Non-Hodgkin lymphomas (NHLs) are a class of hematologic malignancies arising in cells of either B-cell or T-cell lineages. There are several different ways of classifying this family of diseases, but a common one is based on the pace of progression. In this scheme, NHLs are termed either aggressive if characterized by rapid progression or indolent if slower-growing and typically presenting with fewer symptoms at diagnosis. Two of the most diagnosed indolent NHLs in adults are follicular lymphoma (FL) and marginal zone lymphoma (MZL).
Although these are distinct diseases, they often are managed similarly; the anti-CD20 monoclonal antibody rituximab approved for the treatment of FL and MZL is frequently utilized in these patient populations. Preclinical studies performed in mice have suggested that there may be clinical synergy between rituximab and the thalidomide analog lenalidomide (Br J Haematol 2008;140:36-45).
This combination is currently being evaluated in relapsed or refractory indolent lymphoma patients in the phase III international AUGMENT clinical trial (NCT01938001). Patients included in this study have either relapsed or refractory FL or MZL. One of the leading clinicians on this study is John P. Leonard, MD, of Weill Cornell Medicine and NewYork-Presbyterian Hospital, and results were recently published (J Clin Oncol 2019: doi:10.1200/JCO.19.00010).
“The study met its primary endpoint of progression-free survival (PFS), showing a clinically significant and meaningful advantage for the lenalidomide-rituximab combination relative to the placebo-rituximab combination, especially for those patients with relapsed or refractory FL,” Leonard noted.
Based on results from the AUGMENT study presented at the 2018 ASH Annual Meeting, the FDA granted priority review in February 2019 to the combination of lenalidomide and rituximab for previously treated FL or MZL patients.
FL is one of the more common B-cell lymphomas, accounting for approximately 20-30 percent of all NHL cases. Although some patients do not display overt signs of disease when diagnosed with FL, symptoms may include swollen lymph nodes (axilla, neck, groin, or abdomen), dyspnea, fatigue, weight loss, and night sweats.
FL is considered a chronic disease, but can be effectively managed, with many patients living decades after their diagnosis. In January 2011, the FDA approved the use of rituximab as maintenance therapy for FL patients after receiving rituximab plus chemotherapy as induction therapy.
MZL accounts for roughly 8 percent of all NHL cases. It is slightly more common in men than women and has an average age of 60 years at first diagnosis. One common form of MZL is extranodal MZL (also called mucosa-associated lymphoid tissue, or MALT), which makes up nearly two-thirds of all MZL cases annually. This MZL subtype is further divided into two major categories: gastric MALT occurs in the stomach and non-gastric MALT can occur in the salivary glands, thyroid, eyes, and lungs. Frequently, MALT lymphoma patients will have prior medical histories of inflammation, chronic infection, or autoimmune disorders for the affected organs.
Another distinct variety is nodal MZL, which has sometimes been referred to as monocytoid B-cell lymphoma. This disease constitutes approximately 10 percent of all MZL cases and is found within the patients' lymph nodes. Another category of MZL is splenic, which accounts for approximately 20 percent of annual MZL diagnoses. This subtype is found in the blood and the spleen, and it has an association with hepatitis C infection.
As previously noted, preclinical studies evaluated the lenalidomide-rituximab combination using an in vivo human lymphoma xenograft model in immunodeficient mice. In this study, the use of lenalidomide was shown to significantly enhance natural killer cell recruitment to tumor sites. This increased recruitment was thought to arise from dendritic cell stimulation and cytokine microenvironment modification. The combination was also thought to enhance rituximab-associated antibody-dependent cytotoxicity. In addition, these studies showed that lenalidomide had an anti-angiogenic effect, which could have a positive impact on tumor growth by hindering the supply of blood to those lesions.
