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The clinical relevance of fluctuations in absolute-lymphocyte counts during follow-up of large granular lymphocyte proliferations.

The Yorkshire Leukaemia Group (YLG) study was performed to determine the clinical, morphological, immunophenotypic, and genotypic characteristics of persistent large granular lymphocyte (LGL)/natural killer (NK) cell proliferations.’ The study showed that persistent LGL expansions may occur within normal white blood cell (WBC) counts and/or normal absolute lymphocyte counts. Furthermore, the lymphocytosis may show marked fluctuations and in some cases spontaneous resolution (‘self-limiting’). A further evaluation of the original cohort of patients was carried out in order to (1) define the clinical and laboratory characteristics of ‘self-limiting’ and ‘non-self-limiting’ LGL proliferations, and (2) identify clinical and laboratory characteristics that may differentiate a ‘self-limiting’/ ‘non-self-limiting’ clinical course. The absolute lymphocyte counts of 92 patients with chronic LGL/ NK cell expansions were studied prospectively at regular intervals (6 to 9 months) for 24 months. Based on the absolute lymphocyte counts at 24 months, patients were subdivided into two categories: (1) group A-lymphocyte count <4 X 109L (‘self-limiting’), and (2) group B-lymphocyte count >4 X 109L (‘non-self-limiting’). The clinical and laboratory parameters including genotypes of the LGL expansions, as identified by Southern blot analysis of T-cell receptor (TCR) gene (p, 7, and 6) rearrangements, of the cases recorded on initial registration were correlated with the clinical course. Statistical analysis of the data was performed using a x’ test with Yates correction. The lymphocyte counts of 44 (48%) of the 92 cases included in the YLG study returned to within normal limits during the followup period, but in 48 cases (52%) it remained high. Autoimmune diseases accounted for 11% of group A and 31% of group B ( P = .W) (Table 1). The associations between non-self-limiting lymphocytosis and ischemic heart disease andor peripheral arterial diseases were not statistically significant. The number of cases with other conditions were too small for statistical analysis. None of the patients with the combination of self-limiting lymphocytosis and viral infections or carcinomatosis had clonal disease, confirming ‘reactive’ lymphocyte abnormalities. Four of the five cases whose lymphocyte abnormalities were diagnosed on routine tests had non-self-limiting abnormalities. Anemia was recorded in 16 cases in group A, and 12 cases in group B. The difference was not statistically significant ( P = .33). Similarly the difference in the incidence of neutropenia was not significant. However, the association between high WBC counts (WBC > l 1 X 109L) at presentation and occurrence of non-selflimiting lymphocyte abnormalities was significant ( P = .008). Immunologic abnormalities including autoantibodies, rheumatoid factor, and hyperlhypogarnmaglobulinemia were more common in the group B than group A, but the differences were not significant. Rearranged TCR genes were more common in the non-self-limiting group although the difference was not significant ( P = ,228). Eight of the 23 cases with rearranged TCR genes were associated with a self-limiting lymphocytosis. Based on the above results, we conclude the following (1): nonself-limiting LGL expansions are more commonly associated with autoimmune disease; (2) neither anemia nor neutropenia has a predictive value for discriminating self-limiting and non-self-limiting abnormalities; (3) immunological abnormalities have no predictive value for persistent disease; (4) leukocytosis (WBC > l 1 X 109L) on presentation has a strong predictive value for persistent disease; and ( 5 ) clonal proliferations may show normalization of absolute lymphocyte counts.