scholarly journals CLINICAL AND RADIOGRAPHIC FACTORS PRIOR TO CAR T‐CELL THERAPY ACCURATELY IDENTIFY RELAPSED/REFRACTORY LYMPHOMA PATIENTS AT HIGH RISK FOR PROGRESSION AND POOR SURVIVAL

2021 ◽  
Vol 39 (S2) ◽  
Author(s):  
G. Jodon ◽  
M. D. Colton ◽  
A. R. Cai ◽  
B. Haverkos ◽  
R. Morgan ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cell Therapy ◽  
Poor Survival ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Refractory Lymphoma

KarMMa-4: Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy in high-risk newly diagnosed multiple myeloma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS8053-TPS8053
Author(s):  
Saad Z. Usmani ◽  
Jesus G. Berdeja ◽  
Anna Truppel-Hartmann ◽  
Yizhou Fei ◽  
Honeylet Wortman-Vayn ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cell Therapy ◽  
Stage Iii ◽  
Newly Diagnosed ◽  
Target Dose ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

TPS8053 Background: High-risk (R-ISS stage III) newly diagnosed multiple myeloma (NDMM) has a poor prognosis (median PFS, 29 mo), highlighting the need for novel disease-targeting approaches (Palumbo A, et al. J Clin Oncol 2015;33:2863-2869). Ide-cel, a BCMA-directed CAR T cell therapy, demonstrated deep, durable responses in heavily pretreated patients (pts) with relapsed and refractory MM (RRMM; Raje N, et al. N Engl J Med 2019;380:1726-1737; Munshi NC, et al. J Clin Oncol 2020;38[suppl 15]. Abstract 8503), including those with high-risk (R-ISS stage III) RRMM. In this population, earlier use of ide cel—when there may be more bone marrow reserve, more healthy peripheral blood mononuclear cells, a less compromised immune status, and less extensive disease to debulk before cell therapy—may result in improved outcomes vs standard therapies and offer an opportunity to replace transplant with CAR T cell therapy. Methods: KarMMa-4 (NCT04196491), a multicenter, open-label, phase 1, single-arm study, is currently evaluating ide-cel in pts with high-risk NDMM, defined as R-ISS stage III (ISS stage III [serum ß2 microglobulin ≥ 5.5 mg/L] and cytogenetic abnormalities t(4;14), del(17p), and/or t(14;16) by interphase FISH; or ISS stage III and serum LDH > ULN). Pts must have received ≤ 3 cycles of the induction regimens listed below, be aged ≥ 18 years, and have ECOG PS 0-1. Nonsecretory MM and CNS involvement are exclusion criteria. Pts can enroll between induction cycles 1 and 3. Permitted cycle 1 regimens are carfilzomib + lenalidomide (LEN) + dexamethasone (DEX) ± daratumumab (DARA; KRd ± DARA), LEN + bortezomib (BOR) + DEX ± DARA (RVd ± DARA), or cyclophosphamide + BOR + DEX (CyBorD). Induction cycles 2-4 are limited to KRd or RVd, with DEX omitted during cycle 3. Pts will undergo T cell collection via leukapheresis after cycle 3, and ide-cel will be manufactured during cycle 4. Stem cell collection for future use may be conducted after cycle 3 (following leukapheresis) or 4 (before lymphodepletion). Ide-cel is infused after 2 days of rest following lymphodepletion with 3 days of fludarabine 30 mg/m2 + cyclophosphamide 300 mg/m2. LEN-based maintenance may be provided upon bone marrow recovery or 90 days after ide-cel infusion, whichever is later. Dose-limiting toxicity and safety are the primary endpoints. Secondary endpoints include complete response (CR) rate and overall response rate, duration of response, time to CR, time to start of maintenance, feasibility of initiating maintenance, PFS, overall survival, and pharmacokinetics. Exploratory endpoints include LEN maintenance safety, minimal residual disease, immunogenicity and biomarkers. The starting ide-cel target dose is 450 × 106 CAR+ T cells, with dose escalation/de-escalation (150, 300, and 800 × 106 CAR+ T cells). Upon determination of optimal target dose, 12 pts will be enrolled in the dose-expansion phase. Clinical trial information: NCT04196491.

