Bruton tyrosine-kinase inhibitor on the rise: acalabrutinib in Waldenström macroglobulinemia
Mené en Europe et aux Etats-Unis sur 106 patients atteints d'une macroglobulinémie de Waldenström, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse globale, et la toxicité de l'acalabrutinib, un inhibiteur de tyrosine kinase de Bruton dispensé en monothérapie (durée médiane de suivi : 27,4 mois)
A major goal for Waldenström's macroglobulinemia is the development of non-toxic, chemotherapy-free treatment regimens that allow long-lasting control of this indolent B cell lymphoma. A key step has been the introduction of the Bruton tyrosine-kinase inhibitor, ibrutinib, which is the most potent single agent in Waldenström's macroglobulinemia, is well tolerated by the majority of patients, and showed favourable activity in MYD88 wildtype patients when combined with rituximab. However, ibrutinib treatment has its challenges and limitations: effectiveness of ibrutinib depends on the mutational status of the MYD88 and CXCR4 genes, with a substantial drop in responses for patients harbouring a CXCR4 mutations, or those with no mutations in both genes. Moreover, time to response is delayed in these two patient groups compared with patients who carry a MYD88 mutation with wild-type CXCR4. Finally, ibrutinib is given for a non-fixed duration, so patients must be able to tolerate the treatment for a long time. Although side effects of ibrutinib are generally well tolerated, the drug is known to cause bleeding and atrial fibrillation. Dose reductions occurred in ten (16%) of 63 patients in the ibrutinib trial, and three patients discontinued treatment due to treatment-related adverse events after lock of the database. In total, 32% of all patients discontinued treatment for any reason. There is therefore room for improvement, and the idea to develop second generation Bruton tyrosine-kinase inhibitors to minimise toxicity and increase efficacy is intriguing. Acalabrutinib is a second generation Bruton tyrosine-kinase inhibitor that has shown fewer side-effects than ibrutinib and does not affect other kinases, such as the EGFR, Tec, or interleukin-2-inducible kinase (ITK), associated with side effects such as rash, atrial fibrillation, or suppression of NK cell activity. Furthermore, a large body of data for acalabrutinib shows high activity and low toxicity in other B-cell lymphomas such as mantle cell lymphoma and chronic lymphocytic lymphoma, which lead to the approval of the drug for relapsed or refractory mantle cell lymphoma in the USA. In The Lancet Haematology, Roger Owen and colleagues present the first clinical trial testing this promising Bruton tyrosine-kinase inhibitor in Waldenström macroglobulinemia. For a rare lymphoma, the study was large, including over 100 patients mostly with relapsed disease in an international, multicentre trial. The results convincingly show that acalabrutinib is an active and well tolerated drug that can be safely administered to patients with Waldenström macroglobulinemia achieving disease control. This is reflected by the overall and major response results (99 [93%] of 106 patients achieved an overall response; 83 [78%] a major response), with a 2-year progression free survival of 82% (95% CI 72–89) in patients with relapsed or refractory disease. Importantly, the number of patients discontinuing acalabrutinib because of adverse events was low (seven [7%] of 106 patients).
The Lancet Haematology , commentaire, 2018