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 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.

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.

Outreach: Preliminary safety and efficacy results from a phase 2 study of lisocabtagene maraleucel (liso-cel) in the nonuniversity setting.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19513-e19513
Author(s):  
John E. Godwin ◽  
Bassam Ibrahim Mattar ◽  
Michael B. Maris ◽  
Carlos R. Bachier ◽  
Don A. Stevens ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
Multidisciplinary Teams ◽  
Inpatient Setting ◽  
T Cell Therapy ◽  
Safety And Efficacy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

e19513 Background: Concerns about adverse events (AEs) related to CAR T cell therapy have resulted in administration of this therapy largely in an inpatient setting. OUTREACH (NCT03744676) evaluates safety and efficacy of liso-cel in patients (pts) with R/R large B-cell lymphoma (LBCL) across inpatient and outpatient settings at nonuniversity medical centers (NMCs). Methods: NMCs, including centers naïve to CAR T cell therapy, enrolled adults with R/R LBCL in this open-label, multicenter study. Eligible pts had R/R PET-positive disease after ≥2 lines of prior systemic therapy, ECOG PS ≤1, and adequate organ function. Prior autologous HSCT was allowed. Pts received sequential infusions of equal target doses of CD8+ and CD4+ cells at a total target dose of 100 × 106 CAR+ T cells. Primary endpoint was incidence of grade (G) ≥3 cytokine release syndrome (CRS) graded per 2014 Lee criteria, neurological events (NEs), prolonged cytopenias (Day 29 G ≥3 lab values), and infections. Secondary endpoints were safety and overall response rate (ORR). Outpatient AE monitoring/management was managed by a multidisciplinary CAR T cell therapy team following standard operating procedures (SOPs). Results: At data cutoff, 46 pts (inpatients n = 16, outpatients n = 30) were treated with liso-cel. Inpatients and outpatients had similar demographics and baseline disease characteristics; median age was 63 y (range, 34–83), 63% had diffuse LBCL not otherwise specified, and 91% were refractory to last therapy. Safety data were similar across inpatients and outpatients (Table). Early (study Day ≤4) and overall hospitalization in outpatients was reported in 27% and 63%, respectively; median time to hospitalization was 5 (2–61) days and median length of stay was 6 (1–28) days. For efficacy-evaluable pts (n = 44), ORR was 75% for inpatients and 79% for outpatients; CR rates were 50% and 61%, respectively. Conclusions: Liso-cel was successfully administered to pts with R/R LBCL in the outpatient setting and pts were monitored for CAR T cell therapy–related toxicities by multidisciplinary teams using SOPs. The incidences of severe CRS and NEs and use of tocilizumab and/or corticosteroids were similar in inpatients and outpatients, and consistent with the pivotal study observations (Abramson, The Lancet 2020). Updated data with longer follow-up will be presented. Clinical trial information: NCT03744676. [Table: see text]

NCMP-10. DYSGRAPHIA AS THE EARLIEST PRESENTING SYMPTOM OF SEVERE CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY NEUROTOXICITY: A SINGLE CENTER EXPERIENCE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi149-vi149
Author(s):  
Carlen Yuen ◽  
Kourosh Rezania ◽  
Thomas Kelly ◽  
Michael Bishop
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
B Cell Lymphoma ◽  
Motor Dysfunction ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract INTRODUCTION Chimeric antigen receptor (CAR) T-cell therapy, including axicabtagene ciloleucel (axi-cel; Yescarta®) and tisagenlecleucel (tisa-cel; Kymriah®), are FDA approved for the treatment of adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Neurotoxicity (NT) associated with CAR T-cell therapy (immune effector cell-associated neurotoxicity syndrome [ICANS]) can be fatal. Timely data, in the form of an abbreviated bedside mini-mental status exam, is thought to lead to earlier identification of NT. However, existing literature validating this method is limited. MATERIALS AND METHODS In this retrospective study, patients with R/R DLBCL treated with commercial axi-cel or tisa-cel in our center from December 2017 to September 2018 were assessed for NT with the CTCAE v4 criteria and the CAR-T-cell-therapy-associated TOXicity (CARTOX-10) scoring system. RESULTS Twenty-six patients with R/R DLBCL were treated with CAR T-cell therapy (25 axi-cel/[Yescarta®] and 1 tisagenlecleucel [Kymriah®]). Twenty-three (88%) developed NT with 8 (31%) experiencing severe NT (Grade III-IV). Tremor and dysgraphia occurred in all patients with severe NT. Lower average CARTOX-10 score (p=&lt; 0.01), dysgraphia (p&lt; 0.01), inattention (p=.018), and disorientation (p=.01) were significantly associated in patients with severe NT. A trend towards significance was observed between tremor and severe NT (p=.08). All patients with severe NT had both dysgraphia and tremor 8/8 (100%) and 2/8 (25%) had concurrent dysnomia. Death occurred in 12/26 (46%) of patients due to disease progression (n=11) and cardiac failure due to myositis (n=1). CONCLUSION In our limited cohort, dysgraphia, inattention, and disorientation are heralding symptoms of severe NT in adult R/R DLBCL patients treated with commercial CAR T-cell therapy. Dysgraphia was the earliest presenting symptom in patients with severe CAR T-cell neurotoxicity and was likely a manifestation of motor dysfunction rather than a component of dysphasia. Further studies with a larger cohort are needed to validate our findings.

