Ibrutinib—a new standard treatment for relapsed mantle cell lymphoma?

Abstract

728 www.thelancet.com Vol 387 February 20, 2016 In The Lancet, Martin Dreyling and colleagues present the results of a large, international, randomised phase 3 trial comparing the only two drugs approved for previously treated mantle cell lymphoma in Europe: temsirolimus and ibrutinib. Among 280 patients, those randomly assigned to daily oral ibrutinib 560 mg (n=139) showed a signifi cant improvement in progression-free survival, the trial’s primary endpoint, compared with patients (n=141) assigned to daily intravenous temsirolimus 175 mg (14·6 months vs 6·2 months; hazard ratio 0·43 [95% CI 0·32–0·58]). Ibrutinib was also better tolerated than temsirolimus, with fewer study discontinuations because of adverse events. Therefore, the results from this trial clearly establish ibrutinib as a new standard for treatment of relapsed mantle cell lymphoma. Representing only 5% of all non-Hodgkin lymphomas, mantle cell lymphoma is not the most epidemiologically relevant disease. Its natural history and poor prognosis, however, have garnered substantial attention. After an initial chemotherapy-induced remission of varying duration, patients with mantle cell lymphoma generally undergo a series of subsequent therapies, with successes measured in months as the disease and treatment-related side-eff ects slowly take their toll. A constant unmet need, mantle cell lymphoma has been a model for the accelerated development of novel targeted drugs. The US Food and Drug Administration (FDA) approved bortezomib and lenalidomide for patients with mantle cell lymphoma who had received previous treatments, on the basis of results from phase 2 trials that showed an overall response rate of about 30% and equally high occurrences of study discontinuation because of adverse events. The development of temsirolimus was less straightforward. Results from two clinical trials showed that temsirolimus possessed substantial activity against mantle cell lymphoma (with overall response rates of about 40%), but also a therapeutic index that favoured lower doses. An international phase 3 trial compared two doses of temsirolimus against investigator’s choice of treatment (a variety of single chemotherapy drugs), and showed that 22% of patients receiving higher-dose temsirolimus (175 mg per week for 3 weeks followed by 75 mg per week thereafter) achieved an objective response, with a median progression-free survival of 4·8 months, compared with investigator’s choice (2% and 1·9 months, respectively). 22% of patients receiving the higher dose of temsirolimus discontinued treatment because of an adverse event, compared with 11% of patients receiving the investigator’s choice who discontinued for the same reason. These results were suffi cient for approval of temsirolimus for the treatment of mantle cell lymphoma by the European Medicines Agency (EMA) in 2008, but not by the FDA. In 2009, the fi rst-in-class, oral, small molecule inhibitor of Bruton’s tyrosine kinase, ibrutinib, entered clinical development. On the basis of promising results in seven of nine patients with mantle cell lymphoma treated in a phase 1 trial, a non-pivotal, phase 2 trial (PCYC-1104) was designed with the intention of better Ibrutinib—a new standard treatment for relapsed mantle cell lymphoma? 4 Marr KA, Schlamm HT, Herbrecht R, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med 2015; 162: 81–89. 5 Miceli MH, Kauff man CA. Isavuconazole: a new broad-spectrum triazole antifungal agent. Clin Infect Dis 2015; 61: 1558–65. 6 Teusink A, Vinks AA, Zhang K, et al. Genotype-directed dosing leads to optimized voriconazole levels in pediatric patients receiving hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2015; published oline Nov 23. DOI:10.1016/j.bbmt.2015.11.011. 7 Lutsar I, Hodges MR, Tomaszewski K, Troke PF, Wood ND. Safety of voriconazole and dose individualization. Clin Infect Dis 2003; 36: 1087–88. 8 Ashbee HR, Barnes RA, Johnson EM, Richardson MD, Gorton R, Hope WW. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother 2014; 69: 1162–76. 9 Ananda-Rajah MR, Cheng A, Morrissey CO, et al. Attributable hospital cost and antifungal treatment of invasive fungal diseases in high-risk hematology patients: an economic modeling approach. Antimicrob Agents Chemother 2011; 55: 1953–60. 10 Munoz P, Valerio M, Vena A, Bouza E. Antifungal stewardship in daily practice and health economic implications. Mycoses 2015; 58 (suppl 2): 14–25. 11 Ananda-Rajah MR, Slavin MA, Thursky KT. The case for antifungal stewardship. Curr Opin Infect Dis 2012; 25: 107–15. 12 Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347: 408–15.