IGH translocations in chronic lymphocytic leukemia: Clinicopathologic features and clinical outcomes

Abstract

The prevalence, clinicopathologic correlates, and outcomes of previously untreated chronic lymphocytic leukemia (CLL) patients with IGH‐BCL2 and IGH‐BCL3 translocations are not well known. Using the Mayo Clinic CLL database, we identified patients seen between March 1, 2002 and September 30, 2016 who had FISH testing performed within 3 years of CLL diagnosis. The prognostic profile, time to first therapy (TTT), and overall survival (OS) of patients with IGH‐BCL2 and IGH‐BCL3 translocation were compared to patients without these abnormalities (non‐IGH group). Of 1684 patients who met the inclusion criteria, 38 (2.2%) had IGH‐BCL2, and 16 (0.9%) had IGH‐BCL3 translocation at diagnosis. Patients with IGH‐BCL3 translocation were more likely to have high and very‐high CLL‐International Prognostic Index, compared to patients with IGH‐BCL2 translocation and the non‐IGH group. The 5‐year probability of requiring therapy was significantly higher for IGH‐BCL3 compared to IGH‐BCL2 and non‐IGH groups (84% vs 33% vs 29%, respectively, P < 0.0001). The 5‐year OS was significantly shorter for IGH‐BCL3 compared to IGH‐BCL2 and non‐IGH groups (45% vs 89% vs 86%, respectively, P < 0.0001). On multivariable analyses, IGH‐BCL3 translocation was associated with a shorter TTT (hazard ratio [HR] = 2.7; P = 0.005) and shorter OS (HR = 5.5; P < 0.0001); IGH‐BCL2 translocation did not impact TTT and OS. In conclusion, approximately 3% of all newly diagnosed CLL patients have either an IGH‐BCL2 or IGH‐BCL3 translocation. Patients with IGH‐BCL3 translocations have a distinct prognostic profile and outcome. These results support the inclusion of an IGH probe during the routine evaluation of FISH abnormalities in newly diagnosed CLL.

Chronic lymphocytic leukemia patients withIGHtranslocations are characterized by a distinct genetic landscape with prognostic implications

“…These observations are in line with previous findings regarding the molecular pathways frequently altered at transformation 46,47 . Altogether, these molecular characteristics could be the underlying mechanisms of the IGH R ‐CLLs poorer outcome 25 …”

“…The median TFT was shorter in IGH R ‐CLLs than that of patients with low‐risk cytogenetic alterations, but similar to that of patients with trisomy 12 (Supplementary Figure S4A), indicating that IGH translocations could be associated with an intermediate‐adverse outcome. Indeed, 6.7% of CLL patients who would be considered “normal FISH” using the customary four‐probe CLL FISH panel in our study, carried the IGH translocation and also had a worse prognosis than CLLs lacking IGH R (Figure 3A), thus highlighting the value of including the IGH probe in the CLL FISH panel to improve patient outcome prediction 25 …”

“…The clinical impact of IGH translocations is currently under discussion 19‐25 . The median TFT was shorter in IGH R ‐CLLs than that of patients with low‐risk cytogenetic alterations, but similar to that of patients with trisomy 12 (Supplementary Figure S4A), indicating that IGH translocations could be associated with an intermediate‐adverse outcome.…”

“…Previous studies have shown that patients carrying 14q32 rearrangements (IGH R ‐CLLs) have an intermediate‐adverse outcome, 19‐21 particularly when compared to favorable and intermediate‐risk cytogenetics 22,23 . However, some studies have reported that patients carrying 14q32 rearrangements with BCL2 have a better clinical course 24,25 …”

“…22,23 However, some studies have reported that patients carrying 14q32 rearrangements with BCL2 have a better clinical course. 24,25 CLL patients with IGH rearrangements remain poorly characterized at the molecular level, partly due to the low incidence of cases, the IGHR cooccurrence with other cytogenetic alterations, and the difficulty of distinguishing between IGHR-CLLs and forms of non-Hodgkin lymphoma (NHL). 26 Furthermore, the IGH probe is not included in the classic four-probe CLL FISH panel for the 13q14, 12p11.1-q11, 11q22 and 17p13 regions used in routine clinical practice, 26 which is partially responsible for this subgroup passing unnoticed.…”