RESUMEN
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.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Antígenos CD19 , Supervivencia sin Enfermedad , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , Estudios Prospectivos , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Linfocitos TRESUMEN
PURPOSE: CD19-targeted chimeric antigen receptor (CAR)-modified T cells demonstrate unprecedented responses in B-cell acute lymphoblastic leukemia (B-ALL); however, relapse remains a substantial challenge. Short CAR T-cell persistence contributes to this risk; therefore, strategies to improve persistence are needed. METHODS: We conducted a pilot clinical trial of a humanized CD19 CAR T-cell product (huCART19) in children and young adults with relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (n = 2), treated in two cohorts: with (retreatment, n = 33) or without (CAR-naive, n = 41) prior CAR exposure. Patients were monitored for toxicity, response, and persistence of huCART19. RESULTS: Seventy-four patients 1-29 years of age received huCART19. Cytokine release syndrome developed in 62 (84%) patients and was grade 4 in five (6.8%). Neurologic toxicities were reported in 29 (39%), three (4%) grade 3 or 4, and fully resolved in all cases. The overall response rate at 1 month after infusion was 98% (100% in B-ALL) in the CAR-naive cohort and 64% in the retreatment cohort. At 6 months, the probability of losing huCART19 persistence was 27% (95% CI, 14 to 41) for CAR-naive and 48% (95% CI, 30 to 64) for retreatment patients, whereas the incidence of B-cell recovery was 15% (95% CI, 6 to 28) and 58% (95% CI, 33 to 77), respectively. Relapse-free survival at 12 and 24 months, respectively, was 84% (95% CI, 72 to 97) and 74% (95% CI, 60 to 90) in CAR-naive and 74% (95% CI, 56 to 97) and 58% (95% CI, 37 to 90) in retreatment cohorts. CONCLUSION: HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-ALL, including after failure of prior CAR T-cell therapy.
Asunto(s)
Antígenos CD19/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Proyectos Piloto , Adulto JovenRESUMEN
PURPOSE: To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen receptor T-cell therapy. METHODS: Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial. RESULTS: The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC (P < .001), but persistence was not different (P = .73). Event-free and overall survival were worse in the HTBC (P = .004, P < .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively (P = .18). CONCLUSION: Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos CD19/inmunología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Resistencia a Antineoplásicos , Inmunoterapia Adoptiva/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Terapia Recuperativa , Adolescente , Adulto , Niño , Preescolar , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/patología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Proyectos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Adulto JovenRESUMEN
Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both cytokine release syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We identified 23 different cytokines that were significantly different between patients with sepsis and CRS. Using elastic net prediction modeling and tree classification, we identified cytokines that were able to classify subjects as having CRS or sepsis accurately. A markedly elevated interferon γ (IFNγ) or a mildly elevated IFNγ in combination with a low IL1ß were associated with CRS. A normal to mildly elevated IFNγ in combination with an elevated IL1ß was associated with sepsis. This combination of IFNγ and IL1ß was able to categorize subjects as having CRS or sepsis with 97% accuracy. As CAR-T therapies become more common, these data provide important novel information to better manage potential associated toxicities.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Sepsis , Niño , Enfermedad Crítica , Síndrome de Liberación de Citoquinas , Humanos , Receptores de Antígenos de Linfocitos T , Sepsis/diagnósticoAsunto(s)
