Discussion
myalgia, arrhythmia, toxicities, Rash, CLL, liver failure/dysfunction, purpura, Infections, hematuria, B-cell NHL, Weiss syndrome, Myelosuppression-related, sinusitis, rash, hemorrhage, cystitis, nausea, diarrhea, fatigue, anemia, infection, secondary malignant tumors, B-NHL, neutropenia, constipation, PCNSL, headache
ARRHYTHMIA, RASH, PURPURA, INFECTIONS, OCULOMUCOCUTANEOUS SYNDROME, EAR HEMORRHAGE, HEMATURIA, B-CELL NHL, EVENTS, ADVERSE DRUG REACTIONS, SINUSITIS, THROMBOCYTOPENIA, HEMORRHAGE, BONE MARROW SUPPRESSION, INTERSTITIAL LUNG DISEASE, CYSTITIS, TUMOR LYSIS SYNDROME, ANEMIA, INFECTION, HYPERSENSITIVITY, CLL, NEUTROPENIA, ERYTHEMA MULTIFORME
This Phase I study was performed to investigate the maximum tolerated dose of tirabrutinib, as well as its safety, efficacy, and pharmacokinetics, in Japanese patients with relapsed or refractory B-cell NHL or CLL. Results at an earlier cutoff (January 4, 2018) were reported in our previous manuscript [The safety data in this study are generally consistent with those in prior studies of tirabrutinib. For example, in prior Japanese studies, rash, hematologic AEs, erythema multiforme, and constipation were frequent AEs in a Phase I/II study of 44 patients with PCNSL [The Japanese product label for ibrutinib, a first-generation BTK inhibitor, lists 11 categories of adverse drug reactions (ADR) as identified/potential risks in the risk management plan (hemorrhage, bone marrow suppression, infection, arrhythmia, hypersensitivity, tumor lysis syndrome, liver failure/dysfunction, interstitial lung disease, secondary malignant tumors, leukostasis, and oculomucocutaneous syndrome) [Hemorrhage-related AEs are a potential class effect of BTK inhibitors. In our study, these events included ear hemorrhage, hematuria, PT-INR increased, Mallory–Weiss syndrome, and purpura, each of which occurred in one patient (5.9%) (Table Infections were also evaluated as AEs of specific interest, and included cystitis, nasopharyngitis, pharyngitis, and sinusitis in 2 patients each (11.8%) (Table Myelosuppression-related AEs included neutropenia/neutrophil count decreased in 4 patients (23.5%), anemia in 3 patients (17.6%), thrombocytopenia/platelet count decreased in 2 patients (11.8%), and leukopenia/white blood cell count decreased in 2 patients (11.8%). These values are generally similar to those reported in the package insert for ibrutinib (anemia, 9.6%; neutropenia, 12.5%; thrombocytopenia, 9.8%) [Rash, diarrhea, headache, nausea, fatigue, and myalgia have been reported for other second-generation BTK inhibitors [From an efficacy perspective, although this was a Phase I study with a limited number of patients, the study enrolled several patients with MCL, WM, and CLL who were treated with tirabrutinib for a long period of time with long responses. These data suggest that tirabrutinib may be effective in patients with MCL, WM, and CLL.Limitations of this Phase I study include its small sample, dose-escalation design, and the inclusion of multiple subtypes of B-NHL and CLL. These factors may limit the generalizability of the results to broader clinical practice. However, these limitations must be considered in relation to the primary objective of this Phase I study, which was to evaluate the safety and detect potential dose-limiting toxicities, and hence the recommended dose in Japanese patients. Larger studies may be necessary to confirm our results.With a median follow-up of 4.3 years, this study comprises the longest data set of any tirabrutinib study published to date and 4 patients were continuing treatment for ≥ 5 years. This allowed us to evaluate the long-term safety of tirabrutinib. We observed no additional risks or emergence of Grade ≥ 3 drug-related AEs since the prior cutoff at which time the median follow-up was 2.3 years. The current results, as well as those from the prior report, demonstrate the long-term tolerability of tirabrutinib at doses of 480 mg QD or 300 mg BID in patients with relapsed or refractory B-NHL or CLL, with a low rate of discontinuation due to AEs/drug-related AEs.