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Among the different biomarkers predicting response in chronic lymphocytic leukemia (CLL), the most influential parameters are the mutational status of the IGHV genes and the presence of TP53 gene disruptions. Nevertheless, these important assessments are not readily available in most centers dealing with CLL patients. To provide this molecular testing across the country, the Spanish Cooperative Group on CLL (GELLC) established a network of four analytical reference centers. A total of 2153 samples from 256 centers were analyzed over a period of 30 months. In 9% of the patients, we found pathological mutations in the TP53 gene, whereas 48.96% were classified as IGHV unmutated. Results of the satisfaction survey of the program showed a Net Promoter Score of 85.15. Building a national network for molecular testing in CLL allowed the CLL population a broad access to complex biomarkers analysis that should translate into a more accurate and informed therapeutic decision-making.
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Servicios de Laboratorio Clínico/organización & administración , Análisis Mutacional de ADN , Cadenas Pesadas de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Derivación y Consulta/organización & administración , Proteína p53 Supresora de Tumor/genética , Biomarcadores de Tumor/genética , Servicios de Laboratorio Clínico/provisión & distribución , Estudios de Cohortes , Redes Comunitarias/organización & administración , Análisis Mutacional de ADN/métodos , Humanos , Ciencia de la Implementación , Colaboración Intersectorial , Satisfacción en el Trabajo , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/epidemiología , Técnicas de Diagnóstico Molecular/métodos , Mutación , Pronóstico , España/epidemiología , Encuestas y CuestionariosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antivirales/uso terapéutico , COVID-19/mortalidad , Leucemia Linfocítica Crónica de Células B/mortalidad , SARS-CoV-2/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/complicaciones , COVID-19/terapia , COVID-19/virología , Manejo de la Enfermedad , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/terapia , Leucemia Linfocítica Crónica de Células B/virología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , SARS-CoV-2/aislamiento & purificación , Tasa de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
Background: BTK inhibitors have been concurrently administered with anti-CD20 monoclonal antibodies (mAbs) in chronic lymphocytic leukemia (CLL). However, the optimal regimen for combining these two drugs remains pending. Methods: This multi-center phase 2 study aimed to analyze whether consolidation with ofatumumab improved the response in patients with CLL receiving front-line treatment with ibrutinib. Patients received 12 cycles of ibrutinib monotherapy. Those who achieved CR after this induction were maintained on ibrutinib. Conversely, those who did not attain CR continued with ibrutinib in addition to a consolidation, which involved 7 doses of ofatumumab. The primary objective was the complete response (CR) rate at cycle 20. This study is registered within the EU Clinical Trials Register (EudraCT 2016-004937-26). Findings: Between September 8, 2017, and May 21, 2018, 84 patients (median age, 69 years) were included. After completion of 12 cycles of ibrutinib (n = 80), 4 patients (5%) were in CR, 67 (84%) in partial response (PR), and 6 patients (7%) had a PR with lymphocytosis (PRL). After consolidation with ofatumumab, 20 patients improved the response from PR to CR and 6 patients with PRL obtained a PR. Seventy-one patients (85%) completed 20 cycles of treatment, with a CR rate of 24/71 (34%). According to the intention-to-treat analysis at cycle 20, the ORR was 69/84 (82.2%), with a CRR of 24/84 (28.6%). Progression-free survival and overall survival at 48-months were 89.9% (CI: 82.4-95.5) and 92.2% (CI: 85.3-97.1), respectively. Interpretation: These findings underscore the potential for a consolidation strategy in CLL, wherein the addition of a mAb in patients with low tumor burden might enhance the quality of the response. Funding: The study was funded by Janssen that also supplied ibrutinib, whereas ofatumumab was supplied by Novartis.