Transdiferenciación Celular , Inmunoterapia/efectos adversos , Linfoma de Células del Manto/terapia , Neoplasias Primarias Secundarias/etiología , Sarcoma/etiología , Adenina/administración & dosificación , Adenina/efectos adversos , Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Transdiferenciación Celular/genética , Transdiferenciación Celular/inmunología , Reprogramación Celular/genética , Reprogramación Celular/inmunología , Reprogramación Celular/fisiología , Terapia Combinada , Epigénesis Genética/fisiología , Epigenoma/inmunología , Reordenamiento Génico , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Humanos , Inmunoterapia/métodos , Ganglios Linfáticos/patología , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/inmunología , Neoplasias Primarias Secundarias/diagnóstico , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Receptores de Antígenos de Linfocitos T/uso terapéutico , Rituximab/administración & dosificación , Rituximab/efectos adversos , Sarcoma/genética , Sarcoma/inmunología , Sarcoma/patología , Trasplante Autólogo/efectos adversos , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Inmunoterapia Adoptiva/métodos , Leucemia Linfocítica Crónica de Células B/terapia , Anciano , Antígenos CD19/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Relación Dosis-Respuesta Inmunológica , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Leucemia Linfocítica Crónica de Células B/inmunología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Receptores Quiméricos de Antígenos/inmunología , Recurrencia , Tasa de Supervivencia , Linfocitos T/inmunología , Linfocitos T/trasplanteRESUMEN
OBJECTIVES: Systemic endothelial activation may contribute to sepsis-associated organ injury, including acute respiratory distress syndrome. We hypothesized that children with extrapulmonary sepsis with versus without acute respiratory distress syndrome would have plasma biomarkers indicative of increased endothelial activation and that persistent biomarker changes would be associated with poor outcome. DESIGN: Observational cohort. SETTING: Academic PICU. PATIENTS: Patients less than 18 years old with sepsis from extrapulmonary infection with (n = 46) or without (n = 54) acute respiratory distress syndrome and noninfected controls (n = 19). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Endothelial (angiopoietin-1, angiopoietin-2, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin) and inflammatory biomarkers (C-reactive protein, interleukin-6, and interleukin-8) were measured from peripheral plasma collected within 3 days (time 1) of sepsis recognition and at 3-6 days (time 2) and 7-14 days (time 3). Time 1 biomarkers and longitudinal measurements were compared for sepsis patients with versus without acute respiratory distress syndrome and in relation to complicated course, defined as greater than or equal to two organ dysfunctions at day 7 or death by day 28. Angiopoietin-2, angiopoietin-2/angiopoietin-1 ratio, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin, endocan, C-reactive protein, interleukin-6, and interleukin-8 were different between sepsis and noninfected control patients at time 1. Among patients with sepsis, those with acute respiratory distress syndrome had higher angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor, vascular cell adhesion molecule, thrombomodulin, endocan, interleukin-6, and interleukin-8 than those without acute respiratory distress syndrome (all p < 0.003). Angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratio remained higher in sepsis with versus without acute respiratory distress syndrome after multivariable analyses. Time 1 measures of angiopoietin-2, angiopoietin-2/-1 ratio, von Willebrand factor, and endocan were indicative of complicated course in all sepsis patients (all area under the receiver operating curve ≥ 0.80). In sepsis without acute respiratory distress syndrome, soluble fms-like tyrosine kinase decreased more quickly and von Willebrand factor and thrombomodulin decreased more slowly in those with complicated course. CONCLUSIONS: Children with extrapulmonary sepsis with acute respiratory distress syndrome had plasma biomarkers indicative of greater systemic endothelial activation than those without acute respiratory distress syndrome. Several endothelial biomarkers measured near sepsis recognition were associated with complicated course, whereas longitudinal biomarker changes yielded prognostic information only in those without sepsis-associated acute respiratory distress syndrome.
Asunto(s)
Endotelio/fisiopatología , Unidades de Cuidado Intensivo Pediátrico/estadística & datos numéricos , Síndrome de Dificultad Respiratoria/epidemiología , Sepsis/epidemiología , Sepsis/fisiopatología , Adolescente , Biomarcadores , Proteínas Sanguíneas/metabolismo , Moléculas de Adhesión Celular/metabolismo , Niño , Preescolar , Femenino , Mortalidad Hospitalaria , Humanos , Lactante , Mediadores de Inflamación , Estudios Longitudinales , Masculino , Puntuaciones en la Disfunción de Órganos , Pronóstico , Síndrome de Dificultad Respiratoria/sangre , Sepsis/sangre , Factores de TiempoRESUMEN
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.