scholarly journals KarMMa-4: Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T-Cell Therapy, in High-Risk Newly Diagnosed Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Saad Z. Usmani ◽  
Jesus G. Berdeja ◽  
Anna Truppel-Hartmann ◽  
Marie-Laure Casadebaig ◽  
Honeylet Wortman-Vayn ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cell Therapy ◽  
Research Funding ◽  
Complete Response ◽  
Stage Iii ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

BACKGROUND: Despite the introduction of novel agents, patients with high-risk (Revised International Staging System [R-ISS] stage III) newly diagnosed multiple myeloma (NDMM) have a poor prognosis (median progression-free survival [PFS], 29 months), highlighting the need for novel disease-targeting approaches (Palumbo A, et al. J Clin Oncol. 2015;33:2863-2869). The BCMA-directed CAR T cell therapy ide-cel demonstrated deep, durable responses in heavily pretreated patients with relapsed and refractory MM (RRMM; Raje N, et al. N Engl J Med. 2019;380:1726-1737; Munshi NC, et al. J Clin Oncol. 2020;38[suppl] [abstract 8503]), including those with high-risk (R-ISS stage III) RRMM. Earlier use in this population-where there is potentially more bone marrow reserve, more healthy peripheral blood mononuclear cells, a less compromised immune status, and less extensive disease to debulk before cell therapy-may result in improved outcomes and offer an opportunity to replace transplant with CAR T cell therapy. KarMMa-4 is a multicenter, open-label, phase 1, single-arm study of ide-cel in patients with high-risk NDMM (R-ISS stage III disease per International Myeloma Working Group criteria). STUDY DESIGN: KarMMa-4 is enrolling patients with NDMM who have high-risk disease, defined as R-ISS stage III (ISS stage III [serum b2 microglobulin ≥ 5.5 mg/L] and cytogenetic abnormalities t(4;14), del(17p), and/or t(14;16) by interphase fluorescence in situ hybridization; or ISS stage III and serum lactate dehydrogenase > upper limit of normal). Patients must have received ≤ 3 cycles of the induction regimens listed below, be aged ≥ 18 years, and have Eastern Cooperative Oncology Group performance status 0-1. Patients with nonsecretory myeloma or central nervous system involvement are excluded. Patients can enroll between cycle 1 and cycle 3 of induction. Permitted induction regimens for cycle 1 are carfilzomib + lenalidomide + dexamethasone ± daratumumab (KRd ± DARA), lenalidomide + bortezomib + dexamethasone ± daratumumab (RVd ± DARA), or cyclophosphamide + bortezomib + dexamethasone (CyBorD). Induction regimens for cycles 2-4 are limited to KRd or RVd, with dexamethasone omitted during cycle 3. All patients will undergo leukapheresis for T cell collection after cycle 3, and ide-cel will be manufactured during cycle 4 of induction. Stem cell collection for future use may be conducted after cycle 3 (following leukapheresis) or cycle 4 (before lymphodepletion). Ide-cel is infused after 2 days of rest following lymphodepletion with 3 days of fludarabine 30 mg/m2 + cyclophosphamide 300 mg/m2. Lenalidomide-based maintenance may be provided upon bone marrow recovery or 90 days after ide-cel infusion, whichever is later. The primary endpoints are dose-limiting toxicity and safety. Secondary endpoints include complete response rate and overall response rate, duration of response, time to complete response, time to start of maintenance, feasibility of initiating maintenance, PFS, overall survival, and pharmacokinetics. Exploratory endpoints include safety of lenalidomide maintenance therapy, minimal residual disease, immunogenicity and biomarkers. The starting ide-cel target dose is 450 × 106 CAR+ T cells, with dose escalation/de-escalation (150, 300, and 800 × 106 CAR+ T cells). After identification of the optimal target dose, 12 patients will be enrolled in the dose-expansion phase. KarMMa-4 is registered at ClinicalTrials.gov: NCT04196491. Disclosures Usmani: Celgene: Other; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Research Funding; GSK: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Berdeja:Servier: Consultancy; Poseida: Research Funding; Lilly: Research Funding; Legend: Consultancy; Kite Pharma: Consultancy; Kesios: Research Funding; Karyopharm: Consultancy; Prothena: Consultancy; Acetylon: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Research Funding; Vivolux: Research Funding; Novartis: Research Funding; Bluebird: Research Funding; Bioclinica: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; CURIS: Research Funding; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Janssen: Consultancy, Research Funding; Glenmark: Research Funding; Teva: Research Funding; Takeda: Consultancy, Research Funding. Truppel-Hartmann:bluebird bio, Inc: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); F. Hoffmann La Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Casadebaig:Bristol-Myers Squibb Company: Current Employment. Wortman-Vayn:Bristol-Myers Squibb Company: Current Employment. Shelat:Bristol-Myers Squibb Company: Current Employment. Novick:Bristol-Myers Squibb Company: Current Employment. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding.

