overall survival (OS) was 80.3% (Figure 1a). There was no significant difference in 4-year RFS for patients with relapsed versus primary refractory disease (80.2% vs 74.8%, p=0.59). PMBCL patients had better RFS than DLBCL patients (92.3% vs 67.8%, p=0.12). Using the composite sAAIPI score was highly prognostic with worse outcomes for patients with higher risk sAAIPI scores. By sAAIPI score, 4-year RFS was 80.0% for a score of 0, 90.2% for a score of 1, and 0% for scores of 2 and 3. Patients with low- and low-intermediate risk sAAIPI scores of 0 and 1 had improved RFS as compared to patients with sAAIPI scores of 2 and 3 (87.0% vs 0%, p<0.0001 (Figure 1b). Conclusions: Patients with chemorefractory rel/ref DLBCL who have had minimal or no response to systemic salvage therapy may benefit from salvage RT to the residual PET-avid disease followed by HDT-AHCT, particularly if their sAAIPI score is ≤ 1. The outcome of this retrospective cohort is markedly superior to outcomes described in the literature for this high-risk population and represents a promising treatment paradigm to be further explored. Emerging data suggest similar patients may benefit from CAR T-cell therapy. Given the limited availability and high cost of CAR T-cell therapy, we suggest there may be a role for sequencing this combined-modality salvage paradigm prior to CAR T-cell therapy in order to provide these poor-risk patients with an additional line of therapy. Disclosures Scordo: Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Sauter:Sanofi-Genzyme: Consultancy, Research Funding; GSK: Consultancy; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; Juno Therapeutics: Consultancy, Research Funding.

scholarly journals Clinical Efficacy of Polatuzumab Vedotin in Patients with Relapsed/Refractory Large B-Cell Lymphoma after Standard of Care Axicabtagene Ciloleucel

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Paolo Strati ◽  
Grace Watson ◽  
Sandra B. Horowitz ◽  
Ranjit Nair ◽  
Maria Alma Rodriguez ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Standard Of Care ◽  
Median Number ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Introduction. The outcome of patients with large B-cell lymphoma (LBCL) relapsing or progressing after anti-CD19 CAR T-cell therapy is dismal, and novel therapeutic strategies are needed. Polatuzumab vedotin (PV) is a CD79b-directed antibody-drug conjugate, approved by the FDA in combination with bendamustine and rituximab for the treatment of patients with LBCL who relapse or progress after at least 2 lines of systemic therapy. CD79b targeting is an appealing strategy after failure of anti-CD19 CAR T-cell therapy, but the activity of PV in this setting has not been investigated. Methods. This is a retrospective analysis of patients with relapsed/refractory LBCL after standard of care axicabtagene ciloleucel (axi-cel), and treated with standard of care PV at MD Anderson Cancer Center between 07/2019 and 03/2020. PV was given at the standard dose of 1.8 mg/kg IV every 3 weeks in all patients. PV was administered with rituximab, with or without bendamustine. Response to treatment and progression were defined according to 2014 Lugano