Guidelines on the diagnosis and management of chronic lymphocytic leukaemia

The purpose of this guideline is to provide a rational approach to the diagnosis and management of patients with chronic lymphocytic leukaemia (CLL). This guideline has been compiled by the Guidelines Working Group of the UK CLL Forum on behalf of the British Committee for Standards in Haematology (BCSH). Recommendations are based on a review of the literature using Medline/Pubmed searches under the heading, CLL, up to October 2003 and data presented at the American Society of Hematology in 2003 and at the 10th International Workshop on CLL in 2003. The results of meta-analyses and phase 3 studies that have been published or presented in abstract form are included. Treatment recommendations were influenced by current and proposed clinical trials in the UK and by guidance from The National Institute for Clinical Excellence (NICE). A draft guideline was reviewed by members of the UK CLL Forum, patient representatives, members of the BCSH and a panel of approximately 60 UK haematologists. Their comments were incorporated where appropriate. To ensure widespread dissemination, the guideline is available on the BCSH website. Criteria for levels of evidence and grades of recommendation are shown in Table I. The guideline will be reviewed and updated in 2005, and a full guideline revision is planned for 2007. Chronic lymphocytic leukaemia is the most common type of leukaemia in the western world, accounting for 40% of all leukaemias in individuals over the age of 65 years. The median age of presentation is between 65 and 70 years. CLL is extremely rare below the age of 30 years but 20–30% of patients present under the age of 55 years. The overall incidence is approximately 3 per 100 000 per year. Studies on the racial and geographic distribution show that CLL is 20–30 times commoner in Europe, Australasia and North American white and black populations than in India, China and Japan. The male/female ratio in all populations is approximately 2:1 (Sgambati et al, 2001). There is no good evidence that exposure to chemicals or radiation, diet, cigarette smoking, viral infections or autoimmune disease are risk factors for the development of CLL. However, there is an increase in both lymphoid malignancies, including CLL, and a subclinical monoclonal B-cell expansion in first and second degree relatives of patients with CLL (Houlston et al, 2002; Rawstron et al, 2002). The phenomenon of anticipation in which the disease presents earlier and in a more severe form in successive generations is seen in many families with CLL (Yuille et al, 1998). The incidence of second malignancies is increased both in treated and untreated CLL. Patients may present with lymphadenopathy, systemic symptoms such as tiredness, night sweats and weight loss or the symptoms of anaemia or infection. However, 70–80% of patients are now diagnosed as an incidental finding on a routine full blood count. The initial clinical evaluation to a of lymphoid to and the of lymphadenopathy, and A diagnosis of CLL is based on the of a and and count. for the diagnosis of CLL a of Patients routine blood a of may CLL. for patients with a of between 3 and and with CLL or a blood count. However, there is no evidence that diagnosis of patients with clinical of CLL be using et al, CLL of are or with or and of the is to the of or of be in all and is of in the in with to the diagnosis of CLL and and in patients with to or CLL and or and A panel of monoclonal and for the diagnosis of CLL is shown in Table et al, this of CLL or 3 and or chronic B-cell and leukaemias or but a that may be at presentation the of the disease in all patients and and and is for the diagnosis of CLL, the of and of and a diagnosis of CLL in with and a is for the of and the to is for the diagnosis of CLL but may be where the diagnosis is in patients to and to to or an of in with and studies are for the diagnosis of CLL. However, may be there is is to a in with a may be the of is on where the finding of or disease the or and to in patients with to The clinical in CLL is a of the with which the disease is diagnosed in a in the of disease between and the to The median is approximately years but this is of to an patient to the in the of this studies have shown that the median of CLL is of patients present or below years et al, et al, et al, However, patients are more to of patients more of including second from the CLL trials have shown that to and is in than in et al, factors and more which to provide are shown in Table and the Clinical The clinical by et and et are the and of is to and of anaemia or a patient to or the of both the of a to of the of the and the to the of disease in patients with a A of patients with A disease have CLL be based on the et al, Group on Chronic or no of a of of patients disease years and were at years et al, Patients the 3 with A disease have a to with and et al, et al, et al, et al, 2002). have been shown to and in A but is by the of a between or the of in a studies have shown that a of on is a both in and in patients of clinical and levels et al, et al, et al, et al, 2002; et al, 2002; et al, The with is studies have of or may the of the disease et al, and there is a between and is a for There is a in the between patients with or et al, patients with a median of years with years for patients with et al, However, there is as to the of which with clinical and to the et al, 2002). data that the of such as the may a of et al, 2002). data that of and using with et al, et al, et al, has shown between and clinical in CLL. Patients with a or an of have a than with as the or with a et al, both and of were shown to be with et al, a using a panel of patients with an of