Among the key inclusion criteria for the study included the following:
- age 18 years or older;
- histologically confirmed diagnosis of MZL or grade 1, 2, or 3a FL;
- prior treatment with one or more systemic chemotherapy, immunotherapy, or chemoimmunotherapy and two or more prior doses of rituximab;
- documented relapsed, refractory, or progressive disease after prior systemic therapy; however, disease could not have been rituximab refractory (defined as no response or PD fewer than 6 months after last rituximab dose);
- ECOG performance status of 2 or less; and
- measurable disease (in two dimensions) having at least one nodal lesion greater than 1.5 cm in diameter or at least one extranodal lesion greater than 1.0 cm in both long and short axes.
Among the exclusion criteria were the following:
- disease type other than FL or MZL or clinical proof of transformed lymphoma, grade 3b FL;
- systemic therapy within 28 days prior to dosing on cycle 1 day 1;
- prior lenalidomide therapy;
- neuropathy greater than grade 1;
- prior or current CNS involvement by lymphoma; and
- if at risk for venous thromboembolism, unwillingness to receive prophylaxis for that condition.
Patients were randomized in a 1:1 ratio to either the lenalidomide plus rituximab or the placebo plus rituximab groups. Stratification was done according to a number of criteria, including disease histology (FL vs. MZL), prior rituximab therapy (yes vs. no), and time since last therapy (2 years or less vs. more than 2 years). Dosing was continued for 12 cycles or until relapse, progressive disease, consent withdrawal, or unacceptable toxicity was noted. Dosing for the lenalidomide plus rituximab group consisted of oral lenalidomide (20 mg daily, or 10 mg daily for patients with creatinine clearance 30-59 mL/min) on days 1-21 plus IV rituximab 375 mg/m2 days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2-5 every 28 days. Dosing for the placebo plus rituximab group was delivered similarly.
“The rituximab regimen was selected using efficacy and statistical assumptions from the LYM3001 trial (NCT00312845), which was conducted in a similar patient population,” Leonard stated. “The choice of the rituximab schedule took into consideration studies showing that extended dosing of rituximab with four additional infusions, for a total of eight infusions, further improves efficacy with acceptable toxicity, which has led to the approval of 4 or 8 doses of rituximab in certain countries, including the U.S.”
The lenalidomide dose of 20 mg was chosen based on prior studies that showed that the combination of lenalidomide at that dosage with rituximab was well-tolerated and active in relapsed/refractory indolent NHL (J Clin Oncol 2015;33:3635-3640). Lenalidomide-associated toxicities were managed via dose reductions or interruptions of the drug. In the event of lenalidomide or placebo discontinuation, protocol-specified rituximab therapy could continue. Rituximab dose reduction was not permitted in this study. However, in the event of rituximab-associated toxicity, that therapy could be discontinued with continued protocol-specified placebo or lenalidomide dosing.
Primary efficacy data were reported for the intention-to-treat population (i.e., all patients randomly assigned, whether treated or not). The primary endpoint was independent review committee (IRC)-assessed PFS as per 2007 International Working Group criteria, without PET imaging.
Among the secondary endpoints for this study overall response rate (ORR), complete response, duration of response (DOR), overall survival (OS), event-free survival, and time to next anti-lymphoma treatment. Exploratory endpoints included time to next chemotherapy treatment and histologic transformation.
Assessment of response and progression outcomes was performed by blinded, independent central review using 2007 International Working Group criteria based on computed axial tomography/MRI scans. Safety analyses included all patients receiving at least one dose of study medication.
Between Feb. 13, 2014, and Jan. 26, 2017, a total of 358 patients were enrolled at 97 treatment centers in 15 countries. These participants were randomized to either the lenalidomide plus rituximab group (n=178) or the placebo plus rituximab group (n=180). Baseline characteristics were generally similar for both groups. The median patient age was 63 years (range: 26-88 years), with 295 patients (82%) having FL and 63 (18%) having MZL. Patients had a median number of one prior therapy (range: 1-12) with 86 patients (24%) having three or more prior systemic treatments. Four patients were lost to follow-up.
