Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Authors: B. Eichhorst, M. Dreyling, T. Robak, E. Montserrat, M. Hallek
Journal: Annals of Oncology (2011)

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world with an incidence of 4.2/100 000/year [1.Altekruse S.F. Kosari C.L. Krapcho M. et al.SEER Clinical Statistics Review, 1975–2007. National Cancer Insitute,, Bethesda, MD2010Google Scholar]. The incidence increases to >30/100 000/year at an age of >80 years. The median age at diagnosis is 72 years. About 10% of CLL patients are reported to be younger than 55 years. The diagnosis of CLL is established by the following criteria [2.Hallek M. Cheson B.D. Catovsky D. et al.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.Blood. 2008; 111: 5446-5456Crossref PubMed Scopus (2717) Google Scholar]:•The presence in the peripheral blood of ≥5000 monoclonal B lymphocytes/μl for the duration of at least 3 months. The clonality of the circulating B lymphocytes needs to be confirmed by flow cytometry.•The leukemia cells found in the blood smear are characteristically small, mature lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli and having partially aggregated chromatin. CLL cells co-express the CD5 antigen and B-cell surface antigens CD19, CD20 and CD23. The levels of surface immunoglobulin, CD20 and CD79b are characteristically low compared with those found on normal B cells. Each clone of leukemia cells is restricted to expression of either κ or λ immunoglobulin light chains. In contrast, the leukemia cells of mantle cell lymphoma, despite also expressing B-cell surface antigens and CD5, generally do not express CD23. For cases which express CD23, cyclin D1 staining or fluorescence in situ hybridization (FISH) for detecting a translocation (11;14) are useful to diagnose mantle cell lymphoma in leukemic phase. Other lymphoma entities to be separated from CLL are marginal zone lymphoma and immunocytoma. In the World Health Organization (WHO) classification, small lymphocytic lymphoma (SLL) and CLL are considered to be the same entity. The diagnosis of SLL requires the presence of lymphadenopathy and/or splenomegaly, with the number of B lymphocytes in the peripheral blood not exceeding 5×109/l. SLL cells show the same immunophenotype as CLL cells. The diagnosis of SLL should be confirmed by histopathological evaluation of a lymph node biopsy whenever possible. In the absence of lymphadenopathy and organomegaly, cytopenias and clinical symptoms, the presence of <5000 monoclonal B lymphocytes/μl is defined as 'monoclonal B-lymphocytosis' (MBL) [2.Hallek M. Cheson B.D. Catovsky D. et al.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.Blood. 2008; 111: 5446-5456Crossref PubMed Scopus (2717) Google Scholar]. Progress to CLL occurs in 1–2% of MBL cases per year [3.Rawstron A.C. Bennett F.L. O'Connor S.J. et al.Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.N Engl J Med. 2008; 359: 575-583Crossref PubMed Scopus (461) Google Scholar]. The following examinations are recommended prior to treatment initiation [III, B] [2.Hallek M. Cheson B.D. Catovsky D. et al.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.Blood. 2008; 111: 5446-5456Crossref PubMed Scopus (2717) Google Scholar]: •History and physical examination including a careful palpation of all lymph node areas, spleen and liver.•Complete blood cell count and differential count.•Serum chemistry including lactate dehydrogenase (LDH), bilirubin, serum immunoglobulin, direct antiglobulin test (DAT).•The status of relevant infections [hepatitis B and C, cytomegalovirus (CMV), human immunodeficiency virus (HIV)] should be evaluated prior to chemoimmunotherapy, alemtuzumab or allogeneic stem cell transplantation to avoid virus (re-)activation. The following additional examinations prior to treatment are desirable [III, B] [2.Hallek M. Cheson B.D. Catovsky D. et al.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.Blood. 2008; 111: 5446-5456Crossref PubMed Scopus (2717) Google Scholar]:•Although a bone marrow biopsy is not required for diagnosis, it is strongly recommended prior to initiating myelosuppressive therapies and for the diagnostic evaluation of unclear cytopenias.