Fogliatto, Laura Maria

Introduction: The primary analysis of the phase 3 ECHO trial (NCT02972840) demonstrated that acalabrutinib plus bendamustine-rituximab (ABR) significantly improved progression-free survival (PFS) vs placebo plus bendamustine-rituximab (PBR) in older patients (pts) with previously untreated mantle cell lymphoma (MCL) (Wang et al. EHA 2024, Abstract #LB3439). Here we present additional efficacy and safety results from the ECHO trial. Methods: Pts aged ≥65 years (y) with previously untreated MCL and ECOG PS ≤2 were randomly assigned 1:1 to receive ABR or PBR. Acalabrutinib (100 mg twice daily) or placebo was administered until progressive disease (PD) or unacceptable toxicity. Induction with BR was administered for 6 cycles followed by rituximab maintenance (A±R maintenance, cycles 7-30) in pts achieving a partial or complete response (PR or CR). Pts progressing on PBR could cross over to receive acalabrutinib monotherapy. PFS (primary endpoint) was assessed by independent review committee. Minimal residual disease (MRD) negativity rate (10-5) was assessed in peripheral blood (every 24 weeks [wks], at CR, and at PD) and bone marrow (at CR) by NGS-based ClonoSEQ assay (Adaptive Biotechnologies). Results: Among the 598 pts randomized to ABR or PBR (299 in each arm), high-risk baseline characteristics included high-risk simplified MIPI score in 24.1% and 24.4%, blastoid histology in 8.7% and 6.7%, pleomorphic histology in 5.0% and 6.0%, centrally tested Ki-67 ≥30% in 46.5% and 49.2%, and known TP53 mutation in 7.4% and 9.7%, respectively. PFS hazard ratios (HRs) for subgroups were 0.78 (95% confidence interval [CI] 0.51-1.19) in pts with high-risk simplified MIPI score, 0.68 (95% CI 0.29-1.58) in pts with blastoid histology, 0.64 (95% CI 0.25-1.66) in pts with pleomorphic histology, 0.69 (95% CI 0.49-0.98) in pts with Ki-67 ≥30%, and 0.88 (95% CI 0.42-1.78) in pts with known TP53 mutation. In the ABR arm, median PFS was 22.2 months (mo) among pts who discontinued acalabrutinib during induction for reasons other than PD or death, 29.4 mo in pts who discontinued acalabrutinib during A±R maintenance (cycles 7-30) for reasons other than PD or death, and not reached in pts who received acalabrutinib for 31 cycles or more. Among evaluable patients who were MRD negative at the end of induction (24 wks), the rate of conversion to MRD positive during maintenance was lower in the ABR arm (5.85%; n=11/188) than in the PBR arm (15%; n=26/171). Conversely, among evaluable pts who were MRD positive at the end of induction (24 wks), 37.5% (n=3/8) in the ABR arm and 20% (n=3/15) in the PBR arm converted to MRD negative during maintenance. Overall rates of AEs were similar in each arm during induction, but were higher in ABR during A±R maintenance (cycles 7-30) and more so in the monotherapy phase (cycle 31+). Grade ≥3 TEAEs (ABR vs PBR) were 70.0% vs 68.7% during induction, 64.9% vs 62.9% during A±R maintenance (cycles 7-30), and 57.0% vs 45.3% during monotherapy (cycle 31+). Similarly, rates of TEAEs leading to discontinuation of acalabrutinib/placebo were 8.1% vs 8.8% during induction, 23.9% vs 19.0% during A±R maintenance (cycles 7-30), and 25.9% vs 13.7% during monotherapy (cycle 31+). Exposure-adjusted incidence rates per 100 person-years reduced the difference between ABR and PBR for clinically relevant TEAE rates (32.6 vs 29.3 for grade ≥3 serious TEAEs; 4.2 vs 4.0 for grade 5 TEAEs; 15.5 vs 12.4 for TEAEs leading to acalabrutinib/placebo discontinuation), possibly due to longer median exposure to acalabrutinib (28.6 vs 24.6 mo). Conclusion: Acalabrutinib in combination with BR provides a significant PFS benefit in pts with previously untreated MCL, including those with high-risk features. Furthermore, the addition of acalabrutinib to BR provided a greater PFS effect among pts in the ABR arm with the longest exposure to acalabrutinib. The PFS improvement may be partially driven by the contribution of acalabrutinib to sustained MRD-negative status and deepened responses after the end of induction. ABR provides this clinical benefit without excess toxicity as shown by attenuated differences between arms in exposure-adjusted incidence rates, suggesting that higher AE rates in the ABR arm are likely due in part to the longer duration of acalabrutinib treatment vs placebo. These data emphasize the benefits of acalabrutinib in frontline MCL treatment in high-risk pts and the additional benefit of continuous therapy.

