Draft article for GPs

I have been asked to write a short article on CLL for GPs and palliative care staff. Here is the first draft. Any comments?

Chronic lymphocytic leukaemia (CLL) is the commonest type of leukaemia in Europe and North America. It has an incidence of between 4 and 5 per 100,000 in the general population and the median age of presentation is 70, though occasional patients as young as 20 are seen and the disease becomes commoner still in very old age. It is about twice as common in men as women and much less common in individuals with African and especially East Asian ethnicity. The cause is unknown, though in 5-10 percent of cases there is a family history of CLL or other lymphoid neoplasm. American authorities have recognised exposure to the defoliant, Agent Orange, in Viet Nam as justification for receiving compensation.

There is a long history of changes in the definition of the condition and the latest World Health Organisation classification couples it with small lymphocytic lymphoma (SLL), a histologically and immunologically identical condition without overspill into the blood, as a single entity, CLL/SLL.

There are many causes of chronic lymphocytosis and CLL cannot be definitively diagnosed without the aid of flow cytometry to detect the range of marker molecules on the surface of the leukaemia cells. They should first be monoclonal, defined for simplicity by the presence of only one immunoglobulin light chain type – either kappa or lambda, but not both – on the cell surface. The following markers should also be present: CD5, CD19, CD20 and CD23. Expression of surface immunoglobulin, CD79b and CD20 is usually less dense than is normally found on normal B lymphocytes and the antibody, FMC7, which detects an epitope of CD20, usually fails to react. There are, however, atypical cases with aberrant markers that require expert diagnosis, which should be available from the laboratory performing the assay.

All cases of CLL are now known to be tumours of B lymphocytes. Previous reports of T-lymphocyte CLL are now known to refer either to cases of T-prolymphocytic leukaemia of to cases of T-cell large granular lymphocytic leukaemia. Other conditions that cause diagnostic difficulties include splenic marginal zone lymphoma, mantle cell lymphoma and polyclonal B-cell lymphocytosis.

Since all cases of CLL have to be diagnosed by flow cytometry, it has been possible to refine further the diagnosis. Rather surprisingly, it was found in 2002 that one normal individual in thirty over the age of 40 has a population of cells identical to CLL cells in his or her blood, and in people who have a family history of CLL the prevalence of this monoclonal B-cell lymphocytosis (MBL) is nearer one in seven. In some cases the population is tiny and only detectable by careful scrutiny, but in sizeable numbers the population is easily detectable by routine blood count, and many individuals have been told that they have leukaemia. Since individuals with MBL have only an annual risk of one in a hundred of their condition becoming CLL they have, in my opinion, been worried unnecessarily.

In order to prevent this new Guidelines have been produced by the International Workshop (IW) on CLL which require the presence of at least 5 x 109 B lymphocytes/L in the peripheral blood to make the diagnosis of CLL. Fewer lymphocytes than this establishes the diagnosis of MBL, or SLL if there is lymph node enlargement.

CLL is staged according to the Binet system in Europe and the Rai system in North America. (Table 1) Both depend on the clinical assessment of tumour bulk and the laboratory assessment of the degree of bone marrow suppression reflected in anaemia and thrombocytopenia. The natural history of the condition depends on the pace of progression. Staging tells us how far that progression has gone. Since CLL may be asymptomatic at first, many patients, three-quarters in one series, are diagnosed by a blood test done for something else entirely. Rate of progression was formerly only assessable by measuring the rate of increase of lymphocyte count. A decade ago it was discovered that the biological nature of the leukaemia determined progression rates.

As a B-lymphocyte matures it rearranges its immunoglobulin genes so as to eventually produce an antibody that fits best to its target antigen. The final rearrangement takes place in germinal centres of lymph nodes and is known as somatic mutation. The degree of somatic mutation is thought to influence cell signalling through receptor molecules. It turns out that patients whose CLL is derived from somatically mutated lymphocytes have a much more benign prognosis than those derived from unmutated cells, with a median survival of 25 years against 8 years. in clinical trials, mutational analysis also predicts the length of remission attainable. Unfortunately, this test, though standardised and much cheaper than a single course of chemotherapy, is only available from a few specialised centres and is mainly used for clinical trials. Surrogate tests using flow cytometry, such as CD38 or ZAP-70 levels are much less reliable.

All patients with CLL have impaired immunity. In two thirds of patients there is hypogammaglobulinaemia, but even in untreated stage A patients there is a reduced response to vaccinations. The immunodeficiency is complex and involves both B cell and T cell arms of the immune response. It never recovers, even after treatment; indeed treatment can make it much worse and render the patient susceptible to unusual viral and fungal infections. Impaired immune surveillance is also blamed for an apparent increase in second malignancies, especially those with an obvious viral origin such as Merckel cell tumours. As far as the common carcinomas are concerned the picture is confused because of so many confounding variables.