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UNLABELLED: The prognosis for fit patients with mantle cell lymphoma has improved with intensive strategies. Currently, the role of maintenance/consolidation approaches is being tested as relapses continue to appear. In this trial we evaluated the feasibility, safety and efficacy of rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine followed by consolidation with (90)Y-ibritumomab tiuxetan. Patients received six cycles followed by a single dose of (90)Y-ibritumomab tiuxetan. Thirty patients were enrolled; their median age was 59 years. Twenty-four patients finished the induction treatment, 23 achieved complete remission (77%, 95% confidence interval 60-93) and one patient had progressive disease (3%). Eighteen patients (60%), all in complete remission, received consolidation therapy. In the intent-to-treat population, failure-free, progression-free and overall survival rates at 4 years were 40% (95% confidence interval 20.4-59.6), 52% (95% confidence interval 32.4-71.6) and 81% (95% confidence interval 67.28-94.72), respectively. For patients who received consolidation, failure-free and overall survival rates were 55% (95% confidence interval 31.48-78.52) and 87% (95% confidence interval 70-100), respectively. Hematologic toxicity was significant during induction and responsible for one death (3.3%). After consolidation, grade 3-4 neutropenia and thrombocytopenia were observed in 72% and 83% of patients, with a median duration of 5 and 12 weeks, respectively. Six (20%) patients died, three due to secondary malignancies (myelodysplastic syndrome and bladder and rectum carcinomas). In conclusion, in our experience, rituximab-hyperCVAD alternated with rituximab-methotrexate-cytarabine and followed by consolidation with (90)Y-ibritumomab tiuxetan was efficacious although less feasible than expected. The unacceptable toxicity observed, especially secondary malignancies, advise against the use of this strategy. TRIAL REGISTRATION: clinical.gov identifier: NCT2005-004400-37.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/epidemiología , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Linfoma de Células del Manto/diagnóstico , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Rituximab , Resultado del TratamientoRESUMEN
The SRealCLL study aimed to obtain real-world evidence on the clinical characteristics and treatment patterns of patients with chronic lymphocytic leukemia (CLL) using natural language processing (NLP). Electronic health records (EHRs) from seven Spanish hospitals (January 2016-December 2018) were analyzed using EHRead® technology, based on NLP and machine learning. A total of 534 CLL patients were assessed. No treatment was detected in 270 (50.6%) patients (watch-and-wait, W&W). First-line (1L) treatment was identified in 230 (43.1%) patients and relapsed/refractory (2L) treatment was identified in 58 (10.9%). The median age ranged from 71 to 75 years, with a uniform male predominance (54.8-63.8%). The main comorbidities included hypertension (W&W: 35.6%; 1L: 38.3%; 2L: 39.7%), diabetes mellitus (W&W: 24.4%; 1L: 24.3%; 2L: 31%), cardiac arrhythmia (W&W: 16.7%; 1L: 17.8%; 2L: 17.2%), heart failure (W&W 16.3%, 1L 17.4%, 2L 17.2%), and dyslipidemia (W&W: 13.7%; 1L: 18.7%; 2L: 19.0%). The most common antineoplastic treatment was ibrutinib in 1L (64.8%) and 2L (62.1%), followed by bendamustine + rituximab (12.6%), obinutuzumab + chlorambucil (5.2%), rituximab + chlorambucil (4.8%), and idelalisib + rituximab (3.9%) in 1L and venetoclax (15.5%), idelalisib + rituximab (6.9%), bendamustine + rituximab (3.5%), and venetoclax + rituximab (3.5%) in 2L. This study expands the information available on patients with CLL in Spain, describing the diversity in patient characteristics and therapeutic approaches in clinical practice.
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Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with an aggressive behavior, characterized by the t(11;14)(q13;q32). Several secondary genetic abnormalities with a potential role in the oncogenic process have been described. Studies of large MCL series using conventional cytogenetics, and correlating with proliferation and survival, are scarce. We selected 145 MCL cases at diagnosis, displaying an aberrant karyotype, from centers belonging to the Spanish Cooperative Group for Hematological Cytogenetics. Histological subtype, proliferative index and survival data were ascertained. Combined cytogenetic and molecular analyses detected CCND1 translocations in all cases, mostly t(11;14)(q13;q32). Secondary aberrations were present in 58% of patients, the most frequent being deletions of 1p, 13q and 17p, 10p alterations and 3q gains. The most recurrent breakpoints were identified at 1p31-32, 1p21-22, 17p13, and 1p36. Aggressive blastoid/pleomorphic variants displayed a higher karyotypic complexity, a higher frequency of 1p and 17p deletions and 10p alterations, a higher proliferation index and poor survival. Gains of 3q and 13q and 17p13 losses were associated with reduced survival times. Interestingly, gains of 3q and 17p losses added prognostic significance to the morphology in a multivariate analysis. Our findings confirm previous observations indicating that proliferation index, morphology and several secondary genetic alterations (3q gains and 13q and 17p losses) have prognostic value in patients with MCL. Additionally, we observed that 3q gains and 17p losses detected by conventional cytogenetics are proliferation-independent prognostic markers indicating poor outcome.
