Mdn090 60.62

Annals of Oncology 19 (Supplement 2): ii60–ii62, 2008 Chronic lymphocytic leukemia: ESMO ClinicalRecommendations for diagnosis, treatment and follow-up B. Eichhorst1, M. Hallek1 & M. Dreyling2On behalf of the ESMO Guidelines Working Group*1Department of Internal Medicine I, University of Ko¨ln, Ko¨ln, Germany; 2Department of Medicine III, University Hospital Grosshadern, Munich, Germany  Chest X-ray.
 Because the detection of cytogenetic abnormalities by Chronic lymphocytic leukemia (CLL) has an incidence of 3–5/ fluorescent in situ hybridization (FISH) has apparent 100 000/year in the western hemisphere. The incidence is prognostic value, this examination should be carried out increasing up to 50/100 000/year after the age of 70 years.
during the initial evaluation of a patient with CLL.
Though the incidence has been reported to increase in younger  For prognostic and therapeutic reasons, every effort should be patients, with about one-third of CLL patients younger than made for adequate differential diagnosis against mantle zone 55 years, the overall incidence of CLL has rather decreased lymphoma using morphology, immunophenotyping and during the past 15 years. CLL represents the most frequent FISH and/or molecular biology for detection of (t11;14) translocation and staining for cyclin D1.
 Newer prognostic parameters such as the expression of CD38, ZAP70 and the immunoglobulin mutational status (IgVHmutation) may predict the time to progression from an early The diagnosis of CLL is established by the following criteria: stage to advanced disease, but should not be used fora treatment indication in CLL. At present, their value should  Sustained increase of peripheral blood lymphocytes ‡5 · 109 be further investigated in clinical trials.
cells/l not explained by other clinical disorders.
 Predominance of small, morphologically mature lymphocytes  Immunophenotyping: the composite immunophenotype The median survival at diagnosis varies between 1 and >10 CD5+, CD19+, CD20+ (low), CD23+, sIg low, CD79b low, years according to the initial stage of the disease. Two clinical FMC7– allows the distinction of most cases of B-cell type CLL staging systems are used. In Europe, the Binet staging system is generally more accepted. It separates three groups of different  Bone marrow biopsy is not needed for diagnosis, but is recommended before initiating therapy, in order to evaluateunclear cytopenia.
The following additional examinations are recommended for Binet stage A and B without symptoms; Rai 0, I and II without  Physical examination including a careful palpation of all  LDH, bilirubin, serum protein electrophoresis, Coombs test.
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.
Taddei 4, CH-6962 Viganello-Lugano, Switzerland Approved by the ESMO Guidelines Working Group: August 2003, last update July 2007.
This publication supercedes the previously published version—Ann Oncol 2007; 18 Conflict of interest: Dr. Eichhorst has reported that she is currently conducting research sponsored by Roche and Mundipharm and that she is member of the speakers’ bureau of Schering; Prof. Hallek has reported that he is currently conducting research ª 2008 European Society for Medical Oncology The standard treatment of patients with early disease is  Monoclonal antibody (alemtuzumab), especially in a watch and wait strategy with controls of blood cell counts and clinical examinations every 3 months [I, A]. Patients with active  Bendamustine 6 monoclonal antibodies after chlorambucil disease as defined by rapid disease progression (e.g. lymphocyte doubling time <6 months) should be treated as patients with  High-dose therapy followed by autologous or allogeneic progenitor cell transplantation remains investigational.
 Allogeneic progenitor cell transplantation is the only curative therapy so far and is indicated in high-risk [del(17p),del(11q)] and/or refractory disease Binet stage A and B with symptoms, Binet stage C; Rai II withsymptoms, Rai III–IV.
Significant B symptoms, cytopenias not caused by autoimmune Response evaluation includes careful physical examination and phenomena and symptoms or complications from a blood cell count. A marrow biopsy is only necessary in lymphadenopathy, splenomegaly or hepatomegaly as well as patients with complete hematologic remission and in clinical autoimmune anemia and/or thrombocytopenia poorly responsive trials. Chest X-ray and an abdominal ultrasound or to corticosteroid therapy are indications for chemotherapy [I, A].
computed tomography for response evaluation can be Options are purine analogs (fludarabine, cladribine) alone or considered for response evaluation, if abnormal before therapy in combination with cyclophosphamide or chlorambucil.
