Association of gene mutations with time-to-first treatment in 384 treatment-naive chronic lymphocytic leukaemia patients

This study correlated somatic mutation results and known prognostic factors with time-to-first treatment (TTFT) in 384 treatment-naïve (TN) chronic lymphocytic leukaemia (CLL) patients to help determine disease-specific drivers of early untreated CLL. CLL DNA from either peripheral blood or bone marrow underwent next generation targeted sequencing with a 29-gene panel. Gene mutation data and concurrent clinical characteristics, such as Rai/Binet stage, fluorescence in situ hybridisation (FISH), ZAP70/CD38, karyotype and IGHV mutation, status were analysed in univariable and multivariable analyses to identify associations with TTFT. TTFT was defined as time from diagnosis to initial treatment. In univariable analyses, mutated ATM (P < 0·001), NOTCH1 (P < 0·001) and SF3B1 (P = 0·002) as well as unmutated IGHV (P < 0·001), del(11q) (P < 0·001) and trisomy 12 (P < 0·001) by hierarchal FISH and advanced Rai (P = 0·05) and Binet (P < 0·001) stages were associated with shorter TTFT. Importantly, del(17p), mutated TP53 and complex karyotype were not associated with shorter TTFT. In a reduced multivariable analysis, mutated ATM (P < 0·001) and unmutated IGHV status (P < 0·001) remained significant, showing their importance in early leukaemogenesis. High-risk prognostic markers such as del(17p), mutated TP53 and complex karyotype, were not correlated with TTFT, suggesting that these abnormalities have limited roles in early disease progression but are more important in relapsed CLL.     

The morphology of CLL revisited: the clinical significance of prolymphocytes and correlations with prognostic/molecular markers in the LRF CLL4 trial

Historically, an increase in the percentage and number of circulating prolymphocytes in chronic lymphocytic leukaemia (CLL) has been associated with strong expression of surface immunoglobulin, trisomy 12 and a poor outcome. This study re‐examines the biological and clinical significance of increased peripheral blood prolymphocytes in 508 patients at entry into the randomized UK Leukaemia Research Fund CLL4 trial. It also investigates the associations between increased prolymphocytes and a comprehensive array of biomarkers. 270 patients (53%) had <5% prolymphocytes, 167 (33%) had 5–9%, 60 (12%) had 10–14% and 11 (2%) had ≥15% prolymphocytes. We show that a higher proportion of prolymphocytes (≥10%) was independently associated with NOTCH1 mutations (P = 0·006), absence of 13q deletion (P = 0·001), high CD38 expression (P = 0·02) and unmutated IGHV genes (P = 0·01). Deaths due to Richter syndrome were significantly more common amongst patients who had ≥10% vs <10% prolymphocytes (13% vs 2%) respectively (P < 0·0001). ≥10% prolymphocytes was also associated with a shorter progression‐free survival (Hazard ratio [HR] 1·50 [95% confidence interval [CI]: 1·16–1·93], P = 0·002) and overall survival (HR 1·99 [95% CI: 1·53–2·59], P < 0·0001). Our data support the routine examination of blood films in CLL and suggest that a finding of an increased proportion of prolymphocytes may be a trigger for further evaluation of clinical and laboratory features of progressive disease.     

Flow cytometric identification of 76 patients with biclonal disease among 5523 patients with chronic lymphocytic leukaemia (B‐CLL) and its genetic characterization

Multiparameter flow cytometry (MFC) identifies rare cases of biclonal disease in chronic lymphocytic leukaemia (CLL). By MFC, we identified 76 patients with biclonal disease in a cohort of 5523 CLL patients (1·4%). Fluorescence in situ hybridization and chromosome banding analysis revealed five and six cases, respectively, with two different cytogenetic aberrations due to clonal evolution. Two different B‐cell receptor rearrangements and IGHV subtypes were more frequent in biclonal than in monoclonal CLL by MFC (37·1% vs. 2·7%; P < 0·001). Patients with biclonal CLL by MFC showed a trend to a shorter time to treatment than monoclonal CLL (P = 0·080).     