criteria. Results. Eight patients were included in the analysis: median age was 54 (range, 41-70 years), 7 (87.5%) were male, and all had an IPI score &gt; 3. Median number of systemic therapies before axi-cel was 3 (range, 2-7), and median number of systemic therapies between axi-cel and PV use was 1 (range, 0-3); 1 patient previously had autologous stem cell transplant (SCT), and 2 had allogeneic SCT. Three (37.5%) patients were primary refractory to axi-cel therapy, and median time from axi-cel to PV was 6 months (range, 1-12 months). All patients were biopsied at time of relapse after axi-cel, and in all cases lymphoma was CD19+ CD79b+ by immunohistochemistry/flow cytometry. At time of PV initiation, median absolute neutrophil count was 2.6 (range, 0.4-4.7 X109/L), median platelet count was 141 X109/L (range, 7-245 X109/L), median serum creatinine was 0.9 mg/dL (range, 0.5-1.5 mg/dL), and all patients had LDH above upper limit of normal. Median number of PV cycles was 2 (range, 1-3): PV was combined with rituximab in all patients but administered with bendamustine in only 3 (37.5%). No significant toxicity, prompting dose reduction or treatment discontinuation, was observed. A response was achieved in 4 (50%) patients, represented by partial remission (PR) in all cases, whereas 4 (50%) patients were refractory. All patients stopped PV, 6 (75%) because of progression, 1 (12.5%) to proceed to allogeneic SCT while in PR, and 1 (12.5%) to proceed to an immunotherapy clinical trial (despite absence of progression). After a median follow up of 29 weeks (95% CI, 16-31 weeks), all patients progressed/died, and median PFS was 5 weeks (95% CI, 2-8 weeks) (Figure). At most recent follow-up, 5 (62.5%) died, and median OS was 15 weeks (95% CI, 9-21 weeks)(Figure); causes of death included progression in 4 patients, and transplant-related complications in 1. Discussion. PV in combination with rituximab is safe but has limited and short-lasting activity in relapsed/refractory LBCL after anti-CD19 CAR T-cell therapy. These findings need to be confirmed in larger and prospective studies. The activity of PV, alone or in combination with novel drugs, for the treatment of patients with CD19-negative relapses after CAR T-cell therapy remains to be investigated. Figure Disclosures Westin: 47 Inc:Consultancy;Curis:Consultancy;Janssen:Consultancy;Novartis:Consultancy;Genentech:Consultancy;Juno:Consultancy;Kite:Consultancy;MorphoSys:Consultancy;Unum:Consultancy.Neelapu:Acerta:Research Funding;Takeda Pharmaceuticals:Patents & Royalties;Pfizer:Other: personal fees;Unum Therapeutics:Other, Research Funding;N/A:Other;Novartis:Other: personal fees;Adicet Bio:Other;Legend Biotech:Other;Bristol-Myers Squibb:Other: personal fees, Research Funding;Merck:Other: personal fees, Research Funding;Kite, a Gilead Company:Other: personal fees, Research Funding;Incyte:Other: personal fees;Calibr:Other;Precision Biosciences:Other: personal fees, Research Funding;Allogene Therapeutics:Other: personal fees, Research Funding;Cell Medica/Kuur:Other: personal fees;Poseida:Research Funding;Celgene:Other: personal fees, Research Funding;Cellectis:Research Funding;Karus Therapeutics:Research Funding.

