Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment
TLDR
A large number of patients diagnosed with chronic lymphocytic leukemia have a history of atypical clinical course, suggesting that the disease typically occurs in elderly patients and has a highly variable clinical course.Abstract:
Disease Overview
Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B cells.
Diagnosis
The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen and B-cell markers.
Prognosis
Two prognostic staging systems exist, the Rai and Binet staging systems, which are established by physical examination and blood counts. Various biological and genetic markers also have prognostic value. Deletions of the short arm of chromosome 17 (del(17p)) and/or mutations of the TP53 gene predict resistance to available chemotherapies. A comprehensive prognostic score (CLL-IPI) using genetic, biological, and clinical variables has recently been developed allowing to classify CLL into very distinct risk groups.
Therapy
Patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. For physically fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab remains the current standard therapy. For unfit patients, currently available evidence supports two options for a first-line therapy: chlorambucil combined with an anti-CD20 antibody (obinutuzumab or rituximab or ofatumumab) or a continuous therapy with ibrutinib. At relapse, the initial treatment may be repeated, if the treatment-free interval exceeds 3 years. If the disease relapses earlier, therapy should be changed using alternative agents such as bendamustine (plus rituximab), alemtuzumab, lenalidomide, ofatumumab, ibrutinib, idelalisib, or venetoclax. Patients with a del(17p) or TP53 mutation can be treated with ibrutinib, venetoclax, or a combination of idelalisib and rituximab. An allogeneic SCT may be considered in relapsing patients with TP53 mutations or del(17p) or patients that are refractory to chemoimmunotherapy and the novel inhibitors.
Future Challenges
The new agents (ibrutinib, idelalisib, venetoclax, and obinutuzumab) hold the potential to significantly improve the outcome of CLL patients. However, their optimal use (in terms of combination, sequence, and duration) remains unknown. Therefore, CLL patients should be treated in clinical trials whenever possible.read more
Citations
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Journal ArticleDOI
Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma
Talha Munir,Jennifer R. Brown,Susan O'Brien,Jacqueline C. Barrientos,Paul M. Barr,Nishitha Reddy,Steven Coutre,Constantine S. Tam,Stephen P. Mulligan,Ulrich Jaeger,Thomas J. Kipps,Carol Moreno,Marco Montillo,Jan A. Burger,John C. Byrd,Peter Hillmen,Sandra Dai,Anita Szoke,James P. Dean,Jennifer A. Woyach +19 more
TL;DR: The robust efficacy of single‐agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL irrespective of high‐risk clinical or genomic features, with no unexpected AEs is confirmed.
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Past, Present, and Future of Rituximab-The World's First Oncology Monoclonal Antibody Therapy.
TL;DR: Current research into mechanisms and potential biomarkers of rituximab response are discussed, as well as its biosimilars and the newer CD20 binding mAb therapies.
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Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab.
John C. Byrd,Peter Hillmen,Susan O'Brien,Jacqueline C. Barrientos,Nishitha Reddy,Steven Coutre,Constantine S. Tam,Stephen P. Mulligan,Ulrich Jaeger,Paul M. Barr,Richard R. Furman,Thomas J. Kipps,Patrick Thornton,Carol Moreno,Marco Montillo,John M. Pagel,Jan A. Burger,Jennifer A. Woyach,Sandra Dai,Remus Vezan,Danelle F. James,Jennifer R. Brown +21 more
TL;DR: Long-term follow-up of patients treated in RESONATE provides support for sustained efficacy and safety of ibrutinib in relapsed/refractory CLL and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated.
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Chronic lymphocytic leukaemia: from genetics to treatment.
TL;DR: Next-generation sequencing of the coding genome has identified the most common somatic genetic alterations associated with the pathogenesis of chronic lymphocytic leukaemia and how these genetic insights influence clinical management and the development of new therapeutic strategies for this disease is discussed.
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DNA damage checkpoint kinases in cancer
TL;DR: This review will focus on the ATM- CHK2-p53-p21 pathway and the ATR-CHK1-WEE1 pathway and ongoing efforts to target these pathways for patient benefit.
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