RESUMEN
OBJECTIVE: Venetoclax in combination with obinutuzumab has significantly improved efficacy versus immunochemotherapy (progression-free survival) in patients with chronic lymphocytic leukaemia who have not received prior treatment. The objective of this study was to evaluate its efficiency in Spain using a cost-utility analysis. METHOD: Using a partitioned-survival analysis model adapted to the Spanish context and based on three health states (progression-free survival, survival after progression, and death), a simulation of the evolution of patients who were candidates for initiating first-line treatment was conducted for a lifetime time horizon. Venetoclax in combination with obinutuzumab was compared to the most commonly used therapeutic options for these patients at the time of study design: chlorambucil in combination with obinutuzumab, ibrutinib, fludarabine in combination with cyclophosphamide and rituximab, and bendamustine in combination with rituximab. In order to estimate survival curves, efficacy data were derived from the CLL14 trial and a network meta- analysis. The analysis was conducted from the perspective of the Spanish National Healthcare System and included direct healthcare costs (i.e. pharmacological costs and their administration), and those associated with the management of the disease and adverse events. The resource use was validated by an expert group. Quality of life data were used to estimate the quality-adjusted life years obtained for each alternative. A threshold of 25,000/quality-adjusted life years was used. The robustness of the model was evaluated using deterministic and probabilistic sensitivity analyses. RESULTS: Venetoclax in combination with obinutuzumab was shown to be a dominant alternative compared to the rest of the treatment alternatives, with a lower cost per patient (-67,869 compared to chlorambucil in combination with obinutuzumab, -375,952 compared to ibrutinib, -61,996 compared to fludarabine in combination with cyclophosphamide and rituximab, and - 77,398 compared to bendamustine in combination with rituximab). It also had a greater gain in quality-adjusted life years (0.551 quality-adjusted life years gained compared to chlorambucil in combination with obinutuzumab and ibrutinib, 1.639 quality-adjusted life years gained compared to fludarabine in combination with cyclophosphamide and rituximab, and 1.186 quality-adjusted life years gained compared to bendamustine in combination with rituximab). Between 68% and 85% of the simulations performed in the sensitivity analysis showed that venetoclax in combination with obinutuzumab had lower costs and more quality-adjusted life years gained. CONCLUSIONS: Venetoclax in combination with obinutuzumab is an efficient and dominant alternative for treating previously untreated patients with chronic lymphocytic leukaemia compared to the available alternatives and from the perspective of the Spanish National Health System.
OBJETIVO: Venetoclax en combinación con obinutuzumab ha mostrado frente a la inmunoquimioterapia mejoras significativas en términos de eficacia (supervivencia libre de progresión) en pacientes con leucemia infocítica crónica que no han recibido tratamiento previo. El objetivo de este estudio fue evaluar su eficiencia en España a partir de un análisis de coste- utilidad.Método: A partir de un modelo de análisis de la supervivencia adaptado al contexto español y basado en tres estados de salud (supervivencia libre de progresión, supervivencia tras progresión y muerte), se llevó a cabo una simulación de la evolución de los pacientes candidatos a iniciar una primera línea de tratamiento para un horizonte temporal de toda la vida. Venetoclax en combinación con obinutuzumab se comparó frente a las opciones terapéuticas más utilizadas para estos pacientes en el momento del diseño del estudio: clorambucilo en combinación con obinutuzumab, ibrutinib, fludarabina en combinación con ciclofosfamida y rituximab, y bendamustina en combinación con rituximab. Los datos de eficacia para estimar las curvas de supervivencia fueron derivados del estudio CLL14 y de un metaanálisis en red. El análisis consideró la perspectiva del Sistema Nacional de Salud incluyendo los costes sanitarios directos, en concreto los farmacológicos y su administración, y los asociados al manejo de la enfermedad y acontecimientos adversos. El uso de recursos fue validado por un grupo de expertos. Se emplearon datos de calidad de vida para estimar los años de vida ajustados por calidad obtenidos para cada alternativa. Se consideró un umbral de 25.000 /años de vida ajustados por calidad. La robustez del modelo se evaluó mediante análisis de sensibilidad determinísticos y probabilísticos. RESULTADOS: Venetoclax en combinación con obinutuzumab se mostró como una alternativa dominante frente al resto de alternativas de tratamiento, con un menor coste por paciente (67.869 frente a clorambucilo en combinación con obinutuzumab, 375.952 frente a ibrutinib, 61.996 frente a ludarabina en combinación con ciclofosfamida y rituximab, y 77.398 frente a bendamustina en combinación con rituximab) y una mayor ganancia en años de vida ajustados por calidad (0,551 años de vida ajustados por calidad ganados frente a clorambucilo en combinación con obinutuzumab e ibrutinib, 1,639 años de vida ajustados por calidad ganados frente a fludarabina en combinación con ciclofosfamida y rituximab, y 1,186 años de vida ajustados por calidad ganados frente a bendamustina en combinación con rituximab). Entre el 68% y el 85% de las simulaciones realizadas en el análisis de sensibilidad mostraban a venetoclax en combinación con obinutuzumab con un menor coste y un mayor número de años de vida ajustados por calidad ganados. CONCLUSIONES: Venetoclax en combinación con obinutuzumab se muestra como una alternativa eficiente y dominante como tratamiento de pacientes con leucemia linfocítica crónica no tratados previamente frente a las alternativas disponibles y desde la perspectiva del Sistema Nacional de Salud.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes , Clorambucilo/efectos adversos , Clorambucilo/uso terapéutico , Análisis Costo-Beneficio , Ciclofosfamida , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Calidad de Vida , Rituximab/uso terapéutico , España , SulfonamidasRESUMEN