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Aberraciones Cromosómicas , Linfoma de Células del Manto/genética , Adulto , Anciano , Anciano de 80 o más Años , Procesos de Crecimiento Celular/genética , Distribución de Chi-Cuadrado , Estudios de Cohortes , Ciclina D1/genética , Análisis Citogenético , Femenino , Reordenamiento Génico , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/patología , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: Mechanisms driving the progression of chronic lymphocytic leukemia (CLL) from its early stages are not fully understood. The acquisition of molecular changes at the time of progression has been observed in a small fraction of patients, suggesting that CLL progression is not mainly driven by dynamic clonal evolution. In order to shed light on mechanisms that lead to CLL progression, we investigated longitudinal changes in both the genetic and immunological scenarios. METHODS: We performed genetic and immunological longitudinal analysis using paired primary samples from untreated CLL patients that underwent clinical progression (sampling at diagnosis and progression) and from patients with stable disease (sampling at diagnosis and at long-term asymptomatic follow-up). RESULTS: Molecular analysis showed limited and non-recurrent molecular changes at progression, indicating that clonal evolution is not the main driver of clinical progression. Our analysis of the immune kinetics found an increasingly dysfunctional CD8+ T cell compartment in progressing patients that was not observed in those patients that remained asymptomatic. Specifically, terminally exhausted effector CD8+ T cells (T-betdim/-EomeshiPD1hi) accumulated, while the the co-expression of inhibitory receptors (PD1, CD244 and CD160) increased, along with an altered gene expression profile in T cells only in those patients that progressed. In addition, malignant cells from patients at clinical progression showed enhanced capacity to induce exhaustion-related markers in CD8+ T cells ex vivo mainly through a mechanism dependent on soluble factors including IL-10. CONCLUSIONS: Altogether, we demonstrate that the interaction with the immune microenvironment plays a key role in clinical progression in CLL, thereby providing a rationale for the use of early immunotherapeutic intervention.
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Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79-7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.
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Betacoronavirus , Infecciones por Coronavirus/patología , Leucemia Linfocítica Crónica de Células B/complicaciones , Neumonía Viral/patología , Adenina/análogos & derivados , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , COVID-19 , Comorbilidad , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/mortalidad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pandemias , Piperidinas , Neumonía Viral/diagnóstico , Neumonía Viral/mortalidad , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Estudios Retrospectivos , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
Minimal residual disease (MRD) assessment is an important endpoint in the treatment of chronic lymphocytic leukaemia (CLL). It is highly predictive of prolonged progression-free survival (PFS) and overall survival and could be considered a surrogate for PFS in the context of chemoimmunotherapy based treatment. Evaluation of MRD level by flow cytometry or molecular techniques in the era of the new BCR and Bcl-2 targeted inhibitors could identify the most cost-effective and durable treatment sequencing. A therapeutic approach guided by the level of MRD might also determine which patients would benefit from an early stop or consolidation therapy. In this review, we discuss the different MRD methods of analysis, which source of tumour samples must be analysed, the future role of the detection of circulating tumour DNA, and the potential role of MRD negativity in clinical practice in the modern era of CLL therapy.
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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 , Neoplasia Residual/tratamiento farmacológico , Humanos , PronósticoRESUMEN
Chronic lymphocytic leukemia (CLL) is an incurable lymphoproliferative disorder with a heterogeneous genetic and clinical course. Two kinase inhibitors, ibrutinib and idelalisib, have demonstrated achievement of complete and durable remissions in relapse/refractory genetically unselected CLL patients. We present a case of relapsed CLL with extensive disease and hourglass deformity of urinary bladder as a result of the compression of two extraperitoneal paravesical soft tissue bulky masses, with excellent response to sequential kinase inhibitor therapy.
