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We reviewed the literature (January 2010-June 2021) on the effectiveness of debulking strategies before venetoclax initiation in patients with chronic lymphocytic leukemia to reduce tumor burden, downgrade tumor lysis syndrome (TLS) risk, and avoid hospitalization. Low TLS incidence and reduced TLS risk based on tumor burden were reported following debulking in clinical trials. Real-world observational studies reporting debulking regimens recorded no TLS events, and those without debulking strategies had greater TLS incidence. Debulking prior to venetoclax considerably reduces TLS incidence. Further clinical trials and real-world studies may provide additional evidence on effectiveness of debulking in reducing TLS incidence and hospitalization need.
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BACKGROUND: Clinically validated prognostic models for overall survival do not exist for patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who are on targeted therapies. We aimed to create a prognostic model to identify high-risk individuals who do not achieve a good outcome with available targeted therapies. METHODS: In this retrospective, pooled cohort study, 2475 patients with CLL treated between June 22, 2012, and Sept 23, 2015, in six randomised trials of ibrutinib, idelalisib, and venetoclax, or at the Mayo Clinic CLL Database (MCCD) were included. Eligible patients had CLL, were previously treated, were aged 18 years or older, had ECOG performance status 0-1, and required further treatment as per the international workshop on CLL 2008 criteria. There was heterogeneity in other eligibility criteria. We evaluated 28 candidate factors known to affect the overall survival of these patients and applied univariate and multivariate analyses to derive the risk score in a training dataset (n=727) of patients treated with ibrutinib or chemoimmunotherapy. We validated the score in an internal-validation dataset (n=242) of patients treated with ibrutinib or chemoimmunotherapy and three external-validation datasets (idelalisib or chemoimmunotherapy dataset, n=897; venetoclax or chemoimmunotherapy dataset, n=389; and the MCCD [including patients treated with heterogeneous therapies], n=220), applying C-statistics as a measure of discrimination. FINDINGS: The derived model consisted of four factors (one point each; serum ß2-microglobulin ≥5 mg/dL, lactate dehydrogenase >upper limit of normal, haemoglobin <110 g/L for women or <120 g/L for men, and time from initiation of last therapy <24 months), separating patients into low (score 0-1), intermediate (score 2-3), and high risk (score 4) groups. The risk score was prognostic for overall survival in the training dataset (CS=0·74, 95% CI 0·60-0·85, log-rank p<0·0001), and in the internal-validation (CS=0·79, 0·56-0·97, log-rank p=0·0003), and all three external-validation cohorts (idelalisib or chemoimmunotherapy: CS=0·71, 0·59-0·81, log-rank p<0·0001; venetoclax or chemoimmunotherapy: CS =0·76, 0·66-0·85, log-rank p=0·014; MCCD cohort: CS=0·61, 0·56-0·66), log-rank p<0·0001). The risk score is available on Calculate by QxMD. INTERPRETATION: We present the first validated risk score to predict overall survival in patients with relapsed or refractory CLL treated with targeted therapy. The model is applicable to patients treated with all currently approved targeted therapies (ibrutinib, idelalisib, and venetoclax) and chemoimmunotherapy. This tool allows the identification of a well defined cohort of previously treated patients with CLL who are at high risk of death, and could be used in future prospective trials to test therapeutic options for these patients with an unmet clinical need. FUNDING: Lymphoma Research Foundation, Lymphoma Research Fund (Andrew D Zelenetz), and National Institutes of Health/National Cancer Institute.
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Antineoplásicos/uso terapéutico , Inmunoterapia , Leucemia Linfocítica Crónica de Células B/terapia , Adenina/análogos & derivados , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Bases de Datos Factuales , Femenino , Hemoglobinas/análisis , Humanos , L-Lactato Deshidrogenasa/sangre , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Piperidinas , Pronóstico , Modelos de Riesgos Proporcionales , Purinas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Quinazolinonas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Factores de Riesgo , Sulfonamidas/uso terapéutico , Tasa de Supervivencia , Microglobulina beta-2/sangreRESUMEN
Purpose Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate used in the treatment of several types of lymphomas. Expression of the target antigen has also been reported on a variety of malignant tumors of nonlymphoid origin. This phase 2, open-label study evaluated the safety and antitumor activity of BV in patients with CD30-expressing nonlymphomatous malignancies. Methods Patients were dosed with 1.8 or 2.4 mg/kg BV once every three weeks. Antitumor activity was assessed at Cycles 2, 4, and every 4 cycles thereafter. Patients with stable disease or better were eligible to continue treatment until disease progression, unacceptable toxicity, or study closure. Results Of the 2693 patients screened, 3.8% had solid tumors with CD30 expression and 63 eligible patients with solid tumors enrolled in this study. The most common CD30 positive solid tumors were testicular cancer and mesothelioma. Both subtypes had more than one patient with an objective response. The median duration of BV exposure was 6.1 weeks. The disease control rate, defined as achieving stable disease or better at any point during the study, was 55%. The objective response rate was 11%, with a median duration of response of 2.92 months. The most common adverse events reported were fatigue (57%), nausea (33%), and decreased appetite (32%). Conclusion The safety profile of BV in patients with solid tumors was similar to the known safety profile of BV. In solid tumors, BV had modest activity as a single agent, which was similar to other second-line treatments already available to patients.
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Antineoplásicos Inmunológicos/uso terapéutico , Brentuximab Vedotina/uso terapéutico , Antígeno Ki-1/metabolismo , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/efectos adversos , Brentuximab Vedotina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
The CLL-IPI is a risk-weighted prognostic model for previously untreated patients with chronic lymphocytic leukemia (CLL), but has not been evaluated in patients with relapsed CLL or on novel therapies. We evaluated the CLL-IPI in 897 patients with relapsed/refractory CLL in 3 randomized trials testing idelalisib (PI3Kδ inhibitor). The CLL-IPI identified patients as low (2.2%), intermediate (12.8%), high (48.7%), and very high (36.2%) risk and was prognostic for survival (log-rank p < .0001; C-statistic 0.706). Of CLL-IPI factors, age >65, ß2-microglobulin >3.5mg/L, unmutated immunoglobulin heavy chain variable region gene, and deletion 17p/TP53 mutation were independently prognostic, but Rai I-IV or Binet B/C was not. The CLL-IPI is prognostic for survival in relapsed CLL and with idelalisib therapy. However, low/intermediate risk is uncommon, and regression parameters of individual factors in this risk-weighted model appear different in relapsed CLL. Reassessment of the weighting of the individual variables might optimize the model in this setting.