At final analysis, the median follow-up was 28.3 months. The primary endpoint of IRC-assessed PFS was significantly superior in the lenalidomide plus rituximab group, with a median value of 39.4 months (95% CI: 22.9 months-not reached) for the lenalidomide plus rituximab group as compared to 14.1 months (95% CI: 11.4-16.7 months) for the placebo plus rituximab group, affording an HR of 0.46 (95%CI: 0.34-0.62; p< .001). The investigator-assessed PFS also showed superiority for the lenalidomide plus rituximab group, with an HR of 0.51 (95% CI: 0.38-0.69; p< .001).
The IRC-assessed rate of best overall response was 78 percent (95% CI: 71%-83%) and 53 percent (95% CI: 46-61%) for patients in the lenalidomide plus rituximab and placebo plus rituximab groups, respectively.
“OS results are still maturing,” Leonard noted, “with an HR of 0.61 (95% CI: 0.33-1.13).” Although the trial was not powered to detect OS differences, fewer deaths were noted in the lenalidomide plus rituximab group (15) than the placebo plus rituximab group (26). The estimated 2-year survival in the lenalidomide plus rituximab group was 93 percent (95% CI: 87-96%), while, for the placebo plus rituximab group, that value was 87 percent (95% CI: 81-92%).
“For study participants having FL, OS results favored the lenalidomide plus rituximab group, showing an HR of 0.45 (95% CI: 0.22-0.92; p=.02), with 11 deaths with lenalidomide plus rituximab versus 24 with placebo plus rituximab,” Leonard stated. “Interestingly, no difference was seen between the two study groups in the minority of study patients having MZL. In this analysis, an HR of 2.89 (95% CI: 0.56-14.92) was obtained, although there were few events—five with lenalidomide plus rituximab versus two with placebo plus rituximab.”
In the safety population, 71 percent of patients in the lenalidomide plus rituximab group and 61 percent in the placebo plus rituximab group completed their full treatment course. AEs requiring dose interruptions were more frequently observed in the lenalidomide plus rituximab group than the lenalidomide plus placebo group (64% vs. 26%). This same trend was also noted for dose reductions (26% vs. 3%), as well as dosing discontinuations (9% vs. 5%).
The most commonly noted AE that led to dose reduction (18%) and dose interruption (39%) of lenalidomide was neutropenia. “Dose modifications successfully addressed neutropenia in most patients, with only five patients (3%) requiring discontinuation of lenalidomide because of neutropenia,” Leonard explained. Treatment discontinuation as a result of disease progression occurred in 21 patients (12%) in the lenalidomide plus rituximab group and 54 patients (30%) in the placebo plus rituximab group.
Regarding their findings, Leonard observed, “PFS improvements were consistent with those of the overall population in all pre-specified subgroups, with the exception of the smaller MZL subgroup (n=63), for which PFS was not significantly different between the two treatment groups. In that analysis, an unstratified HR of 1.00 (95% CI: 0.47-2.13) was obtained, with wide confidence intervals clearly implying that the data are uninformative.
“PFS results for this subgroup are difficult to interpret,” Leonard explained, “because of the small sample size and an imbalance in the baseline prognostic factors.”
When discussing AEs for this study, Leonard noted, “Neutropenia was managed primarily via dose interruptions and/or reductions and growth-factor support. As a result of this management, only five patients had neutropenia leading to lenalidomide discontinuation.” It is of interest to note that post hoc analyses showed that, in the lenalidomide plus rituximab group, efficacy was similar regardless of occurrence of grade 3 or 4 neutropenia.
“Median PFS advantages favoring the lenalidomide-containing arm were observed in both the IRC-based investigator-based assessments,” Leonard said. “The HRs and P values were similar between assessments, which indicated consistency in PFS results between IRC and investigator assessments.”
Citing interesting results obtained for this study, Leonard noted, “The OS analyses for FL patients are somewhat promising, although additional follow-up is clearly needed to further evaluate these findings.
“One possible future area of research could be expanding to triplet therapy that could include targeted chemotherapies such as Bruton's tyrosine kinase inhibitors or perhaps phosphoinositide 3-kinase inhibitors,” he concluded.
Richard Simoneaux is a contributing writer.