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Summary Hairy cell leukaemia (HCL) was first described 50 years ago. Median survival was then 4 years. The purine analogues, introduced in the 1980s, transformed this prognosis. We reviewed data retrospectively from 233 patients, treated with pentostatin (n = 188) or cladribine (n = 45), to investigate the current long‐term outlook. Median follow‐up was 16 years. There were no significant differences in outcome between the two agents. Overall, the complete response (CR) rate was 80% and median relapse‐free survival was 16 years. After relapse (n = 79) or non‐response (n = 5), 26 patients received pentostatin and 58 cladribine; 69% achieved CR and median relapse‐free survival was 11 years. After third‐line therapy (n = 23), 50% achieved CR and median relapse‐free survival was 6·5 years. However, CRs were equally durable, whether after first, second or third‐line therapy. Complete responders and those with both haemoglobin >100 g/l and platelet count >100 × 109/l before treatment had the longest relapse‐free survival (P < 0·0001). Patients still in CR at 5 years had only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease improved with the monoclonal antibody rituximab, combined with either purine analogue. Overall only eight patients died of HCL‐related causes. Patients achieving a CR can expect a normal lifespan.

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. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients

Key Points• This is the first study to validate the importance of NOTCH1 and SF3B1 gene mutations in the context of a randomized, prospective clinical trial.• Mutations in both genes are independent prognostic biomarkers, and therefore have clinical utility in the accurate risk-adapted stratification of CLL patients. Continuing Medical Education onlineThis activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and the American Society of Hematology. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s) ™ . Physicians should claim only the credit commensurate with the extent of their participationin the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 566. Disclosures Associate Editor John G. Gribben served as an advisor or consultant for Celgene and Roche and as a speaker or a member of a speakers bureau for Roche, Jensen, and Celgene. The authors and CME questions author Laurie Barclay, freelance writer and reviewer, Medscape, LLC, declare no competing financial interests. For personal use only. on May 9, 2018. by guest www.bloodjournal.org From Continuing Medical Education online Learning objectivesUpon completion of this activity, participants will be able to:1. Describe the frequency of NOTCH1 and SF3B1 mutations in patients with chronic lymphocytic leukemia (CLL), and their correlations with other genetic markers.2. Describe survival in CLL patients with NOTCH1 mutations, and the prognostic value of this mutation. 3. Describe survival in CLL patients with SF3B1 mutations, and the prognostic value of this mutation.

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