Monoclonal gammopathy and serum immunoglobulin levels as prognostic factors in chronic lymphocytic leukaemia

The relationship between chronic lymphocytic leukaemia (CLL) and qualitative/quantitative gammaglobulin abnormalities is well established. Nevertheless, in order to better understand this kind of connection, we examined 1505 patients with CLL and divided them into four subgroups on the basis of immunoglobulin (Ig) aberrations at diagnosis. A total of 73 (4·8%), 149 (10%), 200 (13·2%) and 1083 (72%) patients were identified with IgM monoclonal gammopathy (IgM/CLL), IgG monoclonal gammopathy (IgG/CLL), hypogammaglobulinaemia (hypo-γ) and normal Ig levels (γ-normal) respectively. IgM paraprotein was significantly associated with a more advanced Binet/Rai stage and del(17p)/TP53 mutation, while IgG abnormalities correlated with a higher occurrence of trisomy 12. Patients with any type of Ig abnormality had shorter treatment-free survival (TFS) but no significant impact affecting overall survival (OS) compared to those with normal Ig levels.     

Long‐term follow‐up of patients receiving allogeneic stem cell transplant for chronic lymphocytic leukaemia: mixed T‐cell chimerism is associated with high relapse risk and inferior survival

There is limited information regarding the immunological predictors of post‐allogeneic stem cell transplant (alloSCT) outcome in chronic lymphocytic leukaemia (CLL), such as mixed T‐cell chimerism. We analysed 143 consecutive patients with relapsed/refractory CLL, transplanted between 2000 and 2012, to determine the prognostic relevance of mixed chimerism post‐alloSCT and the ability of post‐transplant immunomodulation to treat relapse. Mixed T‐cell chimerism occurred in 50% of patients at 3 months and 43% at 6 months post‐alloSCT; upon 3‐ and 6‐month landmark analysis, this was associated with inferior progression‐free survival (PFS) [Hazard ratio (HR) 1·93, P = 0·003 and HR 2·58, P < 0·001] and survival (HR 1·66, P = 0·05 and HR 2·17, P < 0·001), independent of baseline patient characteristics, and a lower rate of grade II–IV acute graft‐versus‐host disease (GHVD) (16% vs. 52%, P < 0·001). Thirty‐three patients were treated with immunomodulation for relapse post‐alloSCT (immunosuppression withdrawal, n = 6, donor lymphocyte infusion, n = 27); 17 achieved complete response (CR), which predicted superior PFS (53 months vs. 10 months, P < 0·001) and survival (117 months vs. 30 months, P = 0·006). Relapsed patients with mixed chimerism had inferior response to immunomodulation; conversion to full donor chimerism was highly correlated both with CR and with the development of severe acute GVHD, which was fatal in 3/8 patients. Novel therapeutic strategies are required for patients with mixed T‐cell chimerism post‐alloSCT for CLL.     

Diffuse large B‐cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients

Nearly all information about patients with chronic lymphocytic leukaemia (CLL) who develop diffuse large B‐cell lymphoma [Richter syndrome (RS)] is derived from retrospective case series or patients treated on clinical trials. We used the Mayo Clinic CLL Database to identify patients with newly diagnosed CLL between January 2000 and July 2011. Individuals who developed biopsy‐proven RS during follow‐up were identified. After a median follow‐up of 4 years, 37/1641 (2·3%) CLL patients developed RS. The rate of RS was approximately 0·5%/year. Risk of RS was associated with advanced Rai stage at diagnosis (P < 0·001), high‐risk genetic abnormalitites on fluorescence in situ hybridization (P < 0·0001), unmutated IGHV (P = 0·003), and expression of ZAP70 (P = 0·02) and CD38 (P = 0·001). The rate of RS doubled in patients after treatment for CLL (1%/year). Stereotyped B‐cell receptors (odds‐ratio = 4·2; P = 0·01) but not IGHV4‐39 family usage was associated with increased risk of RS. Treatment with combination of purine analogues and alkylating agents increased the risk of RS three‐fold (odds‐ratio = 3·26, P = 0·0003). Median survival after RS diagnosis was 2·1 years. The RS prognosis score stratified patients into three risk groups with median survivals of 0·5 years, 2·1 years and not reached. Both underlying characteristics of the CLL clone and subsequent CLL therapy influence the risk of RS. Survival after RS remains poor and new therapies are needed.     

