Jia Ruan, MD, PhD
The combination of lenalidomide (Revlimid) and rituximab (Rituxan) demonstrated an objective response rate (ORR) of 92% as initial therapy for patients with mantle cell lymphoma (MCL), according to findings from a phase II study published in The New England Journal of Medicine
After a median follow-up of 30 months for 36 evaluable patients in the study, the complete response rate was 64% (95% CI, 46-79). Additionally, responses were associated with improvement in quality of life, according to the FACT-Lym questionnaire.
“For patients, their quality of life was preserved or improved, and that’s a huge step up from regular chemotherapy,” lead author Jia Ruan, MD, PhD, an associate professor of clinical medicine at Weill Cornell Medicine, said in a statement. “With this frontline treatment, we were able to achieve a very high quality and durable response rate without needing to use chemotherapy. It’s very meaningful for the patients who have always been told that their disease is without a cure.”
In the phase II study, 38 patients at a median age of 65 years received the combination. Most patients (97%) had an ECOG PS between 0 and 1 and most were male (71%). Patients were evenly distributed between low- (34%), intermediate- (34%), and high-risk (32%) groups, according to MCL International Prognostic Index (MIPI) scores. Overall, 39% of patients had elevated lactate dehydrogenase levels and 89% had bone marrow involvement.
Rituximab was administered at a standard dose weekly for the first 4 weeks followed by biweekly until disease progression. During a 12-cycle induction phase, patients received lenalidomide at 20 mg/daily on days 1 to 21 of a 28-day cycle. Following the first cycle, the dose was escalated to 25 mg/daily, if there weren't any dose-limiting events.
Following induction, those who responded continued to receive maintenance therapy. In this phase, the rituximab dose was maintained while lenalidomide was reduced to 15 mg/daily. The primary endpoint of the study was ORR, with key secondary outcome measures focused on survival, safety, and quality of life.
In the full intent-to-treat population of the study (N = 38), which included two patients who were not evaluable for response, the ORR was 87% and the complete response rate was 61%. The median time to a partial response was 3 months (range, 3-13 months).
Complete responses increased steadily over the course of the study, with 11% observed within the first 6 months, 24% by month 9, and 50% by month 12. The median time to a complete response was 11 months (range, 3-22 months).
At the 30-month analysis, the median progression-free survival (PFS) and overall survival (OS) had not yet been reached with the combination. The estimated 2-year PFS rate was 85% (95% CI, 67-94). The 2-year OS rate at 30 months was 97% (95% CI, 79-99). Those with a high-risk MIPI score were found to have an unfavorable OS compared with lower risk individuals (P
The most common grade ≥3 adverse events (AEs) associated with the combination were neutropenia (50%), rash (29%), thrombocytopenia (13%), an inflammatory syndrome (11%), anemia (11%), serum sickness (8%), and fatigue (8%).
In 33 patients with normal renal function, 36% were able to tolerate dose escalations for lenalidomide. However, 42% required a dose reduction. There were no treatment-related deaths in the study.
“Conventional, intensive treatment may be out of reach or undesirable for many MCL patients, who often receive less intensive or palliative care that is of limited benefit,” Ruan said. “This inspired us to look for a less toxic, biological option with novel drugs that could be easily administered and more widely applicable.”
FACT-Lym quality-of-life questionnaire completion rates ranged from 62% to 88%. At baseline, the mean total score was 130.8 (standard deviation, ±22.8). The trial outcome index score was 91.0 (±17.5).
At 12 months, quality-of-life scores were significantly better compared with baseline (P
= .04). At this point, the mean score was 139.1±19.1. A repeat of the questionnaire at month 21 demonstrated a similar improvement, with a score of 139.3±24.1 (P
“I’m inspired by the fact that patients are enthusiastic about this approach,” senior author John P. Leonard, MD, associate dean for clinical research at Weill Cornell Medicine, said in a statement. “I’m also excited that lymphoma physicians are thinking out of the box, that many in the community now think that a non-chemotherapy-based paradigm with novel agents is something important to take forward and more broadly assess.”
Historically, PFS has ranged from 16.6 to 35.4 months for patients with MCL treated with standard chemoimmunotherapy regimens. Based on traditional responses to therapy, the investigators noted that lenalidomide and rituximab should be explored further.
In fact, numerous studies are assessing the combination of lenalidomide and rituximab for patients with MCL. The phase III MAGNIFY study is looking at lenalidomide plus rituximab followed by maintenance with lenalidomide or rituximab for relapsed/refractory MCL and other types of lymphoma (NCT01996865). Additionally, a phase III study is currently exploring R-CHOP plus R-HAD compared with R-CHOP followed by maintenance lenalidomide plus rituximab or rituximab alone for older (>60 years) patients with MCL (NCT01865110).
In order to explore the use of novel agents in MCL further, a phase II study is looking at the addition of the BTK inhibitor ibrutinib to the combination of lenalidomide and rituximab for patients with relapsed/refractory MCL. This study hopes to enroll 50 patients (NCT02460276).
Ruan J, Martin P, Shah B, et al. Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma. N Engl J Med. 2015;373:1835-44.