scholarly journals Outcomes of Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma (r/r B-NHL) Patients with TP53 Gene Disruption Treated with CD19/22 Cocktail CAR T-Cell Therapy Alone or Incorporated with Autologous Stem Cell Transplantation (ASCT)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 94-94
Author(s):  
JIA Wei ◽  
Min Xiao ◽  
Zekai Mao ◽  
Yang Cao ◽  
Yi Xiao ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Tp53 Mutation ◽  
Tp53 Gene ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Group B

Abstract Disruption of TP53 gene occur in a subset of patients with refractory/relapse B-cell non-Hodgkin lymphoma (r/r B-NHL) and confer inferior prognosis. Recently, we reported the safety and efficacy of two clinical trials, administrating CAR T-cell infusion either alone (Trail A) or incorporated in ASCT (Trial B), in the treatment of r/r B-NHL. To address the prognostic impact of TP53 alterations on r/r aggressive B-cell lymphoma when treated with CAR T-cell therapy, in the present study, we systemically evaluate the therapeutic effects among the patients with TP53 alterations in these 2 trials with expanded cohort size and extended follow-up. In two trials, we enrolled 34 patients in group A (TP53wt in trial A), 32 patients in group B (TP53 alteration in trial A) and 28 patients in group C (TP53 alteration in trial B). Baseline features of patients in three groups were balanced. Heterozygous mutations and/or deletions of TP53 gene detected in 60 patients. A total of 42 (70.0%) patients carried either TP53 mutation(s) or sole del(17p), including 27 (45.0%) harboring TP53 mutation(s) and 15 (25.0%) carrying TP53 deletions. Biallelic TP53 aberration was revealed in the remaining 18 (30.0%) patients. They harbored TP53 mutation also carried del(17p) in the second allele. Among the 51 mutations that identified (Figure 1A), 37 were missense mutations, 6 were splice-site mutations, 4 were nonsense mutations, 3 were frameshift insertions or deletions (indels), and 1 was non-frameshift indel. Forty-five mutations (88.0%) located in DNA-binding domain (DBD, amino acid 101 - 294). Totally, 40 (66.7%) patients carried loss-of-function aberrations that resulted in TP53 inactivation, including either copy number loss or truncated mutations. Of the patients harboring TP53 alterations (group B), with a median follow-up of 16.7 months (range: 3.1 to 41.0 months), the median DOR and OS was not reached. The median PFS was 14.8 months (95% CI: 5.1 - NE). The estimated 24-month PFS and OS rates were 48.4% (95% CI: 30.2% - 64.4%) and 56.3% (95% CI: 36.6% - 72.0%). Notably, the DoR, PFS and OS were similar between the patients with (group B) or without (group A) TP53 alterations when treated with CAR19/22 T-cell cocktail therapy (Figure 1B). Since prognostic relevance varied according to distinct TP53 alterations, four different functional classification systems were applied to further elucidate whether CAR T-cell cocktail therapy can overcome the unfavorable prognostic impact conferred from TP53 alterations. Remarkably, in each classification system, either best ORR or survivals did not differ significantly between patients stratified in distinct risk subgroups, indicating CAR19/22 T-cell cocktail therapy could overcome the negative impact of TP53 alterations in these patients. Among the 28 patients (group C in trial B) who had TP53 alterations and were treated with ASCT incorporating CAR19/22 T-cell cocktail, 26 patients (92.9%, 95% CI: 77.4% - 98.7%) achieved best ORR, with 23 (82.1%, 95% CI: 64.4% - 92.1%) having a CR. With a median follow-up of 21.2 (range: 4.0 - 48.7) months, the median DOR, PFS and OS were not reached. The estimated 24-month PFS and OS rates were 77.5% (95% CI: 56.5% to 89.3%) and 89.3% (95% CI: 70.4% - 96.4%), respectively. At data cutoff date, 22 patients (78.6%, 95% CI: 60.5% - 89.8%) maintained their initial responses while 6 patients (21.4%, 95% CI: 10.2% - 39.5%) experienced disease progression. Strikingly, among the patients with TP53 alterations, as compared with CAR19/22 T-cell cocktail therapy (Group B), significantly extended DOR (P = .040), PFS (P = .024) and OS (P = .012) were achieved when CAR T-cell cocktail infusion was incorporated in ASCT (Figure 1C). In conclusion, our study, at first time, has proved that CAR T-cell cocktail therapy is effective for TP53-disrupted r/r aggressive B-NHL. Incorporating CAR-T cell infusion in ASCT can further improve the long-term outcome of these patients. Future clinical trials need to be performed with larger cohort to get more definitive conclusion that if CAR T-cell therapy should be moved earlier for r/r B-NHL in the coming era of immunotherapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Influence of TP53 Mutation on Survival of Diffuse Large B-Cell Lymphoma in the CAR T-Cell Era