scholarly journals Neurotoxicity of Axicabtagene Ciloleucel and Long-Term Outcomes - in a Minority Rich, Ethnically Diverse Real World Cohort

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4842-4842
Author(s):  
Ryann Quinn ◽  
Astha Thakkar ◽  
Sumaira Zareef ◽  
Richard Elkind ◽  
Karen Wright ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Research Funding ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract Introduction Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of B- cell malignancies leading to durable responses in patients with relapsed/refractory disease. 1,2 One of the most severe toxicities associated with this treatment is immune effector cell-associated neurotoxicity syndrome (ICANS), which was seen in 65-75% of patients treated with axicabtagene ciloleucel (axi-cel) in initial clinical trials. ICANS can range from mild headache to coma, and can occur with or without cytokine release syndrome (CRS). Due to the recent development of CAR T-cell therapy, the long-term effects of ICANS are unknown. This study sought to determine the long-term outcomes in patients with neurotoxicity from axi-cel. Methods We conducted a retrospective chart review of patients who received CAR T-cell therapy with axi-cel between June 2018 and June 2021. Neurotoxicity was graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) ICANS grading system. 3 The primary outcome was percentage of patients who had neurotoxicity defined as ICANS grade ≥ 1 as well as the percentage of patients with neurotoxicity lasting ≥ 1 month. We captured descriptive data such as age, sex, ethnicity, comorbidities, IPI score, stage, baseline neurologic dysfunction, performance status, and number of prior treatments. Secondary outcomes included progression free survival (PFS) and overall survival (OS). Results Thirty-four patients received axi-cel between June 2018 and June 2021 at our institution. Median age of patients was 65. Twenty patients (59%) were male and 14 (41%) were female. The majority of patients received axi-cel for diffuse large B-cell lymphoma (97%). Study population was predominantly hispanic (35%), white (32%), African american (29%) and asian (3%). (Sixteen patients (47%) developed neurotoxicity of any grade, with 7 patients (21%) ≥ grade 3. Of note, 4 patients (12%) died during admission for CAR T-cell therapy and 3/4 deaths were in patients with ICANS ≥ grade 3. Median follow up time was 8 months. Of the 12 patients with neurotoxicity who survived initial admission for CAR-T, 9 (75%) patients recovered from neurotoxicity and mental status was at baseline at discharge without recurrence during follow up. Three (25%) of patients had prolonged neurotoxicity lasting &gt; 1 month. Long-term neurotoxicity included confusion, disorientation, and mild cognitive impairment in the three patients. One patient recovered 15 months after CAR T-cell infusion. 2 patients had prolonged neurotoxicity resulting in deterioration of functional status and death in 1 patient, and 1 patient transitioning to hospice and being lost to follow up. Conclusions Neurotoxicity from axicabtagene ciloleucel is a common adverse event, with half of patients in our cohort having neurotoxicity of some degree, and 20% ≥ grade 3. Twenty-five percent of patients that developed neurotoxicity had long-term effects lasting &gt; 1 month, which resulted in deterioration of functional status in 2 patients. Long-term neurotoxicity included disorientation, confusion, and memory impairment. Our study is limited by a small sample size. Larger studies with longer follow-up times are needed to further characterize the long-term outcomes of neurotoxicity associated with CAR T-cell therapy. Neurotoxicity can be confounded by other causes of neurological dysfunction in these patients such as hospital delirium, chemotherapy toxicity, encephalopathy from infection, and subtle baseline neurologic dysfunction that may not be apparent at presentation. Next steps include prospective evaluation of patients with formal neurology evaluation prior to CAR T-cell therapy and periodically after treatment, in order to objectively monitor late neurologic effects of CAR T-cell therapy. 1. Fl, L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 20, (2019). 2. Jacobson, C. Primary Analysis of Zuma-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL). in (ASH, 2020). 3. Dw, L. et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant. 25, (2019). Disclosures Gritsman: iOnctura: Research Funding. Shastri: Onclive: Honoraria; Guidepoint: Consultancy; GLC: Consultancy; Kymera Therapeutics: Research Funding. Verma: Celgene: Consultancy; BMS: Research Funding; Stelexis: Current equity holder in publicly-traded company; Curis: Research Funding; Eli Lilly: Research Funding; Medpacto: Research Funding; Novartis: Consultancy; Acceleron: Consultancy; Stelexis: Consultancy, Current equity holder in publicly-traded company; Incyte: Research Funding; GSK: Research Funding; Throws Exception: Current equity holder in publicly-traded company.

