Gene mutations in lenalidomide-treated CLL

In this issue of Blood, Takahashi et al provide evidence that cancer gene mutations in patients with chronic lymphocytic leukemia (CLL) have a prognostic role and significantly affect response to lenalidomide-based therapy.¹ 

The last several years have witnessed a significant increase in the understanding of the biology of CLL. IGHV mutational status and the presence of deletion/mutation of the TP53 gene have a significant impact on the outcomes of patients with CLL and have been incorporated into the CLL International Prognostic Index, which divides patients into 4 prognostic groups.

It is well known that TP53 disruptions are associated with chemotherapy refractoriness and with a poor outcome. Indeed, patients carrying TP53 aberrations benefit from chemotherapy-free treatments based on the use of BCR and BCL-2 inhibitors. At present, TP53 aberrations are the only recognized factor affecting treatment choice in patients with CLL.

Next-generation sequencing studies have added remarkable new information about the pathogenesis and outcomes of patients with CLL.^2-6  These studies have identified other genes recurrently mutated in CLL, primarily NOTCH1, SF3B1, and BIRC3, which have shown a prognostic impact in CLL. To date, however, the clinical significance of these mutations is not well established compared with that of TP53 aberrations and IGHV mutational status.

In the German CLL8 trial, TP53 and SF3B1 mutations showed the strongest adverse prognostic effect in previously untreated patients with CLL receiving fludarabine and cyclophosphamide (FC) or FC plus rituximab treatment (see figure).⁷  In the same study, patients carrying NOTCH1 mutations had less benefit from the addition of rituximab to FC compared with those without that mutation. In the CLL11 trial including treatment-naïve patients with CLL treated with chlorambucil-based chemotherapy or chemoimmunotherapy, other mutated genes, KRAS and POT1, also had a significant impact on survival (see figure).⁸  In a retrospective study including patients with CLL who received fludarabine-based treatment, ≥1 mutations involving TP53, NOTCH1, SF3B1, and BIRC3 were detected in refractory patients.⁹  Conversely, no clonal mutations of NOTCH1, BIRC3, SF3B1, or TP53 were found in ultrastable patients with CLL who were progression free for >10 years.¹⁰ 

In the presence of broad genomic information, it has become challenging to understand how best to incorporate data derived from next-generation sequencing studies into the management of patients with CLL. From this perspective, the results of the study by Takahashi et al contribute more information to the growing field of novel mutations and demonstrate that somatic mutations add to and complement the risk stratification schema of patients with CLL.

A panel of 295 cancer genes recurrently mutated in hematologic malignancies was analyzed in a large cohort of treatment-naïve and relapsed/refractory patients who were treated at the MD Anderson Cancer Center in lenalidomide-based trials. The study goal was to define the overall landscape of CLL gene mutations and the association between gene mutations and the clinical characteristics and outcomes of both treatment-naïve and relapsed/refractory patients who received lenalidomide-based treatment. The results of this study highlight the marked genomic diversity among patients with CLL. A majority of patients had mutations in genes involved in different molecular pathways: MAPK-ERK (KRAS and BRAF), NOTCH (NOTCH1 and FBXW7), messenger RNA processing/translation (SF3B1, XPO1, and DDX3X), DNA damage repair (ATM, TP53, and POT1), and inflammatory pathways (MYD88, DDX3X, and BIRC3). The most frequently mutated genes were, in order of frequency, SF3B1, NOTCH1, and TP53 genes (see figure). A higher number of mutations were detected in patients with unmutated IGHV than in patients with mutated IGHV. As previously reported,⁶  a close relationship was observed between IGHV mutational status and the distribution of some specific gene mutations. MYD88 mutation was enriched in the group of IGHV-mutated patients, whereas NOTCH1 and XPO1 mutations were more frequently observed in unmutated patients. In addition, multiple statistically significant mutational cooccurrences were detected in this study. Among these was the cooccurrence of NOTCH1 mutation and SPEN mutation. The coexistence of these mutated genes has also been observed in other lymphoproliferative disorders and supports the hypothesis of a shared oncogenic mechanism of the 2 mutations.

Not surprisingly, in both treatment-naïve and relapsed/refractory patients, a worse outcome in terms of response to treatment and overall and progression-free survival was associated with the following already known high-risk factors: del(17p), TP53 mutations, and complex karyotype. This adverse genetic profile was more frequently observed in relapsed/refractory patients.

The unfavorable outcome of relapsed/refractory patients was also related to an additional gene mutation, the SF3B1 mutation, which was associated with a lower response to treatment and significantly inferior survival. In multivariate analysis, SF3B1 mutation maintained an independent adverse effect on overall survival of relapsed/refractory patients, along with del(17p)/TP53 mutation and complex karyotype. The unfavorable effect of SF3B1 mutation could be related to the generation of alternatively spliced transcripts.

Sequencing technologies have dramatically improved insights into the mutational landscape of CLL, and the number of recurrently mutated genes identified is growing. Many mutated genes in this and other studies have shown a prognostic effect on the outcomes of patients with CLL. However, the identification, reproducibility, and validation of the clinical effect of novel gene mutations require large series of cases uniformly treated and analyzed. The sample size was not sufficient in this study to achieve adequate power to demonstrate a predictive impact of IKZF3 mutations on response to lenalidomide or to better clarify the clinical significance of other recurrent mutated genes. Larger prospective studies are therefore needed to elevate the multitude of novel mutations identifiable with the always advancing technologies from the research to the clinical setting.

There is also a growing need for data from studies exploring the effects of the genetic background on the outcomes of patients included in clinical trials comparing chemoimmunotherapy with targeted agents. These studies could better define the best treatment option for patients with a given genetic profile. Overall, large, cooperative studies applying next-generation sequencing techniques with standardized methods in uniformly treated or untreated patients are needed to rigorously ascertain the role of each or multiple gene mutations in the pathogenesis, outcome, and treatment management of patients with CLL.