RESUMO
BACKGROUND: The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern. METHODS: We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient. RESULTS: A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques. CONCLUSIONS: Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).
Assuntos
Antineoplásicos Imunológicos , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Linfoma de Células T , Segunda Neoplasia Primária , Receptores de Antígenos Quiméricos , Feminino , Humanos , Pessoa de Meia-Idade , Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Hematopoiese Clonal , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/genética , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/terapia , Linfoma de Células T/etiologia , Linfoma de Células T/genética , Linfoma de Células T/imunologia , Linfoma de Células T/terapia , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/etiologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Integração ViralRESUMO
BACKGROUND: In an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes. METHODS: In this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization. RESULTS: A total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P = 0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival. CONCLUSIONS: At a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).
Assuntos
Antineoplásicos Imunológicos , Produtos Biológicos , Linfoma Difuso de Grandes Células B , Humanos , Antígenos CD19/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Análise de SobrevidaRESUMO
ABSTRACT: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell-associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.
Assuntos
Produtos Biológicos , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antígenos CD19/imunologia , Antígenos CD19/uso terapêutico , Produtos Biológicos/uso terapêutico , Etnicidade , Linfoma Difuso de Grandes Células B/terapia , Resultado do Tratamento , Negro ou Afro-Americano , Brancos , Asiático , Ensaios Clínicos como AssuntoRESUMO
While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).
RESUMO
BACKGROUND: Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study. METHODS: In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment. FINDINGS: From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome. INTERPRETATION: This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach. FUNDING: National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.
Assuntos
Antígenos CD19 , Imunoterapia Adotiva , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/imunologia , Dose Máxima Tolerável , Receptores de Antígenos Quiméricos/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor. METHODS: In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed. RESULTS: A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; P<0.001). A response occurred in 83% of the patients in the axi-cel group and in 50% of those in the standard-care group (with a complete response in 65% and 32%, respectively). In an interim analysis, the estimated overall survival at 2 years was 61% in the axi-cel group and 52% in the standard-care group. Adverse events of grade 3 or higher occurred in 91% of the patients who received axi-cel and in 83% of those who received standard care. Among patients who received axi-cel, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21%. No deaths related to cytokine release syndrome or neurologic events occurred. CONCLUSIONS: Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Receptores de Antígenos Quiméricos/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Produtos Biológicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Transplante de Células-Tronco , Transplante AutólogoRESUMO
The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade after the approval of brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for patients with R/R cHL who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011 to 2020 (N = 183) compared with those from 2001 to 2010 (N = 159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era with a trend toward lower nonrelapse mortality beyond 2 years after transplant. Among patients who progressed after AHCT, 4-year postprogression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients that underwent transplant in the modern era, age ≥45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, whereas receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS. Extranodal disease at relapse was associated with inferior OS. Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Humanos , Pessoa de Meia-Idade , Doença de Hodgkin/patologia , Transplante Autólogo , Inibidores de Checkpoint Imunológico/uso terapêutico , Recidiva Local de Neoplasia/terapia , Brentuximab Vedotin/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% of patients at data cutoff. Median overall survival (OS) was 25.8 months, and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91% of patients. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. This trial was registered at ClinicalTrials.gov, as #NCT02348216.
Assuntos
Produtos Biológicos , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Adulto , Humanos , Seguimentos , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/patologia , Antígenos CD19/uso terapêuticoRESUMO
We evaluated patients with relapsed multiple myeloma with renal impairment (RI) treated with standard of care idecabtagene vicleucel (ide-cel), as outcomes with chimeric antigen receptor (CAR) T-cell therapy are unknown in this population. RI was defined as creatinine clearance (CrCl) <50 mL/min. CrCl of <30 mL/min or dialysis dependence were defined as severe RI. The study cohort included 214 patients, 28 (13%) patients with RI, including 11 patients severe RI (dialysis, N=1). Patients with RI were older, more likely to be female and had higher likelihood of having Revised International Staging System stage 3 disease. Rates and severity of cytokine release syndrome (89% vs. 84%, grade ≥3: 7% vs. 2%) and immune effector cell-associated neurotoxicity syndrome (23% vs. 20%) were similar in patients with and without RI, respectively. Patients with RI had higher incidence of short-term grade ≥3 cytopenias, although cytopenias were similar by 3 months following CAR T-cell therapy. Renal function did not worsen after CAR T-cell therapy in patients with RI. Response rates (93% vs. 82%) and survival outcomes (median progression-free survival: 9 vs. 8 months; P=0.26) were comparable in patients with and without RI, respectively. Treatment with ide-cel is feasible in patients with RI, with a comparable safety and efficacy profile as patients without RI, with notable exception of higher short-term high-grade cytopenias.