Randomized trials have not demonstrated a survival benefit foreither option so far [I, A].
In physically fit patients (physically active, no major health problems) the combination of fludarabine and Follow up of asymptomatic patients should include a blood cell cyclophosphamide (FC) is currently recommended as initial count every three months, as well as a regular examinations of treatment, because this combination induces a higher rate of lymph nodes, liver and spleen. Special attention should be paid complete remission and longer progression- and treatment-free to the appearance of autoimmune cytopenias (autoimmune survival than chlorambucil or purine analog monotherapy [I, hemolytic anemia, autoimmune thrombocytopenia) that occur A]. The combination of cladribine plus cyclophosphamide has not produced significantly longer progression-free survival(PFS) than cladribine alone. The addition of monoclonalantibodies such as rituximab (R) or alemtuzumab (A) to purine analog-based treatment regimens results in very high and Levels of evidence [I–V] and grades of recommendation qualitatively better remission, but a benefit in PFS is currently [A–D] as used by the American Society of Clinical Oncology being tested in randomized trials [III, B].
are given in square brackets. Statements without grading were In patients with relevant co-morbidity (in particular renal considered justified standard clinical practice by the experts and insufficiency) chlorambucil or a dose-reduced fludarabine monotherapy can be given as first-line therapy, because theyappear to be less myelotoxic than the FC combination.
Patients showing the chromosomal defect del(17p) frequently do not respond to conventional chemotherapy with 1. Robak T, Blonski JZ, Kasznicki M et al. Cladribine with prednisone versus fludarabine or FC. These patients may be initially treated with chlorambucil with prednisone as first-line therapy in chronic lymphocytic alemtuzumab monotherapy or combination therapy.
leukemia: report of a prospective, randomized, multicenter trial. Blood 2000; 96: Allogeneic transplantation within clinical trials might be considered as first-line therapy in these patients.
2. CLL Trialists’ Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. J Natl Cancer Inst1999; 91: 861–868.
3. Dighiero G, Maloum K, Desablens B et al. Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic The first line treatment may be repeated, if the relapse or Leukemia. N Engl J Med 1998; 338: 1506–1514.
progression occurs >12 months after initial therapy [V, D].
4. Eichhorst BF, Busch R, Hopfinger G et al. Fludarabine plus cyclophosphamide If relapse occurs within 12 months or if the disease does not versus fludarabine alone in first line therapy of younger patients with chronic respond to the first-line therapy, the following options are lymphocytic leukemia. Blood 2006; 107: 885–891.
recommended in accordance with the administered first-line 5. Flinn IW, Neuberg DS, Grever MR et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previouslyuntreated chronic lymphocytic leukemia: US Intergroup Trial E2997. JCO 2007;25: 793–798.
 Fludarabine, FC or cladribine after chlorambucil.
6. Byrd JC, Rai K, Peterson BL, Appelbaum FR et al. Addition of rituximab to  Fludarabine combinations [with cyclophosphamide (FC) fludarabine may prolong progression-free survival and overall survival in patients and/or mitoxantrone (FCM)] 6 monoclonal antibodies (FR, with previously untreated chronic lymphocytic leukemia: an updated FCR, FA) in fludarabine-refractory patients or relapse after retrospective comparative analysis of CALGB 9712 and CALGB 901. Blood 2005; 7. Binet JL, Caligaris-Cappio F, Catovsky D et al. Perspectives on the use of new diagnostic randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood 2006; tools in the treatment of chronic lymphocytic leukemia. Blood 2006; 107: 859–861.
8. Robak T, Blonski JZ, Gora-Tybor J et al. Cladribine alone and in combination with 9. Dreger P, Corradini P, Kimby E et al. Indications for allogeneic stem cell cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus.
progressive chronic lymphocytic leukemia: report of a prospective, multicenter,

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