CD49d associates with nodal presentation and subsequent development of lymphadenopathy in patients with chronic lymphocytic leukaemia

CD 49d is a surface integrin that is expressed on chronic lymphocytic leukaemia (CLL ) cells, and strongly correlates with more aggressive disease. Given its association with cell‐cell adhesion and leucocyte trafficking, we hypothesized that patients with high CD 49d expression would experience a clinical course dominated by lymphadenopathy. CD 49d expression was measured by flow cytometry and considered positive if expressed by ≥30% of CLL cells. The study included 797 newly diagnosed CLL /small lymphocytic leukaemia patients; 279 (35%) were CD 49d positive. CD 49d‐positive patients were more likely to present with lymphadenopathy (P  <  0·001); a finding that persisted after adjusting for fluorescence in situ hybridisation (FISH ) and IGHV mutation status [odds ratio (OR ) 2·51; 95% confidence interval (CI ) 1·64–3·83; P  <  0·001]. Among CLL Rai 0 patients, CD 49d positivity was associated with shorter time to development of lymphadenopathy (3·2 years vs not reached, P  <  0·01). This association was maintained after adjusting for either FISH [hazard ratio (HR ) 2·18; 95% CI 1·25–3·81; P  =  0·006) or IGHV status (HR 2·02; 95% CI 1·11–3·69; P  =  0·02) individually, but was attenuated when adjusting by both (HR 1·72; 95% CI 0·88–3·38; P  =  0·11).These data demonstrate that CD 49d‐positive CLL patients experience a disease course dominated by lymphadenopathy. These findings could have implications for therapy selection and disease monitoring.     

Subjects with chronic lymphocytic leukaemia‐like B‐cell clones with stereotyped B‐cell receptors frequently show MDS‐associated phenotypes on myeloid cells

An increasing body of evidence suggests the potential occurrence of antigen encounter by the cell of origin in chronic lymphocytic leukaemia (CLL) and CLL‐like monoclonal B‐cell lymphocytosis (MBL). However, the scenario in which this event might occur remains unknown. In order to gain insight into this scenario we investigated the molecular, cytogenetic and haematological features of 223 CLL‐like (n = 84) and CLL (n = 139) clones with stereotyped (n = 32) versus non‐stereotyped (n = 191) immunoglobulin heavy chain variable region (IGHV) amino acid sequences. Overall, stereotyped CLL‐like MBL and CLL clones showed a unique IGHV profile, associated with higher IGHV1 and lower IGHV3 gene family usage (P = 0·03), longer IGHV complementary determining region 3 (HCDR3) sequences (P = 0·007) and unmutated IGHV (P < 0·001) versus non‐stereotyped clones. Whilst the overall size of the stereotyped B‐cell clones in peripheral blood did not appear to be associated with the CLL‐related cytogenetic profile of B‐cells (P > 0·05), it did show a significant association with the presence of myelodysplastic syndrome (MDS)‐associated immunophenotypes on peripheral blood neutrophils and/or monocytes (P = 0·01). Altogether our results point to the potential involvement of different selection forces in the expansion of stereotyped vs. non‐stereotyped CLL and CLL‐like MBL clones, the former being potentially favoured by an underlying altered haematopoiesis.     