It has been postulated that monitoring measurable residual disease (MRD) could be used as a surrogate marker of progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients after treatment with immunochemotherapy regimens. In this study, we analyzed the outcome of 84 patients at 3 years of follow-up after first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) induction followed by 36 months of rituximab maintenance thearpy. MRD was assessed by a quantitative four-color flow cytometry panel with a sensitivity level of 10-4 Eighty out of 84 evaluable patients (95.2%) achieved at least a partial response or better at the end of induction. After clinical evaluation, 74 patients went into rituximab maintenance and the primary endpoint was assessed in the final analysis at 3 years of follow-up. Bone marrow (BM) MRD analysis was performed after the last planned induction course and every 6 months in cases with detectable residual disease during the 36 months of maintenance therapy. Thirty-seven patients (44%) did not have detectable residual disease in the BM prior to maintenance therapy. Interestingly, 29 patients with detectable residual disease in the BM after induction no longer had detectable disease in the BM following maintenance therapy. After a median followup of 6.30 years, the median overall survival (OS) and PFS had not been reached in patients with either undetectable or detectable residual disease in the BM, who had achieved a complete response at the time of starting maintenance therapy. Interestingly, univariate analysis showed that after rituximab maintenance OS was not affected by IGHV status (mutated vs unmutated OS: 85.7% alive at 7.2 years vs 79.6% alive at 7.3 years, respectively). As per protocol, 15 patients (17.8%), who achieved a complete response and undetectable peripheral blood and BM residual disease after four courses of induction, were allowed to stop fludarabine and cyclophosphamide and complete two additional courses of rituximab and continue with maintenance therapy for 18 cycles. Surprisingly, the outcome in this population was similar to that observed in patients who received the full six cycles of the induction regimen. These data show that, compared to historic controls, patients treated with FCR followed by rituximab maintenance have high-quality responses with fewer relapses and improved OS. The tolerability of this regime is favorable. Furthermore, attaining an early undetectable residual disease status could shorten the duration of chemoimmunotherapy, reducing toxicities and preventing long-term side effects. The analysis of BM MRD after fludarabine-based induction could be a powerful predictor of post-maintenance outcomes in patients with CLL undergoing rituximab maintenance and could be a valuable tool to identify patients at high risk of relapse, influencing further treatment strategies. This trial is registered with EudraCT n. 2007-002733-36 and ClinicalTrials.gov Identifier: NCT00545714.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasia Residual/diagnóstico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/etiología , Leucemia Linfocítica Crónica de Células B/mortalidad , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Pronóstico , Inducción de Remisión , Rituximab/administración & dosificación , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
BACKGROUND AND OBJECTIVE: Classification of acute myeloid leukemia (AML) based on karyotype provides an important tool for therapy selection. There are two standardized criteria for the classification of patients into groups of cytogenetic risk. One of them was established by the UK Medical Research Council (MRC) and the other by the US Southwest Oncology Group (SWOG). They define three and four cytogenetic categories, respectively. The aim of this study was to define the frequency of chromosomal abnormalities and to compare the groups of cytogenetic risk in patients with AML who received intensive chemotherapy, as a guide for future investigations. PATIENTS AND METHOD: Chromosomal analysis was performed using standard techniques on bone marrow samples from 146 adult patients between January 1995 and December 2001. Kaplan-Meier and Cox's regression models were used for statistical analysis. RESULTS: Cytogenetic results were obtained in 142 patients. The incidence of a complex karyotype and del(5q) was higher in patients with secondary AML. Classification by cytogenetic risk was performed in 105 treated patients. The classification using both models was identical in 82 patients and different in 23. Results in univariate analysis were significant for EFS (p < 0.000 for MRC and p < 0.02 for SWOG). Nevertheless, only the MRC model was significant for OS (p < 0.001). In multivariate analysis, age and cytogenetics were the only variables having prognostic value. CONCLUSIONS: There was some relation between secondary AML, advanced age and adverse karyotype. Both classification models have a great prognostic value. In our experience, codification according to MRC criteria appears to be more effective to detect patients at high risk of relapse.