Greil, R.

Hallek, M.

Stahel, R. A.

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ESMO Minimum Clinical Recommendations for diagnosis,treatment and follow-up of chronic lymphocytic leukemiaIncidence. B-chronic lymphocytic leukemia (B-CLL) has an incidenceof 3/100 000 per year in the western hemisphere. The inci-dence is increasing up to almost 50/100 000 per year afterthe age of 70 years. The incidence was reported to increasein younger patients, with about one-third of B-CLL patientsyounger than 55 years old. However, this trend does notseem to have changed the overall incidence of B-CLL sofar. B-CLL represents the most frequent non-Hodgkin’slymphoma (11%) and leukemia of adults (25%).Diagnosis. The diagnosis of B-CLL is established by the followingcriteria:Sustained increase of peripheral blood lymphocytes>_5 109 cells/l not explained by other clinicaldisorders.Predominance of small, morphologically maturelymphocytes in the blood smear.Immunophenotyping: The composite immunopheno-type CD5 + , CD23 + , CD20 dim + , sIg dim + ,FMC7 allows one to distinguish most cases ofB-CLL from other CD5 + B-cell lymphoma. TheMatutes score may be helpful in this regard.Lymph node biopsy: Histological confirmation isrecommended whenever an enlarged, accessible, per-ipheral lymph node allows the procedure withoutadditional risk.The following additional examinations are rec-ommended for the initial evaluation [V, D]:Physical examination including a careful palpationof all lymph node areas.LDH, b2-microglobulin, bilirubin, serum–proteinelectrophoresis, Coombs test.Chest X-ray, abdominal ultrasound or computertomography.. FISH is becoming increasingly used for risk stratificationand for choosing the treatment of choice in selected youngerhigh risk patients.. For prognostic and therapeutic reasons, every effort should bemade for adequate differential diagnosis against mantle celllymphoma using morphology, immunophenotyping and fluo-rescence in situ hybridization and/or molecular biology fordetection of (t11;14) translocation and staining for cyclin D1.Staging and prognosis. The median survival at diagnosis varies between 2 and >10years according to the initial stage of the disease. Twoclinical staging systems are used. In Europe, the Binet sta-ging system is generally more accepted. It separates threegroups of different prognosis (Table 1).Treatment of early disease. (Binet stage A and B without symptoms; Rai 0, I and IIwithout symptoms.). The standard treatment of patients with early disease is awatch and wait strategy with controls of blood cell countsand clinical examinations every three months [I, A]. Patientswith rapid disease progression (lymphocyte doubling time<12 months) should be treated as below.Treatment of advanced disease. (Binet stage A and B with symptoms, Binet stage C; Rai IIwith symptoms, Rai III–IV.). B-symptoms, cytopenias not caused by autoimmunephenomena and symptoms or complications from lymphade-nopathy, splenomegaly or hepatomegaly are indications forchemotherapy [I, A].. Options are purine analogues (fludarabine, cladribine) orchlorambucil. Randomized trials have not demonstrated asurvival benefit for either option so far [I, A].. In younger patients (<_65 years, physically active, nomajor health problems) purine analogues may be rec-ommended as initial treatment, because they achieve ahigher rate of complete remissions and a longer pro-gression- and treatment-free survival than chlorambucil.The risks and benefits of fludarabine are better documen-ted than those of other purine analogues. Combinationsof purine analogues with other drugs, in particular cyclo-phosphamide appear to result in a higher complete remis-sion rate than single agent therapy, but with a highertoxicity.. In older patients (>65 years, with high comorbidity) chlor-ambucil can be given as first line therapy, because it is lessmyelotoxic and immunosuppressive than purine analoguesthus resulting in fewer infections.Second-line chemotherapy. The first line treatment may be repeated, if the relapse or pro-gression occurs >6 months after the initial therapy [V, D].. If the relapse occurs within 6 months or if the disease doesnot respond to the first line