•The detection of cytogenetic abnormalities, in particular of a deletion of chromosome 17 [del(17p)] and 11 [del(11q)] by FISH may have therapeutic consequences. Therefore, a FISH analysis is recommended prior to the start of therapy.•Computed tomography (CT) scans are recommended for baseline and final assessment in clinical trials [III, C], but not as a routine practice outside of clinical trials. Clinical staging should not be based on imaging studies. The median survival from diagnosis varies between 18 months and >10 years. Two clinical staging systems are used [4.Binet J.L. Auquier A. Dighiero G. et al.A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis.Cancer. 1981; 48: 198-206Crossref PubMed Scopus (1492) Google Scholar, 5.Rai K.R. Sawitsky A. Cronkite E.P. Chanana A.D. Levy R.N. Pasternack B.S. Clinical staging of chronic lymphocytic leukemia.Blood. 1975; 46: 219-234Crossref PubMed Google Scholar]. In Europe, the Binet staging system is the more widely used. These staging systems separate three groups of different prognosis (Table 1) [4.Binet J.L. Auquier A. Dighiero G. et al.A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis.Cancer. 1981; 48: 198-206Crossref PubMed Scopus (1492) Google Scholar, 5.Rai K.R. Sawitsky A. Cronkite E.P. Chanana A.D. Levy R.N. Pasternack B.S. Clinical staging of chronic lymphocytic leukemia.Blood. 1975; 46: 219-234Crossref PubMed Google Scholar]. With the new treatment options available, the overall survival of patients with advanced stages has improved [6.Wierda W.G. Kipps T.J. Mayer J. et al.Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia.J Clin Oncol. 2010; 28: 1749-1755Crossref PubMed Scopus (513) Google Scholar].Table 1Staging systems for CLLStageDefinitionMedian survivalBinet systemBinet AHb ≥10.0 g/dl, platelets ≥100×109/l, <3 lymph node regions>10 yearsBinet BHb ≥10.0 g/dl, platelets ≥100×109/l, ≥3 lymph node regions>8 yearsBinet CHb <10.0 g/dl, platelets <100×109/l6.5 yearsRai systemLow riskRai 0Lymphocytosis >15×109/l>10 yearsIntermediate riskRai ILymphocytosis and lymphadenopathyRai IILymphocytosis and hepatomegaly and/or splenomegaly with/without lymphadenopathy>8 yearsHigh riskRai IIILymphocytosis and Hb <11.0 g/dl with/without lymphadenopathy/organomegalyRai IVLymphocytosis and platelets <100×109/l with/without lymphadenopathy/organomegaly6.5 yearsThe overall survival times included in this table are adapted to recently published data [29.Wierda W.G. O'Brien S. Wang X. et al.Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment.J Clin Oncol. 2009; 27: 1637-1643Crossref PubMed Scopus (67) Google Scholar].Hb, hemoglobin. Open table in a new tab The overall survival times included in this table are adapted to recently published data [29.Wierda W.G. O'Brien S. Wang X. et al.Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment.J Clin Oncol. 2009; 27: 1637-1643Crossref PubMed Scopus (67) Google Scholar]. Hb, hemoglobin. Additional prognostic markers are available to predict the prognosis of patients with CLL, in particular at early stages [7.Döhner H. Stilgenbauer S. Benner A. et al.Genomic aberrations and survival in chronic lymphocytic leukemia.N Engl J Med. 2000; 343: 1910-1916Crossref PubMed Scopus (2722) Google Scholar]. Patients with a detectable del(17p) or a mutation of the p53 gene (5–10% of the patients) have the poorest prognosis, with a median overall survival of 2–3 years. Another poor prognostic marker has been del(11q), which is found in ∼20% of the patients. However, the poor outcome of patients with del(11q) is overcome by chemoimmunotherapy with FCR (fludarabine, cyclophosphamide and rituximab) [8.Hallek M. Fischer K. Fingerle-Rowson G. et al.Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: a randomised, open-label, phase III trial.Lancet. 2010; 376: 1164-1174Abstract Full Text Full Text PDF PubMed Scopus (1555) Google Scholar]. About 50% of CLL patients present with an unmutated IGHV (immunoglobulin heavy chain variable) status [9.Damle R.N. Wasil T. Fais F. et al.Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.Blood. 1999; 94: 1840-1847Crossref PubMed Google Scholar, 10.Hamblin T.J. Orchard J.A. Ibbotson R.E. et al.CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease.Blood. 2002; 99: 1023-1029Crossref PubMed Scopus (559) Google Scholar]. These patients have a significantly shorter overall survival time and shorter time to treatment intervention. The expression of CD38, ZAP70 seems to correlate with the IGHV mutational status to some extent [11.Krober A. Seiler T. Benner A. et al.V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia.Blood. 2002; 100: 1410-1416Crossref PubMed Google Scholar]. The prognostic value of these markers needs further assessment in prospective clinical trials, but, in contrast to molecular cytogenetics (FISH), they do not influence treatment modality [III, C]. Treatment should only be given to patients with active, symptomatic disease. The following conditions define active disease: significant B-symptoms, cytopenias not caused by autoimmune phenomena and symptoms or complications from lymphadenopathy, splenomegaly or hepatomegaly, lymphocyte doubling time of <6 months (only in patients with >30 000 lymphoyctes/μl) as well as autoimmune anemia and/or thrombocytopenia poorly responsive to conventional therapy [I, A]. (Binet stage A and B without active disease; Rai 0, I and II without active disease) Previous studies have shown that early treatment with alkylating agents does not translate into a survival advantage in patients with early stage CLL [12.Dighiero G. Maloum K. Desablens B. et al.Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia.N Engl J Med. 1998; 338: 1506-1514Crossref PubMed Scopus (384) Google Scholar]. The standard treatment of patients with early disease is a watch and wait strategy [I, A]. Blood cell counts and clinical examinations should be performed every 3–12 months. (Binet stage A and B with active disease, Binet stage C; Rai 0–II with symptoms, Rai III–IV) The fitness and co-morbidity of patients need to be evaluated for the choice of the treatment. For assessing the co-morbidity burden, the cumulative illness rating scale represents a helpful tool [13.Extermann M. Overcash J. Lyman G.H. Parr J. Balducci L. Comorbidity and functional status are independent in older cancer patients.J Clin Oncol. 1998; 16: 1582-1587Crossref PubMed Scopus (864) Google Scholar]. An improved survival has been demonstrated following first-line chemoimmunotherapy with FCR in physically fit patients with CLL [I, A] [8.Hallek M. Fischer K. Fingerle-Rowson G. et al.Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: a randomised, open-label, phase III trial.Lancet. 2010; 376: 1164-1174Abstract Full Text Full Text PDF PubMed Scopus (1555) Google Scholar]. Therefore, in this patient group (physically active, no major health problems, normal renal function) FCR is the standard first-line therapy. Combinations based on other purine analogs such as cladribine [14.Robak T. Jamroziak K. Gora-Tybor J. et al.Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study).J Clin Oncol. 2010; 28: 1863-1869Crossref PubMed Scopus (95) Google Scholar] or pentostatin [15.Kay N.E. Geyer S.M. Call T.G. et al.Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia.Blood. 2007; 109: 405-411Crossref PubMed Scopus (255) Google Scholar] have shown similar activity, but it is uncertain whether they can replace fludarabine in the FCR regimen [II, B]. In patients with relevant co-morbidity, chlorambucil [II, B] seems to be the standard therapy [16.Eichhorst B.F. Busch R. Stilgenbauer S. et al.First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia.Blood. 2009; 114: 3382-3391Crossref PubMed Scopus (304) Google Scholar]. Alternatives are dose-reduced purine analog-based therapies [FC, PCR (pentostatin, cyclophosphamide and rituximab] [III, B] or bendamustine [II, B] [17.Knauf W.U. Lissichkov T. Aldaoud A. et al.Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia.J Clin Oncol. 