Concurrent treatment with two B-cell receptor pathway inhibitors

Abstract

The prognosis of B-cell lymphoid malignancies has improved after the implementation of ibrutinib and idelalisib: two orally-available drugs targeting the B-cell receptor signalling pathway. Ibrutinib is a Bruton tyrosine kinase inhibitor (BTKi) approved for chronic lymphocytic leukaemia, mantle cell lymphoma, and Waldenstrom macroglobulinaemia. 1 Byrd JC Brown JR O'Brien S et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014; 371: 213-223 Crossref PubMed Scopus (1232) Google Scholar , 2 Robak T Burger JA Tedeschi A et al. Single-agent ibrutinib versus chemoimmunotherapy regimens for treatment-naïve patients with chronic lymphocytic leukemia: A cross-trial comparison of phase 3 studies. Am J Hematol. 2018; 93: 1402-1410 Crossref PubMed Scopus (19) Google Scholar , 3 Wang ML Rule S Martin P et al. Targeting BTK with ibrutinib in relapsed or refractory 507 mantle-cell lymphoma. N Engl J Med. 2013; 369: 507-516 Crossref PubMed Scopus (1215) Google Scholar Idelalisib is also an approved B-cell receptor pathway inhibitor. It is a first-in-class, orally-bioavailable, selective competitive inhibitor of phosphoinositol-3-kinase δ (PI3K-δ), which has been approved for the treatment of chronic lymphocytic leukaemia, in association with rituximab, and for follicular lymphoma as monotherapy. 4 Furman RR Sharman JP Coutre SE et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014; 370: 997-1007 Crossref PubMed Scopus (1369) Google Scholar However, idelalisib can induce severe hepatotoxicity, diarrhoea or colitis, pneumonitis, fatal or serious infections, and intestinal perforation. To address these issues, next-generation PI3K inhibitors, including umbralisib, duvelisib, copanlisib, and buparlisib, are also being investigated for B-cell disorders. These drugs seem to be more potent and better tolerated than idelalisib. Umbralisib is a next-generation inhibitor of PI3K-δ and casein kinase-1ε, and it appears to be well tolerated, has a reduced inhibitory activity on T regulatory cells, and has a lower rate of hepatotoxicity than idelalisib. 5 Burris 3rd, HA Flinn IW Patel MR et al. Umbralisib, a novel PI3Kδ and casein kinase-1ɛ inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018; 19: 486-496 Summary Full Text Full Text PDF PubMed Scopus (138) Google Scholar Umbralisib also showed a favourable safety profile and good clinical activity when administered as a single drug to patients with B-cell lymphoma in a phase 1 study. 5 Burris 3rd, HA Flinn IW Patel MR et al. Umbralisib, a novel PI3Kδ and casein kinase-1ɛ inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018; 19: 486-496 Summary Full Text Full Text PDF PubMed Scopus (138) Google Scholar In contrast to idelalisib, patients given umbralisib had no observed cases of grade 3 hepatotoxicity or colitis, and the only grade 3 or higher adverse event was neutropenia. Umbralisib in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma: a multicentre phase 1–1b studyUmbralisib plus ibrutinib is well tolerated and active in relapsed or refractory chronic lymphocytic leukaemia and mantle cell lymphoma, with a recommended phase 2 dose of umbralisib 800 mg once daily. To the best of our knowledge, these are the first clinical data on a BTKi and PI3K-δi doublet in B-cell malignancies, and the results suggest that this approach is feasible and worthy of further study. Full-Text PDF