Response: Letters regarding Blood. 2008;111:5446-5456 by Hanson et al and Mulligan et al

Response

We are grateful to both Hanson and colleagues and Mulligan and his colleagues for welcoming our recent revision of the 1996 NCI CLL Guidelines and for raising several issues surrounding the diagnostic criteria of CLL and monoclonal B lymphocytosis (MBL). They particularly referred to the change in the criteria for CLL from an absolute lymphocyte count (ALC) greater than 5 × 10⁹/L (in the 1996 NCI criteria) to a circulating B-cell count greater than 5 × 10⁹/L. There are several recent developments that have made this change necessary.

The development of multiparameter flow cytometry has enhanced the ability to detect and accurately quantitate low levels of CLL cells. This has led to increasing numbers of patients with minimal lymphocytosis being found to have low levels of circulating CLL cells. Individuals with less than 5 × 10⁹/L B cells have recently been defined as having MBL, as many of these did not fulfill the old criteria for a diagnosis of CLL.¹  In contrast to the comments made by both Mulligan et al and Hanson et al, we believe that the technique to identify CLL cells has been standardized and validated sufficiently and should be reproducible in laboratories thoughout the world.² 

A major component in interlaboratory variation for absolute lymphocyte subset enumeration is the hematology analyzer result when the ALC is used to calculate the absolute B-cell count from a FACS percentage. The most reproducible results are instead provided by single platform technology, using just quantitative flow cytometry beads to directly measure B-cell concentration. We recognize that this is the “gold standard,” but it is unlikely to be widely adopted due to the additional complexity of the test. Thus, there will continue to be variation among laboratories for lymphocyte counts close to the 5000/μL cutoff if hematology analyzer lymphocyte count is used. However, the change in criteria for the diagnosis of CLL will have no impact on this variation. We believe that the statement by Hanson et al that “moving … to a B-cell count using a flow cytometry–based procedure will also have unintended consequences affecting cost and access” is incorrect. The use of the B-cell count instead of absolute lymphocyte count should have no financial or access implications as a diagnosis of CLL according to the 1996 criteria already requires basic immunophenotyping, which includes assessment of CD19 expression.³ 

The change in diagnostic criteria for CLL will have an impact on epidemiologic studies, but this will be positive in terms of including patients who are better defined and therefore results will be easier to interpret. It is important to remember that even with potential interlaboratory variations, the changes to the diagnostic criteria will have no impact on clinical management of CLL, as both MBL and Rai stage 0 CLL cases will continue to be approached with watchful waiting.

Furthermore, Mulligan et al make a strong case for redefining the diagnosis of CLL to complement the current definition of MBL, as has been done in the recent Guidelines. In their cohort of 322 patients who fulfilled the criteria for MBL with a typical CLL phenotype they found that 166 (52%) patients also fulfilled the 1988/1996 criteria for CLL, thus creating confusion. We believe that patients should fall only into one of the 2 diagnostic groups to give clarity to future studies. Both Mulligan et al and Hanson et al indicate that further information on the natural history of MBL is required before such a change in classification is merited. One of the problems with the current classification systems is that they are insensitive in defining whether patients within the large group of early-stage CLL (Rai 0 or Binet A) will or will not progress over time. Recent evidence indicates that the CLL count of an individual patient is the most important predictor of the likelihood of progression and future requirements for therapy.⁴  The accurate classification of CLL and MBL is essential for the prospective testing of biologic markers that may, in the future, separate MBL into patients who have little likelihood of progression and those who are very likely to progress. Without the reclassification of early-stage CLL and MBL there will be continued confusion over this entity.

We strongly disagree with the final statement made by Hanson et al. At present there is confusion over the definitions of MBL and CLL, which will eventually hamper efforts to identify biologic variables that predict outcome. Inappropriately labeling individual patients with a diagnosis of “leukemia” can create major problems both psychologically and potentially financially regarding insurance coverage. In addition, clarifying the diagnosis on a population basis will allow the definition of predictors of progression and will therefore benefit patients in the future. It is true that these guidelines will “create more questions,” and that is appropriate and stimulating to further research. But at least these questions will be based on a timely consensus using the best available techniques rather than criteria established more than a decade ago when the biology of CLL was less well understood. Although any cutoff, using either lymphocyte or B-cell count, to define CLL and MBL will be somewhat arbitrary, it is important to have widely accepted definitions that are straightforward and do not overlap to bring clarity and consistency to our future studies of the disease.