Guidelines for the management of CLL were issued in 1988 and 1996 and these are about to be replaced by a new set of guidelines produced by a group from the IWCLL led by Michael Hallek. There are several changes. Here are the most important.
1 The new WHO classification makes it clear that we no longer have to talk about B-CLL. What used to be called T-CLL is now recognized as T-PLL, so all true CLL is B-CLL and just needs to be called CLL. CLL is only distinguishable from SLL by appearing in the blood. Thus SLL with a lymphocyte count of at least 5000 per microliter is called CLL. CLL with less than 5000 lymphocytes per microliter is called SLL if there enlargement of lymph nodes, spleen or liver (either by physical examination or an imaging technique or if there is a cytopenia caused by marrow infiltration; if there is not it is called monoclonal B-lymphocytosis (MBL), which may or may not progress to CLL.
2. The diagnosis of CLL, as well as having a lymphocytosis of at least 5000 per microliter, must have lymphocytes that are small and mature with a narrow border of cytoplasm and a dense nucleus lacking discernable nucleoli and having partially aggregated chromatin. There may be an admixture of atypical cells, cleaved cells or prolymphocytes. The matter may under extremes circumstances comprise up to 55% of cells. If there are more then the condition is B-PLL. Smudge cells (also known as Gumprecht shadows) are often a feature of CLL.
3. For diagnosis of CLL it is essential to do an immunophenotype. CLL cells co-express CD5, CD19, CD20 and CD23. The levels of surface immunoglobulin, CD20 and CD79b are characteristically lower than what is seen on normal B cells. There is restricted expression of either kappa or lambda chains of immunoglobulin. There is no such thing as 'polyclonal' CLL, but there is a 'polyclonal lymphocytosis' characterized by binucleate lymphocytes, which characteristically occurs in female smokers. It is a benign condition, but sometimes confused with CLL.
4. No other tests are necessary for diagnosis and only one other test currently influences treatment decisions. A FISH test showing deletion of the short arm of chromosome 17 (del 17p13) signifies that the disease is unlikely to respond to conventional agents and that alemtuzumab (Campath), either alone or in combination, will be required.
5. Five other markers: Unmutated IgVH genes, use of VH3.21, increased expression of CD38 or ZAP-70, and del 11q23 are all associated with poor outcome. It is uncertain from clinical trials whether any of these, alone or together, influence response to treatment or overall survival once treatment is required. Trials are ongoing to establish this point. On the other hand the mutational status of IgVH genes in particular, and probably the other tests are useful for predicting the clinical course in individual cases, and may be recommended for patients who want a better prediction of the rate at which their disease might progress.
6 Several studies have found that the serum markers CD23, thymidine kinase and beta-2-microglobulin may predict survival or progression-free survival. Standardized assays for these and those in section 5 should be incorporated into all future clinical trials, but are not essential in general practice.
7. Bone marrow aspirate and biopsy are not required for the diagnosis of CLL. They may be useful to evaluate the factors that might contribute to cytopenias, and therefore they are recommended immediately prior to starting treatment.
8. Clinical staging is unchanged. It is emphasized that both Rai and Binet staging rely on physical examination and imaging techniques should not be used.
9. Evaluation before treatment is different for patients treated in general practice and those entered into clinical trials. The following are regarded as essential for all patients: CBC (including retics), immunophenotyping (if not already performed), history, physical examination, performance status, serum chemistry (creatinine, bilirubin, LDH, transaminases, alkaline phosphatase), serum immunoglobulins, Coombs test (DAT), chest X-ray, infectious disease status (HIV, Hep B and C, CMV). A marrow aspirate and biopsy is desirable. FISH for del 17p should always be performed. In general practice imaging tests are unnecessary unless the aim of treatment is CR, in which case the investigation of choice in CT scan, and not MRI or PET scan. US scan for abdominal nodes is used in some countries, but suffers from observer variability.
10. PET scans are only indicated where there is suspicion of Richter's disease and they are not 100% reliable for this.
11. Lymph node biopsy is not required except for the diagnosis of SLL or if Richter's transformation is suspected.
12. The indications for treatment are unchanged, but some of the details have been clarified. Lymphocyte doubling time can be determined by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of two weeks over an observation period of 2-3 months; patients with lymphocyte counts of less than 30,000 per microliter may require longer periods of observation. Other factors contributing to lymphocytosis such as infection or steroid ingestion must be excluded. Fatigue must be ECOG performance score 2 or worse (unable to work or carry out normal activities).
13. Neither a high white count nor low serum immunoglobulins are indications in themselves for starting treatment.
The rest of the new guidelines relate to clinical trials and I shall summarize these in a separate posting.