Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial

Follicular lymphoma (FL) is an incurable, indolent non-Hodgkin’s lymphoma (NHL) subtype that follows a relapsing course[1, 2]. Although the introduction of new therapies and treatment approaches over the past couple of decades has improved progression-free survival (PFS)[3] and overall survival (OS)[4, 5], prognosis differs significantly between patients according to multiple demographic and disease-related characteristics[5‐10]. Adverse prognostic factors in FL include a high (≥3) FL International Prognostic Index (FLIPI) score, representing patients aged >60 years, and/or with stage III–IV disease, anemia, >4 involved nodal areas, and/or elevated lactate dehydrogenase (LDH)[7, 10, 11], which has been validated in the first-line setting[11] and shown to have prognostic value at first relapse[10]. In addition, another indicator of poor prognosis is a high tumor burden by modified Groupe d’Etude des Lymphomas Folliculaires (GELF) criteria[12], which includes involvement of ≥3 nodal sites of ≥3 cm diameter, any nodal/extranodal tumor mass of ≥7 cm diameter, splenomegaly, pleural effusion or peritoneal ascites, leukocytes <1.0 x 10⁹/L, or platelets <100 x 10⁹/L[12, 13].

Patients with high-risk FL typically have a poor prognosis, including a higher probability of relapse and lower survival rates[7, 10, 11], and need better treatment options[10, 14, 15]. These patients may particularly benefit from novel, active regimens[10]. Rituximab is widely used in previously untreated and relapsed FL[16], having been shown to enhance the efficacy of chemotherapeutic regimens[17‐19] and to improve PFS when used as maintenance therapy[3, 20]. The proteasome inhibitor bortezomib has shown single-agent activity in heavily pretreated indolent lymphoma patients, with response rates of up to 50%[21‐23], and bortezomib plus rituximab has been shown to be active and generally well tolerated in phase 2 studies in FL and other NHL subtypes[24‐27].

The randomized, multicenter, international phase 3 LYM3001 trial compared bortezomib plus rituximab with rituximab alone in 676 patients with relapsed, rituximab-naïve or rituximab-sensitive FL[28]. Results from the overall study population showed that the addition of bortezomib resulted in prolonged PFS (primary endpoint; median 12.8 vs. 11.0 months, hazard ratio [HR] 0.822; P=0.039), a higher overall response rate (ORR; 63% vs. 49%, P<0.001), a higher complete response (CR)/unconfirmed CR (CRu) rate (25% vs. 18%, P=0.035), and more durable responses. In this ad-hoc subgroup analysis of LYM3001, we report the activity and safety of rituximab ± bortezomib in patients with high-risk disease, defining ‘high-risk’ patients as those having both a high (≥3) FLIPI score and high tumor burden by modified GELF criteria[12], both of which were independent pre-defined subgroups.

This ad-hoc subgroup analysis of the phase 3 LYM3001 study[28] of relapsed FL patients with the high-risk features of both high FLIPI score (≥3) and high tumor burden by modified GELF criteria[12] demonstrated a number of key efficacy findings. In particular, we showed that patients with high-risk FL treated with bortezomib-rituximab had significantly higher response rates and longer PFS than patients receiving rituximab alone. Furthermore, while overall median DOR appeared similar between arms, the durability of CR/CRu appeared enhanced with the addition of bortezomib in this high-risk patient population. The higher rate and durability of CR/CRu with bortezomib-rituximab is notable, as CR has been associated with improved outcomes in FL[29]. Additionally, the bortezomib-rituximab combination was associated with a significantly longer TTP, and a longer TTNT and associated TFI compared with rituximab alone. No significant difference was seen in OS between arms, as might be expected after a median follow-up of 3 years in a patient population with a typically indolent disease course and a reported median OS from diagnosis of up to approximately 14 years[4]. However, the 1-year OS rate appeared slightly higher in the bortezomib-rituximab arm, possibly due to an increased rate of progressive disease-related deaths in the rituximab arm during this period.