2009; 27: 4378-4384Crossref PubMed Scopus (397) Google Scholar]. Patients showing a chromosomal defect del(17p) or p53 mutation frequently do not respond to conventional chemotherapy with fludarabine or FC. Even after FCR therapy, progression-free survival of these patients remains short [8.Hallek M. Fischer K. Fingerle-Rowson G. et al.Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: a randomised, open-label, phase III trial.Lancet. 2010; 376: 1164-1174Abstract Full Text Full Text PDF PubMed Scopus (1555) Google Scholar]. Therefore, physically fit (and young) patients should be offered an effective initial regimen, of which alemtuzumab is currently the most widely explored, followed by an allogeneic stem cell transplantation within clinical trials [III, B] [18.Dreger P. Corradini P. Kimby E. et al.Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus.Leukemia. 2007; 21: 12-17Crossref PubMed Scopus (323) Google Scholar, 19.Dreger P. Dohner H. Ritgen M. et al.Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia:long-term clinical and MRD results of the GCLLSG CLL3X trial.Blood. 2010; 116: 2438-2447Crossref PubMed Scopus (257) Google Scholar].Table 2Diagnostic and staging work-upPretreatment evaluationStagingHistory, physical examination and performance status++Complete blood count and differential++Serum chemistry including serum immunoglobulin and direct antiglobulin test++Cytogenetics (FISH) for del (17p)+–Marrow aspirate and biopsy+aOnly if clinically indicated.+bOnly for confirmation of complete response.Hepatitis B and C, CMV and HIV serology+–CMV, cytomegalovirus; FISH, fluorescence in situ hybridization; HIV, human immonodeficiency virus.a Only if clinically indicated.b Only for confirmation of complete response. Open table in a new tab Table 3Management by stage, risk categories and physical fitnessStageFitnessMolecular cytogeneticsFirst-line therapyAsymptomatic Binet A–B or Rai 0–IIIrrelevantIrrelevantNoneBinet C or Rai III–IV, or symptomatic disease (any stage)Go GoNo del(17p)FCRdel(17p)FCR, A or FA→Allo SCTSlow GoNo del(17p)CLBdel(17p)ARelapseFitnessMolecular cytogeneticsRelapse therapyEarly (<12–24 months after monotherapy or <24–36 months after chemoimmunotherapy)Go GoNo del(17p)After chemoimmunotherapy: BR, A or FA→Allo SCT After monotherapy: FCRdel(17p)A or FA→Allo SCTSlow GoNo del(17p)FCRaNot recommended for patients refractory to fludarabine., B, A, O, R + HDSdel(17p)ALate (>12–24 months after monotherapy or >24–36 months after chemoimmunotherapy)Go Go and Slow GoRepeat first line'Go go' defines patients with a good physical fitness and low co-morbidity burden, 'Slow Go' defines patients with impaired physical fitness and relevant comorbidity burden).A, alemtuzumab; Allo SCT, allogeneic stem cell transplantation; B, bendamustine; C, cyclophosphamide; Clb, chlorambucil; F, fludarabine; HDS, high-dose steroids; O, ofatumumab; R, rituximab.a Not recommended for patients refractory to fludarabine. Open table in a new tab CMV, cytomegalovirus; FISH, fluorescence in situ hybridization; HIV, human immonodeficiency virus. 'Go go' defines patients with a good physical fitness and low co-morbidity burden, 'Slow Go' defines patients with impaired physical fitness and relevant comorbidity burden). A, alemtuzumab; Allo SCT, allogeneic stem cell transplantation; B, bendamustine; C, cyclophosphamide; Clb, chlorambucil; F, fludarabine; HDS, high-dose steroids; O, ofatumumab; R, rituximab. The first-line treatment may be repeated, if the relapse or progression occurs at least 12–24 months after a monotherapy or 24–36 months after chemoimmunotherapy, respectively [III, B]. If relapse occurs within 12–24 months after monotherapy or 24–36 months after chemoimmunotherapy, or if the disease does not respond to any first-line therapy, the therapeutic regimen needs to be changed to one of the following options [III, B]:•Salvage regimen, e.g. alemtuzumab, followed by allogeneic stem cell transplantation in physically fit patients [18.Dreger P. Corradini P. Kimby E. et al.Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus.Leukemia. 