Low Expression of ROR1 on Chronic Lymphocytic Leukemia Is Associated with Other Atypical Findings

Abstract 4588

ROR1 is a developmental embryonic surface antigen that also is expressed on chronic lymphocytic leukemia (CLL) cells, but not on most tissues or cells of healthy adults, including secondary lymphoid tissues or normal CD5 B cells. Studies involving relatively small numbers of patients have identified expression of ROR1 on the neoplastic cells of nearly all patients examined. However, it is not established whether there are cases of bona fide CLL that lack expression of this antigen or whether cases of putative CLL that lack expression of ROR1 actually represent a disease subset that has biologic and/or clinical features distinct from that of CLL that express ROR1. To further explore the significance of low levels of ROR1 on CLL, we analyzed 268 cases of CLL for surface expression of ROR1 via multiparameter flow cytometry using a fluorochrome-conjugated mAb specific for ROR1. The percentage of CLL cells with ROR1 for each case had a median of 94, mean of 81 and a standard deviation of 26. By visual inspection of the histograms, the distribution of ROR1 expression for each case approximated that of a Gaussian distribution. For 14 of these cases (5.2%), less than 20% of their neoplastic B cells expressed ROR1. Three of these 14 cases (21%) had features of “typical” CLL by immunophenotype. These cases did not have cytogenetic abnormalities as detected by fluorescence in situ hybridization (FISH), were negative for ZAP-70, and expressed mutated IGHV genes (Table 1). The 11 other cases had some features in common with that of typical CLL including small, mature, lymphocyte morphology, a persistent absolute lymphocyte count of greater than 5K/ul, expression of CD5, and lack of translocations characteristic of mantle cell lymphoma [e.g t(11;14)]. However, these 11 cases also showed variably atypical features. Three cases had dim or partial expression of CD23 (cases #1, 8, 11), one case lacked expression of CD23 (#4). Trisomy 12 was detected in three of the 14 cases (21%; 95% confidence interval 8–48%), not significantly different than the reported frequency of 14%. 13qdel as the sole cytogenetic/ FISH abnormality was present in another three of the 14 cases (21%; 95% confidence interval 8–48%), which is significantly lower than the reported frequency of 60% (p<0.05). The clonal IGHV gene had somatic mutations in 9 of 12 cases analyzed (75%; 95% confidence interval 47–91%). These findings indicate that low levels of ROR1 are rare in typical CLL, and that CLL with low level expression of ROR1 have a high frequency of other atypical immunophenotypic and cytogenetic findings.