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Hairy cell leukemia (HCL) is a lymphoproliferative B-cell disorder characterized by pancytopenia, splenomegaly, and characteristic cytoplasmic hairy projections. Precise diagnosis is essential in order to differentiate classic forms from HCL variants, such as the HCL-variant and VH4-34 molecular variant, which are more resistant to available treatments. The current standard of care is treatment with purine analogs (PAs), such as cladribine or pentostatin, which provide a high rate of long-lasting clinical remissions. Nevertheless, ~30%-40% of the patients relapse, and moreover, some of these are difficult-to-treat refractory cases. The use of the monoclonal antibody rituximab in combination with PA appears to produce even higher responses, and it is often employed to minimize or eliminate residual disease. Currently, research in the field of HCL is focused on identifying novel therapeutic targets and potential agents that are safe and can universally cure the disease. The discovery of the BRAF mutation and progress in understanding the biology of the disease has enabled the scientific community to explore new therapeutic targets. Ongoing clinical trials are assessing various treatment strategies such as the combination of PA and anti-CD20 monoclonal antibodies, recombinant immunotoxins targeting CD22, BRAF inhibitors, and B-cell receptor signal inhibitors.
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Vascular endothelial growth factor (VEGF)-mediated angiogenesis contributes to the pathogenesis of B-cell chronic lymphocytic leukaemia (CLL). We investigated the impact of VEGFA gene diversity on the clinical outcome of patients with this disease. A VEGFA haplotype conformed by positions rs699947 (-1540C>A), rs833061 (-460T>C) and rs2010963 (405C>G) and two additional single-nucleotide polymorphisms (SNPs), rs3025039 (936C>T) and rs25648 (1032C>T), were analysed in 239 patients at the time of their CLL diagnosis. Here, we showed that homozygosity for rs699947/rs833061/rs2010963 ACG haplotype (ACG+/+ genotype) correlated with a reduced survival in CLL patients (ACG+/+ vs other genotypes: HRâ=â2.3, pâ=â0.002; recessive model). In multivariate analysis, the ACG+/+ genotype was identified as a novel independent prognostic factor (HRâ=â2.1, pâ=â0.005). Moreover, ACG homozygosity subdivided patients with CLL with otherwise indolent parameters into prognostic subgroups with different outcomes. Specifically, patients carrying the ACG+/+ genotype with mutated IgVH, very low and low-risk cytogenetics, initial clinical stage, CD38 negative status or early age at diagnosis showed a shorter survival (ACG+/+ vs other genotypes: HRâ=â3.5, pâ=â0.035; HRâ=â3.4, pâ=â0.001; HRâ=â2.2, pâ=â0.035; HRâ=â3.4, pâ=â0.0001 and HRâ=â3.1, pâ=â0.009, respectively). In conclusion, VEGFA ACG+/+ genotype confers an adverse effect in overall survival in CLL patients with an indolent course of the disease. These observations support the biological and prognostic implications of VEGFA genetics in CLL.
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Biomarcadores de Tumor/genética , Leucemia Linfocítica Crónica de Células B/genética , Polimorfismo de Nucleótido Simple , Factor A de Crecimiento Endotelial Vascular/genética , Anciano , Estudios de Casos y Controles , Femenino , Haplotipos , Homocigoto , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
OBJECTIVES: We evaluated the cost-effectiveness of rituximab added to the chemotherapy regimen of fludarabine plus cyclophosphamide (R-FC) versus fludarabine plus cyclophosphamide (FC) for the treatment of patients with previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL). METHODS: Two Markov models were built, using published results on progression-free survival (PFS) in patients receiving first- or second-line therapy with R-FC vs FC, rates of disease progression and mortality rates in Spain. Patient-elicited utilities were applied to PFS and progressed health states. The cost of drugs, supportive care, and quality-adjusted life years (QALY) were estimated over a 10-year period. Univariate and probabilistic (Monte Carlo) sensitivity analyses were performed. RESULTS: The addition of rituximab to chemotherapy in first- and second-line therapy increased life-years gained (LYG) and QALYs compared with chemotherapy. The incremental cost per LYG and QALY gained was 20,703 and 19,343 for first-line treatment and was 23,183 and 24,781 for second-line treatment. CONCLUSION: In patients with previously untreated or relapsed/refractory CLL, the addition of rituximab to the FC regimen increased life expectancy and quality-adjusted life expectancy. In both types of patient, the treatment was cost-effective.