of or of loss of of the on a median of and et al, studies have that using the by using the and in et al, The of the in second is in the the finding of good risk factors be to A evidence that the of the factors clinical is This is in trials such as the and the CLL the the of of the be in phase 3 clinical trials and shown to provide to in current The of factors for a to et al, and et al, but to or such as the disease such as and may be the the and of for factors are are and be in which of and and both that and loss or of the using a of to the to of was in a of was et al, 2002; et al, 2002). The management of CLL a approach between and a from a may be in the management of for to a the of or and the of a the is or there is anaemia or The management of patients be at a The of patients seen in may be in or a on and patient with a may be by for to a are Chronic lymphocytic leukaemia is a for which the is in years and is that patients are to a and with the Patients are for a and management will and are to be A is to the diagnosis of CLL to an patient with A disease diagnosed on a routine blood count. by the of the be by a and of the of the a to a patient is this be to ensure that the diagnosis The of patients and be CLL in and The of the of the the in to of and may be influenced by or may be from a of as and a of including on CLL and on with to The a of and to be more than published by A of is at There are from the that for by published by by published by and A for Patients by published by and has and a that a to all of The are from the There are that or for are current and are a of at International CLL at at There are is that patients be to a that are to be to of for patients to CLL at by CLL of and an of at of CLL at American Society at UK at National Institute at The patients to CLL from the at patients may to a of with the where There is a for CLL, for more on this and that may be of the is Patients may the UK CLL Forum, which a The for by the are shown in Table et al, will the of patients with or disease and a of patients with A of disease A patients autoimmune anaemia or be treated for autoimmune but may The of patients present with with or with disease and and are may be there is evidence of or to is rare in CLL and a in the of a is an for the of a are for The for or to by the are shown in Table et al, Patients the for a but lymphoid have been as a the of the have available for disease A of are available to A that CLL from based on of and is to all patients and CLL in are et al, 2001). may be using et al, 2002). However, this is and in The of in patients a by with monoclonal or for clinical However, patients may et al, 2002). be to such as and patient such as the of symptoms and the of and factors including the degree and of to and and are Chronic lymphocytic leukaemia presents management by of the in both the age of in the of the disease and the with which CLL is diagnosed in a The median of patients with CLL is to that seen in many malignancies and the of a most patients a of the of the The to a to in the overall such that which as initial may a to in the are The phenomenon is seen in trials in which the between for patients have to initial is to the of to that this a is more for the management of CLL, in patients with good in malignancies and to on in CLL is to a approach and disease with or to for in the that this will overall Treatment of CLL. the Group on CLL the of trials initial or disease in A CLL et al, 1998). to no or The second patients to no or to and for per for 3 years. with the of disease but there was no in overall in between and A of patients in trials of with or no in years the untreated of the first Group of patients disease and of A patients of There is current in clinical trials to A patients with risk disease from and more than The of and is under Treatment of disease with is A There are no studies no in patients with disease the for from the and clinical as as the seen in patients to with 2002). studies with or The and from no was there in of or overall with the of to et al, there was no between and et al, Patients are of may to studies have with in patients et al, Group on Chronic et al, et al, in more and a but there was no in and overall the Group a for patients with untreated disease using a a of than the for the of with Group on Chronic this the than in A of patients in with with or an of in both of the studies an and a of trials no with A of studies have the of in CLL. A of patients were to or with Patients a and median years 3 A untreated patients to at a of a 3 or to a of et al, This phase was by with at a of to The of the the using the proposed by the Group on CLL. of were by with at in a overall and median a median of Studies on were from the of trials are to in with phase 3 trials of as a and a diagnosis of based on a of for or for a of There is no for of 70–80% with a of approximately and a median of as a at a of for age than disease and to the of a et al, 1998). The of has no on overall et al, at a of for a with et al, 2001). studies have with including an with or an et al, et al, et al, 2001). a and of than or However, there was no in the for patients the studies of et and et this was to the of the studies and the to second with in patients or The risk of severe was with than with or in including an the were with a incidence of and the the incidence of leukaemia was in patients and in patients and in patients treated with et al, 2002). for and Treatment of with has and and et al, of a phase 3 CLL with in untreated patients over the age of 65 years with CLL, a overall and in the but no in with a median of was in patients but there was no in the incidence of severe infections et al, of the of the CLL which patients years with A or disease