(chronic myeloid leukaemia (cml)
chronic myeloid leukaemia is a myeloproliferative stem cell disorder resulting in proliferation of all haematopoietic lineages but manifesting predominantly in the granulocytic series. maturation proceeds fairly normally. the disease occurs chiefly between the ages of 30 and 80 years, with a peak incidence at 55 years. it is rare, with an annual incidence in the uk of 1.8/100 000. and accounts for 20% of all leukaemias. the disease is found in all races. the aetiology is unknown.
cytogenetic and molecular aspects approximately 95% of patients with cml have a chromosome abnormality known as the philadelphia (ph) chromosome. this is a shortened chromosome 22 and is the result of a reciprocal translocation of material with chromosome 9. the break on chromosome 22 occurs in the breakpoint cluster region (bcr). the fragment from chromosome 9 that joins the bcr carries the abl oncogene, which forms a chimeric gene with the remains of the bcr. this bcr abl chimeric gene codes for a 210 kda protein with tyrosine kinase activity, which plays a causative role in the disease, influencing cellular proliferation, differentiation and survival. in some apparently ph chromosome-negative patients, the bcr abl gene product is detectable by molecular techniques.
natural history
the disease has three phases:
• a chronic phase, in which the disease is responsive to treatment and is easily controlled, typically lasting 3-5 years
• an accelerated phase not always seen), in which disease control becomes more difficult
• blast crisis, in which the disease transforms into an acute leukaemia, either myeloid (70%) or lymphoblastic (30%), which is relativelv° refractory to treatment. blast crisis occurs at a rate of 10% per year and is the cause of death in the majority of patients. patient survival is therefore dictated by the timins of blast crisis. which cannot be predicted.
patients who are ph chromosome- and also bcr abl¬negative tend to be older, mostly male. with lower platelet counts and higher absolute monocwz counts. and respond poorly to treatment, with a median survival of less than 1 year.
clinical features
the frequency of the more common symptoms at presentation is given in box 24.45. about 25% of patients are asymptomatic at diagnosis. on examination the principal clinical finding is splenomzgaly. which is present in 90% of patients. in about locmhe enlargement is massive, extending to over li cm beloa the costal margin. a friction rub may be heard in cases of splenic infarction. hepato¬megaly occurs in about 509-c of patients. lymphadenopathy is unusual.
investigations
examination of the blood usuallc shows a normocytic, normochromic anaemia. the mean haemoglobin is 105 g/1 with a range of 70-150 g/1. the mean leucocyte count is 220 x 109/1 with a range of 9_lc00. the mean platelet count is 445 x 109/1 with a ranae of 162-2000. in the blood film the full range of granulocye precursors from myeloblasts to mature neutrophil is seen but the predominant cells are neutrophils with a second peak at the myelocyte stage of maturation. \is eloblasts usually constitute less than 10% of all white cells. there is often an absolute increase in eosinophils and basophils, and nucleated red cells are common. if the disease progresses through an accelerated phase. the percentage of the more primitive cells increases. there is a dramatic increase in the number of circulating blasts as the disease enters blast transformation. in about one-third of patients very high
24.45 symptoms at presentation of chronic myeloid leukaemia
tiredness weight loss breathlessness abdominal pain and discomfort lethargy
anorexia sweating abdominal fullness bruising
vague ill health
haematological malignancies
platelet counts are seen during treatment, both in chronic and accelerated phases, but these usually dropinging dramatically at blast transformation. basophilia tends to increase as the disease progresses.
the peripheral blood is useful diagnostically but bone marrow material should be obtained for chromosome analysis to demonstrate the presence of the ph chromosome, and rna analysis to demonstrate the presence of the bcr abl gene product. other characteristic findings on investi¬gation include a very low neutrophil alkaline phosphatase score and very high vitamin btz levels in the plasma. ldh levels are also elevated and the uric acid level may be high due to increased cell breakdown.