scholarly journals Mantle Cell Lymphoma: Updates in the Management of Relapsed/Refractory Disease

2021 ◽  
Vol 19 (11.5) ◽  
pp. 1331-1333
Author(s):  
Mazyar Shadman
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cell Therapy ◽  
Cell Lymphoma ◽  
Refractory Disease ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Mantle Cell

Mantle cell lymphoma remains incurable despite recent treatment advances, and most patients experience relapsed/refractory disease. BTK inhibitors are the preferred choice in the relapsed setting, especially in patients with early relapse. For patients with high-risk features such as TP53 mutation, early referral for CAR T-cell therapy should be considered, even in those with stable disease on a BTK inhibitor. Patients without high-risk features may be monitored and initiate CAR T-cell therapy after clinical disease progression. CAR T-cell therapy is an effective treatment with high rate of complete remissions. For patients who do not achieve a complete remission 3 months after CAR-T therapy, bridging therapy with chemotherapy or targeted therapy agents and referral for allogeneic transplant are recommended.

scholarly journals Axicabtagene ciloleucel for relapsed or refractory lymphoma after prior treatment with a different CD19-directed CAR T-cell therapy

2020 ◽  
Vol 4 (19) ◽  
pp. 4869-4872 ◽  
Author(s):  
Victor A. Chow ◽  
Ajay K. Gopal ◽  
Jordan Gauthier ◽  
Yolanda D. Tseng ◽  
Cameron J. Turtle ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Key Points ◽  
Car T ◽  
Refractory Lymphoma ◽  
Large B Cell

Key Points No meaningful responses were observed when axicabtagene ciloleucel was used for progression after a different CD19-directed CAR T cell. Further research is needed to understand how to sequence cell-based therapies for relapsed/refractory large B-cell lymphomas.

scholarly journals CD19 and CD30 CAR T-Cell Immunotherapy for High-Risk Classical Hodgkin’s Lymphoma

2021 ◽  
Vol 10 ◽  
Author(s):  
YuanBo Xue ◽  
Xun Lai ◽  
RuiLei Li ◽  
ChunLei Ge ◽  
BaoZhen Zeng ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Adverse Events ◽  
Cell Therapy ◽  
Low Doses ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Severe Adverse Events

BackgroundIn clinical applications of CAR T-cell therapy, life-threatening adverse events including cytokine release syndrome and neurotoxicity can lead to treatment failure. Outcomes of patients treated with anti-CD30 CAR T- cell have been disappointing in relapsing/refractory (r/r) classical Hodgkin’s Lymphoma (cHL).MethodsIn order to understand the applicable population of multiple CAR T-cell therapy, we examined the expression of CD19, CD20, and CD30 by immunohistochemistry (IHC) in 38 paraffin-embedded specimens of cHL. In the past two years, we found only one patient with cHL who is eligible for combined anti-CD19 and CD30 CAR T-cell treatment. This patient’s baseline characteristics were prone to severe adverse events. We treated this patient with low doses and multiple infusions of anti-CD19 and CD30 CAR T-cell.ResultsThe positive expression of CD19+ + CD30+ in Reed-Sternberg (RS) cells is approximately 5.2% (2/38). The patient we treated with combined anti-CD19 and CD30 CAR T-cell did not experience severe adverse events related to CAR T-cell therapy and received long term progression-free survival (PFS).ConclusionFor high risk r/r cHL patients, low doses of CAR T-cell used over different days at different times might be safe and effective. More clinical trials are warranted for CD19 and CD30 CAR T-cell combination therapy.