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Anticuerpos Monoclonales de Origen Murino/economía , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Ciclofosfamida/economía , Leucemia Linfocítica Crónica de Células B/economía , Vidarabina/análogos & derivados , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Análisis Costo-Beneficio , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Costos de la Atención en Salud , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Cadenas de Markov , Modelos Teóricos , Método de Montecarlo , Años de Vida Ajustados por Calidad de Vida , Rituximab , Terapia Recuperativa/economía , España , Vidarabina/administración & dosificación , Vidarabina/economíaRESUMEN
OBJECTIVE: Despite a fludarabine-based treatment is the first choice of therapy in chronic lymphocytic leukemia (CLL), not all patients achieve a partial or complete response and some of them develop autoimmune manifestations. The aim of this study was to evaluate the influence of CD154 on these adverse effects because CD154 is involved in both B-cell survival and autoimmunity. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMC) from 36 patients with CLL were cultured in vitro with fludarabine or 2-chlorodeoxyadenosine for 24, 48, and 72 hours. RESULTS: Seven patients (19.4%) presented CD154 expression in PBMC cultured with purine analogues in vitro for 24 and/or 48 hours, while no expression was found when cultured in media alone. These seven patients showed a decreased apoptotic rate in vitro after purine analogues compared with those patients who did not express CD154 (p = 0.01 for fludarabine; p < 0.001 for 2-chlorodeoxyadenosine). CD154 expression was found to have prognostic value for response to fludarabine in vivo and was associated with the development of autoimmune manifestations (odds ratio = 25; 95% confidence interval = 3.5-166.7; p < 0.001). CONCLUSION: Our preliminary results suggest that CD154 expression in CLL patients, which may be induced by purine analogues, is associated with resistance to fludarabine and with development of autoimmune manifestations.
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Ligando de CD40/biosíntesis , Cladribina/farmacología , Vidarabina/análogos & derivados , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Autoinmunidad/efectos de los fármacos , Células Cultivadas , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud/métodos , Pronóstico , Vidarabina/farmacologíaRESUMEN
PURPOSE: The addition of monoclonal antibodies to chemotherapy has significantly improved treatment of chronic lymphocytic leukemia (CLL). Based on excellent results with the chemotherapy-only regimen fludarabine, cyclophosphamide, and mitoxantrone (FCM), we built a new chemoimmunotherapy combination--rituximab plus FCM (R-FCM). We report a phase II clinical trial consisting of an initial treatment with R-FCM followed by rituximab maintenance. PATIENTS AND METHODS: Seventy-two untreated CLL patients age 70 years or younger received rituximab 500 mg/m(2) on day 1 (375 mg/m(2) the first cycle), fludarabine 25 mg/m(2) IV on days 1 to 3, cyclophosphamide 200 mg/m(2) on days 1 to 3, and mitoxantrone 6 mg/m(2) IV on day 1, given at 4-week intervals with up to six cycles supported with colony-stimulating factor. Patients achieving response received maintenance with rituximab 375 mg/m(2) every 3 months for 2 years. RESULTS: The overall response, minimal residual disease (MRD) -negative complete response (CR), MRD-positive CR, and partial response rates were 93%, 46%, 36%, and 11%, respectively. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Advanced clinical stage, del(17p), or increased serum beta2-microglobulin levels correlated with a lower CR rate. CONCLUSION: R-FCM is highly effective in previously untreated CLL, with an 82% CR rate and a high proportion of MRD-negative CRs (46%). Treatment toxicity is acceptable. Parameters correlating with a lower response rate were advanced clinical stage, high serum beta2-microglobulin levels, and del(17p). Based on these results, R-FCM warrants further investigation in randomized clinical trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Ciclofosfamida/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Rituximab , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