to or in with has shown that the results in a a and a incidence of severe but more severe and There was no in the incidence of severe infections et al, The of in untreated patients results in of approximately with et al, et al, The of is years. A phase 3 with for in a and for patients but no in overall et al, per of patients to to but of patients from second with results were to with the of the evidence is and is to as a routine to for the initial of CLL. To disease all patients treated with a blood There is no evidence that with or is an initial for CLL. However, is that patients with disease be a of to untreated patients in and et al, A phase in which was at a of 30 times per for up to to an of with The median to has been et al, 2002). results in in untreated CLL but is and over has been per of patients of blood is in untreated The of with in patients to initial with the is et al, A phase with or a overall and for the but the median and have been for a median of et al, to in with and are than using a of was in and were in using a of patients of but is to the clinical of a et al, the of patients are for a and in there is no to or an autoimmune the be This patients to or and and the of factors and of as as and are for patients to the Patients in is and for a approach has been be treated with A There is no for including an with in the initial of CLL A studies using are be as an initial for CLL a patient is for the or for an initial such as or and which is to in a or good be is for untreated CLL is in untreated CLL with or evaluation in untreated CLL There has been a for patients with or of is based on data and the results of trials of initial in which patients to to of the are over to The of patients may be or and may have or the results of many second studies to The for second and are as for initial with than such as may be in or in first The to second on a of factors including clinical the of and to the The second in the is to the of the in for patients initial are below and a is shown in Treatment in CLL. and are current UK UK CLL Forum trials risk A for patients to and Treatment for patients are or to or is shown in and Patients have to an such as be on or more However, the and of is to that with the initial and of in the of et al, et al, The to in patients initial with is the of patients to et al, a between and and of patients to et al, is to and in patients initial with et al, evidence for the of in treated patients is A phase 3 with in patients an for more than and than 3 an of in the with in the Group on CLL, A by the et al, patients between and or of patients to The data that are than in patients treated with but have in patients phase and phase studies have the of treated patients to et al, et al, et al, from to and from to are in patients have been were to have a and are years to in patients to an from to in patients to from to et al, et al, et al, to are seen in 40% of patients to to as first et al, 2001). guidance as second for patients have or are of first with an and or 2001). per of patients to to with the but the to in patients are to has been than and there are in as to of However, are to that with et al, et al, The results of a which from in patients were to et al, was by the of However, a by the and et al, in of patients for in phase studies show that are in with to treated the are than with are shown in Table there is published data on the of in CLL. A of or at a of for was in of were to et al, of was with a median of were seen in of patients with loss of the The and overall was in than in Patients to of the is in patients with an or and be with in patients with or A of patients to have been treated with in studies The was and with a median with data on the of patients with were seen in patients with a and with of et al, may be in patients with to 2002). data that the of and may be in patients to both et al, 2002). has been to patients with disease with et al, and to et al, 2002). and have been patients have of and this be in a clinical has in CLL, the to in treated patients are at to times the all the are to in with or with and to patients with or CLL are to seen with second such as or The of and has been in patients with treated CLL, of were with more than of per of patients been to and been to using were in of patients of patients and of et al, 2001). A of treated patients with or and or and a and median of and and and and et al, The of patients with CLL are and in patients the increased and of with or this of patients are years. may be to a more approach with or a To the for CLL is is based on the that for there is a and that be by There is to this in CLL, as results in increased There are no studies with of for CLL. The first published studies of from et al, and were et al, 1998). this patients with CLL were of a good to The was and and the was in with a of monoclonal and The was but the most was that the was at years and the overall was have shown that from to of patients are at years from et al, of this data is by in patient of and of in or in the of studies data from the of or from the of This a as approximately of patients for an is the of a to or et al, with is to the with disease and data have shown that more than of is with as is a of more than between and et al, The and and the of blood or to blood in patients treated with and et al, for the of is based on the of that are with with second in the a of risk patients with an than et al, 2002). The to be in patients with et al, in are in at the of and in patients a et al, Patients with have a of an et al, The of a in and the risk of clinical in patients to a or a that is in CLL. The of is This is in the which with the of in patients a good or to first or second There have been no trials the of