Asunto(s)
Inmunoterapia Adoptiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Adulto , Factores de Edad , Anciano , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Adulto JovenAsunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Inmunoterapia Adoptiva , Terapia Molecular Dirigida , Mieloma Múltiple/inmunología , Mieloma Múltiple/terapia , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Resistencia a Antineoplásicos , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Recurrencia , Retratamiento , Resultado del TratamientoRESUMEN
OBJECTIVE: To characterize the incidence and clinical characteristics of neurotoxicity in the month following CTL019 infusion in children and young adults, to define the relationship between neurotoxicity and cytokine release syndrome (CRS), and to identify predictive biomarkers for development of neurotoxicity following CTL019 infusion. METHODS: We analyzed data on 51 subjects, 4 to 22 years old, who received CTL019, a chimeric antigen receptor-modified T-cell therapy against CD19, between January 1, 2010 and December 1, 2015 through a safety/feasibility clinical trial (NCT01626495) at our institution. We recorded incidence of significant neurotoxicity (encephalopathy, seizures, and focal deficits) and CRS, and compared serum cytokine levels in the first month postinfusion between subjects who did and did not develop neurotoxicity. RESULTS: Neurotoxicity occurred in 23 of 51 subjects (45%, 95% confidence interval = 31-60%) and was positively associated with higher CRS grade (p < 0.0001) but was not associated with demographic characteristics or prior oncologic treatment history. Serum interleukin (IL)-2, IL-15, soluble IL-4, and hepatocyte growth factor concentrations were higher in subjects with neurotoxicity than those with isolated CRS. Differences in peak levels of select cytokines including IL-12 and soluble tumor necrosis factor receptor-1 within the first 3 days were seen in subjects with neurotoxicity. INTERPRETATION: Neurotoxicity is common after CTL019 infusion in children and young adults, and is associated with higher CRS grade. Differences in serum cytokine profiles between subjects with neurotoxicity and those with isolated CRS suggest unique pathophysiological mechanisms. Serum cytokine profiles in the first 3 days postinfusion may help identify children and young adults at risk for neurotoxicity, and may provide a foundation for investigation into potential mitigation strategies. Ann Neurol 2018;84:537-546.
Asunto(s)
Antígenos CD19/metabolismo , Síndromes de Neurotoxicidad/diagnóstico , Síndromes de Neurotoxicidad/metabolismo , Receptores de Antígenos de Linfocitos T/administración & dosificación , Receptores de Antígenos de Linfocitos T/metabolismo , Adolescente , Niño , Preescolar , Estudios de Cohortes , Citocinas/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
Chimeric antigen receptor (CAR)-modified T cells are being investigated in many settings, including classical Hodgkin lymphoma (cHL). The unique biology of cHL, characterized by scant Hodgkin and Reed-Sternberg (HRS) cells within an immunosuppressive tumor microenvironment (TME), may pose challenges for cellular therapies directly targeting antigens expressed on HRS cells. We hypothesized that eradicating CD19+ B cells within the TME and the putative circulating CD19+ HRS clonotypic cells using anti-CD19-directed CAR-modified T cells (CART19) may indirectly affect HRS cells, which do not express CD19. Here we describe our pilot trial using CART19 in patients with relapsed or refractory cHL. To limit potential toxicities, we used nonviral RNA CART19 cells, which are expected to express CAR protein for only a few days, as opposed to CART19 generated by viral vector transduction, which expand in vivo and retain CAR expression. All 5 enrolled patients underwent successful manufacturing of nonviral RNA CART19, and 4 were infused with protocol-specified cell dose. There were no severe toxicities. Responses were seen, but these were transient. To our knowledge, this is the first CART19 clinical trial to use nonviral RNA gene delivery. This trial was registered at www.clinicaltrials.gov as #NCT02277522 (adult) and #NCT02624258 (pediatric).