Approximately 70% of chronic lymphocytic leukaemia (CLL) patients present with early stage disease, therefore defining which patients will progress and require treatment is a major clinical challenge. Here, we present the largest study of prognostic markers ever carried out in Binet stage A patients (n?=?1154) with a median follow-up of 8?years. We assessed the prognostic impact of lymphocyte doubling time (LDT), immunoglobulin gene (IGHV) mutation status, CD38 expression, ZAP-70 expression and fluorescence in situ hybridization (FISH) cytogenetics with regards to time to first treatment (TTFT) and overall survival (OS). Univariate analysis revealed LDT as the most prognostic parameter for TTFT, with IGHV mutation status most prognostic for OS. CD38 expression, ZAP-70 expression and FISH were also prognostic variables; combinations of these markers increased prognostic power in concordant cases. Multivariate analysis revealed that only LDT, IGHV mutation status, CD38 and age at diagnosis were independent prognostic variables for TTFT and OS. Therefore, IGHV mutation status and CD38 expression have independent prognostic value in early stage CLL and should be performed as part of the routine diagnostic workup. ZAP-70 expression and FISH were not independent prognostic markers in early stage disease and can be omitted at diagnosis but FISH analysis should be undertaken at disease progression to direct treatment strategy.
Deletion of ATM detected by fluorescent in situ hybridization (FISH) in chronic lymphocytic leukemia predicts short treatment free survival and poor outcome following alkylator/purine analogue therapy. We describe five cases, with a diminished ATM FISH signal, investigated by TP53 mutation/dysfunction studies and single nucleotide polymorphism (SNP) array. The diminished signal represented loss of the ATM gene, which could have been missed were the cases not further investigated. These rare cases highlight the need for careful consideration of the choice of probe and interpretation of unusual signal patterns in FISH screening. We define a new minimal region of deletion at 11q22.3.
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