scholarly journals A Multi-Center Retrospective Study of Polatuzumab for Patients with Large B-Cell Lymphoma Relapsed after Standard of Care CAR T-Cell Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2495-2495
Author(s):  
Sushanth Gouni ◽  
Allison C. Rosenthal ◽  
Jennifer L. Crombie ◽  
Andrew Ip ◽  
Manali Kamdar ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Median Number ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Introduction. About 60% of patients with large B-cell lymphoma (LBCL) relapse after standard of care (SOC) anti-CD19 autologous chimeric antigen receptor (CAR) T-cell therapy, CD19 downregulation representing a major mechanism of resistance. Therefore, agents able to target B-cell antigens other than CD19 could be clinically effective for these patients. Polatuzumab vedotin (PV) is an antibody-drug conjugate targeting CD79b, and approved by the FDA in combination with bendamustine and rituximab for patients with relapsed or refractory (r/r) LBCL. Patients who relapsed after CAR T-cell therapy were not included in the registration study, and reports of PV use after CAR T-cells in real world practice are very limited. Methods. This is a multi-center retrospective analysis of patients with LBCL who relapsed after SOC CAR T-cell therapy and subsequently received SOC PV with or without rituximab and bendamustine between 07/2019 and 04/2021. PV was given at the standard dose of 1.8 mg/kg IV every 3 weeks in all patients (except for one patient, who received 1.4 mg/Kg). Response to treatment and progression were defined according to 2014 Lugano criteria. Survival curves were calculated using Kaplan-Meier estimates, and were compared between subgroups using the log-rank test. Cox regression was used for multivariate analysis (MVA). Results. Fifty-four patients were included in the study: median age was 59 (range, 22-79 years), 38 (70%) were male, and 30 (56%) had an internal prognostic index score &gt; 3. Median number of systemic therapies before CAR T-cell therapy was 2 (range, 2-6), 16 (30%) patients previously had autologous stem cell transplant (SCT), and 2 (4%) had allogeneic SCT. Sixteen (30%) patients were primary refractory to CAR T-cell therapy, and median time from CAR T-cell therapy to PV was 5 months (range, 1-40 months). CD19 status at time of relapse after CAR T-cell therapy was assessed by immunohistochemistry and/or flow cytometry in 41 patients, and positive in 34 (83%); CD79b status was assessed in 14 patients, and positive in all cases (100%). Thirty-two (59%) patients received PV-based therapy immediately after CAR T cell therapy, while 22 (41%) had intervening treatments (median 1, range 1-5). At time of PV initiation, median absolute neutrophil count was 2.9 (range 0.5-19 X10 9/L), median platelet count was 87 X10 9/L (range 15-437 X10 9/L), median serum creatinine was 0.9 mg/dL (range 0.4-22 mg/dL), and 44 (81%) patients had elevated serum lactate dehydrogenase (LDH). The median number of PV cycles was 2 (range, 1-16): PV was combined with rituximab in 51 (94%) patients, and administered with bendamustine in 33 (61%). A response was achieved in 24 (45%) patients, including complete remission (CR) in 8 (14%) patients and partial remission in 16 (30%)(Figure A), with a median duration of response of 11 weeks (95%CI, 5-17 weeks). No significant association between baseline characteristics and response was observed. To date, 49 (91%) patients stopped PV: 38 (70%) due to progression, 7 (13%) because of CR/patient decision, 3 (6%) to proceed to allogeneic SCT, and 1 (2%) to proceed to an immunotherapy clinical trial (despite absence of progression). No patients stopped therapy because of toxicity. After a median follow up of 45 weeks (95% CI, 20-70 weeks), 44 (81%) patients progressed/died, and median PFS was 9 weeks (95% CI, 4-14 weeks). To date, 34 (63%) died, and median OS was 16 weeks (95% CI, 13-19 weeks)(Figure B). Causes of death included progression in 31 patients and transplant-related complications in 3. On univariate analysis, a shorter median progression-free survival (PFS) was observed for patients with bone marrow (BM) involvement (3 vs 10 weeks, p=0.002), prior central nervous system involvement (4 vs 10 weeks, p=0.02), and elevated LDH (6 months vs not reached, p=0.004). On MVA, the association was maintained only for BM involvement (hazard ratio [HR] 4.8; 95% confidence interval [CI] 1.6-12.5, p=0.004) and elevated LDH (HR 5; 1.4-16.7, p=0.01)(Figure C). Discussion. PV is safe and effective, but has short duration of response in r/r LBCL after anti-CD19 CAR T-cell therapy, except for patients with normal LDH. Studies aimed at better characterizing intrinsic mechanism of resistance, including upregulation of BCL2 family proteins, to favor the development of more effective PV-based combination strategies for these patients, are warranted. Figure 1 Figure 1. Disclosures Crombie: Roche: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding; Karyopharm: Consultancy; Incyte: Consultancy. Kamdar: Celgene (BMS): Consultancy; Adaptive Biotechnologies: Consultancy; Genentech: Research Funding; Kite: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Genetech: Other; TG Therapeutics: Research Funding; SeaGen: Speakers Bureau; Celgene: Other; KaryoPharm: Consultancy; AbbVie: Consultancy. Hess: ADC Therapeutics: Consultancy; BMS: Speakers Bureau. Neelapu: Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Lin: Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Gamida Cell: Consultancy; Sorrento: Consultancy; Legend: Consultancy; Takeda: Research Funding; Merck: Research Funding; Vineti: Consultancy. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy.