therapy, the following optionsare recommended [V, D]:Annals of Oncology 16 (Supplement 1): i50–i51, 2005doi:10.1093/annonc/mdi806q 2005 European Society for Medical Oncology. Fludarabine after chlorambucil.. Fludarabine combinations (with cyclophosphamide and / ormitoxantrone (FCM) in fludarabine refractory patients.. Monoclonal antibody (alemtuzumab) in chemotherapyrefractory patients.. High dose therapy followed by autologous or allogeneicprogenitor cell transplantation remains investigational.Response evaluation. Response evaluation includes a blood cell count and a mar-row biopsy (only in patients with complete hematologicremission), as well as a chest X-ray and an abdominal ultra-sound or computer tomography [V, D].Follow-up. Follow up of asymptomatic patients should include a bloodcell count every 3 months, as well as a regular examinationsof lymph nodes, liver and spleen. Special attention shouldbe given to the number of atypical lymphocytes in particularto prolymphocytes [V, D].NoteLevels of Evidence [I–V] and Grades of Recommendation[A–D] as used by the American Society of Clinical Oncologyare given in square brackets. Statements without grading wereconsidered justified standard clinical practice by the expertsand the ESMO faculty.Literature1. de Lima M, O’Brien S, Lerner S, Keating M. Chronic lymphocyticleukemia in the young patient. Semin Oncol 1998; 25: 107–116.2. Herrinton LJ. Epidemiology, of the Revised European–AmericanLymphoma Classification Subtypes. Epidemiol Rev 1998; 20:187–203.3. Cheson BD, Bennett JM, Grever M et al. National Cancer Institute-Sponsored Working Group guidelines for chronic lymphocytic leuke-mia: revised guidelines for diagnosis and treatment. Blood 1996; 87:4990–4997.4. DiGiuseppe JA, Borowitz MJ. Clinical utility of flow cytometry in thechronic lymphoid leukemias. Semin Oncol 1998; 25: 6–10.5. Do¨hner H, Stilgenbauer S, Benner A et al. Genomic Aberrations andSurvival in Chronic Lymphocytic Leukemia. N Engl J Med 2000;343: 1910–1916.6. Harris NL, Jaffe ES, Diebold J et al. World Health Organizationclassification of neoplastic diseases of the hematopoietic and lym-phoid tissues: Report of the clinical advisory committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17:3835–3849.7. Rai KR, Peterson BL, Appelbaum FR et al. Fludarabine comparedwith chlorambucil as primary therapy for chronic lymphocytic leuke-mia. N Engl J Med 2000; 343: 1750–1757.8. Robak T, Blonski JZ, Kasznicki M et al. Cladribine with prednisoneversus chlorambucil with prednisone as first-line therapy in chroniclymphocytic leukemia: report of a prospective, randomized, multicen-ter trial. Blood 2000; 96: 2723–2729.9. Morrison VA, Rai KR, Peterson BL et al. Impact of therapy withchlorambucil, fludarabine, or fludarabine plus chlorambucil on infec-tions in patients with chronic lymphocytic leukemia: Intergroup StudyCancer and Leukemia Group B 9011. J Clin Oncol 2001; 19:3611–3621.10. CLL Trialists’ Collaborative Group. Chemotherapeutic options inchronic lymphocytic leukemia: a meta-analysis of the randomizedtrials. J Natl Cancer Inst 1999; 91: 861–868.11. Dighiero G, Maloum K, Desablens B et al. Chlorambucil in indolentchronic lymphocytic leukemia. French Cooperative Group on ChronicLymphocytic Leukemia. N Engl J Med 1998; 338: 1506–1514.Coordinating authors for the ESMO Guidelines Task Force: M. Hallek1,R. A. Stahel2 & R. Greil31LMU, Klinikum Grobhadern, Medizinische Klinik III, Munich,Germany; 2Assigned task force member, Div. of Oncology, UniversityHospital, Ra¨mistr. 100, CH-8091 Zu¨rich, Switzerland; 3Assigned taskforce member, University Hospital Salzburg,Dept of Hematology/Oncology, Muellnerhauptstrasse 48, 5020 Salzburg,AustriaApproved by the ESMO Guidelines Task Force: August 2003, last updateDecember 2004.Correspondence to:ESMO Guidelines Task ForceESMO Head OfficeVia La Santa 7CH-6962 LuganoSwitzerlandTable 1. Prognostic stages of CLLFrequency (%) Median survivalBinet stage:A 63 >10 yearsB 30 5 yearsC 7 1.53 yearsRai stage:0 Low 30 >10 yearsIIntermediate 60 7 yearsIIIIIHigh 10 1.5 yearsIVi51

ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of chronic lymphocytic leukemia

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