in CLL. The results of data and studies are shown in Table et al, 2002). The of patients have of and many are to is a in CLL, based on the of patients have a The overall in data of patients have with both the with and the of risk most patients have from patients with disease have a from an The that patients with may et al, and the clinical of that the is et al, 2002). with the with have the for studies using is but the and in patients with in in of The and approach to is using at the of a incidence of a of patients with a and with and there was no in or overall between patients and A or and A for et al, 2002). A of for CLL in has shown a of with and overall at of and et al, are to the of radiation, the systemic of CLL has that is the to an in the of patients with this of was first in the of CLL in many the available for the of systemic has to the of to where is a and with of patients a in and of and A has been in of patients in et al, The and trials for patients treated with and et al, The of is and may be seen with a of and and is a to as all a to et al, of may be and of to times per has the as no is seen et al, 2001). for A of in has been for in the of CLL. However, the of this disease that of or may be in this A of with a of in over 3 to an be in this et al, 2001). on is that than are may be in of with a in for are as There have been no studies with for CLL. A in which 55 patients were and of from with 55 patients no in of et al, a of studies more than the from with a of et al, et al, et al, et al, et al, factors for or were patients of were to anaemia or the were and are 3 years. factors for have been Patients an initial to may be treated with a of Patients to be treated with is an for patients for Patients disease more than and CLL to may be treated with Patients disease of may be treated with a of and Patients are or to have a the is as a for patients are to in with is for and in patients lymphadenopathy, treated with and to is for treated CLL with or may be in CLL and evaluation in this be for patients in or good are to and be in the of a such as the The of an be for patients with good have been treated and have risk patients be with a at an in disease the development of disease for a clinical may be in and in to or are a common clinical in CLL, with an incidence of per patient accounting for up to of all The increased to is both to the disease and from factors including and and factors for of and et al, 2002; et al, infections are with and and infections the most viral and infections were rare but are with the of and 2001). the of as is for patients with infections to or there are no studies to the and of this approach in patients with CLL. with or be for all patients or and for a of or and infections be for patients or there is a of or infection. Patients treated with with of in of patients treated with with the incidence of with be in patients A is an for with may be in the incidence of in patients such as and and in the of which is common et al, in of patients with CLL, more common in patients with disease and in with a disease The incidence of with with levels studies using to show studies using have in both the and of a patients with levels of of the of or a of or more infections 3 for or et al, Patients infections and a from the of the to that of first infection. The of at this was in a in which patients for to A patients to at a of or for et al, There was no in the or of infections between the in a patients at a of 3 for year. with the to patients and et al, has an on the incidence of viral or infections or on overall et al, there is the of in patients with CLL there has been Patients with and in have be treated with A Patients with CLL have been shown to have a to and et al, are and to a and more A of CLL patients to but with a type this to et al, 2001). levels were between CLL patients and but the to an most CLL patients A form of has been but no data as to in CLL are is to for patients with CLL, the of this is and studies on infections in CLL are et al, Patients and to be the of and the to as as symptoms Patients with infections be treated as but with infections will and to full including many infections are the common be as as all have been The incidence of autoimmune is than in the and with the incidence of and 2001). may be diagnosed at or more the of the in patients with disease studies have an between and with The incidence of from in untreated patients to more than in There have been no trials for autoimmune in CLL. a of of the rare with an the et al, is that patients with or are treated to the for patients with or are severe and may be et al, et al, 1998). The of patients have have on to There have been of of patients in has been patients are on A et al, 2001). However, with a be in a patient has a The risk of in patients with a of with is but be with in this with of the and There are of patients with autoimmune to and et al, 2002; that be in patients with and to 2002; et al, 2002; et al, 2002). The of in of patients with CLL was by A are diagnosed with CLL, but most are diagnosed the of the the of lymphadenopathy, or weight loss and a of most are diagnosed as a but are present in may as a of the CLL or be The of is but the has been in the in with Studies of the of in the of CLL are or of The at the has been in et al, 1998). that of patients is B-cell a of 40% with and that and are at et al, the of by using based is with et al, but the of may overall et al, 2001). the of in which of disease has been the of such as is with of 40% or and overall of However, results are from in patients with disease are over 60 years with or disease et al, 1998). be for of clinical to the and in this guideline are to be and at the of to the the or for or that may be