La evaluación de la enfermedad mínima residual (EMR) es un objetivo importante en el tratamiento de la leucemia linfocítica crónica (LLC). Su obtención es predictiva de una supervivencia libre de progresión (SLP) y una supervivencia global prolongadas y podría considerarse una variable subrogada de la SLP en el contexto del tratamiento con quimioinmunoterapia. La evaluación de la EMR mediante citometría de flujo o técnicas moleculares en la era de los nuevos inhibidores de BCR o Bcl-2 podría identificar la secuencia de tratamiento más coste-efectiva y la duración de la misma. Una aproximación terapéutica guiada por el nivel de EMR también podría determinar qué pacientes se beneficiarían de un tratamiento de consolidación o de una finalización precoz del mismo. En esta revisión discutimos los diferentes métodos de análisis de la EMR, qué muestras deben ser analizadas, el papel futuro de la detección del ADN tumoral circulante y el papel potencial de la negatividad de la EMR en la práctica clínica en la era moderna del tratamiento de la LLC (AU)
Minimal residual disease (MRD) assessment is an important endpoint in the treatment of chronic lymphocytic leukaemia (CLL). It is highly predictive of prolonged progression-free survival (PFS) and overall survival and could be considered a surrogate for PFS in the context of chemoimmunotherapy based treatment. Evaluation of MRD level by flow cytometry or molecular techniques in the era of the new BCR and Bcl-2 targeted inhibitors could identify the most cost-effective and durable treatment sequencing. A therapeutic approach guided by the level of MRD might also determine which patients would benefit from an early stop or consolidation therapy. In this review, we discuss the different MRD methods of analysis, which source of tumour samples must be analysed, the future role of the detection of circulating tumour DNA, and the potential role of MRD negativity in clinical practice in the modern era of CLL therapy (AU)
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neoplasia Residual/etiología , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/diagnóstico , ADN de Neoplasias/análisis , Inmunoterapia , Fosfotransferasas/antagonistas & inhibidores , Leucemia Linfocítica Crónica de Células B/terapia , Citometría de Flujo/métodos , Leucemia Linfocítica Crónica de Células B/genética , Neoplasia Residual/terapia , Terapia Combinada/métodosRESUMEN
Objetivos: Evaluar el coste-efectividad del esquema de rituximab, fludarabina y ciclofosfamida (R-FC) encomparación con el de fludarabina y ciclofosfamida (FC) en dos tipos de pacientes con leucemia linfáticacrónica (LLC): no tratados previamente o bien en recidiva/resistentes al tratamiento previo.Métodos: Dos modelos de Markov, utilizando los resultados publicados de superviviencia libre de progresión(SLP) de pacientes con LLC tratados con R-FC o FC en primera o segunda línea, las tasas de progresiónde la enfermedad y las tasas de mortalidad en Espana. A los estados de SLP y progresión se les asignaronutilidades obtenidas en un estudio sobre LLC. Los costes de los medicamentos y de los tratamientos desoporte, así como los anos de vida ajustados por calidad (AVAC), se estimaron para un periodo de 10 anos.Se efectuaron análisis de sensibilidad univariados y probabilísticos (Monte Carlo).Resultados: La adición de rituximab a la quimioterapia con FC aumentó los anos de vida ganados (AVG) ylos AVAC tanto en primera como en segunda línea de tratamiento. La razón de coste-eficacia incrementalfue de 20.703 D por AVG y de 19.343 D por AVAC con la primera línea de tratamiento, y de 23.183 D porAVG y 24.781 D por AVAC con la segunda línea de tratamiento.Conclusiones: En los pacientes con LLC no tratados previamente y en aquellos en recaída o resistentes altratamiento previo, la adición de rituximab al esquema FC aumentó la esperanza de vida y los AVAC, y enambos casos resultó ser un tratamiento coste-efectivo (AU)
Objectives: We evaluated the cost-effectiveness of rituximab added to the chemotherapy regimen of fludarabineplus cyclophosphamide (R-FC) versus fludarabine plus cyclophosphamide (FC) for the treatmentof patients with previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL).Methods: Two Markov models were built, using published results on progression-free survival (PFS) inpatients receiving first- or second-line therapy with R-FC vs FC, rates of disease progression and mortalityrates in Spain. Patient-elicited utilities were applied to PFS and progressed health states. The cost of drugs,supportive care, and quality-adjusted life years (QALY) were estimated over a 10-year period. Univariateand probabilistic (Monte Carlo) sensitivity analyses were performed.Results: The addition of rituximab to chemotherapy in first- and second-line therapy increased lifeyearsgained (LYG) and QALYs compared with chemotherapy. The incremental cost per LYG and QALYgained was D 20,703 and D 19,343 for first-line treatment and was D 23,183 and D 24,781 for second-linetreatment (AU)