Notably, the consistent relative clinical benefit with bortezomib-rituximab versus rituximab in this subgroup of high-risk patients was greater than that seen in the overall study population[28], as indicated by HRs more in favor of bortezomib-rituximab. For example, the HR for PFS benefit with bortezomib-rituximab versus rituximab was 0.667 in these high-risk patients, compared with 0.882 in the overall study population[28]. Similarly, the odds ratios for ORR (0.399 vs. 0.569), CR/CRu rate (0.472 vs. 0.665), and durable (≥6 months) response rate (0.440 vs. 0.608), and the HRs for TTP (0.656 vs. 0.808), TTNT (0.762 vs. 0.799), and OS (0.907 vs. 0.971) indicated greater clinical benefit with bortezomib-rituximab versus rituximab in the high-risk subgroup versus the overall population. All these data suggest that the addition of bortezomib might thus provide greater tumor reduction and subsequent sustained clinical benefit in these patients who have a greater disease burden or more proliferative FL.

The patient population included in these analyses represented a true ‘high-risk’ subset of FL patients because they presented with both a high (≥3) FLIPI score and high tumor burden, both of which are factors that define cohorts of FL patients with disease that is high-risk in nature. The poor prognostic nature of each of these factors is supported by our efficacy analyses in the specific individual subsets with high FLIPI score or with high tumor burden, which demonstrated poorer outcomes compared with in the overall study population[28]; furthermore, our efficacy findings suggest that the presence of both high FLIPI score and high tumor burden defines a population with poorer prognosis than either factor alone. In supportive evidence from the literature, a FLIPI score of ≥3 has been associated with poor prognosis in terms of PFS and OS in a number of studies and analyses in both previously untreated and relapsed FL patients treated with various different regimens and modalities[7, 9‐11, 30, 31]. Similarly, the presence of a high tumor burden has been shown to be a significant poor prognostic factor[13]. As previously noted[28], there is no standard of care for relapsed FL, with various different approaches recommended as possible therapeutic options in guidelines from the European Society for Medical Oncology[32] and the US National Comprehensive Cancer Network[33], including rituximab-chemotherapy and rituximab maintenance[3, 16]. However, there is no specific management strategy defined for FL patients with high FLIPI score and/or high tumor burden, and thus identifying treatment options offering relatively greater clinical benefit in patients with these poor prognostic factors is of interest.

It is important to note that, per protocol, none of the patients in LYM3001 were rituximab-refractory, another factor representing a high-risk, difficult-to-treat population. Nevertheless, non-clinical studies provide a rationale for the potential utility of the bortezomib-rituximab combination in this patient subset; some preclinical data suggest that addition of bortezomib might be useful for overcoming resistance in FL and for resensitizing patients to treatment, including rituximab[34‐36].

Regarding the safety profiles of bortezomib-rituximab and rituximab alone in this subgroup analysis of patients with high-risk FL, our findings reflect those in the overall study population but with somewhat elevated rates of toxicity in these high-risk patients[28]. As would be expected, bortezomib-rituximab was associated with additional toxicity and rates of AEs were higher in the combination arm compared with in the rituximab arm; however this did not affect treatment feasibility, with patients receiving a median of five cycles of treatment in both arms and a higher proportion completing all five planned cycles in the bortezomib-rituximab arm than in the rituximab arm. As reported previously[28], the addition of bortezomib to rituximab was associated with peripheral neuropathy AEs, with 15% of patients in the bortezomib-ritxumab arm experiencing peripheral sensory neuropathy and 1% experiencing peripheral motor neuropathy; however, only one grade 3 AE, of peripheral sensory neuropathy, was reported in these high-risk patients. As noted previously[28], this rate and severity of peripheral neuropathy appeared limited compared with previous reports in myeloma, which was likely associated with the use of a weekly, instead of a twice-weekly, bortezomib dosing regimen.

In conclusion, bortezomib-rituximab appears an effective regimen for the management of patients with relapsed FL, offering clinical benefit compared with rituximab alone in this high-risk subgroup of patients with the poor prognostic features of high FLIPI score (≥3) and high tumor burden. Further prospective validation of these findings is warranted; an Eastern Cooperative Oncology Group (ECOG) phase 2 study is currently investigating bendamustine-rituximab with or without bortezomib in patients with either high FLIPI score (≥3) or high tumor burden by GELF criteria (NCT01216683). Ongoing biomarker analyses of the LYM3001 study may enable identification of specific patient subgroups deriving greater benefit from bortezomib-rituximab versus rituximab treatment.

This research was funded by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and Millennium Pharmaceuticals, Inc.