The biologic doublet of lenalidomide (Revlimid) plus rituximab (Rituxan) can achieve high response rates and durable remissions in lymphoma, according to a parade of phase II studies presented at the 2013 American Society of Hematology (ASH) Annual Meeting in New Orleans.

The immunomodulatory agent lenalidomide enhances rituximab-induced apoptosis in preclinical models, has single-agent activity in relapsed indolent lymphoma, and in combination with rituximab has shown strong activity in relapsed and previously untreated follicular lymphoma. The combination of these agents—dubbed the “R-squared” regimen—has gained attention lately, and ongoing trials are evaluating whether this treatment can take the place of traditional chemotherapy. It is also now serving as a backbone for a number of investigational regimens.

Mantle Cell Lymphoma

In mantle cell lymphoma, Jia Ruan, MD, PhD, of Weill Cornell Medical College, New York, presented the results of a multicenter phase II study of 32 treatment-naive patients whose objective response rate was 87%, with 57% of evaluable patients achieving complete responses.¹

The high response rates translated into encouraging progression-free and overall survival. At a median follow-up of 16 months, the 12-month progression-free survival rate was 93%, and the overall survival rate was estimated at 100%, Dr. Ruan reported. Responses deepened over time, with complete responses increasing from just over 10% at 6 months to more than 50% by 21 months. All subjects remain alive as of last follow-up.

Induction included lenalidomide at 20 mg daily on days 1 to 21 of a 28-day cycle for 12 cycles, with dose escalation to 25 mg daily if tolerated. The standard dose of rituximab was given weekly for four treatments during cycle 1, then once every other cycle, for a total of nine doses. During the maintenance phase, starting with cycle 13, lenalidomide was given at 15 mg daily on days 1 to 21 of a 28-day cycle, with rituximab given as maintenance once every other cycle until progression of disease.

Dose reductions were necessary in 40% of patients, usually to 15 mg daily; 17% tolerated an escalation of the dose to 25 mg.

The main toxicities were related to inflammation, including grade ≥ 3 rash (22%), fatigue (9%), and tumor flare (9%). “The symptoms were largely related to inflammatory syndromes. These can be concerning to the patient, but they tend to occur in cycle 1. After their initial assessment, patients generally cruise along with close and regular follow-ups,” according to Dr. Ruan.

“The initial treatment of [mantle cell lymphoma] is not standardized. Current conventional upfront chemoimmunotherapies are generally not curative and can be deferred in some patients,” she said. “We believe our findings justify further evaluation of the lenalidomide plus rituximab regimen, both alone and as a platform in combination with other novel agents in [mantle cell lymphoma] therapy, and in both the upfront and relapsed settings.”

Follicular Lymphoma

French investigators reported phase II results of adding lenalidomide to R-CHOP (rituximab, doxorubicin, vincristine, prednisone) in 80 patients with previously untreated follicular lymphoma, grade 1, 2, or 3a with a high tumor burden.²

Patients received induction with six cycles of R-CHOP plus lenalidomide (lenalidomide at 25 mg on days 1–14 each cycle) followed by two additional rituximab infusions. Responders received rituximab maintenance every 8 weeks for 2 years.

“This phase II study confirmed the safety of the combination. R-squared–CHOP yielded a high rate of complete response in patients with high tumor burden follicular lymphoma,” said Hervé Tilly, MD, of the Centre Henri Becquerel in Rouen.

The response rate at the end of induction by International Working Group criteria was 94%, including 44% with a complete response, 30% with an unconfirmed complete response, and 20% with a partial response. At this evaluation, PET scan was negative in 83% of the patients, according to Deauville criteria.

Hematologic toxicity was in the range of that observed with R-CHOP, with a 65% incidence of grade 4 neutropenia, 12.5% grade 4 thrombocytopenia, 7.5% grade 3/4 febrile neutropenia, and no toxic deaths. Grade 3 rash was observed in < 5%.

“The future of this combination will depend on the results of ongoing trials exploring R-squared as front-line treatment in this population,” Dr. Tilly said.

FcγRIIIa Phenylalanine Carrier Status

Individuals with Fc-gamma receptor RIIIa polymorphisms at amino acid 158 (ie, FcγRIIIa-158 phenylalanine carriers) are reported to respond poorly to rituximab and to have limited progression-free survival. In a study from the University of Pennsylvania, the R-squared regimen appeared to overcome the impact of this adverse genetic profile.³

“In our study, not only were patients relapsed or refractory to rituximab, but additionally they were FcγRIIIa-158 phenylalanine carriers. After a single 4-week course of rituximab during continuous lenalidomide treatment, subjects achieved high response rates and prolonged 2-year progression-free survival,” reported Elise A. Chong, MD, of the Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia.

“Our findings suggest that the immunologic effects of lenalidomide may potentiate the action of rituximab,” she said.

The study was a single-center phase II trial of R-squared in 42 patients with rituximab-refractory or -resistant indolent B-cell lymphoma or mantle cell lymphoma; 39 patients were also FcγRIIIa-158 phenylalanine carriers. Patients first received lenalidomide at 10 mg daily for 8 weeks; then patients were assessed for response. Rituximab was added from weeks 9 though 12, and response was reassessed at week 21.

The response rate to lenalidomide monotherapy was 32%, which increased to 65% with the addition of rituximab.

“The improvement with rituximab was most pronounced in patients with follicular lymphoma (20% vs 66%)—a threefold increase—while in contrast, [mantle cell lymphoma patients] had the highest overall response rate to single-agent lenalidomide (60% vs 60%). This did not change with the addition of rituximab,” she said, “but two partial responses improved to complete responses.”

Median progression-free survival was 20.8 months for all patients. The 2-year progression-free survival rate was 44%. “Putting this in context, progression-free survival with rituximab monotherapy at 2 years is reported at 14%. We report 44%—a dramatic increase,” Dr. Chong noted.

The regimen was generally well tolerated.

Disclosure: Dr. Ruan is a consultant and member of the speakers bureau for and has received research funding from Celgene. Dr. Tilly has received honoraria from Roche, Celgene, Pfizer, and Janssen, research funding from Celgene and Amgen, and is an advisor for Celegene and Takeda. Dr. Chong reported no potential conflicts of interest. ■

References

1. Ruan J, et al. 2013 ASH Annual Meeting. Abstract 247. Presented December 9, 2013.

2. Tilly H, et al. 2013 ASH Annual Meeting. Abstract 248. Presented December 9, 2013.

3. Chong EA, et al. 2013 ASH Annual Meeting. Abstract 250. Presented December 9, 2013.