scholarly journals Six-Month Follow-up for Infectious Complications after Lymphodepletion and Application of CD19-Chimeric Antigen Receptor T (CAR-T) Cell Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4835-4835
Author(s):  
Felix Korell ◽  
Maria-Luisa Schubert ◽  
Tim Sauer ◽  
Anita Schmitt ◽  
Patrick Derigs ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Research Funding ◽  
Infectious Complications ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Travel Grant

Abstract Background: In the past years, chimeric antigen receptor T (CAR-T) cell therapy targeting CD19 have been shown to be a new and effective treatment option in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL). However, infections with severe and potentially life-threatening complications can be induced by either lymphodepleting chemotherapy and/or the infusion of CAR-T cells, while side effects such as cytokine release syndrome (CRS) might further complicate differential diagnosis. Methods: Infections and complications were evaluated during inpatient treatment as well as in a follow-up period of the first six months after dosing. Eighty-one dosings of CAR-T cells in seventy-three adult patients with either NHL (88%) or ALL (12%) were analyzed. Bacterial and viral pathogen were detected with blood cultures or examination of potential sources of infection such as catheter tips. Panel and serum testing for viral infection was carried out either as a screening or in case of suspicion, while fungal infections were diagnosed according to the 2008 revised European Organization for Research and Treatment of Cancer (EORTC) Consensus Group criteria to determine proven, probable and possible invasive fungal disease. Results: In 52 patients (64%, Table 1) fever was detected following lymphodepletion and CAR-T cell dosing . Microbiological or radiological findings were seen in 20% of cases. Of those, eight were of bacterial (10%), three of viral (4%), and five of fungal (6%) origin. Overall, more lines of therapy as well as more severe CRS were associated with early infection. Cytokine release syndrome was diagnosed in 41 patients (51%, Table 1), with a simultaneous detection in five bacterial (6%), two viral (2%), and five fungal (6%) infections (Figure 1). In the six months follow-up period seven patients with fever (9%) had microbiological or radiological findings, in most cases during the first 90 days after CAR T cell infusion (6 patients, 7%). Only one patient died of infection (pathogen: cytomegalovirus). Conclusions: Infections are common in CAR-T cell patients; therefore, fast and suitable identification and initiation of treatment are important in the heavily pretreated and immunocompromised patient population. While infectious complications are mostly manageable, the frequency of infectious complications in patients receiving CAR-T cell therapy underlines the value of standardized anti-infective prophylaxis and supportive therapy for reduction of morbidity and mortality. Figure 1 Figure 1. Disclosures Schubert: Gilead: Consultancy. Sauer: Pfizer: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Matterhorn Biosciences AG: Consultancy, Other: DSMB/SAB Member; Takeda: Consultancy, Other: DSMB/SAB Member. Schmitt: Hexal: Other: Travel grant; TolerogenixX Ltd: Current Employment; Therakos/Mallinckrodt: Research Funding; Jazz Pharmaceuticals: Other: Travel grant. Müller-Tidow: Bioline: Research Funding; Pfizer: Research Funding; Janssen: Consultancy, Research Funding. Dreger: AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; BMS: Consultancy; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Schmitt: Bluebird Bio: Other: Travel grants; MSD: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Travel grants, Research Funding; Hexal: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; Apogenix: Research Funding; TolerogenixX: Current holder of individual stocks in a privately-held company.

scholarly journals Unbiased Metabolomic Screening Reveals Pre-Existing Plasma Signatures in Large B-Cell Lymphoma Patients Treated with Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cells: Association with Cytokine Release Syndrome (CRS) and Neurotoxicity (ICANS)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Akansha Jalota ◽  
Courtney E. Hershberger ◽  
Manishkumar S. Patel ◽  
Agrima Mian ◽  
Daniel M. Rotroff ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T