Complement and cytokine response in acute Thrombotic Thrombocytopenic Purpura

Complement dysregulation is key in the pathogenesis of atypical Haemolytic Uraemic Syndrome (aHUS), but no clear role for complement has been identified in Thrombotic Thrombocytopenic Purpura (TTP). We aimed to assess complement activation and cytokine response in acute antibody‐mediated TTP. Complement C3a and C5a and cytokines (interleukin (IL)‐2, IL‐4, IL‐6, IL‐10, tumour necrosis factor, interferon‐γ and IL‐17a) were measured in 20 acute TTP patients and 49 remission cases. Anti‐ADAMTS13 immunoglobulin G (IgG) subtypes were measured in acute patients in order to study the association with complement activation. In acute TTP, median C3a and C5a were significantly elevated compared to remission, C3a 63·9 ng/ml vs. 38·2 ng/ml (P < 0·001) and C5a 16·4 ng/ml vs. 9·29 ng/ml (P < 0·001), respectively. Median IL‐6 and IL‐10 levels were significantly higher in the acute vs. remission groups, IL‐6: 8 pg/ml vs. 2 pg/ml (P = 0·003), IL‐10: 6 pg/ml vs. 2 pg/ml (P < 0·001). C3a levels correlated with both anti‐ADAMTS13 IgG (r_s = 0·604, P = 0·017) and IL‐10 (r_s = 0·692, P = 0·006). No anti‐ADAMTS13 IgG subtype was associated with higher complement activation, but patients with the highest C3a levels had 3 or 4 IgG subtypes present. These results suggest complement anaphylatoxin levels are higher in acute TTP cases than in remission, and the complement response seen acutely may relate to anti‐ADAMTS13 IgG antibody and IL‐10 levels.     

A risk stratification for systemic immunoglobulin light-chain amyloidosis with renal involvement

Renal involvement is found in about 70% of patients with systemic immunoglobulin light-chain (AL) amyloidosis. However, there is no risk stratification system specialized for renal AL concerning patients’ survival. Galectin-3 (Gal-3) has been reported to portend poor prognosis in other renal diseases. We measured Gal-3 and several traditional risk biomarkers of AL in baseline samples from 253 consecutive patients diagnosed with renal AL. At baseline, Gal-3 [Hazard ratio (HR): 1·46; P = 0·033], high-sensitivity cardiac troponin T (hs-cTnT) (HR: 2·65; P < 0·001) and difference between involved and uninvolved free light chains (dFLC) (HR: 1·81; P = 0·001) were independent predictors of all-cause mortality. The cut-off points for Gal-3, hs-cTnT, and dFLC were 20·24 ng/ml, 0·026 ng/ml, and 75·89 mg/l, respectively. Patients were stratified into four stages by assigning a score of 1 for each of the three biomarkers above the cut-off point. The proportions of patients with disease stages 1, 2, 3 and 4 were 17·0%, 37·2%, 29·2% and 16·6%, and the median overall survival times from diagnosis were 100, 60, 29 and 15 months, respectively (P < 0·01). Higher level of Gal-3 is associated with increased risk for mortality, and the risk stratification based on Gal-3 is a reliable model for predicting mortality in AL amyloidosis with renal involvement.     

A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B‐chronic lymphocytic leukaemia

Deletion 13q14 on fluorescence in situ hybridization (FISH) analysis is the most common cytogenetic abnormality in chronic lymphocytic leukaemia (CLL), and is a favourable prognostic biomarker when detected as a sole abnormality. We intensively interrogated clinical outcome in 323 consecutive, untreated CLL patients with isolated 13q‐ identified within 2 years of diagnosis. We also analyzed outcome in 217 additional patients with deletion 11q22.3 or 17p13.1, or trisomy 12, based on whether these occurred in isolation or in conjunction with 13q‐. Patients with a heterozygous 13q‐ and those with a homozygous deletion had similar time to first treatment (TFT) and overall survival (OS). In contrast, a higher percentage of 13q‐ nuclei was associated with significantly shorter TFT (P < 0·001). The 5‐year untreated rate was 79% for patients with isolated 13q‐ in ≤65·5% of nuclei compared to 38% among those with 13q‐ in >65·5% of nuclei (P < 0·001). The percentage of nuclei exhibiting 13q‐ remained an independent predictor of TFT after controlling for ZAP‐70, IGHV, or CD38 (all P < 0·001). Among patients with 13q‐ plus one other FISH abnormality, concomitant 13q‐ appeared to attenuate the shorter survival associated with 17p‐ (P = 0·019). The clinical implications of 13q‐ in CLL appear more complex than originally appreciated.     

Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia,even in patients with early stage disease

Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high‐resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere ‘fusogenic’ range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P < 0·0001; Hazard ratio [HR] = 13·2, 95% confidence interval [CI] = 11·6–106·4) and this was preserved in early‐stage disease patients (P < 0·0001, HR=19·3, 95% CI = 17·8–802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high‐resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL.     

Routine sequencing in CLL has prognostic implications and provides new insight into pathogenesis and targeted treatments

Chronic lymphocytic leukaemia (CLL) is a genetically heterogeneous disease characterised by genomic alterations and gene mutations that may portend worse survival or resistance to treatments. A total of 680 blood or bone marrow samples underwent targeted sequencing of 29 genes previously identified as being mutated in CLL, which were correlated to known prognostic clinical characteristics. Overall, 400 (59%) patients were treatment-naïve (TN) and 280 (41%) were relapsed/refractory (R/R). Most patients (70%) had ≥1 mutation, with TP53 (22%), SF3B1 (18%), NOTCH1 (13%) and ATM (13%) being the most commonly mutated genes. A higher proportion of R/R patients had mutations in SF3B1 (P = 0·01) and TP53 (P < 0·001). Patients with mutated IGHV CLL more often had mutations in KLHL6 (P = 0·001) and MYD88 (P < 0·001). Pairwise associations showed mutational co-occurrences in the TN group including SF3B1/ATM [false discovery rate (FDR) < 0·05] and NOTCH1/POT1 (FDR < 0·01). Recurrent mutations resulting in premature truncation prior to the ubiquitination domains of NOTCH1 in its PEST domain and BIRC3 in its RING domain can produce proteins that constitutively activate CLL. Frequent missense mutations, such as K700E in SF3B1 and E571K in XPO1, have unknown function but are most likely to be activating mutations. Future directions include using these mutations to identify pathways for therapeutic targeting and rational drug design.     

Graft-versus-host disease and graft-versus-leukaemia effects in secondary acute myeloid leukaemia: a retrospective,multicentre registry analysis from the Acute Leukaemia Working Party of the EBMT

We assessed the susceptibility of secondary acute myeloid leukaemia (sAML) to graft-versus-leukaemia effects. Data from 2414 sAML patients in first (n = 2194) or second (n = 220) complete remission were included. They were given grafts from human leucocyte antigen (HLA)-matched sibling (MSD, n = 1085), 10/10 unrelated donor (MUD, n = 1066) or 9/10 mismatched unrelated donor (MMUD, n = 263). The 100-day incidence of grade II-IV acute graft-versus-host disease (GVHD) was 25% while 2-year incidence of chronic GVHD was 38%. Relapse rates declined steadily by duration of follow-up and were significantly lower in patients with chronic GVHD (P < 0·001). Limited (hazard ratio [HR] = 0·66, P < 0·001) and extensive (HR = 0·52, P < 0·001) chronic GVHD were associated with a lower incidence of relapse. Each grade III-IV acute (HR = 7·04, P < 0·001) as well as limited (HR = 1·42, P = 0·03) and extensive (HR = 3·97, P < 0·001) chronic GVHD were associated with higher non-relapse mortality (NRM). This translated to better overall survival (OS; HR = 0·61, P < 0·001) in patients with limited chronic GVHD. In contrast, grade III-IV acute and extensive chronic GVHD were associated with worse OS (HR = 3·16, P < 0·001 and HR = 1·21, P = 0·03, respectively). Further, in comparison to HLA-identical sibling recipients, MUD recipients had a lower risk of relapse (HR = 0·82, P = 0·03) but higher NRM (HR = 1·38, P = 0·004). In conclusion, these data demonstrate that sAML is susceptible to graft-versus-leukaemia effects.     

Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results

Patients with chronic lymphocytic leukaemia (CLL) whose tumour cells harbour a 17p deletion (17p‐) are universally considered to have a poor prognosis. The deletion can be detected at diagnosis or during the evolution of the disease, particularly in patients who have received chemotherapy. We sought to evaluate the natural history of patients with 17p‐ CLL, identify predictive factors within this prognostic subgroup, and evaluate the results of different therapeutic approaches. Data from 294 patients with 17p‐ CLL followed up at 20 different institutions was retrospectively collected and analysed. Median age was 68 (range 27–98) years at the time of fluorescence in situ hybridization analysis. After 17p‐ documentation, 52% received treatment, achieving an overall response rate of 50%. Median overall survival was 41 months, and was significantly shorter in patients with elevated beta₂‐microglobulin concentration (P < 0·001), B symptoms (P = 0·016), higher percentage of cells with deletion (P < 0·001), and acquired deletions (P = 0·012). These findings suggest that patients with 17p‐ CLL have a variable prognosis that can be refined using simple clinical and laboratory features, including 17p‐ clone size, beta2‐microglobulin concentration, presence of B symptoms and type of deletion (de novo versus acquired).     

High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone

Cereblon (CRBN) has recently been identified as a target for immunomodulatory drugs (IMiDs) and its downregulation has been linked to resistance to lenalidomide. Here, we studied CRBN expression by real time polymerase chain reaction in 49 bone marrow samples of newly diagnosed patients with multiple myeloma treated with lenalidomide and dexamethasone. Median CRBN expression was 3·45 in patients who achieved complete response, and 3·75, 2·01, 0·78, and 0·70 in those with very good partial response, partial response, stable disease and progressive disease respectively. CRBN expression levels correlated significantly with response to lenalidomide treatment (r = 0·48; P < 0·001). Among established prognostic parameters, only beta‐2‐microglobulin correlated with cereblon (r = 0·66; P < 0·001). A close association of CRBN with interferon regulatory factor 4 (IRF4) (P < 0·001) and with CTNNB1 (P < 0·001) was found. Overall, a statistically significant association between baseline CRBN expression and response in MM patients treated with lenalidomide is shown. CRBN expression is closely associated with IRF4, which is an important target of IMiD therapy.     

Cardiorenal AL amyloidosis: risk stratification and outcomes based upon cardiac and renal biomarkers

Systemic AL amyloidosis is a cause of type 5 cardiorenal syndrome. Response to treatment is currently reported according to organ-specific amyloidosis consensus criteria (ACC), which are not validated in cardiorenal AL amyloidosis. Of 1000 patients prospectively enrolled into the UK ALchemy study, 318 (32%) had combined cardiac and renal amyloidotic organ dysfunction at diagnosis, among whom 199 (63%) died; median survival by Kaplan–Meier analysis was 18·5 months. Fifty (16%) patients required renal replacement therapy (RRT). At diagnosis, independent predictors of death and dialysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP) >8500 ng/l (hazard ratio [HR] 3·30, P < 0·001; HR 3·00, P < 0·001), and estimated glomerular filtration rate (eGFR) < 30 ml/min/1·73 m² (HR 1·89, P = 0·011; HR 6·37, P < 0·001). At 6 months, an increase in NT-proBNP of >30% and a reduction in eGFR of ≥25% were independent predictors of death (HR 2·17, P = 0·009) and dialysis (HR 3·07, P = 0·002), respectively. At 12 months, an increase in NT-proBNP >30% was highly predictive of death (HR 3·67, P < 0·001) and dialysis (HR 2·85, P = 0·010), whereas ACC renal response was predictive of neither. Cardiorenal AL amyloidosis is associated with high early mortality. Outcomes are dictated by NT-proBNP and eGFR at diagnosis rather than proteinuria, and thereafter predominantly by changes in NT-proBNP concentration.     