management
imatinib
this new agent specifically inhibits bcr abl tyrosine kinase activity and reduces the uncontrolled proliferation of white cells. it is recommended as first-line therapy in chronic phase cml, producing complete cytogenetic response (disappearance of the ph chromosome) in 76% at 18 months of therapy (box 24.46). it is also recommended for those presenting in accelerated phase or blast crises and for those resistant to other therapies such as interferon.
the oral agent hydroxycarbamide was previously widely used for initial control of disease, and is still useful in this context or in palliative situations. it does not diminish the frequency of the ph chromosome or affect the onset of blast cell transformation.
alpha interferon was considered first-line treatment before imatinib was discovered. it is given alone or with the chemotherapy agent ara-c, and can induce and maintain control of this disease in chronic phase in about 70% of patients. it causes reduction in the percentage of ph-positive cells in about 20% of patients, and prolongs survival in those who achieve this. interferon therapy causes flu-like symptoms initially and although some of these may be controlled with paracetamol, others such as severe bone pain and severe weight loss are reasons for discontinuation.
~ allogeneic or syngeneic bone marrow transplant from a matched sibling donor
in the imatinib era, the role of bmt in cml is less clear. it was previously considered the only cure for this disorder but long-term results with imatinib are awaited. a signi¬ficant role for bmt remains in younger high-risk patients to effect a cure. the best results are obtained in patients in early chronic phase when about 80% can expect probable cure. monitoring for relapse by detecting the presence of the bcr abl protein and the use of donor t -cell infusion in such cases has proven very effective at returning patients to
ebm -
24.46 imatinib and chronic myeloid leukaemia
i `as first-line therapy in civil, imatinib is better tolerated and induces a cytogenetic response in -87% of cases at 18 months, compared with - 35% response to interferon + cytarabine.
0 0 brien sg for the iris investigators. n engl j med 2003 348:994-7004.
blood disorders
durable complete remission. the results of transplantation in accelerated and blast transformation phases are significantly worse. studies are under way to investigate the role of imatinib in transplantation for cml.
treatment of the accelerated phase and blast crisis this is more difficult. in accelerated phase, imatinib is indicated if the patient has not received it hydroxy¬carbamide can be an effective single agent and low-dose cytarabine can also be tried. when blast transformation occurs, the type of blast cell should be ascertained by cytochemical and immunological techniques. response to appropriate treatment (box 24.39, p. 1042) is better if lymphoblastic than if myeloblastic. response to treatment for the latter is very poor. there is a strong case forsupportive therapy only, particularly in older patients.
(chronic lymphocytic leukemia(c.l.l.))
this is the most common variety of leukaemia, accounting for 30% of cases. the male to female ratio is 2:1 and the median age at presentation is between 65 and 70 years. in this disease b lymphocytes, which would normally respond to antigens by transformation and antibody formation, fail to do so. an ever-increasing mass of immuno-incompetent cells accumulate, to the detriment of immune function and normal bone marrow haematopoiesis.
clinical features
the onset is very insidious. indeed, in around 70% of patients the diagnosis is made incidentally on a routine full blood count. presenting problems may be anaemia, infections, painless lymphadenopathy and systemic symptoms such as night sweats or weight loss. however, these more often occur later in the progress of the disease.
investigations
the diagnosis is based on the peripheral blood findings of a mature lymphocytosis (> 5 x 109/1) with characteristic morphology and cell surface markers. immunophenotyping reveals the lymphocytes to be monoclonal b cells expressing the b-cell antigens cd19 and cd23 with either kappa or lambda immunoglobulin light chains and, characteristically, a t-cell antigen, cds.
other useful investigations in cll include a reticulocyte count and a direct coombs test as autoimmune haemolytic anaemia may occur (p. 1033). serum immunoglobulin levels should be estimated to establish the degree of immunosuppression, which is common and progressive. bone marrow examination by aspirate and trephine is not essential for the diagnosis of cll, but may be helpful in difficult cases, for prognosis (patients with diffuse marrow involvement tend to do worse) and to monitor response to therapy. the main prognostic factor is stage of disease (box 24.47) however, newer markers such as cd38 expression, mutations of igvh genes, and cytogenetic abnormalities of chromosome 11 or 17 may also suggest a poorer prognosis.
