Efforts to target key mechanisms in the development of chronic lymphocytic leukemia (CLL), one of the most common lymphoid cancers, have led to several new treatments. Among these, ibrutinib emerged as a strong approach for patients who were too frail for aggressive treatment.1 But for healthier patients with CLL, the benefit of this drug remained unknown for a time.
A phase 3 study published in the New England Journal of Medicine showed a benefit for ibrutinib plus rituximab for these more fit patients.2 Although the data help clarify the potential role of ibrutinib in CLL, they also raise difficult questions about the future of this treatment approach.
The standard first-line treatment for otherwise healthy CLL patients 70 years or younger has been a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab (FCR). Patients with immunoglobulin heavy-chain variable region (IGHV)-mutated disease had particularly good results with this treatment: roughly half remained progression-free for up to 8 years after initial treatment. However, substantial toxic effects in the aftermath of treatment, including myelosuppression, risk of myelodysplasia, and infectious complications, have led researchers to explore other avenues of therapy — in particular, ibrutinib.
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Ibrutinib inhibits Bruton tyrosine kinase (BTK), a B-cell signaling protein involved in B-cell development, differentiation, proliferation, and survival. After studies showed the drug to be effective for patients with relapsed CLL and then frail patients with untreated CLL, researchers have been eager to investigate its role in first-line therapy for younger patients.
Most studies so far have explored the use of ibrutinib as a monotherapy. This trial, however, led by Tait Shanafelt, MD, of Stanford University School of Medicine, California, combined ibrutinib with rituximab, and compared the regimen with the standard treatment of FCR.