2007; 21: 12-17Crossref PubMed Scopus (323) Google Scholar].•FCR for patients relapsed or refractory to first-line therapy with an alkylating agent [20.Robak T. Dmoszynska A. Solal-Celigny P. et al.Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia.J Clin Oncol. 2010; 28: 1756-1765Crossref PubMed Scopus (425) Google Scholar].•A bendamustine- or alemtuzumab-containing regimen in physically non-fit patients without del(17p) [21.Hillmen P. Skotnicki A.B. Robak T. et al.Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia.J Clin Oncol. 2007; 25: 5616-5623Crossref PubMed Scopus (510) Google Scholar]. In subsequent relapses, an attempt with high-dose ofatumumab or rituximab with high-dose steroids can also be made [6.Wierda W.G. Kipps T.J. Mayer J. et al.Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia.J Clin Oncol. 2010; 28: 1749-1755Crossref PubMed Scopus (513) Google Scholar, 22.Castro J.E. James D.F. Sandoval-Sus J.D. et al.Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia.Leukemia. 2009; 23: 1779-1789Crossref PubMed Scopus (85) Google Scholar].•An alemtuzumab-containing regimen in patients with del(17p). In order to achieve better efficacy in patients with bulky disease, alemtuzumab may be combined with fludarabine or steroids [23.Elter T. Borchmann P. Schulz H. et al.Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial.J Clin Oncol. 2005; 23: 7024-7031Crossref PubMed Scopus (199) Google Scholar]. Allogeneic stem cell transplantation is the only curative therapy and is especially indicated in very high risk [del(17p), p53 mutation] and/or refractory disease [18.Dreger P. Corradini P. Kimby E. et al.Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus.Leukemia. 2007; 21: 12-17Crossref PubMed Scopus (323) Google Scholar]. The use of autologous hematopoietic stem cell transplantation does not seem to yield better results than chemoimmunotherapies [III, B]. There is no proven efficacy of consolidation or maintenance therapy in CLL. This strategy cannot be recommended outside clinical trials. Autoimmune cytopenia, especially autoimmune hemolytic anemia (AIHA), appears in 5–10% of CLL patients. In these patients, the prognosis is not as poor as in those cases in which the cytopenia is due to a massive bone marrow infiltration by the disease [24.Moreno C. Hodgson K. Ferrer G. et al.Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance.Blood. 2010; 116: 4771-4776Crossref PubMed Scopus (114) Google Scholar]. Most patients with autoimmune cytopenia respond to corticosteroids [III, B]. For patients not responding to corticosteroids, splenectomy is a reasonable treatment choice. Monoclonal antibodies and thrombopoietin analogs can be used [III, B] in selected cases not responding to corticosteroids and before splenectomy. In patients with resistant immune cytopenia, treatment of the underlying CLL is recommended. Because most CLL patients develop a severe immune defect during the course of the disease, infections are a common complication. The use of prophylactic intravenous immunoglobulin does not have an impact on overall survival [25.Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia A randomized, controlled clinical trial. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia.N Engl J Med. 1988; 319: 902-907PubMed Google Scholar] and is therefore not recommended to be used as routine [II, B]. Antibiotic, antiviral or antifungal prophylaxis might be used in selected patients with recurrent infections and/or very high risk of developing infections (e.g. treatment with alemtuzumab, allogeneic stem cell transplantation) [IV, B]. The development of transformation into an aggressive lymphoma or Hodgkin's lymphoma (HD), a Richter's syndrome or B-cell prolymphocytic leukemia (B-PLL) occurs in 2 –15% of CLL patients during the course of their disease. The diagnosis has to be confirmed by lymph node excision. The transformation of CLL into HD represents a separate entity, since conventional chemotherapy against HD often achieves long-lasting remissions. Otherwise, the prognosis of Richter's syndrome and B-PLL is very poor. A