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5592
Author(s):  
Edit Porpaczy ◽  
Philipp Wohlfarth ◽  
Oliver Königsbrügge ◽  
Werner Rabitsch ◽  
Cathrin Skrabs ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Tp53 Mutation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Refractory/relapsed diffuse large B-cell lymphoma (DLBCL) is associated with poor outcome. The clinical behavior and genetic landscape of DLBCL is heterogeneous and still not fully understood. TP53 mutations in DLBCL have been identified as markers of poor prognosis and are often associated with therapeutic resistance. Chimeric antigen receptor T-cell therapy is an innovative therapeutic concept and represents a game-changing therapeutic option by supporting the patient’s own immune system to kill the tumor cells. We investigated the impact of TP53 mutations on the overall survival of refractory/relapsed DLBCL patients treated with comparable numbers of therapy lines. The minimum number of therapy lines was 2 (median 4), including either anti-CD19 CAR T-cell therapy or conventional salvage therapy. A total of 170 patients with DLBCL and high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements (DHL/THL), diagnosed and treated in our hospital between 2000 and 2021, were included. Twenty-nine of them received CAR T-cell therapy. TP53 mutations were found in 10/29 (35%) and 31/141 (22%) of patients in the CAR T-cell and conventional groups, respectively. Among the 141 patients not treated with CAR T cells, TP53 mutation was an independent prognostic factor for overall survival (OS) (median 12 months with TP53 vs. not reached without TP53 mutation, p < 0.005), but in the CAR T cell treated group, this significance could not be shown (median OS 30 vs. 120 months, p = 0.263). The findings from this monocentric retrospective study indicate that TP53 mutation status does not seem to affect outcomes in DLBCL patients treated with CAR T-cell therapy. Detailed evaluation in large cohorts is warranted.