management
no specific treatment is required for most clinical stage a patients unless progression occurs. life expectancy is
24.47 staging of chronic lymphocytic
leukaemia
clinical stage a (60% patients)
0 no anaemia or thrombocytopenia and less than three areas of
lymphoid enlargement
clinical stage b (30% patients)
v no anaemia or thrombocytopenia, with three or more involved
areas of lymphoid enlargement
clinical stage c (10% patients)
v anaemia and/or thrombocytopenia. regardless of the number of
areas of lymphoid enlargement
usually normal in older patients. the patient should be offered clear information about cll. and reassured about the `benign nature of the disease, as the diagnosis of leukaemia inevitably causes anxiety.
treatment is only required if there ic evidence of bone marrow failure, massive or progressine 1_vmphadenopathy or splenomegaly, systemic symptoms such as weight loss or night sweats, a rapidly increasing lymphocyte count or autoimmune cytopenias. initial therapy for those requiring treatment (stages b and c) usually consists of oral chemo¬therapy with the alkylating agent chlorambucil. this will reduce the abnormal lymphocyte mass and produce sympto¬matic improvement in most patients. the median survival is 5-6 years. the purine analogue fludarabine is also useful, although it may lead to an increased risk of infection. bone marrow failure or autoimmune c5•topenias may respond to corticosteroid treatment.
supportive care is increasingly required in progressive disease, e.g. transfusions for symptomatic anaemia or thrombocytopenia, prompt treatment of infections and for some patients with hypogammaglobulinaemia, immuno¬globulin replacement. radiotherapy may be used for lymph nodes causing discomfort or local obstruction, and for symptomatic splenomegaly. splenectomy may be required to improve low blood counts due to autoimmune destruction or to hypersplenism, and can relieve massive splenomegaly.
prognosis
the overall median survival for patients with cll is about 6 years. the majority of clinical stage a patients have a normal life expectancy but stage c patients have a median survival of between 2 and 3 years. approximately 50% of patients die of infection and 30% of causes unrelated to cll. unlike cml, cll rarely transforms to an aggressive high-grade lymphoma, called richter s transformation.
prolymphocytic leukemia
this is a variant of chronic lymphatic leukaemia found mainly in males over the age of 60 25% of cases are of the t-cell variety. there is massive splenomegaly with little lymphadenopathy and a very high leucocyte count, often in excess of 400 x 109/1 the characteristic cell is a large lymphocyte with a prominent nucleolus. treatment is
haematological malignancies
24.48 haematological malignancy in old age
• median age: approximately 70 years for most haematological malignancies.
• poor-risk biological features: adverse cytogenetics or the presence of a multidrug resistance phenotype are more frequent. • prognosis: increasing age is an independent, adverse variable in myeloma, acute leukaemia and aggressive lymphoma.
• chemotherapy: may be less well tolerated. older people are more likely to have antecedent cardiac, pulmonary or metabolic problems, tolerate systemic infection less well and metabolise cytotoxic drugs differently.
• cure rates: similar to those in younger patients, in those who do tolerate treatment well.
• decision to treat: should be based on the individual s biological status, the level of social support available, and the patient s wishes and those of the immediate family, but not on chronological age.
generally unsuccessful and the prognosis very poor. leuka¬
pharesis, splenectomy and chemotherapy may be tried.
hairy cell leukaemia
this is a rare chronic lymphoproliferative b-cell disorder. the male to female ratio is 6:1 and the median age at diagnosis is 50. presenting symptoms are those of general ill health and recurrent infections. splenomegaly occurs in 90% but lymph node enlargement is unusual.
severe neutropenia, monocytopenia and the characteristic hairy cells in the blood and bone marrow are typical. these cells usually type as b lymphocytes and also characteris¬tically express cd25 and cd103. a useful test is the demonstration that the acid phosphatase staining reaction in the cells is resistant to the action of tamate.
over recent years a number of treatments have been shown to produce long-lasting remissions. cladribine and deoxycoformycin are effective in producing lone periods of disease control.