rituximab-containing regimen, for example rituximab plus hyper CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and cytarabine) or OFAR (oxaliplatin, fludarabine, cytarabine and rituximab) for Richter's syndrome and FCR for B-PLL, is recommended for remission induction [IV, B]. Because of the short response duration of Richter's syndrome, an allogeneic stem cell transplantation should be considered in patients with available donors and sufficient fitness [IV, D]. Response evaluation includes careful physical examination and a blood cell count. A marrow biopsy is recommended for the proper definition of complete remissions, in particular in clinical trials [III, B] [2.Hallek M. Cheson B.D. Catovsky D. et al.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.Blood. 2008; 111: 5446-5456Crossref PubMed Scopus (2717) Google Scholar]. Chest X-ray and an abdominal ultrasound or CT for response evaluation can be performed, if abnormal prior to therapy [IV, C] [2.Hallek M. Cheson B.D. Catovsky D. et al.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.Blood. 2008; 111: 5446-5456Crossref PubMed Scopus (2717) Google Scholar]. Detection of minimal residual disease (MRD) by four-color flow cytometry has prognostic impact [26.Moreton P. Kennedy B. Lucas G. et al.Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival.J Clin Oncol. 2005; 23: 2971-2979Crossref PubMed Scopus (381) Google Scholar]. Patients who have become MRD negative after the end of treatment have a significantly longer response duration and also a longer survival. However, the clinical consequences of an MRD signal after the end of therapy are unclear. Therefore, the analysis of MRD should be performed in clinical trials, but not as a general routine. A large monocentric study has shown that the prognosis of CLL patients has improved during the past 30 years independently of stage of the disease [27.Abrisqueta P. Pereira A. Rozman C. et al.Improving survival in patients with chronic lymphocytic leukemia (1980–2008): the Hospital Clinic of Barcelona experience.Blood. 2009; 114: 2044-2050Crossref PubMed Scopus (119) Google Scholar]. The improved survival was mainly due to a decrease in CLL-attributable mortality in patients younger than 70 years and in patients with Binet stage B or C at diagnosis [III, B]. Moreover, chemoimmunotherapy combinations have been shown to prolong the overall survival in physically fit patients with advanced stage disease [I, A] [8.Hallek M. Fischer K. Fingerle-Rowson G. et al.Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: a randomised, open-label, phase III trial.Lancet. 2010; 376: 1164-1174Abstract Full Text Full Text PDF PubMed Scopus (1555) Google Scholar, 28.Tam C.S. O'Brien S. Wierda W. et al.Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia.Blood. 2008; 112: 975-980Crossref PubMed Scopus (602) Google Scholar]. In spite of these combinations, patients with del(17p) as well as primary refractory patients still have an impaired prognosis with a median overall survival of <36 months [II, A]. Due to the lack of appropriate therapeutic interventions, the prognosis of early stage CLL has remained unchanged and is dependent on the individual risk profile [I, A]. Follow-up of asymptomatic patients should include a blood cell count, and the palpation of lymph nodes, liver and spleen every 3–12 months. Special attention should be paid to the appearance of autoimmune cytopenias as well as the development of a Richter's syndrome or prolymphocytic leukemia. Moreover, patients with CLL have a 2- to 7-fold increased risk of developing secondary malignancies, including secondary myelodysplastic syndromes or acute myelogenous leukemia as well as solid tumors. Thanks are due to Federico Caligaris-Cappio, Peter Dreger, Christian Geisler, John Gribben, Eva Kimby and Stephan Stilgenbauer for helpful comments and suggestions, to Claire Bramley for her assistance, and to the European Research Initiative on CLL (ERIC) for its support. Levels of Evidence [IV] and Grades of Recommendation [AD] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.