scholarly journals Feasibility, and Efficacy of Donor-Derived cd19-Targeted Car t-Cell Therapy in Refractory/Relapsed(r/r)b-Cell Acute Lymphoblastic Leukemia (b-all) Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-6
Author(s):  
Xian Zhang ◽  
Junfang Yang ◽  
Wenqian Li ◽  
Gailing Zhang ◽  
Yunchao Su ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Backgrounds As CAR T-cell therapy is a highly personalized therapy, process of generating autologous CAR-T cells for each patient is complex and can still be problematic, particularly for heavily pre-treated patients and patients with significant leukemia burden. Here, we analyzed the feasibility and efficacy in 37 patients with refractory/relapsed (R/R) B-ALL who received CAR T-cells derived from related donors. Patients and Methods From April 2017 to May 2020, 37 R/R B-ALL patients with a median age of 19 years (3-61 years), were treated with second-generation CD19 CAR-T cells derived from donors. The data was aggregated from three clinical trials (www.clinicaltrials.gov NCT03173417; NCT02546739; and www.chictr.org.cn ChiCTR-ONC-17012829). Of the 37 patients, 28 were relapsed following allogenic hematopoietic stem cell transplant (allo-HSCT) and whose lymphocytes were collected from their transplant donors (3 HLA matched sibling and 25 haploidentical). For the remaining 9 patients without prior transplant, the lymphocytes were collected from HLA identical sibling donors (n=5) or haploidentical donors (n=4) because CAR-T cells manufacture from patient samples either failed (n=5) or blasts in peripheral blood were too high (&gt;40%) to collect quality T-cells. The median CAR-T cell dose infused was 3×105/kg (1-30×105/kg). Results For the 28 patients who relapsed after prior allo-HSCT, 27 (96.4%) achieved CR within 30 days post CAR T-cell infusion, of which 25 (89.3%) were minimal residual disease (MRD) negative. Within one month following CAR T-cell therapy, graft-versus-host disease (GVHD) occurred in 3 patients including 1 with rash and 2 with diarrhea. A total of 19 of the 28 (67.9%) patients had cytokine release syndrome (CRS), including two patients (7.1%) with Grade 3-4 CRS. Four patients had CAR T-cell related neurotoxicity including 3 with Grade 3-4 events. With a medium follow up of 103 days (1-669days), the median overall survival (OS) was 169 days (1-668 days), and the median leukemia-free survival (LFS) was 158 days (1-438 days). After CAR T-cell therapy, 15 patients bridged into a second allo-HSCT and one of 15 patients (6.7%) relapsed following transplant, and two died from infection. There were 11 patients that did not receive a second transplantation, of which three patients (27.3%) relapsed, and four parents died (one due to relapse, one from arrhythmia and two from GVHD/infection). Two patients were lost to follow-up. The remaining nine patients had no prior transplantation. At the time of T-cell collection, the median bone marrow blasts were 90% (range: 18.5%-98.5%), and the median peripheral blood blasts were 10% (range: 0-70%). CR rate within 30 days post CAR-T was 44.4% (4/9 cases). Six patients developed CRS, including four with Grade 3 CRS. Only one patient had Grade 3 neurotoxicity. No GVHD occurred following CAR T-cell therapy. Among the nine patients, five were treated with CAR T-cells derived from HLA-identical sibling donors and three of those five patients achieved CR. One patient who achieved a CR died from disseminated intravascular coagulation (DIC) on day 16. Two patients who achieved a CR bridged into allo-HSCT, including one patient who relapsed and died. One of two patients who did not response to CAR T-cell therapy died from leukemia. Four of the nine patients were treated with CAR T-cells derived from haploidentical related donors. One of the four cases achieved a CR but died from infection on day 90. The other three patients who had no response to CAR T-cell therapy died from disease progression within 3 months (7-90 days). Altogether, seven of the nine patients died with a median time of 19 days (7-505 days). Conclusions We find that manufacturing CD19+ CAR-T cells derived from donors is feasible. For patients who relapse following allo-HSCT, the transplant donor derived CAR-T cells are safe and effective with a CR rate as high as 96.4%. If a patient did not have GVHD prior to CAR T-cell therapy, the incidence of GVHD following CAR T-cell was low. Among patients without a history of transplantation, an inability to collect autologous lymphocytes signaled that the patient's condition had already reached a very advanced stage. However, CAR T-cells derived from HLA identical siblings can still be considered in our experience, no GVHD occurred in these patients. But the efficacy of CAR T-cells from haploidentical donors was very poor. Disclosures No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Cell Transplantation Is Critical to Maintain Remissions after CD19-CAR T-Cell Therapy for Pediatric ALL: A Single Center Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Aimee C Talleur ◽  
Renee M. Madden ◽  
Amr Qudeimat ◽  
Ewelina Mamcarz ◽  
Akshay Sharma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Allogeneic Hct ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

