RESUMO
In October 2021, brexucabtagene autoleucel became the first anti-CD19 chimeric antigen receptor T-cell product to receive approval from the Food and Drug Administration to treat adults with relapsed and refractory B-cell acute lymphoblastic leukemia. The approval is based on results from the Zuma-3 trial and significantly widens treatment options for this patient population. In this article, we review outcomes from this study and its implications.
Assuntos
Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Doença Aguda , Adulto , Antígenos CD19 , Humanos , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêuticoRESUMO
In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.
Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Antígenos CD19 , Intervalo Livre de Doença , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , Estudos Prospectivos , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Linfócitos TRESUMO
Chimeric antigen receptor T-cell therapy targeting CD19 (CART19) has expanded the treatment options for patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). The approval of tisagenlecleucel for pediatric and young adult patients with r/r ALL has allowed broader access for some patients, but the treatment of older adults is available (at the time of this writing) only within a clinical trial. High remission rates have been consistently observed with varied CART19 products and treatment platforms, but durability of remissions and thus the potential role of a consolidative allogeneic stem cell transplant (SCT) is more uncertain and likely to vary by product and population treated. The immunologic characteristics of CARTs that confer high response rates also account for the life-threatening toxicities of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, the severity of which also varies by patient and disease characteristics and product. Further considerations informing a decision to treat include feasibility of leukapheresis and timeline of manufacture, alternative treatment options available, and the appropriateness of a potential consolidative allogeneic SCT. Advances in the field are under way to improve rate and duration of responses and to mitigate toxicity.
Assuntos
Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante de Células-Tronco , Antígenos CD19/imunologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/métodos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodosRESUMO
PURPOSE: To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). METHODS: Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 107) or high (5 × 108) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months). RESULTS: At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups (P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not (P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR (P < .0001). Toxicity was comparable in both dose groups. CONCLUSION: In patients with advanced CLL, a 5 × 108 dose of CART-19 may be more effective than 5 × 107 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.
Assuntos
Imunoterapia Adotiva/métodos , Leucemia Linfocítica Crônica de Células B/terapia , Idoso , Antígenos CD19/imunologia , Síndrome da Liberação de Citocina/imunologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Receptores de Antígenos Quiméricos/imunologia , Recidiva , Taxa de Sobrevida , Linfócitos T/imunologia , Linfócitos T/transplanteRESUMO
PURPOSE: The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy. METHODS: Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity. RESULTS: Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%). CONCLUSION: Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.
Assuntos
Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Adulto JovemRESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) offers a curative option for patients with hematologic malignancies who are unable to undergo myeloablative conditioning, but its success is limited by high rates of relapse. Several studies have suggested a role for T cell doses in peripheral blood stem cell grafts in RIC HSCT. Because T cell dose is typically not known until after the collection, and apheresis blood volume is easily modifiable, we hypothesized that higher donor apheresis blood volumes would improve transplantation outcomes through an effect on graft composition. Thus, we analyzed the relationships between apheresis volume, graft composition, and transplantation outcomes in 142 consecutive patients undergoing unrelated donor allogeneic RIC HSCT. We found that apheresis volume ≥15 L was associated with a significantly decreased risk of relapse (adjusted hazard ratio [aHR], .48; 95% confidence interval [CI], .28 to .84]; P = .01) and improved relapse-free survival (aHR, .56; 95% CI, .35 to .89; P = .02) and overall survival (aHR, .55; 95% CI, .34 to .91; P = .02). A high apheresis volume was not associated with increased rates of acute or chronic graft-versus-host disease. These results demonstrate that an apheresis volume of at least 15 L is independently predictive of improved transplantation outcomes after RIC allogeneic HSCT.