Background: CAR T-cells that target CD19 have been approved by the FDA for treatment of relapsed/refractory large B cell lymphoma (r/r LBCL). Despite clinical efficacy in chemo-refractory patients, the benefit of this approach is often complicated by potentially severe toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The physiological basis of these limitations remains poorly understood, and represents an unmet clinical need. Metabolomics is a global approach that can be used to identify diverse low molecular weight biochemical entities with a wide range of functions. In this study we have employed an untargeted metabolomics approach to identify novel metabolites present in the plasma of patients treated with CAR T-cell therapy that associate with clinical outcomes and toxicities of treatment. Methods: Peripheral blood specimens were collected at the time of apheresis from 41 r/r LBCL patients treated with Axicabtagene Ciloleucel (Axi-cel; n=31) and Tisagenlecleucel (Tisa-cel; n=10). Baseline clinical characteristics and details of prior treatment were captured for all patients. Response outcomes and toxicity grading as measured by ASTCT consensus criteria for CRS and ICANS were recorded. Plasma was isolated from blood and analyzed for metabolites using a commercial Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectrometry platform. Association analysis was performed using ordinal logistic regression to identify the metabolites whose plasma abundance at the time of apheresis correlated with ICANS and CRS grade (FDR ≤0.2). In addition, significant metabolites were utilized to identify perturbations of biologically relevant pathways associated with CRS/ICANS grade. Results: The median age of patients studied was 61 (range 25 - 77), with 25 (61%) males. All patients were previously treated with R-CHOP or R-EPOCH. Twenty (48.8%) patients had high or high-intermediate IPI at baseline. The patients had received a median of 3 (range, 2-6) lines of therapy prior to CAR T-cell therapy, with 21 (51.22%) having received prior autologous stem cell transplantation. At the 3-month time point, response evaluation was available for 28 Axi-cel and 10 Tisa-cel recipients. An objective response was seen in 16 (57%) and 2 (20%) patients, and death was documented in 3 (11%) and 2 (20%) patients, in the Axi-cel and Tisa-cel groups, respectively. Untargeted metabolomics revealed a total of 1,241 metabolites, detected in positive, negative and polar modes, of which 1,011 were named. These include lipids, amino acids, xenobiotics, nucleotides, partially characterized compounds, cofactors and vitamins. In examining toxicities of CAR-T cell treatment, we identified three metabolites whose abundance was negatively associated with ICANS grade (FDR ≤0.2), indicating that high abundance of these metabolites at the time of apheresis was associated with a decreased risk of (i.e. protection from) ICANS. Plasma metabolites were also found to be associated with CRS, with 23 associated with an increased risk (i.e. predisposing to) of CRS, and 204 associated with decreased risk (i.e. protection from) of CRS. Using a hypergeometric test for over-represented metabolites in the KEGG metabolic pathways (FDR ≤0.2), caffeine metabolism, glycine, serine, and threonine metabolism, arginine biosynthesis, and aminoacyl-tRNA biosynthesis were identified as the most significantly represented pathways. Conclusion: Pre-existing biochemical signatures present in the plasma at the time of apheresis are strongly associated with toxicities observed in response to commercial CD19 CAR T-cell therapies. These endogenous metabolites may serve as biomarkers for monitoring risk of toxicity associated with CD19 CAR T cell treatment and provide insight into rational clinical interventions to mitigate such risks. Disclosures Rotroff: Interpares Biomedicine LLC.: Current equity holder in publicly-traded company; CAR-T Response: Patents & Royalties. Hill:Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; AstraZenica: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding.

scholarly journals Resistance to Axicabtagene Ciloleucel Therapy in T Cell/Histiocyte-Rich Large B Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5238-5238
Author(s):  
Jonathan Trujillo ◽  
James Godfrey ◽  
Michael R. Bishop ◽  
Peter A. Riedell ◽  
Justin Kline
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

