Mutations in Toll-like receptor and MYD88 genes (TLR/MYD88) have been found in CLL at low frequency (3.9%) and have been associated with good prognosis in global series of patients. To determine whether this also apply to younger patients we analyzed 146 patients under 50 years of age for the presence of TLR/MYD88, SF3B1, NOTCH1 and TP53 mutations by either whole-exome or Sanger sequencing, and correlated findings with outcome.

The widespread availability of statistical packages has undoubtedly helped hematologists worldwide in the analysis of their data, but has also led to the inappropriate use of statistical methods. In this article, we review some basic concepts of survival analysis and also make recommendations about how and when to perform each particular test using SPSS, Stata and R. In particular, we describe a simple way of defining cut-off points for continuous variables and the appropriate and inappropriate uses of the Kaplan-Meier method and Cox proportional hazard regression models. We also provide practical advice on how to check the proportional hazards assumption and briefly review the role of relative survival and multiple imputation.

Prospective identification of patients with chronic lymphocytic leukemia (CLL) destined to progress would greatly facilitate their clinical management. Recently, whole-genome DNA methylation analyses identified three clinicobiologic CLL subgroups with an epigenetic signature related to different normal B-cell counterparts. Here, we developed a clinically applicable method to identify these subgroups and to study their clinical relevance. Using a support vector machine approach, we built a prediction model using five epigenetic biomarkers that was able to classify CLL patients accurately into the three subgroups, namely naive B-cell-like, intermediate and memory B-cell-like CLL. DNA methylation was quantified by highly reproducible bisulfite pyrosequencing assays in two independent CLL series. In the initial series (n = 211), the three subgroups showed differential levels of IGHV (immunoglobulin heavy-chain locus) mutation (P < 0.001) and VH usage (P < 0.03), as well as different clinical features and outcome in terms of time to first treatment (TTT) and overall survival (P < 0.001). A multivariate Cox model showed that epigenetic classification was the strongest predictor of TTT (P < 0.001) along with Binet stage (P < 0.001). These findings were corroborated in a validation series (n = 97). In this study, we developed a simple and robust method using epigenetic biomarkers to categorize CLLs into three subgroups with different clinicobiologic features and outcome.

Mutations in Toll-like receptor (TLR) and myeloid differentiation primary response 88 (MYD88) genes have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, clinicobiological characteristics, and outcome of patients with TLR/MYD88 mutations in 587 CLL patients. Twenty-three patients (3.9%) had mutations, 19 in MYD88 (one with concurrent IRAK1 mutation), 2 TLR2 (one with concomitant TLR6 mutation), 1 IRAK1, and 1 TLR5. No mutations were found in IRAK2 and IRAK4. TLR/MYD88-mutated CLL overexpressed genes of the nuclear factor κB pathway. Patients with TLR/MYD88 mutations were significantly younger (83% age ≤50 years) than those with no mutations. TLR/MYD88 mutations were the most frequent in young patients. Patients with mutated TLR/MYD88 CLL had a higher frequency of mutated IGHV and low expression of CD38 and ZAP-70. Overall survival (OS) was better in TLR/MYD88-mutated than unmutated patients in the whole series (10-year OS, 100% vs 62%; P = .002), and in the subset of patients age ≤50 years (100% vs 70%; P = .02). In addition, relative OS of TLR/MYD88-mutated patients was similar to that in the age- and gender-matched population. In summary, TLR/MYD88 mutations identify a population of young CLL patients with favorable outcome.

Background The concept of "accelerated" chronic lymphocytic leukemia is frequently used by both pathologists and clinicians. However, neither histological criteria to define this form of chronic lymphocytic leukemia nor its clinical correlates and prognostic impact have been formally defined in large series of patients.Design and Methods Tissue biopsies from 100 patients with chronic lymphocytic leukemia were analyzed for the size of proliferation centers and their proliferation rate as assessed by mitosis count and Ki-67 immunostaining. Histological patterns were correlated with main clinico-biological features and outcome.Results A suspicion of disease transformation was the main reason for carrying out tissue biopsy, which was performed at a median time of 14 months (range, 0 to 204 months) after the diagnosis of chronic lymphocytic leukemia. The biopsy showed histological transformation to diffuse large B-cell lymphoma in 22 cases. In the remaining 78 patients, the presence of expanded proliferation centers (broader than a 20x field) and high proliferation rate (either >2.4 mitoses/proliferation center or Ki-67 >40%/proliferation center) predicted a poor outcome and were selected to define a highly proliferative group. Thus, 23 patients with either expanded proliferation centers or high proliferation rate were considered as having "accelerated" chronic lymphocytic leukemia. These patients displayed particular features, including higher serum lactate dehydrogenase levels and more frequently elevated ZAP-70 than "non-accelerated" cases. The median survival from biopsy of patients with "non-accelerated" chronic lymphocytic leukemia, "accelerated" chronic lymphocytic leukemia and transformation to diffuse large B-cell leukemia was 76, 34, and 4.3 months, respectively (P<0.001).Conclusions The presence of expanded and/or highly active proliferation centers identifies a group of patients with "accelerated" chronic lymphocytic leukemia characterized by an aggressive clinical behavior.

