The immune system is the center for combating potentially dangerous infections, but sometimes this robust and highly sophisticated system can also be the originator of potentially life-threatening disease. Non-Hodgkin lymphoma (NHL) represents an indolent form of cancer that directly and indirectly impacts the immune system (Mayo Clin Proc 2015;90(8):1152-1163).
For patients with refractory NHL that has become resistant to treatment, finding new options for management can become challenging. New and innovative research studies are beginning to focus on therapeutic strategies for maximizing response and improving tolerability in refractory lymphoma patients. Follicular lymphoma and marginal zone lymphoma (MZL) are two types of indolent B-cell NHLs that are the prime focuses of recent research.
Patients with follicular lymphoma often present with disease in its advance stages (Rev Bras Hematol Hemoter 2012;34(1):54-59).
Systemic chemoimmunotherapy is often the standard form of care in follicular lymphoma patients, and the majority of patients respond to initial therapy. Unfortunately, follicular lymphoma is associated with frequent relapses and shorter durations of remissions over time, and some patients become resistant to the typical chemoimmunotherapy agents (Rev Bras Hematol Hemoter 2012;34(1):54-59). Patients with MZL, another slow-growing cancer type, are also at high risk for relapse and becoming resistant to treatment (Am J Hematol 2009;84(12):826-829).
According to Jeff P. Sharman, MD, Medical Director of Hematology Research at The U.S. Oncology Network and the Willamette Valley Cancer Institute, the majority of follicular lymphoma patients are able to experience a sustained clinical benefit from standard chemotherapy. Unfortunately, patients with an aggressive clinical phenotype or those that become resistant to standard treatment will “often progress through multiple lines of therapy,” rather than having the ability to establish a standardized routine.
New treatment options and strategies for follicular lymphoma that has become resistant to standard chemotherapy approaches are beginning to emerge at an increasing rate. For instance, phosphoinositide 3-kinase inhibitors, such as copanlisib, have recently received FDA approval for chemotherapy-resistant patients.
Lenalidomide & Rituximab: A Combining Force
The use of lenalidomide and rituximab for immunomodulation in patients with NHL has shown promising results in previous trials. Clinical trial results reported by Fowler et al. at the American Society of Hematology 2012 Annual Meeting demonstrated a 98 percent overall response rate of lenalidomide and rituximab combination in patients with advanced stage follicular lymphoma (Proc ASH 2012; Abstract 901). Additionally, combined lenalidomide and rituximab resulted in an 89 percent progression-free survival rate at 2 years in evaluable follicular lymphoma patients (n = 46).
The phase III randomized Cancer and Leukemia Group B (Alliance) 50401 trial also strengthens the rationale for the lenalidomide-rituximab combination regimen in follicular lymphoma patients (J Clin Oncol 2012;suppl:abstr 8000). In this study, follicular lymphoma patients received either lenalidomide (n = 45) or lenalidomide and rituximab (n = 46).
The overall response rate in the lenalidomide-rituximab combination group was significantly higher than the lenalidomide-only arm (76% vs. 53%, respectively; P = .029). Time to progression was also greater in the combination regimen versus monotherapy at a median follow-up of 2.5 years (2 years vs. 1.1 years, respectively; P = .0023). According to the investigators, neither arm demonstrated significant differences in terms of overall survival (P = .149).
“Lenalidomide is approved for patients with relapsed mantle cell lymphoma and has significant activity in the indolent lymphoma population as reported in several manuscripts,” said Sharman, who was one of the lead investigators for the MAGNIFY trial. “Our study evaluates the combination of lenalidomide with rituximab where the two agents are very complementary of one another demonstrating robust clinical activity with a well-tolerated side effect profile.”
The phase IIIb, multi-center, open-label MAGNIFY trial is an ongoing study of patients with relapsed or refractory follicular lymphoma, mantle cell lymphoma, or MZL receiving lenalidomide in addition to 12 cycles of rituximab combination therapy (J Clin Oncol 2015;no. 15_suppl).
Following the combination therapy, investigators will randomize patients to either 18 cycles of rituximab maintenance or 18 cycles of rituximab only. The primary endpoint of this trial is progression-free survival, whereas the secondary endpoints include overall response rate (ORR), complete response (CR), improvement of response, duration of response, time to next lymphoma treatment, and overall survival. Currently, this trial is continuing to accrue patients, and investigators have yet to transition into the randomization phase of this study.
Interim results recently announced by the study's lead study investigators at the ASCO 2017 Annual Meeting, however, have demonstrated clinical efficacy of the treatment regimen.
“The study is a large randomized study in which all patients get 1 year of lenalidomide and rituximab prior to randomization of rituximab maintenance versus rituximab maintenance with lenalidomide maintenance,” explained Sharman. “At this point, I think we can reflect that the regimen is both effective and acceptably tolerated in this population.”
During the ASCO session, investigators of the MAGNIFY trial reported their findings in a subset of follicular lymphoma patients that have either relapsed or become refractory (n = 160) with early relapse (n = 52) and double-refractory (n = 50) illness. Among all patients with follicular lymphoma, progression-free survival at 1 year was 70 percent. In addition, progression-free survival for early refractory patients was 49 percent versus 65 percent for double-refractory subjects.
Furthermore, ORR and CR/CRu for a total of 128 follicular lymphoma patients was 66 percent and 38 percent, respectively. Specifically, patients with early refractory disease experienced an ORR and CR/CRu of 47 percent and 21 percent versus 45 percent and 21 percent for double-refractory participants. Fatigue, leukopenia, lymphopenia, thrombocytopenia, and neutropenia were the most common adverse events (grade 3 or 4) observed among all study participants.
“The chemotherapy-free combination of lenalidomide and rituximab, with complementary mechanisms of action that are thought to enhance antibody-dependent cellular cytotoxicity, continues to show encouraging activity and a tolerable safety profile in indolent lymphomas, and particularly in difficult-to-treat patient subsets,” said David J. Andorsky, MD, co-principal investigator of the study and Medical Oncologist at the Rocky Mountain Cancer Centers in Boulder, Colo. “These results in patients who had failed multiple therapies or relapsed early, as well as the activity in marginal zone patients, merit further study in this area of indolent lymphoma.”
In addition to similar trials conducted on lenalidomide and rituximab in lymphoma treatment, the findings of the MAGNIFY study may ultimately play a role in changing the landscape of treatment for patients with refractory carcinoma. “This regimen is associated with significant clinical activity...[and] has a very tolerable side effect profile,” added Sharman. “If lenalidomide can gain approval in this population, it would represent a useful addition to our treatment portfolio.”
“I believe the study is well-designed to answer the questions we're asking,” Andorsky emphasized. Based on his findings, he believes this approach is “a good therapy, particularly for patients who are refractory, and it's a very promising treatment for patients with these diseases and will hopefully standardized patient care.”
Since the MAGNIFY trial is ongoing and has yet to enter the randomization phase, Sharman and study investigators are unsure as to the “optimal duration of lenalidomide maintenance” in the setting of “rituximab maintenance only or rituximab maintenance in combination with lenalidomide.”
The investigators foresee no limitations to the study design or the potential main findings.
Brandon May is a contributing writer.