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The B-cell receptor is the survival switch of B cells. Signals from it pass through BTK to free NF-kappa-B, which keeps the cell alive. B-cell cancers hold it on; BTK inhibitors, proteasome inhibitors and lenalidomide each cut the line at a different point.
Antigen binding to the B-cell receptor activates SYK and BTK, then PLCγ2 and PKCβ, which assemble the CARD11-BCL10-MALT1 complex and activate the IKK kinases. IKK phosphorylates IκB, the protein that holds NF-κB (p65/p50) in the cytoplasm; IκB is ubiquitinated and destroyed by the proteasome, and NF-κB enters the nucleus to switch on BCL2, BCL-XL, IL-6, IL-10 and cyclin D. Toll-like receptors feed the same hub through MYD88 (MYD88 L265P in Waldenström macroglobulinaemia and ABC-type DLBCL), and BAFF and CD40 signals activate the alternative (NIK-dependent) branch, which matters in multiple myeloma. Activated B-cell DLBCL, chronic lymphocytic leukaemia, mantle cell lymphoma and Waldenström macroglobulinaemia depend on this circuit. Ibrutinib and the later BTK inhibitors (acalabrutinib, zanubrutinib, pirtobrutinib) block the receptor arm; bortezomib and carfilzomib stop the proteasome from destroying IκB; lenalidomide and its successors degrade IKZF1/3 and cut IRF4-driven NF-κB output in myeloma and ABC-DLBCL. Resistance comes from BTK C481S mutations, PLCγ2 mutations and CARD11 or MYD88 lesions downstream of BTK.
A guard (IκB) holds a prisoner (NF-kappa-B) who, once free, orders the cell to survive. The B-cell receptor sends a runner (BTK) to hand the guard to the shredder (proteasome). BTK inhibitors stop the runner, proteasome inhibitors jam the shredder, and lenalidomide removes the clerks (IKZF1/3) who file the survival orders.
A second randomised confirmation that adding a Bruton tyrosine kinase inhibitor to first-line bendamustine-rituximab delays progression in older patients with mantle cell lymphoma, with a toxicity profile that did not improve as much as the drug's selectivity promised.
The authors' conclusion is that ibrutinib-rituximab should be considered a new standard-of-care option for first-line treatment of older patients with mantle-cell lymphoma. The subgroup split means it is clearly better than R-CHOP and roughly equivalent to bendamustine-rituximab.
Evidence that the B-cell receptor pathway is worth attacking in follicular lymphoma when a Bruton tyrosine kinase inhibitor is paired with a type II CD20 antibody, after single-agent inhibitors had disappointed in this disease.
Twenty-eight extra months of progression-free survival, with no survival gain and a high rate of severe adverse events in both arms. It set up the two trials that followed: ECHO, which substituted a more selective inhibitor, and ENRICH, which removed the chemotherapy.
A failure worth reading: the drug worked where patients could tolerate the regimen it was added to, and harmed where they could not. It is the strongest argument in lymphoma for designing first-line combinations around what an older patient can finish.
The genetic nosology that precision-medicine trials in diffuse large B-cell lymphoma now use to pick patients. It gives a mechanism, not just a label: two of the four subtypes point at a drug class that already exists.
Shares Cell of origin in practice: Hans against expression profiling, and what it changes, CD79B ITAM mutation, ARCHED, The germinal centre reaction.
Shares A Study of BR Alone Versus in Combination With Acalabrutinib in Subjects With Previously Untreated MCL, Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma, Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma, SHINE.
Shares ROSEWOOD: a phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma, ROSEWOOD, BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors, BTK C481S, PLCG2 and BCL2 G101V resistance mutations.
Shares Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX), MYD88, CD79b, Genetics and pathogenesis of diffuse large B-cell lymphoma.
Shares A Study of BR Alone Versus in Combination With Acalabrutinib in Subjects With Previously Untreated MCL, Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma, Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma, MYD88 L265P and CXCR4 mutations.
Shares A Study of BR Alone Versus in Combination With Acalabrutinib in Subjects With Previously Untreated MCL, BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors, BTK C481S, PLCG2 and BCL2 G101V resistance mutations, ARCHED.
Shares ROSEWOOD: a phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma, ROSEWOOD, A Study of BR Alone Versus in Combination With Acalabrutinib in Subjects With Previously Untreated MCL, ARCHED.
Shares Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma, Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial, ENRICH, BTK (Bruton tyrosine kinase).