The Natural History of Mutated, Stage AO Chronic Lymphocytic Leukemia.
Authors: Oscier David Graham , Gardiner Anne C. , Mould Sarah J. , Glide Sharron , Davis Zadie A. , Corcoran Martin , Wiestner Adrian , Staudt Louis M. , Thomas Peter , Orchard Jenny A. 
Published: October 2019

Abstract
Patients who present with stage AO CLL and have mutated IgVH genes are generally considered to represent a benign sub-set of CLL with prolonged survival .However, within this subgroup there is considerable heterogeneity with regard to disease progression and the need for treatment. From a cohort of 260 patients studied at a single centre, we identified 70 who presented with stage AO disease as an incidental finding on a routine blood count and who had mutated IgVH genes. 47 were followed up for over 10 years without receiving treatment. 31/47 remained stage AO with a lymphocyte count of <20 x 109/l and were considered to have stable disease (SD). 16/41 remained Stage A with a gradually rising lymphocyte count and were designated as having slowly progressive disease (SPD). 23/70 had progressive disease (PD), defined by one or more of the following parameters: an increase in stage, the appearance of lymphadenopathy > 1cm or splenomegaly, a persistent fall in Hb or platelet count, LDT of <1 year or the need for treatment. There was no difference in mean ZAP 70 expression, CD38 expression using 7% and 30% cut-off’s, % of IgVH gene mutations, IgVH gene usage, p2 X7 polymorphisms or presenting serum immunoglobulin levels among the three subgroups. Gene expression profiling using the lymphochip microarray was performed on 14 cases with PD, 8 with SPD and 12 with SD. No significant differences in gene expression were found. Karyotypic abnormalities at presentation were found in 68% of patients with PD, 31% with SPD and 27% SD (p= 0.007). The most frequent abnormality was (t)/del 13q14, found in 43%,0% and 16% of patients with PD, SPD and SD respectively. When interphase FISH and Southern analysis were also used to detect del13q14, the incidence of loss in the 3 groups rose to 91%,68% and 70% respectively, indicating both the high frequency of 13q loss and the greater responsiveness of leukemic cells to mitogens in patients destined to have PD. Loss of the ATM or p53 genes were found at presentation or on sequential testing in 4 patients with PD but not in SPD or SD. Patients with SD and SPD remained asymptomatic on prolonged follow-up and were not prone to recurrent infections. In contrast, 12 patients with PD had recurrent infections and 8 received regular immunoglobulin infusions. There was no significant difference between serum IgG, IgA and IgM levels between patients with PD and those with SPD or SD at presentation. However serum IgG but not IgA or IgM levels were significantly lower on follow-up in patients with PD compared to SPD and SD (p <0.0001). A subset of patients with good prognosis CLL develop progressive disease which is associated with significant morbidity due to immuno-deficiency. Apart from differences in the frequency of cytogenetic abnormalities, these patients are not readily identified at presentation using currently available prognostic markers.