Assuntos
Citopenia , Mieloma Múltiplo , Neoplasias de Plasmócitos , Receptores de Antígenos Quiméricos , Insuficiência Renal , Humanos , Feminino , Masculino , Mieloma Múltiplo/complicações , Mieloma Múltiplo/terapia , Imunoterapia Adotiva/efeitos adversos , Terapia Baseada em Transplante de Células e TecidosRESUMO
Autologous hematopoietic cell transplantation (AHCT) is often used as a consolidation for patients with peripheral T-cell lymphomas (PTCLs) due to the poor prognosis associated with this heterogenous group of disorders. However, a significant number of patients will experience post-AHCT disease relapse. Here, we report a retrospective study of consecutive 124 patients with PTCLs who underwent AHCT from 2008 to 2020. With a median follow-up of 6.01 years following AHCT, 49 patients (40%) experienced disease relapse. As expected, more patients who were not in first complete remission experienced post-AHCT relapse. Following relapse, majority of the patients (70%) receiving systemic therapies intended as bridging to curative allogeneic HCT. However, only 18 (53%) patients eventually underwent allogeneic HCT. The estimated 3-year OS among patients proceeding to allogeneic HCT was 72% (95% CI 46%-87%). Our report details the pattern of post-AHCT relapse and the management of relapsed disease using different therapeutic modalities.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Células T Periférico , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Adulto , Estudos Retrospectivos , Idoso , Linfoma de Células T Periférico/terapia , Linfoma de Células T Periférico/mortalidade , Recidiva , Transplante Autólogo , Recidiva Local de Neoplasia/terapia , Adulto JovemRESUMO
Axicabtagene ciloleucel (axi-cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real-world effectiveness of axi-cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi-cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients treated with CIT for R/R LBCL after ≥2 lines of prior therapy were included from SCHOLAR-1 (an international, multicohort, retrospective study). After propensity score matching, at a median follow-up of 24 months for patients receiving axi-cel and 60 months for patients receiving CIT, 12-month overall survival rates were 62% and 28%, respectively (hazard ratio, 0.30 [95% CI, 0.24-0.37]). Objective response rate (ORR) was 76% (complete response [CR] rate 58%) in patients receiving axi-cel versus 28% (CR rate 16%) for those receiving CIT. A 57% difference in ORR (55% difference in CR rate) favoring axi-cel over CIT was observed among patients aged ≥65 years. Increased magnitude of benefit in response rates for axi-cel versus CIT was also observed among patients with ECOG PS = 2. These findings further support the broader use of axi-cel in older patients and patients with ECOG PS = 2 with R/R LBCL.
Assuntos
Produtos Biológicos , Linfoma Difuso de Grandes Células B , Humanos , Idoso , Estudos Retrospectivos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Resposta Patológica Completa , Imunoterapia Adotiva , Antígenos CD19RESUMO
BACKGROUND: Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma. METHODS: In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×106 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months. RESULTS: A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred. CONCLUSIONS: KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).
Assuntos
Antígenos CD19/uso terapêutico , Imunoterapia Adotiva , Linfoma de Célula do Manto/terapia , Receptores de Antígenos Quiméricos/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos/uso terapêutico , Terapia Combinada , Humanos , Imunoterapia Adotiva/efeitos adversos , Infusões Intravenosas , Leucaférese , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida , Linfócitos T/transplante , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
CD58 or lymphocyte function-associated antigen-3, is a ligand for CD2 receptors on T and NK cells and is required for their activation and target cell killing. We recently showed a trend toward higher frequency of CD58 aberrations in patients with diffuse large B-cell lymphoma (DLBCL) who progressed on chimeric antigen receptor-T-cell treatment compared with those who responded. Given that CD58 status may be an important measure of T-cell-mediated therapy failure, we developed a CD58 immunohistochemical assay and evaluated CD58 status in 748 lymphomas. Our results show that CD58 protein expression is downregulated in a significant proportion of all subtypes of B-, T-, and NK-cell lymphomas. CD58 loss is significantly related to poor prognostic indicators in DLBCL and to ALK and DUSP22 rearrangements in anaplastic large-cell lymphoma. However, it is not associated with overall or progression-free survival in any of the lymphoma subtypes. As eligibility for chimeric antigen receptor-T-cell therapy is being extended to a broader spectrum of lymphomas, mechanisms of resistance, such as target downregulation and CD58 loss, may limit therapeutic success. CD58 status is therefore an important biomarker in lymphoma patients who may benefit from next-generation T-cell-mediated therapies or other novel approaches that mitigate immune escape.
