IGHV Mutational Status Is Prognostic in Del(11q) and Del(17p) Chronic Lymphocytic Leukemia

The importance of interphase fluorescence in-situ hybridization (FISH) DNA analysis as a predictive tool for survival in patients with chronic lymphocytic leukemia (CLL) is well-established. However, even among cytogenetically defined groups, survival varies widely. In CLL patients who harbor del(13q), their IGHV mutational status predicts for Rai stage progression, treatment initiation and overall survival. Here we analyze, the influence of IGHV mutational status upon overall survival in CLL patients harboring the poor prognostic CLL FISH findings of a del(11q) or del(17p).

After IRB approval, we retrospectively reviewed all patients who had IGHV sequence homology analysis performed who also had del(11q) or del (17p) detected by FISH evaluation during the clinical course of their disease. An IGHV non-homologous sequence of <2% was defined as unmutated.

Between 2006 and March 2011, IGHV mutational studies were performed on 159 CLL patients of whom 70 (44%) had a documented del(11q) or del(17p). Four patient’s IGHV mutational status could not be resulted; they were excluded from further analysis. Of the remaining 66 patients: 39 (59%) had del(11q) and 27 (41%) had del(17p): no patient in this series harbored both del(11q) and del(17p). Fifty (71%), had an unmutated IGHV sequence and 16 (29%) were mutated.

The median time from diagnosis to last follow-up for IGHV unmutated patients was 3.1 (range: 0.1–14.6) years and 3.1 (range: 0.6–19.4) years for the IGHV mutated patients (p=0.12). When comparing unmutated to mutated IGHV patients, the median age and Rai stage presentation were similar: in each cohort > 75% were Rai stage 0 or 1. While the majority of patients were treatment naïve at the time of this consultation, unmutated patients were more likely to have received treatment before to this evaluation: 34% vs. 6%, p=0.04. The median time between diagnosis and first FISH analysis was 2.0 (range: 0–13.2) years in the unmutated group and 0.7 (range: 0–18.9) years in the mutated group (p=0.3).

No patient died without first receiving CLL treatment. The most common reasons for treatment initiation were either bulky adenopathy or progression to an advanced Rai stage. The 5 year cumulative probability of receiving treatment for the unmutated group was 76% compared to 57% for the mutated group (log rank p = 0.05). Eleven of 67 patients (16%) underwent allogeneic bone marrow transplantation. All eleven transplants were performed in the IGHV unmutated population (11/50; 22%).

The median survival for the unmutated patients was 11.3 years with a 5 year OS probability of 68%. For mutated patients, the median survival was not reached and the 5 year OS probability was 89% (log rank p = 0.06). Of the 18 deaths, only one death was not a direct result of CLL; this death occurred four years after the CLL diagnosis in a patient with IGHV unmutated, del(17p) disease.

We recently reported del(13q) CLL patients with an unmutated IGHV sequence predictably suffer an aggressive disease phenotype. Here, we did not limit analysis to those who concurrently harbored the salutary del(13q). Again, we found, the IGHV mutational status to be the dominate predictor of clinical outcome: despite the presence of del(11q) and/or del(17p), the presence of a mutated IGHV sequence was associated with an indolent clinical course. These analyses suggest CLL FISH aberrations predict clinical outcome because they track with the IGHV mutational status: del (13q) predicts for indolent disease because it is often accompanied by a mutated IGHV sequence; del(11q) and del (17p) predict for aggressive disease as these aberrations are often accompanied by an unmutated IGHV sequence.

Importantly, we report a high discordance in our high risk cytogenetic patients and their IGHV mutational risk assessment. Nearly a third of our del(17p)/del(11q) patients had a mutated IGVH sequence, offering an explanation for the variable clinical outcomes seen in high risk cytogenetic groups. Moreover, these findings question the prevailing recommendation of allogeneic bone marrow transplantation to all suitable high risk cytogenetic CLL patients in first response. Additional outcomes research needs to be performed to better inform and guide clinical care in CLL patients who harbor both high and low risk factors.

No relevant conflicts of interest to declare.