Lymphocytes, B lymphocytes, and clonal CLL cells: observations on the impact of the new diagnostic criteria in the 2008 Guidelines for Chronic Lymphocytic Leukemia (CLL)

To the editor:

The diagnostic criteria for CLL have been constant for the past 20 years under the 1988 and 1996 Guidelines.^1,2  This has now changed with the 2008 Guidelines.³ 

(1) The effect of change in definition: Moving early CLL to MBL. The 1988 and 1996 Guidelines^1,2  established an absolute lymphocyte count (ALC) of 5.0 × 10⁹/L or more as the diagnostic criterion for CLL. Over the following decade, increasing numbers of patients with small clonal populations below this level were identified. In 2005, criteria for monoclonal B lymphocytosis (MBL) were proposed⁴  that suggested a cutoff of 5.0 × 10⁹/L B lymphocytes (not lymphocytes, ie, ALC). The converse of this criterion has now been recommended as the new definition for CLL. The impact of this change is noteworthy.

We analyzed in our laboratory a cohort of 322 patients who fulfilled the criteria for MBL with a typical CLL phenotype (Table 1). We found that only 156 (48%) did not fulfill 1988/1996 criteria for CLL with an ALC less than 5.0 × 10⁹/L. Hence, 52% previously classified as CLL are now redefined as MBL. Although the natural history of early CLL is well defined,⁵  evidence on clinical outcomes and rates of progression of MBL patients with ALC less than 5.0 × 10⁹/L is still emerging,^6-8  based currently on small numbers identified from differently selected populations that are not easily comparable. Further data are needed on patients with low-level clones of uncertain significance.

(2) Practical observations with the change of definition. There is now significant variation in the ALC for a diagnosis of CLL. Using a B-lymphocyte definition means the ALC ranges from 5.0 × 10⁹/L to more than 10.0 × 10⁹/L (Table 1). This results in some additional complexity for patients, clinicians, and reporting laboratories, especially when patients have a prior diagnosis of CLL under earlier Guidelines. During follow-up of some MBL patients, changes in the ALC may be difficult to interpret without B-cell enumeration. At the MBL/CLL cutoff point, we observed some fluctuation in the level of the clone.

The definition of a B cell is also of interest. The 2 antigens most commonly used for B-cell identification are CD19 and CD20, but a specific definition is not given in either the CLL Guidelines³  or the MBL criteria.⁴  In CLL, CD20 is typically expressed at lower copy number compared with normal B cells.⁹  In theory, a B-cell count increases laboratory measurement uncertainty, as 2 measurands (ALC and percentage B cells) are required.¹⁰  In practice, this effect is minor. Furthermore, we observed that using CD19 or CD20 made a negligible difference in the definition of MBL versus CLL in our patient cohort (Table 1). CD19 appears more accurate for normal B-cell enumeration, but the weakened expression of CD20 facilitates detection of small clones.

Finally, a definition that is consistent and complementary between CLL and MBL is essential. The new Guidelines eliminate the overlap that had developed and provide uniformity for future study.