BACKGROUND:The concept of "accelerated" chronic lymphocytic leukemia is frequently used by both pathologists and clinicians. However, neither histological criteria to define this form of chronic lymphocytic leukemia nor its clinical correlates and prognostic impact have been formally defined in large series of patients. DESIGN AND METHODS:Tissue biopsies from 100 patients with chronic lymphocytic leukemia were analyzed for the size of proliferation centers and their proliferation rate as assessed by mitosis count and Ki-67 immunostaining. Histological patterns were correlated with main clinico-biological features and outcome. RESULTS:A suspicion of disease transformation was the main reason for carrying out tissue biopsy, which was performed at a median time of 14 months (range, 0 to 204 months) after the diagnosis of chronic lymphocytic leukemia. The biopsy showed histological transformation to diffuse large B-cell lymphoma in 22 cases. In the remaining 78 patients, the presence of expanded proliferation centers (broader than a 20x field) and high proliferation rate (either >2.4 mitoses/proliferation center or Ki-67 >40%/proliferation center) predicted a poor outcome and were selected to define a highly proliferative group. Thus, 23 patients with either expanded proliferation centers or high proliferation rate were considered as having "accelerated" chronic lymphocytic leukemia. These patients displayed particular features, including higher serum lactate dehydrogenase levels and more frequently elevated ZAP-70 than "non-accelerated" cases. The median survival from biopsy of patients with "non-accelerated" chronic lymphocytic leukemia, "accelerated" chronic lymphocytic leukemia and transformation to diffuse large B-cell leukemia was 76, 34, and 4.3 months, respectively (P<0.001). CONCLUSIONS:The presence of expanded and/or highly active proliferation centers identifies a group of patients with "accelerated" chronic lymphocytic leukemia characterized by an aggressive clinical behavior.

Whether advances in treatment are prolonging survival of patients with chronic lymphocytic leukemia (CLL) is unclear. We analyzed presentation patterns and survival over time in 929 patients followed from 1980 to 2008 at the Hospital Clinic of Barcelona. The 5- and 10-year relative survival (adjusted for the expected survival in the general population) was estimated in patients seen in 2 periods of time: 1980-1994 (n = 451) and 1995-2004 (n = 365). We found that CLL shortens life expectancy in all age groups independently of clinical features at diagnosis. Nevertheless, survival is improving, particularly in some groups of patients. Thus, relative survival was significantly higher in the 1995-2004 cohort than in the 1980-1994 group both at 5 years (incidence rate ratio [IRR] = 0.46; P = .004) and 10 years (IRR = 0.65; P = .007) from diagnosis. The improved survival was largely due to a decrease in CLL-attributable mortality in patients younger than 70 years in Binet stage B or C at diagnosis (IRR = 0.40; P = .001 at 5 years; IRR = 0.33; P < .001 at 10 years). These results suggest that newer treatments are changing the prognosis of CLL, particularly in younger patients with advanced disease, whereas no improvement is yet observed in older subjects or those with lower-risk disease.

