A 3-decade multicenter European experience with cladribine as upfront treatment in 384 patients with hairy cell leukemia.

Cladribine is regarded as the first treatment of choice for symptomatic hairy cell leukemia. This large international study reports a complete response in 72% of cases and a continuous complete response in 20% of patients.

The association between deaths from infection and mutations of the BRAF, FBXW7, NRAS and XPO1 genes: a report from the LRF CLL4 trial.

Causes of death, in particular deaths due to infection, have not been widely studied in randomised trials in chronic lymphocytic leukaemia. With long-term follow-up (median 13 years) we examined the cause of death in 600/777 patients in the LRF CLL4 trial. Blood samples, taken at randomisation from 499 patients, were available for identifying gene mutations.

Early clinical trials in chronic lymphocytic leukaemia in the UK.

This is an historical account of the randomised trials in chronic lymphocytic leukaemia in the UK between the years 1978 to 2004, describing their gestation, the treatments used and the main lessons learnt. Those lessons include: (1) how best to use chlorambucil, which was the first effective treatment for CLL; (2) the significant difference in survival between the sexes; and (3) the value of prognostic markers, both morphological and molecular, which continue to be relevant to current practice.

Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial.

Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.

Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics.

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development.

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R = 0.

iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL.

The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by physicians and investigators caring for patients with CLL. Recent advances including the discovery of the genomic landscape of the disease, the development of genetic tests with prognostic relevance, and the detection of minimal residual disease (MRD), coupled with the increased availability of novel targeted agents with impressive efficacy, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. These recommendations include a revised version of the iwCLL response criteria, an update on the use of MRD status for clinical evaluation, and recommendations regarding the assessment and prophylaxis of viral diseases during management of CLL.

Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.

Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci.

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790).

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia.

Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression.

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 () co-segregated with CLL. The p.

Genetic Predisposition to Chronic Lymphocytic Leukemia Is Mediated by a BMF Super-Enhancer Polymorphism.

Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk.

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.

Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer.

CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels.

The outcome of Chronic lymphocytic leukaemia patients with 97% IGHV gene identity to germline is distinct from cases with <97% identity and similar to those with 98% identity.

IGHV gene mutational status has prognostic significance in chronic lymphocytic leukaemia (CLL) but the percentage of mutations that correlates best with clinical outcome remains controversial. We initially studied 558 patients from diagnosis and found significant differences in median time to first treatment (TTFT) among Stage A patients and in overall survival (OS) for the whole cohort, between cases with <97% and 97-98·99% identity and between cases with 97-98·99% and ≥99% identity, when cases from the IGHV3-21 Stereotype Subset #2 were excluded. A significant difference in progression-free survival (PFS) and OS between those with <97% and 97-98·99% identity, but not between those with 97-98·99% and ≥99% identity was also observed in a validation cohort comprising 460 patients in the UK CLL4 trial.

Evaluation of serum markers in the LRF CLL4 trial: β2-microglobulin but not serum free light chains, is an independent marker of overall survival.

Chronic lymphocytic leukemia (CLL) is characterized by heterogeneous clinical behavior and there is a need for improved biomarkers. The current study evaluated the prognostic significance of serum free light chains (sFLC, kappa, and lambda) and other serum markers (bar, serum thymidine kinase (sTK), soluble CD23, and LDH) together with established biomarkers in 289 patients enrolled into the LRF CLL4 trial. In a multivariable analysis of serum markers alone, higher big and kappa light chains were statistically significant in predicting disease progression and higher blg, and sTK in predicting mortality.

Long-term follow-up after purine analogue therapy in hairy cell leukaemia.

Since 2006 when we last reviewed the literature concerning the use of purine analogues in hairy cell leukaemia (HCL), results from several new and updated series have been published. Here we examine these reports and consider their implications for patient management. The two purine analogues pentostatin and cladribine remain the first-line treatments of choice for all patients with HCL.

The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years.

With 10+ years follow-up in the Leukaemia Research Fund (LRF) CLL4 trial, we report the effect of salvage therapy, and the clinical/biological features of the 10-year survivors treated for chronic lymphocytic leukaemia (CLL). Overall survival (OS) was similar in the three randomized arms. With fludarabine-plus-cyclophosphamide (FC), progression-free survival (PFS) was significantly longer (P < 0.

An unusual indication for splenectomy in hairy cell leukaemia: a report of three cases with persistent splenomegaly after chemoimmunotherapy.

We describe three cases of relapsed hairy cell leukaemia (HCL) treated with pentostatin plus rituximab. All three achieved bone marrow complete remission but had persistent splenomegaly and hypersplenism. Because of the clinical uncertainty of its significance, they were all splenectomized.