RESUMEN
AIM: To evaluate long-term durability of blinatumomab, a BiTE® (bispecific T-cell engager) molecule, in adults with relapsed/refractory (R/R) Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukaemia (ALL). METHODS: In this final analysis of an open-label, single-arm, phase 2, multicentre ALCANTARA study (NCT02000427), adults (age ≥18 years) with Ph+ ALL who had relapsed or were refractory to at least one TKI were included. The primary endpoint was the proportion of patients who achieved complete remission (CR)/CR with partial haematologic recovery (CRh) during the first two cycles of blinatumomab treatment. RESULTS: The final analysis included 45 patients who completed the study between 3rd January 2014 and 6th January 2017, of which 16 (35.6%; 95% CI, 21.9%-51.2%) achieved CR/CRh within the first two blinatumomab cycles. After a median follow-up of 16.1 months, median relapse-free survival (RFS) was 6.8 (95% CI, 4.4-not estimable [NE]) months. Median overall survival (OS) was 9.0 (95% CI, 5.7-13.5) months with a median follow-up of 25.1 months. Median OS in patients with CR (19.8 [95% CI, 12.1-NE] months) was greater than in those without CR (6.0 [95% CI, 2.9-7.1] months). Of 16 patients with CR/CRh, 14 achieved complete minimal residual disease (MRD) response; the median duration of complete MRD response was 9.7 (95% CI, 5.2-NE) months. Treatment-related adverse events were consistent with those previously reported. CONCLUSION: Long-term durability of responses to blinatumomab was demonstrated in patients with R/R Ph+ ALL.
Asunto(s)
Anticuerpos Biespecíficos/uso terapéutico , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Pronóstico , Terapia Recuperativa , Tasa de Supervivencia , Adulto JovenRESUMEN
Novel therapies are needed for children with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific T-cell engager immunotherapy that simultaneously binds to CD3-positive cytotoxic T cells and CD19-positive B cells and redirects the patient's T cells to lyse malignant and normal B cells. We conducted an open-label phase 1b study to determine the safety, pharmacokinetics, efficacy, and recommended dose of blinatumomab in Japanese children with R/R B-cell precursor ALL. Patients received induction blinatumomab for 4 weeks (5 µg/m2/day week 1; 15 µg/m2/day weeks 2-4), followed by a 2-week treatment-free interval (6-week cycle). In subsequent cycles, patients received blinatumomab 15 µg/m2/day. The primary end point was the incidence of dose-limiting toxicities. Nine patients received blinatumomab. Since no dose-limiting toxicities were reported, the maximum tolerated dose was 5 µg/m2/day for week 1, followed by 15 µg/m2/day weeks 2-4 (5-15 µg/m2/day, the global recommended dose of blinatumomab). All patients had ≥ 1 grade ≥ 3 adverse events; 89% had grade ≥ 3 treatment-related adverse events. M1 remission rate within the first two cycles of treatment was 56%; one patient had a minimal residual disease response. Consistent with global studies, blinatumomab appeared to be safe with preliminary evidence of efficacy in Japanese children with R/R B-cell precursor ALL.
Asunto(s)
Anticuerpos Biespecíficos/administración & dosificación , Antineoplásicos/administración & dosificación , Linfocitos B , Inmunoterapia , Linfocitos T , Adolescente , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/metabolismo , Antineoplásicos/efectos adversos , Antineoplásicos/metabolismo , Pueblo Asiatico , Linfocitos B/metabolismo , Niño , Esquema de Medicación , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Inducción de Remisión , Seguridad , Linfocitos T/metabolismo , Resultado del TratamientoAsunto(s)
Anticuerpos Biespecíficos/uso terapéutico , Antineoplásicos/uso terapéutico , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , RecurrenciaRESUMEN
Adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T-cell engager (BiTE) immuno-oncology therapy with dual specificity for CD19 and CD3 that redirects patients' CD3-positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open-label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B-precursor ALL. Patients received 9 µg/day blinatumomab during week 1 and 28 µg/day during weeks 2-4, with a 2-week treatment-free interval (6-week cycle); patients received 28 µg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose-limiting toxicities (DLT) in phase 1b and complete remission (CR)/CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5-6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL.
Asunto(s)
Anticuerpos Biespecíficos/administración & dosificación , Linfoma de Células B/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/sangre , Anticuerpos Biespecíficos/farmacocinética , Antígenos CD19/genética , Antígenos CD19/inmunología , Linfocitos B/patología , Complejo CD3/genética , Complejo CD3/inmunología , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Interferón gamma/sangre , Estimación de Kaplan-Meier , Linfoma de Células B/sangre , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Neoplasia Residual/sangre , Neoplasia Residual/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inducción de Remisión , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: A single-arm, phase 2 trial demonstrated the efficacy and safety of blinatumomab, a bispecific T-cell-engaging antibody construct, in patients with relapsed/refractory (r/r) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), a rare hematologic malignancy with limited treatment options. This study compared outcomes with blinatumomab with those of a historical control treated with the standard of care (SOC). METHODS: The blinatumomab trial enrolled adult patients with Ph+ ALL who were r/r to at least 1 second-generation tyrosine kinase inhibitor (n = 45). Propensity score analysis (PSA) was used to compare outcomes with blinatumomab with those of an external cohort of similar patients receiving SOC chemotherapy (n = 55). The PSA mitigated confounding variables between studies by adjusting for imbalances in the age at diagnosis and start of treatment, sex, duration from diagnosis to most recent treatment, prior allogeneic hematopoietic stem cell transplantation, prior salvage therapy, and number of salvage therapies. Bayesian data augmentation was applied to improve power to 80% with data from a phase 3 blinatumomab study in r/r Philadelphia chromosome-negative ALL. RESULTS: In the PSA, the rate of complete remission or complete remission with partial hematologic recovery was 36% for blinatumomab and 25% for SOC, and this resulted in an odds ratio of 1.54 (95% confidence interval [CI], 0.61-3.89) or 1.70 (95% credible interval [CrI], 0.94-2.94) with Bayesian data augmentation. Overall survival favored blinatumomab over SOC, with a hazard ratio of 0.81 (95% CI, 0.57-1.14) or 0.77 (95% CrI, 0.61-0.96) with Bayesian data augmentation. CONCLUSIONS: These results further support blinatumomab as a treatment option for patients with r/r Ph+ ALL.