Choosing ibrutinib wisely

In this issue of Blood, Bartlett et al share their experience with the use of ibrutinib in patients with relapsed or refractory follicular lymphoma (FL).¹ 

This study was part of a multicenter, international, phase 2 consortium trial that enrolled 40 patients with recurrent FL, who were treated with ibrutinib 560 mg once per day until disease progression. The clinical activity of ibrutinib in this setting was modest, with an overall response rate (ORR) of 37% and a complete response (CR) rate of 12%. The median progression-free survival (PFS) was 14 months, and median duration of response was 13 months. More importantly, this study was able to explore 2 different measures predictive of response to ibrutinib. They included evaluation of the impact of interim positron emission tomography (PET) scan on PFS outcomes, and the correlation of clinical outcomes with recurrent mutations identified in a cancer gene panel that used next-generation sequencing on pretreatment biopsies.

The advent of the irreversible Bruton tyrosine kinase (BTK) inhibitor ibrutinib has been transformational for the management of various B-cell malignancies. Ibrutinib is currently approved for the treatment of chronic lymphocytic leukemia, Waldenström macroglobulinemia, mantle cell lymphoma, and chronic graft-versus-host disease. However, this report and another report (the DAWN Study [FLR2002]) that included patients with chemotherapy refractory FL show similar activity in this particular patient group.²  In the final analysis of the DAWN study of 110 patients, the ORR was 20% with a CR rate of 10%. Median PFS was 4.6 months, and time to next treatment was 16 months. These results are consistent in terms of their duration of response and PFS when compared with those reported from other similar studies of novel agents such as idelalisib,³  copanlisib,⁴  umbralisib,⁵  and venetoclax,⁶  in patients with relapsed or refractory FL, which reflects the challenging clinical scenario.

As seen in other studies of ibrutinib in various B-cell malignancies,^7,8  ibrutinib is generally well tolerated in these heavily pretreated populations, and common adverse effects were cytopenias, infections, diarrhea, hypertension, atrial fibrillation, and bleeding. These adverse events led to discontinuation of ibrutinib in 6% to 10% of patients in both studies of ibrutinib.

In addition to clinical activity, the Bartlett et al study evaluated the role of PET scans as a predictive tool for response to ibrutinib in patients with FL. Although PET scans are not commonly used for managing patients with FL, these were performed in 20 patients after 8 days of treatment with ibrutinib. The maximum standardized uptake value (SUV) assessed on the day 8 scan was found to correlate with both response and PFS. A recursive partitioning algorithm identified a cutoff point of 13.78 for the day 8 SUV that could predict PFS. Although this is an interesting finding, it needs to be further validated in larger trials.

In addition to having a PET scan, 31 patients underwent core needle biopsies of involved lymph nodes before starting ibrutinib, and fresh tissue was snap-frozen and subjected to Illumina HiSeq sequencing. This resulted in identification of multiple genes with various mutations, some of which correlated with outcomes. Importantly, patients with caspase-associated recruitment domain-11 (CARD11) gene mutations failed to respond to ibrutinib therapy and also had an inferior PFS. Conversely, patients with other mutations, including those in IGLL5, KMT2D, and FOXO1 experienced improved PFS. The presence of a CARD11 gene mutation as one of the more frequent mutations in FL was initially identified in the GLSG2000 cohort analysis and is part of the m7-FLIPI (which combines the mutational status of 7 genes with the Follicular Lymphoma International Prognostic Index) score developed for FL prognostication and predictive of 5-year failure- free survival.⁹  The gene is located on chromosome 7p22.2 and encodes the CARD11 protein, which is a member of the membrane-associated guanylate kinase family and is downstream of SYK and BTK in the B-cell receptor (BCR) signaling pathway. Gain-of-function mutations may result in constitutive activation of NF-κB through its interaction with bcl-10 and independent of the BCR activation.¹⁰  Another important issue to note is that there was a significantly lower response to ibrutinib in patients refractory to rituximab. This correlation with rituximab resistance and CARD11 mutations is uncertain because 4 of the patients with CARD11 mutations were refractory to rituximab and 1 was sensitive to rituximab (Nancy Bartlett, written communication, 13 November 2017). Nevertheless, studies like these are essential for identifying subsets of patients a priori in whom certain targeted therapies may not be effective.

What is the place of ibrutinib in the current landscape of FL? Data regarding the use of a CD20 antibody in combination with chemotherapy is very compelling, and this treatment is still considered the standard of care for initial and relapsed treatment of the majority of patients with FL. However for relapsed patients who may not be candidates for a chemotherapy-based regimen, PI3 kinase inhibitors are an acceptable treatment option approved by the US Food and Drug Administration. With existing data on lenalidomide, rituximab, ibrutinib, and venetoclax among others, patients can potentially have access to multiple effective therapeutic options. Nevertheless, every effort should be made to treat these patients on well-designed clinical trials that will hopefully result in addressing the issues of optimal duration, sequencing of treatment, and identification of resistance mechanisms. In addition, it will clarify the need for a maintenance approach.