Newly acquired chromosome Abnormalities During Course of CLL: a Retrospective Collection Data From 2 Spanish Centers.

Different recurrent cytogenetic abnormalities have shown clear prognostic value in patients with Chronic Lymphocytic Leukemia (CLL). Acquisition of cytogenetic aberrations during evolution of the disease (i.e. clonal evolution) may have clinical implications.

To analyze the frequency of clonal evolution and its potential clinical consequences.

We retrospectively collect data from 80 patients diagnosed of CLL, who had been made at least two Fluorescence In Situ Hybridation (FISH) studies, with probes for gene ATM (11q22), gene p53 (17p13), 13q14 region and centromeric probe for chromosome 12. Clonal evolution was found in 16 out of 80 cases (20%), 8 male and 8 women, median age 70 years (41-80). Initial FISH was normal in 9 cases, deletion (del) of 13q14 region was observed in 5, and trisomy of chromosome 12 (+12) in 2 cases. Median of previous lines of treatment were 1 (0-6): Chlorambucil 7, Fludarabine (F) 1, Cyclophosphamide (C) 1, FC combination 3, FC plus Rituximab (FCR) 2, Alemtuzumab 3, CVP 2, CHOP 1, autologous stem cell transplantation (SCT) 1, Bendamustine 4. By flow cytometry, 5/9 analyzed cases were CD38-positive and 3/6 were ZAP70-positive. Out of 13 treated patients, complete response (CR) criteria (by 2008 iwCLL guidelines) were reached in 2, and PR in 8. Median duration of response (DR) were 14 months (0-42), and median time to retreatment (TTR) were 18 months (1-60).

As clonal evolution, FISH abnormalities detected were: del (p53) in 8 cases, del (ATM) in 7 cases (2 associated with p53 deletion); del(13q) in 3 (homozigous in 2 patients). Treatment were given to 12 patients (75%), indicated in 10 for progressive adenopathies (6/7 cases with del(ATM) y 7/8 with del(p53)), 5 for anemia and 4 for thrombocytopenia (all of them had del(p53)), 3 for short LDT and 3 for B symptoms. Rescue regimens were: FC (4), FR (1), FCR (1), Pentostatin+R (1), Alemtuzumab (1), Cyclophosfamide (2), CHOP+R (1), allogeneic SCT (1). 7/12 responded, including 1 case that reached CR. Median DR was 5 months (0-29), with TTR 9 months (1-41). As following lines they had: Alemtuzumab +/- Methylprednisolone (3), Chlorambucil (1), CVP (1), CHOP (1), Rituximab (1), FR (1), Bendamustine (1). After a median follow-up of 9 months (3-60) from clonal evolution, 5/16 had died, after 3-32 months (median 9). 4 of them died because of disease progression and/or infectious complications. 1 patient had a second malignancy, dying from metastatic prostate cancer.

This retrospective series shows the relevance of clonal evolution in CLL. Selection of clones with deletion of ATM or p53 genes frequently associates with adenopathy progression, while p53 deletion seems to correlate more specifically with cytopenias. Treatment-free and overall survival seem to get compromised. Usefulness of performing FISH at regular intervals might warrant further studies.

No relevant conflicts of interest to declare.