Clinical & Laboratory HaematologyVolume 4, Issue 1 p. 89-90 Ultrastructure of supravitally stained red cells in haemoglobin H disease E Feliu MD, E Feliu MD Central Haematology Laboratory und Postgraduate School of Haematology ‘Farreras Valenti’, Hospital Clinic y Provincial, University of Barcelona, c/Casunova, 143, Barcelona-36, SpainSearch for more papers by this authorC Rozman Prof., C Rozman Prof. Central Haematology Laboratory und Postgraduate School of Haematology ‘Farreras Valenti’, Hospital Clinic y Provincial, University of Barcelona, c/Casunova, 143, Barcelona-36, SpainSearch for more papers by this authorJ. L. Vives Corrons MD, J. L. Vives Corrons MD Central Haematology Laboratory und Postgraduate School of Haematology ‘Farreras Valenti’, Hospital Clinic y Provincial, University of Barcelona, c/Casunova, 143, Barcelona-36, SpainSearch for more papers by this authorJ. LI Aguilar PhD, J. LI Aguilar PhD Central Haematology Laboratory und Postgraduate School of Haematology ‘Farreras Valenti’, Hospital Clinic y Provincial, University of Barcelona, c/Casunova, 143, Barcelona-36, SpainSearch for more papers by this author E Feliu MD, E Feliu MD Central Haematology Laboratory und Postgraduate School of Haematology ‘Farreras Valenti’, Hospital Clinic y Provincial, University of Barcelona, c/Casunova, 143, Barcelona-36, SpainSearch for more papers by this authorC Rozman Prof., C Rozman Prof. Central Haematology Laboratory und Postgraduate School of Haematology ‘Farreras Valenti’, Hospital Clinic y Provincial, University of Barcelona, c/Casunova, 143, Barcelona-36, SpainSearch for more papers by this authorJ. L. Vives Corrons MD, J. L. Vives Corrons MD Central Haematology Laboratory und Postgraduate School of Haematology ‘Farreras Valenti’, Hospital Clinic y Provincial, University of Barcelona, c/Casunova, 143, Barcelona-36, SpainSearch for more papers by this authorJ. LI Aguilar PhD, J. LI Aguilar PhD Central Haematology Laboratory und Postgraduate School of Haematology ‘Farreras Valenti’, Hospital Clinic y Provincial, University of Barcelona, c/Casunova, 143, Barcelona-36, SpainSearch for more papers by this author First published: March 1982 https://doi.org/10.1111/j.1365-2257.1982.tb00065.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume4, Issue1March 1982Pages 89-90 RelatedInformation

In chronic lymphocytic leukaemia (CLL), bone marrow biopsy (BM) sections show different infiltration patterns (nodular, interstitial, mixed diffuse) with a fairly homogeneous distribution when bilateral biopsies are examined. Sequential studies demonstrate that these patterns represent a dynamic process reflecting the degree of lymphocytic burden. Moreover, BM histopathology (diffuse vs non-diffuse) is a highly significant prognostic parameter. Although partly related to clinical stages, BM patterns have prognostic value on their own. A combined clinicopathologic staging system (integrating clinical stages and bone marrow histology) predicts the outcome of CLL patients more accurately than clinical stages alone.

Whether recent advances in the understanding and treatment of CLL are changing referral patterns of patients with this disease to specialized centers and their outcome is largely unknown. We analyzed demographics, disease characteristics, treatments administered, and survival over a period of 28 years in a series of 900 patients with CLL separated in three different cohorts based on the year of referral (table). As shown in the table, one of the main differences observed over the years relies on the stage of the disease, with most patients being currently seen in early phase of the disease, reflecting an earlier diagnosis because of analyses performed for routine reasons. In contrast, no differences were observed in patients' age over the years, in agreement with the stable incidence of CLL in different age groups (SEER). No differences were detected in the proportion of patients developing autoimmune cytopenias, Richter's syndrome or second neoplasias (data not shown). Not unexpectedly, since 1990 most patients receive purine analogs-based therapies. Importantly, the increasing proportion of patients who remain alive in each time period not only reflects an earlier diagnosis but also improvement in clinical management. Thus, median survivals of patients < 65 with Binet B or C disease are 3.9 yrs (1980–1989), 7.5 yrs (1990–1999) and not reached (2000 onwards), and the proportion of patients alive at 5 years in the same periods of time are 43%, 63% and 72% (figure). Unfortunately survival of patients > 65 yrs has not improved (median survival around 5.5 years across the three groups). Also, survival of patients in early stage (Binet A) has remained basically unchanged. From this large, single-institution study it can be concluded that the outcome of patients with CLL has been steadily improving since 1980. Nevertheless, the most significant progress has been made in younger patients with advanced disease, which constitute a small proportion of subjects with CLL. Besides to improving the outcome of these patients, future efforts should be aimed at prolonging survival of all patients, irrespectively of their age, and seeking the cure for the disease.