Writing a chapter

For the past couple of days I have been beavering away on an article for a book that Tom Kipps is editing. I was hindered today when the internet went down for 4 hours, which denied me access to PubMed. Anyway here is a flavor. The spelling is in English English.

Lymphocyte doubling time

Montserrat et al analysed the lymphocyte doubling time (LDT), defined as the time needed to double the peripheral lymphocyte count, in 100 untreated patients with CLL. Although there was some correlation with clinical stage and the pattern of bone marrow infiltration, LTD was shown to have independent prognostic significance [11]. The prognostic significance of lymphocyte trends in peripheral blood was first suggested by Galton [12]. Although, both he [13] and Dameshek [14] independently concluded that CLL was a disease of accumulation rather than proliferation of lymphocytes, tests that measure proliferation rate in vitro, such as tritiated thymidine incorporation [15] or the percentage of lymphocytes in S-phase [16] or the percentage of cells staining with Ki-67 [17] or antibodies against proliferating cell nuclear antigen (PCNA) [18] all provide prognostic information. Cell division increases telomerase activity and shortens telomere length. Not surprisingly shorter telomeres and greater amounts of telomerase correlate with more aggressive CLL [19].

The idea that CLL cells have inconsequential levels of cell division was finally put to rest by experiments by Messmer et al [20] using an in vivo stable isotope labeling technique. They administered heavy water (2H2O) orally for 84 days in order to incorporate deuterium into the deoxyribose moiety of DNA in newly divided CLL cells, which could be measured by gas chromatography/mass spectroscopy. They established that CLL cells had a birth rate of between 0.1% and >1% of the total leukemic clone every day. Those patients with birth rates of >0.35% per day had more active and progressive disease than those with lower birth rates.

LDT is a simple method of measuring proliferation rate and has been confirmed many times to be a useful prognostic marker [21-23] and it has been incorporated into the NCI guidelines [4] in a more stringent form, requiring an LDT of < 6 months before treatment is started. Its drawbacks are that it is not available at diagnosis, that the lymphocyte count may have a misleading transient rise during an infection, therapy with corticosteroids or following vaccination and that, as described by Galton [12], the lymphocyte count may reach a plateau after an initial rise. LDT, therefore, needs to be evaluated in the context of the patient as a whole and not reacted to in a ‘paint-by-numbers’ response.

It was not clear whether proliferation was an intrinsic property of the CLL clone or caused by a subsequent transition to a more aggressive phase. Nor was it clear whether every patient with CLL was susceptible to transition to an aggressive phase or whether this was a danger in only a portion. Without this knowledge every untreated patient must be subjected to a regimen of ‘watch and wait and worry’. Some insight was gained into this problem by the recognition of ‘smouldering’ CLL. The Spanish group [24] defined smouldering cases as stage A patients having Hb >13 g/dL, lymphocyte count <30 x 109/L, non-diffuse bone marrow histology and an LDT >12 months. The French Co-operative group [25] recognized a type of smouldering Binet stage A’ CLL with Hb >12 g/dL and lymphocyte count <30 x 109/L. However, smouldering CLL still progresses. Of patients fulfilling the French criteria 25% had progressed by 5 years. In the Spanish study the actuarial ten year progression-free survival for these was 78%.

The realisation that there were effectively two types of CLL, one inclined to progress and one inclined not to, and that these tendencies were inbuilt and not acquired, came from a study of immunoglobulin heavy chain variable region (IgVH) genes.