Partial responses to ibrutinib in Waldenström macroglobulinaemia ‐ good enough?

The B-cell receptor and Bruton tyrosine kinase (BTK) play a fundamental role in the proliferation of B-cell neoplasia such as Waldenstr€ om macroglobulinaemia (WM). In WM, ibrutinib, a first-generation BTK inhibitor (BTK-i) has obtained high rates of response and progression-free survival (PFS), both in untreated and rituximab-refractory disease. A Phase II trial of 63 patients with relapsed/refractory (R/R) WM demonstrated an overall response rate (ORR) of 91% and a 2-year PFS of 69 1%. Similar results were observed in treatment-na€ıve patients, with an ORR of 100% and 18-month PFS of 92%. Based on these data, ibrutinib has been approved for symptomatic WM. Waldenstr€ om macroglobulinaemia is an indolent nonHodgkin lymphoma that usually responds well to treatment with long survival. Due to its natural history, it is particularly difficult to find early predictors for survival outcomes in WM. In the era of chemo-immunotherapy, several studies have identified a correlation between depth of response and long-term survival. Attainment of at least a partial response (PR) or a very good PR (VGPR) was associated with better PFS in patients treated with rituximab-based regimens. However, with BTK-i this has not been investigated yet. In this scenario, the identification of factors that may predict poor responders would help clinicians to better tailor treatment and is worthy of investigation. In this issue of the British Journal of Haematology, Castillo et al. investigated whether different depth of response to treatment at defined time-points could be a predictor of PFS in patients with WM treated with ibrutinib. A learning cohort and a validation cohort of 93 patients from clinical trials and 190 patients off trial respectively, were tested. Major response at 6 months, considered as PR or better (≥PR) was shown to correlate with higher rates of 3-year PFS in both cohorts [hazard ratio (HR) 0 38 and 0 18 for the learning and validation cohorts respectively]. According to the results of this study, attaining a ≥PR after 6 months of exposure to ibrutinib was a good predictor of treatment efficacy and may be considered as a surrogate of prolonged PFS. Treatment with ibrutinib in WM is characterised by prolonged survival rates, with the median PFS >5 years for patients carrying a myeloid differentiation primary response gene 88 (MYD88) mutation and lacking C-X-C motif chemokine receptor 4 (CXCR4) mutations. Thus, evaluating the advantages of adding new drugs to ibrutinib or comparing new agents with ibrutinib in Phase III trials is difficult, as they would require very prolonged follow-up to show any differences. As Castillo et al. state in their study, attaining a ≥PR at 6 months could be considered as a surrogate endpoint for PFS in clinical trials evaluating ibrutinib or other BTK-i in the WM setting, making the results available in a shorter observation time. The design of the Castillo et al. study considered two depths of response: attainment of ≥PR and ≥VGPR, and two response assessment time-points of 6 and 12 months from treatment initiation. Interestingly, comparing patients with ≥VGPR at 6 months versus others, no significant differences in PFS were observed. Moreover, neither a ≥PR nor ≥VGPR assessed at 12 months correlated with a benefit in terms of 3year PFS. These results are intriguing and difficult to interpret. When rituximab-based treatments are used, the achievement of at least a VGPR is desirable to aspire to a durable effect. However, based on the results of the present study in the treatment of WM with ibrutinib, the speed of the achievement of a good response, that is at least a PR, might affect more favourably the long-term outcome than the depth of the response, but this remains a speculation that requires more data. When univariate and multivariate analyses have been fitted, aside for not attaining a 6-month ≥PR, only the presence of CXCR4 mutations were associated with worse PFS in both Correspondence: Umberto Vitolo, Multidisciplinary Outpatient Oncology Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (Torino), Italy. E-mail: umberto.vitolo@ircc.it commentary