INTRODUCTION: CD19-directed chimeric antigen receptor (CAR) T cell therapy can lead to long-term remissions in a subset of patients with diffuse large B cell lymphoma (DLBCL). However, most patients fail to respond durably, and resistance mechanisms are incompletely defined. Additionally, the relative efficacy of CAR T cell therapy across DLBCL subtypes, such as T-cell/histocyte-rich large B cell lymphoma (T/HRLBCL), is not well established. T/HRLBCL is a distinct variant of large B cell lymphoma characterized histologically by rare malignant B cells scattered amongst infiltrating macrophages and reactive, yet ineffective, T cells. T/HRLBCL tumors frequently harbor genetic amplification of programmed death-ligand 1 (PD-L1) and exhibit robust infiltration by PD-L1-expressing macrophages (Chapuy et al. PMID 2971308, Griffin et al. ASH Abstract 1579, 2018). These features signify an adaptive up-regulation of the PD-L1 pathway, a negative regulator of T cell function. We hypothesized that T/HRLBCL is intrinsically resistant to CAR T cell therapy due to an immunosuppressive tumor microenvironment characterized by high expression of PD-L1 and abundant tumor-associated macrophages. Accordingly, we report 4 consecutive cases of multiply relapsed T/HRLBCL that failed to respond to CD19-directed CAR T cell therapy. METHODS: We identified 4 patients with histologically confirmed primary-refractory T/HRLBCL who were treated with axicabtagene ciloleucel (axi-cel) CAR T cell therapy at our institution according to the FDA dose and schedule. Radiographic follow up was performed by PET/CT imaging at 30 days post-treatment. Tissue specimens were obtained at the time of clinical and radiographic disease progression to confirm persistent disease and to assess the immune context of T/HRLBCL. A fluorescence in-situ hybridization (FISH) assay was used to assess for copy number gains of chromosomal region 9p24.1, containing the PD-L1 and PD-L2 genes. To characterize the tumor-microenvironment in the setting of CAR T cell therapy resistance, multiplex immunofluorescence analysis of baseline and post-progression tumor biopsies, when available, were performed to characterize the immune infiltrate and to evaluate for PD-L1 expression by tumor cells and tumor associated-macrophages. RESULTS: All the patients had primary-refractory T/HRLBCL and had received 2-4 prior lines of therapy before undergoing CAR T cell treatment (Table 1). At 30 days post-axi-cel infusion, all the patients demonstrated progressive disease. Tissue specimens obtained at the time of clinical and radiographic disease progression confirmed persistent lymphoma in all patients. In patients from whom tumor tissue is available, FISH testing for PD-L1 gene alterations, as well as, multiplex immunofluorescence analysis is ongoing and will be reported at the meeting. CONCLUSION: Though small patient numbers, our case series suggests that axi-cel therapy may have limited efficacy in T/HRLBCL. The reasons for this are not entirely clear, though, may be related to the genetic amplification of PD-L1 and robust infiltration by tumor-associated macrophages. A prospective evaluation of disease response to CAR T cell therapy in T/HRLBCL warrants further study. Disclosures Bishop: Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Riedell:Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kline:Merck: Research Funding; Merck: Honoraria.

scholarly journals Portia: A Phase 1b Study Evaluating Safety and Efficacy of Tisagenlecleucel and Pembrolizumab in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5325-5325 ◽  
Author(s):  
Ulrich Jaeger ◽  
Nina Worel ◽  
Joseph P. McGuirk ◽  
Peter A. Riedell ◽  
Isabelle Fleury ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell Therapy ◽  
Car T ◽  
Phase 1B