An ominous form of progression in CLL is the development of Richter’s syndrome, usually a diffuse large B cell lymphoma though some authors include aggressive forms of Hodgkin’s disease or even T-cell lymphomas within the definition. It is now clear that although some forms of Richter’s disease involve transformation of the CLL clone, others are quite separate B-cell tumours.

Another well-recognised form of progression is prolymphocytoid transformation. This is also a confused area. CLL does not transform into prolymphocytic leukaemia, which is a quite separate disease, but may accumulate increased numbers of prolymphocytes in the blood. Sometimes this is a transient phenomenon associated with infection or even vaccination, sometimes it is a stable state, often previously overlooked and frequently associated with the presence of the chromosomal abnormality, trisomy 12. In less than a third of instances it may represent an aggressive change in the nature of the leukaemia.

Paradoxically, as well as immune deficiency, patients with CLL experience autoimmune complications. Most commonly, it is autoimmune haemolytic anaemia (AIHA), which occurs in about 15 per cent of patients, while CLL is itself the commonest known cause of AIHA. Exactly why AIHA is so common in CLL has not been worked out completely, but it is known that it can be triggered by treatment, particularly with the drug, fludarabine, and it is commoner in late stage, multiply-treated disease. Of other types of autoimmune disease, immune thrombocytopenia occurs in about 2 per cent of patients (in one third accompanied by AIHA) and paraneoplastic pemphigus, though even rarer, may also be triggered by fludarabine treatment.

Management

There is no indication for treating CLL merely because it is there. Early trials demonstrated that there was no benefit to the patient from early treatment. A ‘watch and wait’ approach is generally adopted, though patients often call it ‘wait and worry’. Indications for beginning treatment are given in Table 2.

CLL will usually respond well to a variety of drug treatments and it is usual for patients to receive several rounds of chemotherapy, which depending on response may be repeated or varied. Until recently there was no evidence that the order which treatment was given in affected the eventual outcome. However, the CLL 8 trial of the German CLL Study Group has clearly demonstrated a superiority of the combination of fludarabine, cyclophosphamide and rituximab (FCR) over the previous best buy (FC) in terms of overall survival. The large size and well-conducted nature of this randomized controlled trial makes it believable by most haematologist, and measures are being taken for this to become standard therapy, even in countries where the monoclonal antibody, rituximab, was thought too expensive for CLL by regulatory authorities.

The median age for patients entered in this trial was only 61, but patients who were over-65 and over-70 did just as well as the younger individuals. What was crucial was performance status. Other phase II studies have suggested that older patients, especially those with co-morbidities would find difficulties in withstanding the rigours of FCR.

Other agents currently used for treatment include chlorambucil, bendamustine, high dose steroids, lenalidomide, and the monoclonal antibodies, alemtuzumab and ofatumumab. In many countries some of these agents are only available on clinical trials. Interpretation of some clinical trials involving these agents is complex, but chlorambucil is a very safe, cheap and well-tested agent with a reasonable success profile for older patients with co-morbidities, and early phase II data suggest that its effect may be enhanced by combining it with rituximab. With chlorambucil dose is important and in many comparative trials an inadvertently chosen low dose seems to have been used. A dose of 70 mg/m2 every 28 days is recommended.

Trials have shown that certain chromosomal abnormalities predict poor response to standard therapies. Deletions at 11q23, which sometimes involve the ATM gene are associated with poor responses and short remissions following standard chemotherapy, but the addition of rituximab to the cocktail remedies this. Deletions at 17p or mutations of the critical gene at this site (TP53) predicts very poor response to most treatments including FCR. This lesion should be tested for by fluorescent in-situ hybridisation (FISH) before beginning any new therapy. Agents that may be suitable for such patients include high dose steroids, alemtuzumab, flavopiridol and lenalidomide. However, if eligible, such patients should be considered for allogeneic haematopoietic stem cell transplantation. Such a procedure may be performed up to the age of seventy, but carries a high mortality and morbidity.

Supportive care

Often the best support a patient can be given is to remove the inappropriate label of ‘leukaemia’ that has been attached. Patients may need to be supported through autoimmune complications and marrow failure, but the commonest cause of death in CLL is infection. Intravenous immunoglobulin in fusions are recommended for patients with serum IgG levels less than 3g/L who have suffered more than one serious bacterial infection in one year. Prophylactic antibiotics are not recommended except to cover short periods of neutropenia or specific treatments that reduce T cell levels, such as treatment with purine analogues (fludarabine, cladribine or pentostatin) or alemtuzumab. Such patients require prophylaxis against herpes viruses, fungal infections and Pneumocystis jirovecii. Patients receiving alemtuzumab should be screened for reactivation of cytomegalovirus and started on gancyclovir should reactivation occur.