Abstract

In order to develop integrated models utilizing commonly available prognostic factors, we studied the clinical signficance of IGVH mutation, CD38 and ZAP-70 in 477 CLL patients (pts) with low-risk (non-11q, non-17p) FISH findings. All pts were untreated at the time of FISH assessment, and were collected prospectively in the MD Anderson CLL database. Two hundred & fifteen pts (45%) had mono- (n=160) or bi-alleleic (n=55) deletion of 13q {DEL13Q}, 162 pts (34%) had a negative FISH panel {NEG}, and 100 pts (21%) had trisomy 12 as sole FISH abnormality (n=78) or in association with deletion 13q (n=22) {T12}. Compared to other FISH groups, DEL13Q pts had lower B2m (median 2.2 v 2.6mg/L, p=0.01) and were less likely to be IGVH unmutated (33% v 48%, p=0.001). In contrast, T12 pts were more likely to present with advanced stage disease (Rai≥2 36% v 23%, p=0.01), be CD38 positive (44% v 13%, p<0.001), and have karyotypic abnormalities (48% v 7%, p<0.001). One hundred and twenty-three pts had active disease requiring immediate therapy and 354 pts had stable disease, of whom 291 were evaluable for disease progression. At a median follow-up of 20 months, 73 pts had developed active disease with NCI-WG indication(s) for treatment. Actuarial 2 year time to treatment (TTT) was 26%, with no significant difference between 13q, NEG and T12 pts (p=0.27). TTT was associated with elevated B2m (≥1.5ULN), IGVH mutation status and ZAP-70 in DEL13Q and NEG pts, but not in T12 patients (Table). For DEL13Q/NEG pts, a simple model using IGVH mutation and B2m separated high risk pts (unmutated or high B2m, 2yr TTT 43%) from standard risk pts (mutated and low B2m, 2yr TTT 11%, p<0.0001). For T12 pts, a model based on CD38 positivity and karyotypic abnormalities separated high risk pts (2 factors, 2yr TTT 75%) from standard risk pts (0 or 1 factor, 2yr TTT 15%, p=0.008). These results show that the impact of prognostic factors on TTT is dependent on the underlying FISH karyotype, and underscores the need for future studies in CLL prognostic factors to take into account the complete risk profile of the pt.

NEGATIVE FISHDELETION 13QTRISOMY 12
p-valuehazard ratiop-valuehazard ratiop-valuehazard ratio
IGVH Mutation <0.001 8.0 0.003 2.9 0.97 0.98 
B2m ≥1.5ULN <0.001 4.5 0.07 2.2 0.54 0.68 
CD38 Positivity 0.05 2.5 0.05 2.4 0.06 7.4 
Abn Cytogenetics <0.001 11.0 0.27 2.2 0.09 2.8 
ZAP-70 0.02 2.9 0.007 3.1 0.70 1.3 
NEGATIVE FISHDELETION 13QTRISOMY 12
p-valuehazard ratiop-valuehazard ratiop-valuehazard ratio
IGVH Mutation <0.001 8.0 0.003 2.9 0.97 0.98 
B2m ≥1.5ULN <0.001 4.5 0.07 2.2 0.54 0.68 
CD38 Positivity 0.05 2.5 0.05 2.4 0.06 7.4 
Abn Cytogenetics <0.001 11.0 0.27 2.2 0.09 2.8 
ZAP-70 0.02 2.9 0.007 3.1 0.70 1.3 

Author notes

Disclosure: No relevant conflicts of interest to declare.