Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines

Hallek, Michael; Cheson, Bruce D.; Catovsky, Daniel; Caligaris-Cappio, Federico; Dighiero, Guillaume; Döhner, Hartmut; Hillmen, Peter; Keating, Michael J.; Montserrat, Emili; Kanti, R.; Kipps, Thomas J.

doi:10.1182/blood-2007-06-093906

Cited by 2,910 publications

(2,864 citation statements)

References 69 publications

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“…Overall response rate (ORR) was defined as the proportion of patients achieving complete response (CR), CR with incomplete bone marrow recovery (CRi), nodular partial response (nPR), partial response (PR), or PR with lymphocytosis (PR‐L), per the International Workshop on CLL (iwCLL) 2008 criteria modified for treatment‐related lymphocytosis (Hallek et al , 2008, 2012). Efficacy endpoints were based on investigator assessments.…”

Section: Methodsmentioning

confidence: 99%

“…Sustained haematological improvement was defined as an increase in cytopenias that was sustained continuously for ≥56 days without transfusion or growth factors, as measured by the following: an increase in the platelet count or absolute neutrophil count (ANC) from baseline of ≥50% or, for haemoglobin, an increase from baseline of ≥20 g/l. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf), with the exception of haematological toxicities, which were graded per iwCLL 2008 criteria (Hallek et al , 2008). …”

Section: Methodsmentioning

confidence: 99%

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Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

et al. 2018

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SummaryPatients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) with deletion 17p [del(17p)] have poor outcomes with chemoimmunotherapy. Ibrutinib is indicated for the treatment of CLL/SLL, including del(17p) CLL/SLL, and allows for treatment without chemotherapy. This integrated analysis was performed to evaluate outcomes in 230 patients with relapsed/refractory del(17p) CLL/SLL from three ibrutinib studies. With a median of 2 prior therapies (range, 1–12), 18% and 79% of evaluable patients had del(11q) or unmutated IGHV, respectively. With a median follow‐up of 28 months, overall response rate was 85% and estimated 30‐month progression‐free and overall survival rates were 57% [95% confidence interval (CI) 50–64] and 69% (95% CI 61–75), respectively. Patients with normal lactate dehydrogenase or no bulky disease had the most favourable survival outcomes. Sustained haematological improvements in haemoglobin, platelet count and absolute neutrophil count occurred in 61%, 67% and 70% of patients with baseline cytopenias, respectively. New onset severe cytopenias and infections decreased in frequency over time. Progression‐free and overall survival with ibrutinib surpass those of other therapies for patients with del(17p) CLL/SLL. These results provide further evidence of the robust clinical activity of ibrutinib in difficult‐to‐treat CLL/SLL populations.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

et al. 2018

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“…All CLL cases were diagnosed according to the iwCLL guidelines and displayed a typical CLL phenotype 31 . Over 76% of samples were collected before treatment and within a median of 7 months from time of diagnosis (EGR2-mutated cases, median 2 months).…”

Section: Patientsmentioning

confidence: 99%

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

et al. 2016

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EGR2 mutations in CLL 5 AbstractRecurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%), and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

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“…3 Fifty-nine samples were obtained from patients diagnosed with CLL at the Royal Bournemouth Hospital and Southampton General Hospital following ethical committee approvals (06/Q2202/30 and 228/02/t, respectively) under the declaration of Helsinki (Supplementary Table 1). Malignant cell isolation and the determination of their purity have been described previously.…”

Section: Patientsmentioning

confidence: 99%

“…Progressive disease is characterised by unmutated immunoglobulin heavy variable (IGHV) genes, ZAP70 and CD38 expression. 1 Genetic markers including deletions of 17p, 11q and 13q, trisomy 12 and TP53 mutations [2][3][4] have been known to impact prognosis for some time, however with the emergence of next generation sequencing, a plethora of new genetic alterations have been identified including NOTCH1 (10-15%) [5][6][7][8] and SF3B1 (10-17%) [8][9][10] mutations which identify patients with progressive disease. 8 SF3B1 is one of the proteins that make up the spliceosome and regulates excision of introns from premRNA 11 .…”

Section: Introductionmentioning

confidence: 99%

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

et al. 2015

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The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose-and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression.However, normal B and T cells were less sensitive than CLL cells (p=0.006 and p<0.001, respectively).

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Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines

Cited by 2,910 publications

References 69 publications

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

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