Reply to Aron P. Kater et al.

We do wish to thank Kater et al. for their interest in our article about BIRC3 mutations in fludarabine, cyclophosphamide and rituximab (FCR) treated chronic lymphocytic leukemia (CLL) patients and for expanding the knowledge on the clinical implications of BIRC3 mutations in the context of novel biological drugs.1

We conducted a retrospective multicenter real life study on 287 CLL patients treated with first line FCR and observed that BIRC3 mutated patients experienced a poor outcome, superimposable to that of patients with TP53 disruption, that represents the strongest marker of chemorefractoriness.2 Our initial results, corroborated also by other prospective trials and complemented with in vitro evidence, validated BIRC3 as a prognostic biomarker after chemoimmunotherapy in CLL.41

A prognostic biomarker is a biological feature of the tumor that provides information about the disease natural history independent of the treatment received. However, in order to gain solid clinical relevance, a biomarker should also be provided with a predictive value that informs about the likely benefit from a specific treatment.65 Currently, TP53 abnormalities and immunoglobulin variable heavy chain gene (IGHV) mutational status fulfill the criteria of predictive biomarkers whose usage is recommended by guidelines for the clinical management and treatment choice of CLL patients.7

Molecular studies of phase 3 randomized clinical trials are essential to transform a prognostic biomarker into a predictive biomarker by showing the interaction between the biomarker and treatment. In that sense, BIRC3 mutations are a validated prognostic biomarker since they associate with shorter progression free survival when patients are treated with chemoimmunotherapy, but not when treated with fixed duration venetoclax in combination with anti-CD20 monoclonal antibody. In this issue of the journal, Kater et al. report the initial results of the molecular analysis of the MURANO trial dedicated to relapsed/refractory CLL, and show that BIRC3 mutated patients treated with bendamustine rituximab experienced a worse outcome compared to wild-type patients. Conversely, the combination of venetoclax with rituximab was able to overcome the negative impact of BIRC3 mutations (Table 1).1 Similarly, the companion biomarker study of the CLL14 trial indicated that, also in the first line setting, obinutuzumabvenetoclax, but not obinutuzumabchlorambucil is an effective therapeutic option for BIRC3 mutated patients (Table 1).5

Table 1.Clinical impact of BIRC3 mutations in the MURANO and in the CLL14 trial.

Whereas the efficacy of venetoclax in overcoming BIRC3 disruption is validated in two trials, the role of ibrutinib in this context is still unexplored. Mantle cell lymphomas carrying BIRC3 mutations appear to be resistant to ibrutinib in vitro, but in vivo studies are needed to confirm this pre-clinical information.8 Although several phase 3 clinical trials have demonstrated the superiority of ibrutinib versus chemoimmunotherapy in CLL, the predictive value of BIRC3 mutations has not been tested to date in this context.119

The introduction of Bruton tyrosine kinase inhibitors and of venetoclax have changed the natural history of CLL. Despite these advantages, molecular predictors, namely IGHV mutational status and TP53 disruption, are still essential in treatment choices. In this context, BIRC3 is emerging as a novel predictive biomarker that might enter the routine clinical practice allowing a better treatment algorithm for every individual CLL patient.