Determinants of low-quality warfarin anticoagulation in patients with mechanical prosthetic heart valves. The nationwide PLECTRUM study

Quality of warfarin therapy in patients with a mechanical prosthetic heart valve (MPHV) has been barely investigated. We analysed determinants of low time in the therapeutic range (TiTR <60%) in 2111 patients with MPHVs from the nationwide PLECTRUM study by the Italian Federation of Anticoagulation Clinics. Overall, 48·5% of patients had a TiTR of < 60%. At logistic regression analysis, arterial hypertension (odds ratio [OR] 1·502, P < 0·001), diabetes (OR 1·732, P < 0·001), heart failure (OR 1·484, P = 0·004), mitral site (vs. aortic) (OR 1·399, P = 0·006), international normalised ratio (INR) ranges of 2·5–3·5 (OR 2·575, P < 0·001) and 3·0–4·0 (OR 8·215, P < 0·001) associated with TiTR < 60%. TiTR is substantially suboptimal in MPHV patients, particularly in higher INR ranges.     

Liver dysfunction in chronic lymphocytic leukemia: Prevalence,outcomes, and pathological findings

The prevalence of liver dysfunction and its association with outcomes in patients with previously untreated chronic lymphocytic leukemia (CLL) is unknown. Newly diagnosed (<12 months) previously untreated CLL patients seen at Mayo Clinic, Rochester, MN between 9/1993 and 4/2016 who had baseline assessment of at least one liver function test (LFT) were included in this analysis. The prevalence of liver dysfunction at baseline, proportion of patients who acquired LFT abnormalities, time to first therapy (TTFT) and overall survival (OS) were assessed. An abnormal LFT was present in 82/2336 (3.5%) patients at diagnosis and was associated with advanced Rai stage (Rai III–IV) (21% vs. 6%; P < .001), lower hemoglobin (13.1 g/dL vs. 13.9 g/dL; P < .001), and lower platelet count (187 × 109/L vs. 200 × 109/L; P = .03). Additionally, 236 patients with normal LFTs at diagnosis developed acquired liver dysfunction during follow‐up. Patients with abnormal LFTs at diagnosis had a shorter OS compared to those with normal LFTs (HR 1.80 95% CI 1.13‐2.87; P = .014, adjusted for age, sex, Rai stage, and treatment), although TTFT was not different. Of 52 patients who underwent a liver biopsy, CLL was present in liver tissue in 39/52 (73%) patients, with the portal tracts the most common region involved. Histopathology findings of liver involvement by CLL had limited correlation with choice of CLL therapy. In conclusion, approximately 1 of 25 newly diagnosed CLL patients has abnormal LFTs at diagnosis. Although the TTFT was not different among patients with abnormal LFTs, these patients have a shorter OS compared to those with normal LFTs.     

Italian external and multicentric validation of the MD Anderson Cancer Center nomogram and prognostic index for chronic lymphocytic leukaemia patients: analysis of 1502 cases

We performed an external and multicentric validation of the nomogram and prognostic index (PI) proposed by the MD Anderson Cancer Center to prognostically stratify chronic lymphocytic leukaemia (CLL) patients in 1502 CLL cases. All six parameters involved in the nomogram and PI (age, sex, absolute lymphocyte count, number of lymph node groups, Rai stage and β2‐microglobulin) were independently associated with survival. The nomogram was accurate in predicting survival (c‐index = 0·82). According to the PI, 38·7% of patients were at low‐risk, 58·3% at intermediate‐risk and 3% at high‐risk. The estimated median survival times were: not reached for low‐risk, 13·4 years for intermediate‐risk and 3·4 years for high‐risk. The estimated median and 5‐year survival by PI were similar to those originally reported. The PI remained a predictor of survival when analysis was limited to 847 Rai stage 0 (P < 0·0001) and 151 clinical monoclonal B‐cell lymphocytosis (cMBL) cases (P = 0·033). Finally, the PI allowed prediction of time to therapy in all patients (P < 0·0001), in Rai 0 (P < 0·0001) and in cMBL cases (P = 0·044). Our results confirm the ability of the PI to predict prognosis, even in early stage disease cases. The study also extended the utility of the PI to cMBL cases.