CD19-CAR T-cell therapy has shown remarkable efficacy in pediatric patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (r/r ALL). Despite high short-term remission rates, many responses are not durable and the best management of patients who achieve a complete response (CR) post-CAR T-cell therapy remains controversial. In particular, it is unclear if these patients should be observed or proceed to consolidative allogeneic hematopoietic cell transplantation (HCT). To address this question, we reviewed the clinical course of all patients (n=22) who received either an investigational CAR T-cell product (Phase I study: SJCAR19 [NCT03573700]; n=12) or tisagenlecleucel (n=10) at our institution. The investigational CD19-CAR T cells were generated by a standard cGMP-compliant procedure using a lentiviral vector encoding a 2nd generation CD19-CAR with a FMC63-based CD19 binding domain, CD8a stalk and transmembrane domain, and 41BB.ζ signaling domain. Patients received therapy between 8/2018 and 3/2020. All products met manufacturing release specifications. Within the entire cohort, median age at time of infusion was 12.3 years old (range: 1.8-23.5) and median pre-infusion marrow burden using flow-cytometry minimal residual disease (MRD) testing was 6.8% (range: 0.003-100%; 1 patient detectable by next-generation sequencing [NGS] only). All patients received lymphodepleting chemotherapy (fludarabine, 25mg/m2 daily x3, and cyclophosphamide, 900mg/m2 daily x1), followed by a single infusion of CAR T-cells. Phase I product dosing included 1x106 CAR+ T-cells/kg (n=6) or 3x106 CAR+ T-cells/kg (n=6). Therapy was well tolerated, with a low incidence of cytokine release syndrome (any grade: n=10; Grade 3-4: n=4) and neurotoxicity (any grade: n=8; Grade 3-4: n=3). At 4-weeks post-infusion, 15/22 (68.2%) patients achieved a CR in the marrow, of which 13 were MRDneg (MRDneg defined as no detectable leukemia by flow-cytometry, RT-PCR and/or NGS, when available). Among the 2 MRDpos patients, 1 (detectable by NGS only) relapsed 50 days after CAR T-cell infusion and 1 died secondary to invasive fungal infection 35 days after infusion. Within the MRDneg cohort, 6/13 patients proceeded to allogeneic HCT while in MRDneg/CR (time to HCT, range: 1.8-2.9 months post-CAR T-cell infusion). All 6 HCT recipients remain in remission with a median length of follow-up post-HCT of 238.5 days (range 19-441). In contrast, only 1 (14.3%) patient out of 7 MRDneg/CR patients who did not receive allogeneic HCT, remains in remission with a follow up of greater 1 year post-CAR T-cell infusion (HCT vs. no HCT: p&lt;0.01). The remaining 6 patients developed recurrent detectable leukemia within 2 to 9 months post-CAR T-cell infusion (1 patient detectable by NGS only). Notably, recurring leukemia remained CD19+ in 4 of 5 evaluable patients. All 4 patients with CD19+ relapse received a 2nd CAR T-cell infusion (one in combination with pembrolizumab) and 2 achieved MRDneg/CR. There were no significant differences in outcome between SJCAR19 study participants and patients who received tisagenlecleucel. With a median follow up of one year, the 12 month event free survival (EFS) of all 22 patients is 25% (median EFS: 3.5 months) and the 12 month overall survival (OS) 70% (median OS not yet reached). In conclusion, infusion of investigational and FDA-approved autologous CD19-CAR T cells induced high CR rates in pediatric patients with r/r ALL. However, our current experience shows that sustained remission without consolidative allogeneic HCT is not seen in most patients. Our single center experience highlights not only the need to explore maintenance therapies other than HCT for MRDneg/CR patients, but also the need to improve the in vivo persistence of currently available CD19-CAR T-cell products. Disclosures Sharma: Spotlight Therapeutics: Consultancy; Magenta Therapeutics: Other: Research Collaboration; CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis: Other: Clinical Trial PI. Velasquez:St. Jude: Patents & Royalties; Rally! Foundation: Membership on an entity's Board of Directors or advisory committees. Gottschalk:Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; TESSA Therapeutics: Other: research collaboration; Inmatics and Tidal: Membership on an entity's Board of Directors or advisory committees; Merck and ViraCyte: Consultancy.

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.

Quality of life (QOL) in patients undergoing CAR-T therapy versus stem cell transplant (SCT).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6594-6594 ◽  
Author(s):  
Surbhi Sidana ◽  
Amylou C. Dueck ◽  
Michelle Burtis ◽  
Joan M. Griffin ◽  
Gita Thanarajasingam ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Transplant ◽  
Short Term ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Significant Difference ◽  
Car T

