Differentiating chronic lymphocytic leukemia from monoclonal B-lymphocytosis according to clinical outcome: on behalf of the GIMEMA chronic lymphoproliferative diseases working group

Abstract

Background: Optimal lymphocyte parameters and thresholds for the diagnosis of chronic lymphocytic leukemia have been proposed by The National Cancer Institute sponsored Working Group and recently updated by the International Workshop on chronic lymphocytic leukemia. However, it is not clear how these criteria apply to patient management in daily clinical practice and whether the lymphocyte thresholds recommended truly predict clinical outcome in early chronic lymphocytic leukemia.

Design and methods: For the purpose of this study, an observational database of the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) which included 1,158 patients with newly diagnosed Binet stage A chronic lymphocytic leukemia who were observed at different primary hematology centers during the period 1991-2000, was used.

Results: Among 818 consecutive chronic lymphocytic leukemia patients with Rai stage 0 (i.e. no palpable lymphadenopathy or hepatosplenomegaly) who had flow cytometry evaluations at the time of diagnosis and were included in a GIMEMA database, both absolute lymphocyte count and B-cell count were of a similar value in predicting time to first treatment as continuous variables (P<0.0001). Receiver operating characteristic analysis identified an absolute lymphocyte count of 11.5×10(9)/L and an absolute B-cell count of 10.0×10(9)/L as the best thresholds capable of identifying patients who will require treatment from those with stable disease. However, in a Cox's multivariate analysis only the B-cell count retained its discriminating power (P<0.0001) and the estimated rate of progression to chronic lymphocytic leukemia requiring treatment among subjects with a B-cell count less than 10.0×10(9)/L was approximately 2.3% per year (95% CI 2.1-2.5%) while it was 2-fold higher for patients with a B-cell count of 10.0×10(9)/L or over (i.e. 5.2% per year; 95% CI 4.9-5.5%). Finally, in this community-based patient cohort, the B-cell threshold defined by investigators at the Mayo Clinic (i.e. 11.0×10(9)/L) allowed patients to be divided into two subsets with a higher and lower likelihood of treatment (P<0.0001).

Conclusions: Our results, based on a retrospective patients' cohort, provide a clear justification to retain the B-cell count as the reference gold standard of chronic lymphocytic leukemia diagnosis and imply that a count of 10×10(9)/L B cells is the best lymphocyte threshold to predict time to first treatment. The use of clinical outcome to distinguish chronic lymphocytic leukemia from other premalignant conditions, such as monoclonal B-cell lymphocytosis, is a pragmatic approach meeting the patients' need to minimize the psychological discomfort of receiving a diagnosis of leukemia when the risk of adverse clinical consequences is low.

Figure 1.

(A) Relationship between ALC and B-cell count in 818 patients who met the 1988 and 1996 IWCLL-NCI diagnostic CLL criteria (4) (i.e. ALC of at least 5.0×10⁹/L and immunologically confirmed diagnosis of CLL by flow cytometry). (B) Relationship between ALC and B-cell count in 124 patients who would be reclassified as MBL using the 2008 CLL diagnostic criteria.

Figure 2.

Time to first treatment (TFT) for patients reclassified, at the time of this analysis, as MBL using the 2008 CLL diagnostic criteria (i.e. absolute B-cell count <5.0x10⁹/L) and CLL Rai stage 0 (i.e. absolute B-cell count ≥5.0x10⁹/L).

Figure 3.

Receiving operating characteristic (ROC) analysis of the accuracy for ALC (A) and B-cell count (B). The accuracy is measured by the area under the ROC curve.

Figure 4.

Time to first treatment (TFT) of patients stratified by ALC greater than or less than 11.5×10⁹/L.

Figure 5.

Time to first treatment (TFT) of patients stratified by B-cell count greater than or less than 10.0×10⁹/L.

Figure 6.

Time to first treatment (TFT) of patients stratified by B-cell count according to Shanafelt et al. threshold (i.e. greater than or less than 11.0×10⁹/L).