RESUMO
The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.
Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/terapia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Ensaios Clínicos Fase I como Assunto , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Prognóstico , Indução de RemissãoRESUMO
T-cell activation releases inositol 1,4,5-trisphosphate (IP3), inducing cytoplasmic calcium (Ca2+) influx. In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP3 to negatively regulate and thereby tightly control Ca2+ fluxes that are essential for mature T-cell activation and differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca2+, induces apoptosis of activated T cells, and can control T-cell-mediated autoimmunity. In this study, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD). Murine-induced, Itpkb-deleted (Itpkb-/-) T cells attenuated acute GVHD in 2 models without eliminating A20-luciferase B-cell lymphoma graft-versus-leukemia (GVL). A highly potent, selective inhibitor, GNF362, ameliorated acute GVHD without impairing GVL against 2 acute myeloid leukemia lines (MLL-AF9-eGFP and C1498-luciferase). Compared with FK506, GNF362 more selectively deleted donor alloreactive vs nominal antigen-responsive T cells. Consistent with these data and as compared with FK506, GNF362 had favorable acute GVHD and GVL properties against MLL-AF9-eGFP cells. In chronic GVHD preclinical models that have a pathophysiology distinct from acute GVHD, Itpkb-/- donor T cells reduced active chronic GVHD in a multiorgan system model of bronchiolitis obliterans (BO), driven by germinal center reactions and resulting in target organ fibrosis. GNF362 treatment reduced active chronic GVHD in both BO and scleroderma models. Thus, intact Itpkb signaling is essential to drive acute GVHD pathogenesis and sustain active chronic GVHD, pointing toward a novel clinical application to prevent acute or treat chronic GVHD.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Efeito Enxerto vs Leucemia , Leucemia Experimental/complicações , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Tacrolimo/farmacologia , Animais , Doença Crônica , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Imunossupressores/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologiaRESUMO
Patient outcomes for steroid-dependent or -refractory chronic graft-versus-host diesease (cGVHD) are poor, and only ibrutinib has been US Food and Drug Administration (FDA) approved for this indication. cGVHD is often driven by the germinal center (GC) reaction, in which T follicular helper cells interact with GC B cells to produce antibodies that are associated with disease pathogenesis. The transcriptional corepressor B-cell lymphoma 6 (BCL6) is a member of the Broad-complex, Tramtrack, and Bric-abrac/poxvirus and zinc finger (BTB/POZ) transcription factor family and master regulator of the immune cells in the GC reaction. We demonstrate that BCL6 expression in both donor T cells and B cells is necessary for cGVHD development, pointing to BCL6 as a therapeutic cGVHD target. A small-molecule BCL6 inhibitor reversed active cGVHD in a mouse model of multiorgan system injury with bronchiolitis obliterans associated with a robust GC reaction, but not in cGVHD mice with scleroderma as the prominent manifestation. For cGVHD patients with antibody-driven cGVHD, targeting of BCL6 represents a new approach with specificity for a master GC regulator that would extend the currently available second-line agents.