6594 Background: Given the significant short-term adverse effects of CAR-T cell therapy, it is important to evaluate its impact on QOL of patients in addition to efficacy, compared with established forms of cellular therapy like SCT. Methods: QOL was evaluated prospectively in patients undergoing CAR-T therapy, autoSCT & alloSCT for hematologic malignancies. QOL was assessed with FACT-G at baseline, 2 weeks and monthly for 6 months thereafter. Functional well-being (FWB), physical WB (PWB) emotional WB (EWB) & social WB (SWB) and change over time were compared across groups. Results: 45 patients were recruited (CAR-T: 10; Auto SCT: 22; Allo SCT: 13) with follow up for 2 weeks & 1 month available for 23 &15 patients, respectively (Table). There was no statistically significant difference in baseline total QOL scores (p=0.13), though scores were lower in the alloSCT group (85,84,68). EWB &FWB were numerically higher in the CAR-T group, followed by autoSCT group. At 2 weeks, overall QOL decreased by only 2 points in CAR-T group vs. 22 & 18 points in auto & alloSCT groups (p=0.09). Change in PWB vs. baseline was less pronounced in the CAR-T group (-1, -9, -13, p=0.03). At 1 month, overall QOL was 6 points lower than baseline in CAR-T group vs. 3 and 14 points lower in auto & alloSCT groups, respectively (p=0.34). Importantly, PWB had at least returned to baseline in the CAR-T group. Conclusions: Preliminary data show that patients undergoing CAR-T cell therapy do not experience a more significant decline in QOL compared with auto & allo SCT, and may experience fewer physical side effects in the short-term. Accrual & follow-up are ongoing. [Table: see text]

NCMP-02. NEUROTOXICITY RELATED TO CAR T-CELL THERAPY IN PATIENTS WITH SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi147-vi147
Author(s):  
Carlen Yuen ◽  
Sarah Wesley ◽  
Koen Van Besien ◽  
Jing-Mei Hsu ◽  
Ran Reshef ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Systemic Disease ◽  
Central Nervous System Lymphoma ◽  
Leptomeningeal Disease ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract INTRODUCTION Patients with secondary CNS lymphoma (SCNSL) were excluded from the pivotal trials that led to the approval of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory (R/R) B-cell lymphomas due to concern for neurotoxicity (NT). Limited evidence exists for axicabtagene ciloleucel (axi-cel, Yescarta®) in SCNSL patients. METHODS In this retrospective study, 15 R/R lymphomas patients with SCNSL (14 DLBCL, 1 chronic lymphocytic leukemia) were treated with commercial axi-cel between March 2019 and April 2021 for systemic disease and assessed for NT using the Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and CTCAE toxicity grading systems. RESULTS Seven of 15 patients (47%) developed NT, all of whom had cytokine release syndrome (CRS). Four (27%) developed severe NT (Grade III-IV). In the 8 patients (53%) with active SCNSL, 6 (75%) did not develop NT and 2 (25%) developed severe NT. In the 4 severe NT patients, all had multifocal CNS disease and 3/4 (75%) had leptomeningeal disease. Two thirds of patients previously treated with RT developed severe NT (1 whole brain RT, 1 skull base). The third patient had RT to the eye. Four of 8 (50%) patients with prior intrathecal chemotherapy developed severe NT. Five patients relapsed (3 in the CNS), none of whom had NT. At 11.7 month median follow-up, 8 patients remain alive, 5 are deceased (1 from NT, 3 from progression, 1 from infection), 2 lost to follow-up. The patient who died from NT had prior temporal arteritis. Three additional patients with autoimmune disease did not develop severe NT. CONCLUSION In this limited cohort, presence of SCNSL did not increase NT incidence compared to historical outcomes of CAR T-cell therapy patients without SCNSL. This cohort will be compared to CAR T-cell therapy patients without SCNSL. Prospective studies of CAR T-cell therapy in SCNSL patients will be informative.

Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL

2021 ◽  
pp. JCO.20.02262
Author(s):  
Nirali N. Shah ◽  
Daniel W. Lee ◽  
Bonnie Yates ◽  
Constance M. Yuan ◽  
Haneen Shalabi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

PURPOSE CD19 chimeric antigen receptor (CD19-CAR) T cells induce high response rates in children and young adults (CAYAs) with B-cell acute lymphoblastic leukemia (B-ALL), but relapse rates are high. The role for allogeneic hematopoietic stem-cell transplant (alloHSCT) following CD19-CAR T-cell therapy to improve long-term outcomes in CAYAs has not been examined. METHODS We conducted a phase I trial of autologous CD19.28ζ-CAR T cells in CAYAs with relapsed or refractory B-ALL. Response and long-term clinical outcomes were assessed in relation to disease and treatment variables. RESULTS Fifty CAYAs with B-ALL were treated (median age, 13.5 years; range, 4.3-30.4). Thirty-one (62.0%) patients achieved a complete remission (CR), 28 (90.3%) of whom were minimal residual disease−negative by flow cytometry. Utilization of fludarabine/cyclophosphamide–based lymphodepletion was associated with improved CR rates (29/42, 69%) compared with non–fludarabine/cyclophosphamide–based lymphodepletion (2/8, 25%; P = .041). With median follow-up of 4.8 years, median overall survival was 10.5 months (95% CI, 6.3 to 29.2 months). Twenty-one of 28 (75.0%) patients achieving a minimal residual disease−negative CR proceeded to alloHSCT. For those proceeding to alloHSCT, median overall survival was 70.2 months (95% CI, 10.4 months to not estimable). The cumulative incidence of relapse after alloHSCT was 9.5% (95% CI, 1.5 to 26.8) at 24 months; 5-year EFS following alloHSCT was 61.9% (95% CI, 38.1 to 78.8). CONCLUSION We provide the longest follow-up in CAYAs with B-ALL after CD19-CAR T-cell therapy reported to date and demonstrate that sequential therapy with CD19.28ζ-CAR T cells followed by alloHSCT can mediate durable disease control in a sizable fraction of CAYAs with relapsed or refractory B-ALL (ClinicalTrials.gov identifier: NCT01593696 ).

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 JS1.4 Neurological follow-up of neurotoxicity after CAR T cell therapy in lymphoma patients: A French neurological multi-center survey

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii5-iii5
Author(s):  
C Belin ◽  
C Simard ◽  
A Dos Santos ◽  
X Ayrignac ◽  
C Berger ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Transverse Myelitis ◽  
T Cell Therapy ◽  
Duration Of Symptoms ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract BACKGROUND Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine-release syndrome (CRS) and neurotoxicity. The physiopathological mechanisms of neurological complications and their links with CRS remain largely unknown. The aims of this study are: a) to follow-up longitudinally patients treated with CAR-T cell therapy; b) to exhaustively identify neurological signs and symptoms and; c) to describe their occurrence over time. MATERIAL AND METHODS Since September 2018, all patients treated with CD19-targeted CAR T cell therapy for relapsing lymphoma were systematically followed-up and monitored for signs of neurotoxicity by a neurologist. Five different centres (Paris-Saint-Louis, Nantes, Lyon, Montpellier, and Rennes) participated in this study. RESULTS As of April 1st 2019, 57 patients, mean age 49 years (range from 22 to 72 years, median age 50 years), 22 females / 35 males, all treated for lymphoma, were included in this study Neurotoxicity, defined as the presence of at least one neurological sign or symptoms appearing after treatment infusion, was present in 33 % of patients. The median time to onset was 7.5 days after infusion with a median duration of symptoms of 5 days. Neurological symptoms were: Encephalopathy (52%), cerebellar syndrome (26%), aphasia (15%), agraphia (15%), executive syndrome (10%), myoclonus (10%), dysarthria (10%), meningismus (5%), transverse myelitis (5%), seizure (5%), neuralgia (5%), and dysesthesia (5%). The severity grade of neurotoxicity was grade 4: 2 patients, Grade 3: 7 patients, grade 2: 5 patients and grade 1: 5 patients (CTCAE grading). CRS was observed in 75% of patients. All patients who developed neurological disorders also had CRS (grade 1: 68%, grade 2: 10%, grade 3: 15%, grade 4: 5%) that preceded neurotoxicity. As the study is still ongoing, updated results will be presented at the EANO meeting. CONCLUSION Neurotoxicity associated with CAR-T therapies occurs in one third of patients. This high frequency underlines the need: 1 - to neurologically assess all patients before and repeatedly after therapy infusions; 2 - to provide guidelines for neurological assessment and relevant investigations to improve early recognition of neurotoxicity and its management

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.

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