International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia

Abstract

Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.

High percentage of smudge cells in a patient with COVID19: Rediscovering their utility

“…Interestingly, the characteristic ease with which these cells are broken, more than a laboratory artefact is related with the amount of vimentin cellular content [4]. In developing countries with low access to molecular testing, clinical elements such as percentage of smudge cells, palpable adenopathies and absolute lymphocytosis over 15 000/mm 3 are useful to stratify the risk of progression in early CLL [5].…”

Targeting p53 in chronic lymphocytic leukemia

“…In CLL, the prevalence of TP53 abnormalities, including 17p deletion and TP53 mutations, varies across the different phases of the disease. In early stage asymptomatic CLL patients and in CLL patients requiring treatment, TP53 abnormalities are detected in approximately 5-7% and 10%, respectively [3,30,33,34,41]. As previously described, p53 plays a pivotal role in the DDR induced by chemotherapy [5][6][7]14].…”

“…The prevalence of TP53 abnormalities in this group of CLL patients is low and, especially in the presence of mutated IGHV genes, does not predict a worse outcome [49,50]. Recently, the IPS-E (International Prognostic Score-Early) new prognostic model has identified three different subgroups of treatment naïve Binet A CLL patients with a high risk of early treatment requirement according to the combination of lymphocyte count >15,000/ μl, palpable lymph nodes and unmutated IGHV genes [41]. Interestingly, in this model, TP53 abnormalities did not sort out as an independent predictor of shorter time to first treatment, in line with the notion that TP53 disruption interacts with the selective pressure exerted by treatment but not with a watch and wait strategy [41].…”

“…Recently, the IPS-E (International Prognostic Score-Early) new prognostic model has identified three different subgroups of treatment naïve Binet A CLL patients with a high risk of early treatment requirement according to the combination of lymphocyte count >15,000/ μl, palpable lymph nodes and unmutated IGHV genes [41]. Interestingly, in this model, TP53 abnormalities did not sort out as an independent predictor of shorter time to first treatment, in line with the notion that TP53 disruption interacts with the selective pressure exerted by treatment but not with a watch and wait strategy [41]. Conversely, TP53 abnormalities are an important component of the CLL-IPI (CLL International Prognostic score) that is designed using overall survival as primary endpoint, and therefore may be affected by treatment exposure [51].…”

Driver Mutations and Single Copy Number Abnormalities Identify Binet Stage A Patients with Chronic Lymphocytic Leukemia with Aggressive Progression

“…Particularly, deletion 13q14 (del(13q)) has been correlated with a more indolent disease, whereas deletion 11q22.3 (del(11q)) and deletion 17p13 (del(17p)) have been associated with a more aggressive disease and resistance to treatment [9,10]. Recently, an international prognostic score for asymptomatic early-stage CLL has been established [11]. Along the same lines, next-generation sequencing (NGS) techniques have led to the discovery of several unidentified genes that are mutated in CLL, providing invaluable information about the mechanisms involved in the pathogenesis of this disease and therapy resistance.…”