Background: Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) after ≥ 2 prior lines of therapy. T-cell exhaustion due to an immunosuppressive environment has been a hypothesized mechanism for CAR-T cell therapy failure. Subgroup analyses of the JULIET trial suggested an association between programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) interaction in baseline biopsies and lack of response (Agoulnik et al. EHA. 2018). Moreover, the anti-PD-1 monoclonal antibody pembrolizumab has shown clinical activity in r/r DLBCL after failing tisagenlecleucel therapy (Chong et al. Blood. 2017). PORTIA is a phase 1b, multicenter, open-label trial investigating the safety and efficacy of tisagenlecleucel plus pembrolizumab in patients with r/r DLBCL. We report data from a completed cohort of the ongoing study. Methods: Eligible patients must be ≥ 18 years old with a confirmed diagnosis of DLBCL that has relapsed after or is refractory to ≥ 2 prior lines of therapy and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients treated with prior allogeneic stem cell transplantation, anti-CD19 therapies, or checkpoint inhibitors are excluded. Lymphodepleting chemotherapy consists of fludarabine-cyclophosphamide. Patients receive a single tisagenlecleucel intravenous infusion (target dose: 0.6-6.0x108 cells) on Day 1. Pembrolizumab is given at 200 mg every 21 days, for up to 6 doses. Pembrolizumab was started on Day 15 post-tisagenlecleucel in Cohort 1, with the option of moving to Day 8 or 22 in subsequent cohorts, based on observed data and guided by a Bayesian Logistic Regression Model with Escalation with Overdose Control principle, evaluating the distribution of dose-limiting toxicities (DLTs) occurring in the 21 days following the first pembrolizumab dose. As per study protocol, a total of 20 patients will be treated at the optimal dose timing. Primary endpoints are the proportion of patients receiving pembrolizumab per protocol schedule, the incidence of DLTs in the dose-timing selection phase, and the overall response rate in the dose-expansion phase. Secondary outcomes include duration of response, progression-free survival, overall survival, safety, cellular kinetics, and immunogenicity. Results: As of 5 March 2019, 5 patients were screened for Cohort 1. Four patients were enrolled and received tisagenlecleucel and pembrolizumab. Median age was 54 (range, 35-79). Median follow-up from time from tisagenlecleucel infusion to data cut-off was 46 days (range, 36-85). Patients received 1.7-3.0x108 CAR-positive T cells, and 1, 2, 2 and 4 pembrolizumab doses, respectively, with no delays. All 4 patients experienced at least 1 adverse event (AE), with no exacerbation or recurrence of tisagenlecleucel-related AEs following pembrolizumab infusion. No pembrolizumab-related AEs were observed. No DLTs or grade 3-4 treatment-related adverse events (TRAEs) were observed. TRAEs and AEs are summarized in Table 1. Two patients discontinued pembrolizumab treatment (after 1 and 2 doses, respectively) due to disease progression. All 4 patients experienced initial expansion between Days 6 and 15 post-tisagenlecleucel infusion, with peak transgene levels ranging from 1,980 to 77,200 copies/µg DNA (Figure 1). No secondary expansion was observed after pembrolizumab administration. The overall exposure is consistent with the observed exposure in r/r DLBCL patients in the JULIET trial. With very limited follow-up, 1 partial response has been observed. Cohort 2 (pembrolizumab starting Day 8) was ongoing at the time of submission. Conclusions: Overall, PD-1 blockade with pembrolizumab on Day 15 after tisagenlecleucel infusion was feasible and showed a manageable safety profile in the first 4 patients. No DLTs and no clinically significant exacerbation of AEs were observed, supporting the initiation of Cohort 2. Efficacy and safety data with an updated cutoff for Cohort 1 and new data from Cohort 2 will be presented at the congress. Clinical trial information: NCT03630159. Disclosures Jaeger: Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. Worel:Sanofi Genzyme, Malinckrodt Therakos: Research Funding; Jazz, Sanofi, Celgene, Novartis, Malinckrodt Therakos: Honoraria; Sanofi Genzyme, Malinckrodt Therakos: Speakers Bureau. McGuirk:Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Riedell:Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau. Fleury:AstraZeneca: Consultancy; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Chu:Novartis: Employment. Abdelhady:Novartis: Employment. Forcina:Novartis: Employment. Bubuteishvili Pacaud:Novartis: Employment. Waller:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy.

scholarly journals Potential strategies against resistance to CAR T-cell therapy in haematological malignancies

2020 ◽  
Vol 12 ◽  
pp. 175883592096296
Author(s):  
Qing Cai ◽  
Mingzhi Zhang ◽  
Zhaoming Li
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Haematological Malignancies ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy is a rapidly developing method for adoptive immunotherapy of tumours in recent years. CAR T-cell therapies have demonstrated unprecedented efficacy in the treatment of patients with haematological malignancies. A 90% complete response (CR) rate has been reported in patients with advanced relapse or refractory acute lymphoblastic leukaemia, while >50% CR rates have been reported in cases of chronic lymphocytic leukaemia and partial B-cell lymphoma. Despite the high CR rates, a subset of the patients with complete remission still relapse. The mechanism of development of resistance is not clearly understood. Some patients have been reported to demonstrate antigen-positive relapse, whereas others show antigen-negative relapses. Patients who relapse following CAR T-cell therapy, have very poor prognosis and novel approaches to overcome resistance are required urgently. Herein, we have reviewed current literature and research that have investigated the strategies to overcome resistance to CAR T-cell therapy.

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.

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