Expert Point of View: Ranjana Advani, MD

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At the 2013 ASCO Annual Meeting, Ranjana Advani, MD, the Saul A. Rosenberg, MD, Professor of Lymphoma at Stanford University Medical Center, Palo Alto, California, discussed the promise of the B-cell signaling inhibitors idelalisib and ibrutinib in lymphoma.

Biggest Question

Given the single-agent activity of idelalisib in earlier studies, testing the drug in combination, as Leonard et al did, “is a logical step forward,” Dr. Advani said. “Activity was seen in patients exposed to rituximab [Rituxan] and bendamustine [Treanda]—overall, a 78% response rate—and some responses appeared durable,” she said.

But the study was small, the population was heterogeneous, and few patients (about 30%) continued on long-term treatment with idelalisib, she noted. “The biggest question is whether responses are greater with the combination than they would be with single agents,” she suggested. For example, in the study by Benson et al, single-agent activity reached 67% among those optimally dosed. The potential superiority of a regimen containing idelalisib may depend on the backbone, she noted.

With rituximab, McLaughlin et al1 reported a 48% response rate, compared with 72% in the current study of idelalisib/rituximab, in which more than 90% of subjects had prior rituximab. “The combination, therefore, is much more effective than rituximab alone,” she concluded.

With bendamustine alone, a 76% response rate has been reported,2,3 whereas in the current study, bendamustine plus idelalisib yielded an 85% response rate; in this study, 100% had received prior rituximab and 21% prior bendamustine. The combination of bendamustine plus rituximab yielded a 90% response rate in the landmark study by Rummel et al.4 With idelalisib paired with bendamustine, the response rate was 71%; in the study population, 90% had prior rituximab and 30% prior bendamustine. Regarding this comparison, therefore, Dr. ­Advani concluded, “Bendamustine/rituximab in a refractory population already yields very high response rates, and it’s hard to say whether the combination with idelalisib is significantly better or not.”

Uncertain Superiority

For mantle cell lymphoma, idelalisib also seems promising, but the study population was small and heterogeneous. In the bendamustine/rituximab arm, the 100% response rate (50% complete responses) was impressive, but the patients had not received prior bendamustine or bortezomib (Velcade), ie, this was not a refractory population, she emphasized.

In mantle cell lymphoma as well, the potential superiority of adding idelalisib to standard therapies is not yet certain, she said. This is especially true for bendamustine/rituximab, which has been shown to elicit responses in 75% to 92% of patients. The activity of the triplet of idelalisib/bendamustine/rituximab appears similar to what can be achieved with bendamustine/rituximab alone, she suggested.

Enhanced Activity

Commenting on ibrutinib, Dr. ­Advani noted that the drug has shown activity across multiple subtypes of relapsed/refractory non-Hodgkin lymphoma. In the phase I study reported at the ASCO Annual Meeting by Younes et al, combining ibrutinib with R-CHOP as front-line therapy in a variety of B-cell lymphomas, the 100% response rate was “impressive,” she commented, though the study was small, follow-up was short, and disease-specific details were lacking.

“From the safety data we have, these studies show that the new agents can be safely combined without significant additive toxicity,” Dr. Advani continued. “The major issue with the studies is the very small numbers and the relatively short follow-up, but they do set the stage for testing these agents in the front-line setting. Future challenges will be to determine whether to use these drugs as single agents or in combination—it’s not clear if all the combinations tested are better than the single agent—and the optimal sequence for their use.” ■

Disclosure: Dr. Advani has been a consultant or advisor for Celgene, Genentech, Pharmacyclics, and has received research funding from Abbott Laboratories, Genentech, Pharmacyclics, Rigel, and Seattle Genetics.


1. McLaughlin P, Grillo-López AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998.

2. Friedberg JW, Cohen P, Chen L, et al: Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin’s lymphoma: Results from a phase II multicenter, single-agent study. J Clin Oncol 26:204-210, 2008.

3. Kahl BS, Bartlett NL, Leonard JP, et al: Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: Results from a multicenter study. Cancer 116:106-114, 2010.

4. Rummel MJ, Al-Batran SE, Kim SZ, et al: Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s lymphoma. J Clin Oncol 23:3383-3389, 2005.

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