TOP_May 2011_4_TOP 5/13/11 9:30 AM Page 8
Hematologic Malignancies
Emerging Agents and Regimens in the Management of Follicular Lymphomas By Elizabeth Reist, PharmD Department of Pharmacy, Roswell Park Cancer Institute, Buffalo, New York Angie Elefante, PharmD, BCOP Department of Pharmacy, Roswell Park Cancer Institute, Buffalo, New York Francisco Hernandez-Ilizaliturri, MD Assistant Professor of Medicine, Department of Medical Oncology; Assistant Professor of Immunology, Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York
F
ollicular lymphoma (FL) is one of the most common subtypes of indolent non-Hodgkin lymphoma (NHL). Although FL is considered incurable with currently available therapy, the introduction of monoclonal antibodies has improved clinical outcomes for this group of patients. Ongoing research focuses on assisting practicing oncologists with selecting the proper therapeutic options for specific clinical scenarios. This article presents some of the most recent and novel approaches for treatment of FL, with regimens involving rituximab (Rituxan), bendamustine (Treanda), lenalidomide (Revlimid), and bortezomib (Velcade).
Rituximab Maintenance This past January, the US Food and Drug Administration approved rituximab for maintenance therapy in patients with previously untreated FL who achieved a response to rituximab in combination with chemotherapy.1 Updated results from the PRIMA (Primary Rituximab and Maintenance) trial (Table 1) showed sustained benefits from rituximab maintenance therapy in patients with FL who had high tumor burden (n = 1193). In the observational arm, 60.3% of patients achieved 3-year progression-free survival (PFS) compared with 78.6% of patients in the maintenance arm (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.44-0.68).2,3 Similar to what was observed in rituximab maintenance clinical trials in the relapsed/refractory setting, improvements in PFS did not translate into improvement in overall survival (OS).2,3 For asymptomatic patients with nonbulky FL, many clinicians believe watchful waiting is superior to chemotherapy. As research on less toxic and effective therapies such as rituximab continues to emerge, clinicians are questioning the watchful waiting approach. For example, Ardeshna and colleagues reported results of a clinical trial comparing rituximab induction therapy followed by rituximab maintenance versus observation for nonbulky FL grades 1-3a (Table 1). Preliminary results are encouraging, with
8
May 2011 I VOL 4, NO 3
patients in the rituximab arm achieving a significant delay in the need to initiate new therapy compared with those in the watchful waiting arm (P <.001; 95% CI, 0.13-0.29).4 Improvements in more clinically relevant end points, such as PFS and OS, have not yet been observed. The benefit of rituximab maintenance in FL patients was further evaluated by Vidal and associates in a meta-analysis of clinical trials comparing rituximab maintenance with observation in previously untreated or relapsed/refractory FL. Results showed increased OS in the rituximab maintenance arm for relapsed/ refractory FL (HR, 0.75; 95% CI, 0.570.91) but no significant change in OS for previously untreated patients (HR, 0.83; 95% CI, 0.56-1.23).5 In the absence of a clear benefit in OS, clinicians must carefully weigh the benefits and risk for individual patients of starting rituximab maintenance in the firstline or relapsed/refractory setting.
As research on less toxic and effective therapies such as rituximab continues to emerge, clinicians are questioning the watchful waiting approach.
Rituximab in Combination with Lenalidomide Several trials have evaluated the combination of rituximab and lenalidomide in FL patients. Ahmadi and colleagues treated rituximab-resistant relapsed/refractory indolent or mantle cell lymphoma patients with rituximab, lenalidomide, and dexamethasone (Table 2). Preliminary results showed an overall response rate (ORR) of 60% for the subset of 18 patients with FL, and 78% of all patients were progression-free at 12 months.6 Another study evaluated the ability of lenalidomide to overcome the negative impact of low affinity
Table 1 Rituximab Maintenance Studies End Points by Study PRIMA2 3-Year PFS, % 2-Year CR or uCR, No. (%) Grade 3/4 AEs, No. (%) Infections â&#x2030;Ľgrade 2, No. (%) Ardeshna et al4 3-Year PFS, % PR, % PD, % No change, %
Maintenance
Observation
n = 505
n = 513
74.9
57.6
361 (71.5)
268 (52.2)
121 (24)
84 (17)
197 (39)
123 (24)
n = 192
n = 186
81 36
30 6
3 74
3-Year OS, %
96
17 11 96
No new treatment at 3 years, %
91
48
NR at 48
33
10
25
Time to new treatment, mo Serious AEs, No.
AE indicates adverse event; CR, complete response; NR, none reported; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; uCR, unconfirmed complete response.
FCGR3 genotype on rituximab activity. Early analysis suggests that patients with the higher affinity FCGR3 genotype (158V/V) appear to have significantly increased ORR and PFS compared with patients with the low-affinity FCGR3 allele (158F) when treated with rituximab mono therapy.7 Dutia and colleagues formally evaluated whether lenalidomide could improve rituximab activity in FL patients with FCGR3-158V/F or FCGR3-158F/F genotypes. Patients with relapsed/refractory indolent lymphoma were treated with a combination of rituximab and lenalidomide. FcÎłRIIIA genotype was determined in DNA isolated from peripheral blood cells by polymerase chain reaction amplification followed by allele-specific restriction enzyme digestion. Preliminary results suggest an impressive ORR of 100% and median PFS of 14.85 months for patients with the FCGR3-158V/F polymorphism and 8.31 months for patients with the FCGR3-158F/F polymorphism. The subsets of patients with other polymorphisms of the FCGR3 genotype were too small for researchers to draw any preliminary
conclusions. Enrollment into the study continues, and final results might support using lenalidomide in combination with rituximab to treat relapsed/refractory lymphomas.8 Rituximab and lenalidomide were also tested in the first-line setting by Fowler and colleagues in a single-arm study that enrolled 30 patients with previously untreated NHL, including 17 patients with FL (Table 2).9 The ORR was 86%; 79% of all patients and 94% of FL patients achieved a complete response (CR). Grade 3/4 adverse events consisted primarily of rash (6 patients), neutropenia (7 patients), and myalgia (4 patients). Other grade 3/4 adverse events included neuropathy, infection, fatigue, and thrombosis, each of which affected 1 patient. After a median follow-up period of 14.1 months, only 1 patient progressed. Based on these results, planned accrual was increased to 110 patients. Rituximab in Combination with Bortezomib Bortezomib plus rituximab has shown activity in FL patients. Preclinical data suggest rituximab and bortezomib interact biologically. Coiffier and asso-
www.TheOncologyPharmacist.com