scholarly journals Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features

2020 ◽  
Vol 4 (10) ◽  
pp. 2325-2338 ◽  
Author(s):  
Xian Zhang ◽  
Xin-an Lu ◽  
Junfang Yang ◽  
Gailing Zhang ◽  
Jingjing Li ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cell Therapy ◽  
Tp53 Mutation ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is effective in patients with advanced B-cell acute lymphoblastic leukemia (B-ALL). However, efficacy data is sparse in subgroups of patients with high-risk features such as BCR-ABL+, TP53 mutation, extramedullary disease (including central nervous system leukemia) or posttransplant relapse. It is also uncertain whether there is an added benefit of transplantation after anti-CD19 CAR T-cell therapy. We conducted a phase 1/2 study of 115 enrolled patients with CD19+ B-ALL. A total of 110 patients were successfully infused with anti-CD19 CAR T cells. In all, 93% of patients achieved a morphologic complete remission, and 87% became negative for minimal residual disease. Efficacy was seen across all subgroups. One-year leukemia-free survival (LFS) was 58%, and 1-year overall survival (OS) was 64% for the 110 patients. Seventy-five nonrandomly selected patients (73.5%) subsequently received an allogeneic hematopoietic stem cell transplant (allo-HSCT). LFS (76.9% vs 11.6%; P < .0001; 95% confidence interval [CI], 11.6-108.4) and OS (79.1% vs 32.0%; P < .0001; 95% CI, 0.02-0.22) were significantly better among patients who subsequently received allo-HSCT compared with those receiving CAR T-cell therapy alone. This was confirmed in multivariable analyses (hazard ratio, 16.546; 95% CI, 5.499-49.786). Another variate that correlated with worse outcomes was TP53 mutation (hazard ratio, 0.235; 95% CI, 0.089-0.619). There were no differences in complete remission rate, OS, or LFS between groups of patients age 2 to 14 years or age older than 14 years. Most patients had only mild cytokine release syndrome and neurotoxicity. Our data indicate that anti-CD19 CAR T-cell therapy is safe and effective in all B-ALL subgroups that have high-risk features. The benefit of a subsequent allo-HSCT requires confirmation because of nonrandom allocation. This trial was registered at www.clinicaltrials.gov as #NCT03173417.

scholarly journals A U.S. Food and Drug Administration Age Based Pooled Analysis of Cytokine Release Syndrome and Neurotoxicity in Subjects with Relapsed/Refractory Lymphoma Treated with Chimeric Antigen Receptor (CAR) T Cell Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4201-4201 ◽  
Author(s):  
Poornima Sharma ◽  
Harpreet Singh ◽  
Najat Bouchkouj ◽  
Aviva C. Krauss ◽  
Bindu George
Keyword(s):  
Older Adults ◽  
T Cell ◽  
Cell Therapy ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Refractory Lymphoma

Abstract Background: With recent FDA approvals of CAR T cell therapy for the treatment of relapsed/refractory aggressive B cell non-Hodgkin lymphoma, an increasing number of older adults will be treated with this therapy. An improved understanding of the safety of CAR T cell therapy in this population is important to inform clinical decision making for the treatment of older subjects. Methods: Data from two prospective single arm studies (n=214) of two approved CART cell products for the treatment of relapsed/refractory lymphoma were pooled and analyzed. Rates of cytokine release syndrome (CRS), as well as severity and treatment modalities (oxygen, vasopressor support, tocilizumab and steroids) were pooled and analyzed by age. Selected neuropsychiatric events were pooled and analyzed by age. Results: Age was balanced between the two studies. The median age of subjects was 58 years (range 22-76 years). Of the 214 total subjects, 24% were 65 years of age and older. CRS and neurotoxicity were evaluated in the subjects who received treatment with CAR T cell therapy. (Table 1). *Two studies employed different grading methods for CRS; Lee's criteria (Lee DW et al, Blood 2014) and U Penn criteria (Porter DL et al, Blood 2014) Conclusions: This exploratory analysis suggests overall similar rates of CRS and grade 2 and higher CRS in subjects less than 65 years as compared to 65 years of age and older. There appears to be an overall higher rate of encephalopathy and grade 3 and higher delirium/encephalopathy in adults 65 years and older compared to less than 65 years of age. The inclusion of greater numbers of patients ≥ 65 years of age in clinical trials will further inform clinicians about the safety and efficacy of CAR T cell therapy in older adults. Table 1: Adverse Events by Age in subjects treated with CART cell therapy Disclosures No relevant conflicts of interest to declare.

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