Assuntos
Remoção de Componentes Sanguíneos/normas , Volume Sanguíneo , Transplante de Células-Tronco Hematopoéticas/normas , Prognóstico , Doadores não Relacionados , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Risco , Análise de Sobrevida , Transplante Homólogo/métodos , Transplante Homólogo/normas , Resultado do TratamentoRESUMO
T-cell-engaging immunotherapies are exciting new approaches to treat patients with acute lymphoblastic leukemia (ALL). These unique agents, which include blinatumomab, a CD3/CD19 bispecific antibody, and chimeric antigen receptor (CAR) modified T cells targeted to CD19 have shown unprecedented remission rates in the relapsed, refractory ALL setting. Cytokine release syndrome (CRS), resulting from the high magnitude of immune activation by these therapies, is the most significant treatment-related toxicity. CRS manifests with fever and malaise and can progress to life-threatening capillary leak with hypoxia and hypotension. The clinical signs of CRS correlate with T-cell activation and high levels of cytokines, including interleukin 6 (IL-6). Tocilizumab, an anti-IL-6 receptor antagonist, is usually effective in the management of severe CRS induced by CAR T cells and has been adopted by most clinical trial programs. With blinatumomab administration, the goal has been to prevent CRS with corticosteroid premedication, disease cytoreduction, and dose adjustments. Collaborative efforts are underway to harmonize the definition and grading system of CRS to allow for better interpretation of toxicities across trials and allow for informed management algorithms.
Assuntos
Algoritmos , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Interleucina-6 , Leucemia-Linfoma Linfoblástico de Células Precursoras , Anticorpos Biespecíficos/uso terapêutico , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , SíndromeRESUMO
PURPOSE: To characterize the impact of graft T-cell composition on outcomes of reduced-intensity conditioned (RIC) allogeneic hematopoietic stem-cell transplantation (alloHSCT) in adults with hematologic malignancies. PATIENTS AND METHODS: We evaluated associations between graft T-cell doses and outcomes in 200 patients who underwent RIC alloHSCT with a peripheral blood stem-cell graft. We then studied 21 alloHSCT donors to identify predictors of optimal graft T-cell content. RESULTS: Higher CD8 cell doses were associated with a lower risk for relapse (adjusted hazard ratio [aHR], 0.43; P = .009) and improved relapse-free survival (aHR, 0.50; P = .006) and overall survival (aHR, 0.57; P = .04) without a significant increase in graft-versus-host disease or nonrelapse mortality. A cutoff level of 0.72 × 10(8) CD8 cells per kilogram optimally segregated patients receiving CD8(hi) and CD8(lo) grafts with differing overall survival (P = .007). Donor age inversely correlated with graft CD8 dose. Consequently, older donors were unlikely to provide a CD8(hi) graft, whereas approximately half of younger donors provided CD8(hi) grafts. Compared with recipients of older sibling donor grafts (consistently containing CD8(lo) doses), survival was significantly better for recipients of younger unrelated donor grafts with CD8(hi) doses (P = .03), but not for recipients of younger unrelated donor CD8(lo) grafts (P = .28). In addition, graft CD8 content could be predicted by measuring the proportion of CD8 cells in a screening blood sample from stem-cell donors. CONCLUSION: Higher graft CD8 dose, which was restricted to young donors, predicted better survival in patients undergoing RIC alloHSCT.
Assuntos
Linfócitos T CD8-Positivos , Seleção do Doador , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Feminino , Citometria de Fluxo , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Recidiva , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Doadores não RelacionadosRESUMO
The long-term prognosis of adult patients with relapsed Philadelphia chromosome-negative acute lymphoblastic lymphoma (ALL) is poor. Allogeneic stem cell transplant in second remission is the only curative approach and is the goal when feasible. There is no standard chemotherapy regimen for relapsed disease, although a few agents are approved for use in this setting. The bispecific CD19-directed CD3 T-cell engager, blinatumomab, has recently been granted accelerated approval by the US Food and Drug Administration for relapsed or refractory disease of B-cell lineage. For patients with relapsed T-cell ALL, nelarabine is available. Liposomal vincristine is also approved for relapsed disease. When selecting combination chemotherapy salvage options, evaluation of the prior treatment and timing of relapse informs treatment decisions. Monoclonal and cellular investigational therapies are quite promising and should be explored in the appropriate patient.