Clinical Progression and Outcome of Patients with Monoclonal Lymphocytosis of Undetermined Significance.
Authors: Fung Sarah S. , Hillier Kortney L. , Vickars Linda M. , Leger Chantal S. , Galbraith Paul F. , Li Charles H. , Leitch Heather A. 
Published: April 2020

Monoclonal Lymphocytosis of Undetermined Significance (MLUS) is a clonal lymphoproliferation, usually of B-cells. MLUS has the immunophenotype of Chronic Lymphocytic Leukemia (CLL) but an absolute lymphocyte count of 10 X 109/L or less and no lymphadenopathy, organomegaly, cytopenias, or symptoms attributable to the lymphoproliferation. There is little published information as to whether the clinical course of MLUS differs significantly from that of CLL. We performed a retrospective analysis of 335 consecutive patients with clonal lymphocytosis seen at St. Paul’s Hospital diagnosed between January 1969 and July 2005. Patients were identified by a search of the practice database and clinical and pathological data were abstracted by chart review. MLUS was present in 106 patients and CLL in 229. All MLUS were of B-cell phenotype and 227 patients had B-CLL. Median age at diagnosis was 64.5 (range 33–86) y for MLUS and 65 (30–94) y for CLL (p&lt;0.83). 45% of MLUS pts were male vs. 58% of CLL pts (p&lt;0.036). ECOG Performance Status was 0 in 307 pts and was not analyzed further. Lymphocyte count at diagnosis was 7 (range 3–10) x 109/L for MLUS and 14 (range 3–394) x 109/L for CLL (p&lt;0.0001). Lymphocyte doubling time (LDT) ≤12 mo (to an absolute value &gt;50 X 109/L) occurred in 14% of MLUS and 11% of CLL (p&lt;0.84) pts. Rai CLL stage 0, 1, 2, 3 and 4 were 111 pts, 48, 47, 3 and 6 respectively. Immunophenotyping was available in 202 pts; 173 were CD5+ CD19+, 2 were CD5− and 29 were CD19−. Analysis for CD38 was available in 50 pts. At a median follow-up of 49 (0–229) mo for MLUS and 64 (0–369) mo for CLL, 15 (15%) of MLUS pts required treatment, as did 96 (42%) of pts with CLL (p&lt;0.0001). The median time to treatment (TTT) for the whole group was 35 (0–243) mo. Median TTT was 65 (0–202) mo for MLUS and 26 (0–243) mo for CLL; there was no significant difference in progression to active disease as measured by TTT between MLUS and CLL either for the whole groups (p&lt;0.29) or according to age (p&lt;0.54), gender (p&lt;0.91), LDT (p&lt;0.29) or CD38 status (p&lt;0.26). Median OS for all patients was 191 (0–369) mo, for MLUS 218 (0–225) mo, and for CLL 165 (0–369) mo (p&lt;0.04). There was a significant difference in OS favoring female MLUS pts over CLL, but not for males; median OS for females not reached at 225 mo for MLUS and median 153 (0–259) mo for CLL (p&lt;0.02, see Table). There was no significant difference in OS between MLUS and CLL according to age, gender, LDT or CD38 status. One pt with MLUS underwent transformation to aggressive disease (Richter’s transformation) as compared to 15 pts with CLL (8 Richter’s and 7 prolymphocytic, p&lt;0.025).

Characteristic OS at 10 years (%) P (log-rank) MLUS CLL Age ≤65 68 81 0.07 &gt;65 59 45 0.59 Gender M 38 68 0.47 F 100 76 0.02 LDT ≤12 mo 47 74 0.10 &gt;12 mo 80 47 0.93 CD38 negative 90 73 0.60 (positive ≥ 30% of cells) 3 of 3 0 of 2 0.32 Transformation events n=1 n=15 0.025

In conclusion, in this series of 335 patients with clonal lymphoproliferation, MLUS pts had significantly better OS than did pts with CLL, a difference which was seen in female MLUS pts in particular. Significantly fewer MLUS pts required treatment over their course than did pts with CLL. In CLL pts, there appeared to be an increased rate of transformation to aggressive non-Hodgkin's lymphoma or PLL.