scholarly journals DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality

2020 ◽  
Vol 4 (13) ◽  
pp. 3024-3033 ◽  
Author(s):  
Kitsada Wudhikarn ◽  
Martina Pennisi ◽  
Marta Garcia-Recio ◽  
Jessica R. Flynn ◽  
Aishat Afuye ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract Cytokine release syndrome (CRS) immune effector cell–associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell–mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.

scholarly journals Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 125 ◽  
Author(s):  
Aleksei Titov ◽  
Aygul Valiullina ◽  
Ekaterina Zmievskaya ◽  
Ekaterina Zaikova ◽  
Alexey Petukhov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor (CAR) immunotherapy is one of the most promising modern approaches for the treatment of cancer. To date only two CAR T-cell products, Kymriah® and Yescarta®, have been approved by the Food and Drug Administration (FDA) for the treatment of lymphoblastic leukemia and B-cell lymphoma. Administration of CAR T-cells to control solid tumors has long been envisaged as one of the most difficult therapeutic tasks. The first two clinical trials conducted in sarcoma and neuroblastoma patients showed clinical benefits of CAR T-cells, yet multiple obstacles still hold us back from having accessible and efficient therapy. Why did such an effective treatment for relapsed and refractory hematological malignancies demonstrate only relatively modest efficiency in the context of solid tumors? Is it due to the lucky selection of the “magic” CD19 antigen, which might be one of a kind? Or do lymphomas lack the immunosuppressive features of solid tumors? Here we review the existing knowledge in the field of CAR T-cell therapy and address the heterogeneity of solid tumors and their diverse strategies of immunoevasion. We also provide an insight into prospective developments of CAR T-cell technologies against solid tumors.

scholarly journals Impact of Increasing Wait Times on Overall Mortality of Chimeric Antigen Receptor T-Cell Therapy in Large B-Cell Lymphoma: A Discrete Event Simulation Model

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Stephen Tully ◽  
Zeny Feng ◽  
Kelly Grindrod ◽  
Tom McFarlane ◽  
Kelvin K.W. Chan ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
Wait Times ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T ◽  
Large B Cell

PURPOSE The development of chimeric antigen receptor (CAR) T cells has transformed oncology treatment, with the potential to cure certain cancers. Although shown to be effective in selected populations and studies, CAR T-cell technology requires considerable health care resources, which may lead to additional wait times to access this type of treatment in future. The objective of our study was to estimate the potential impact of increasing wait times on CAR T-cell therapy effectiveness compared with standard chemotherapy for patients with relapsed/refractory diffuse large B-cell lymphoma. METHODS A health system–level discrete event simulation model was developed to project the potential impact of wait times on CAR T-cell therapy for patients with relapsed/refractory diffuse large B-cell lymphoma. Waiting queues and health states related to treatment and clinical progression were implemented. Using data from the literature, we evaluated nine scenarios of using CAR T-cell therapy with wait times ranging from 1 to 9 months. The outcome of interest was 1-year all-cause mortality. RESULTS Increasing the wait time of receiving CAR T-cell therapy from 1 to 9 months increased the predicted 1-year mortality rate from 36.1% to 76.3%. Baseline 1-year mortality was 34.0% in patients receiving CAR T-cell therapy with no wait times and 75.1% in patients treated with chemotherapy. This resulted in an increased relative mortality rate of 6.2% to 124.5% over a 1- to 9-month wait time compared with no wait time. CONCLUSION We found that modest delays in CAR T-cell therapy significantly hinder its effectiveness. Because CAR T-cell therapy offers a potential cure, it is expected that the uptake rate will be substantially increased once the therapy is regularly funded by a health care system. Wait times may be prolonged if system resource availability does not match the demand. Strategies must be developed to minimize the impact of delays and reduce complications during waiting.

Sign in / Sign up

Export Citation Format

Share Document