Assuntos
Linfócitos B/imunologia , Bronquiolite Obliterante/complicações , Centro Germinativo/efeitos dos fármacos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-6/fisiologia , Bibliotecas de Moléculas Pequenas/farmacologia , Linfócitos T/imunologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Bronquiolite Obliterante/imunologia , Bronquiolite Obliterante/patologia , Doença Crônica , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell disorder. The optimal treatment approach, including whether to pursue an autologous (auto) or allogeneic (allo) stem cell transplantation (SCT) is not clear, given the lack of clinical trial-based evidence. This single-center retrospective study describes the outcomes of 16 patients with PCL (n = 14 with primary PCL) who underwent either autoSCT (n = 9) or alloSCT (n = 7) for PCL in the era of novel agents, between 2007 and 2019. The median age of the cohort was 58 years. High-risk cytogenetics were found in 50% of the patients. All patients received a proteasome inhibitor and/or immunomodulatory drug-based regimen before transplantation. At the time of transplantation, 10 patients (62%) obtained at least a very good partial response (VGPR). The response after autoSCT (3 months) was at least a VGPR in 6 patients (67%; complete response [CR] in 5). All patients undergoing alloSCT achieved a CR at 3 months. Maintenance therapy was provided to 5 patients (56%) after autoSCT. The median progression-free survival after transplantation was 6 months in the autoSCT group, compared with 18 months in the alloSCT group (P = .09), and median overall survival (OS) after transplantation in the 2 groups was 19 months and 40 months, respectively (P = .41). The median OS from diagnosis was 27 months and 49 months, respectively (P = .50). Of the 11 deaths, 10 patients (91%) died of relapsed disease. AlloSCT was not observed to offer any significant survival advantage over autoSCT in PCL, in agreement with recent reports, and relapse remains the primary cause of death in these patients.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Plasmocitária , Preparações Farmacêuticas , Intervalo Livre de Doença , Humanos , Leucemia Plasmocitária/terapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante de Células-Tronco , Transplante Autólogo , Transplante Homólogo , Resultado do TratamentoRESUMO
BACKGROUND: In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. METHODS: In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. RESULTS: Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response. CONCLUSIONS: In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
Assuntos
Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/transplante , Adulto , Idoso , Antígenos CD19 , Biomarcadores/sangue , Intervalo Livre de Doença , Feminino , Humanos , Interleucinas/sangue , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/induzido quimicamente , Neutropenia/induzido quimicamente , Receptores de Antígenos de Linfócitos T/sangue , Taxa de Sobrevida , Linfócitos T/imunologia , Adulto JovemRESUMO
BACKGROUND: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7-17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. METHODS: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma-including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma-according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2â×â106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days -5, -4, and -3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. FINDINGS: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7-28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2-not estimable). The median overall survival was not reached (12·8-not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3-15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up. INTERPRETATION: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma. FUNDING: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.
Assuntos
Antígenos CD19/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/terapia , Adulto , Idoso , Antígenos CD19/administração & dosagem , Antígenos CD19/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Produtos Biológicos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Feminino , Seguimentos , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
Chronic graft-versus-host disease (cGVHD) is a life-threatening complication of allogeneic stem cell transplantation. In a Phase 1b/2, open-label study (PCYC-1129; ClinicalTrials.gov identifier NCT02195869) involving 42 patients with active cGVHD who were steroid-dependent or -refractory, the activity and safety of ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, was demonstrated. Here we report extended follow-up for patients in this study. After a median follow-up of 26 months (range, .53 to 36.7 months), best overall response rate in the all treated population was 69% (29 of 42), with 13 patients (31%) achieving a complete response and 16 patients (38%) achieving a partial response. Sustained responses of ≥20, ≥32, and ≥44 weeks were seen in 20 (69%), 18 (62%), and 16 (55%) of the 29 responders, respectively. Of 26 patients with ≥2 involved organs, 19 (73%) showed responses in ≥2 organs. Six of 10 patients (60%) with ≥3 involved organs showed responses in ≥3 organs. Eleven of 18 patients (61%) who had sclerosis at baseline showed a sclerotic response (39% with complete response, 22% with partial response). Twenty-seven of 42 patients (64%) reached a corticosteroid dose of <.15 mg/kg/day during the study; 8 discontinued corticosteroid treatment and remained off corticosteroid at study closure. Safety findings for this updated analysis were consistent with the safety profile seen at the time of the original analysis. Common grade ≥3 adverse events (AEs) were pneumonia (nâ¯=â¯6), fatigue (nâ¯=â¯5), and diarrhea (nâ¯=â¯4). The onset of new grade ≥3 AEs decreased from 71% in the first year of treatment to 25% in the second year (nâ¯=â¯12). AEs leading to discontinuation occurred in 18 patients (43%). At a median follow-up of >2 years, ibrutinib continued to produce durable responses in patients with cGVHD who had failed previous systemic therapy. In this pretreated, high-risk population, clinically meaningful benefit and an acceptable safety profile were observed with additional follow-up for ibrutinib. These results demonstrate a substantial advance in the therapeutic management of patients with cGVHD.