7514 Background: Relapse is expected in treated indolent lymphoma patients, and an unmet need exists to prolong remission with effective therapies. Lenalidomide + rituximab (R2) may improve the efficacy of next treatment by their unique mechanisms. Methods: The AUGMENT phase III study evaluated patients with R/R FL gr 1-3a (82%) and MZL (18%) after ≥ 1 prior systemic therapy (not rituximab refractory). Randomization was 1:1 to R2 (lenalidomide PO 20 mg/d, d1-21/28 X12 cycles [c] + rituximab [R] IV 375 mg/m2/wk, c1, d1, 8, 15, 22 and c2-5, d1) and R/placebo (same dosing schedule). The primary endpoint was PFS by 2007 IWG; secondary/exploratory analyses were time to next antilymphoma/chemotherapy treatment (TTNLT/TTNCT) and response to next treatment. Per regulatory guidance, PFS2 was defined as time from randomization to first PD or death from any cause after next antilymphoma treatment, or initiation of a third antilymphoma treatment. Results: Median PFS was superior for R2 over R/placebo (39.4 vs 14.1 mo; HR = 0.46; P < 0.0001). As of 22June2018, median TTNLT, TTNCT, and PFS2 were not reached for R2, and were significantly longer than R/placebo (HR = 0.54, 0.50, and 0.52, respectively). For 49/178 (28%) R2 and 80/180 (44%) R/placebo patients receiving next antilymphoma therapy, response was generally higher with R2 (57% ORR; 31% CR) than R/placebo (36% ORR; 16% CR; Table). Conclusions: These analyses suggest that R2 (vs R/placebo) prolonged time to subsequent treatment and is associated with longer PFS2, enabling greater response to next therapy. Although patient numbers were modest, it is hypothesized that patients who received R2 were generally more sensitive to subsequent therapy than those treated with R/placebo. Clinical trial information: NCT01938001. [Table: see text]

Abstract Background: Indolent non-Hodgkin lymphoma (iNHL), including follicular lymphoma (FL) and marginal zone lymphoma (MZL), is typically responsive to initial chemoimmunotherapy, but relapse is expected. Single-agent rituximab is FDA approved and frequently administered for patients with relapsed/refractory (R/R) low-grade or follicular CD20-positive B-cell NHL. Lenalidomide is an immunomodulatory agent with preclinical and clinical antilymphoma activity alone and in combination with rituximab. We compared the efficacy and safety of lenalidomide plus rituximab (R2) to rituximab (plus placebo) in patients with R/R iNHL. Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase III study of R2 vs rituximab/placebo (control) in patients with FL grade 1-3a or MZL who were previously treated with ≥ 1 prior systemic therapy with documented relapsed or refractory disease but not refractory to rituximab (refractory was defined as < partial response to rituximab or rituximab-chemotherapy OR disease progression < 6 months after last rituximab dose). Patients were stratified by prior rituximab treatment (yes vs no), time since last antilymphoma therapy (≤ 2 vs > 2 years), and histology (FL vs MZL), and then randomized 1:1 to R2 or control for up to 1 year. R2 patients received oral lenalidomide 20 mg/day (d), d1-21/28 for 12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2-5. Control patients received rituximab and placebo on the same schedule. Dose modifications were pre-specified in the protocol to manage toxicities. The primary endpoint was progression-free survival (PFS) per 2007 IWG criteria without PET as assessed by Independent Review Committee (IRC; central review). Secondary endpoints included overall response rate (ORR), complete response (CR), duration of response (DOR), time-to-next antilymphoma treatment (TTNLT), overall survival (OS), and safety. Results: A total of 358 patients were randomized (n = 178 R2; n = 180 control), median age was 63 years (range, 26 - 88), 34% FLIPI score ≥ 3, and histologies of 82% FL/18% MZL. Median number of prior systemic treatments was 1 (range, 1 - 12); 84% received prior rituximab and 51% had prior antilymphoma therapy within 2 years of enrollment. At median follow-up of 28.3 months, the study met its primary endpoint of PFS with HR = 0.46 (95% CI, 0.34 - 0.62; P < 0.0001) (Figure 1). Median PFS was 39.4 months for R2 vs 14.1 months for control. IRC-assessed ORR for R2 was 78% vs 53% for control (P < 0.0001). CR was 34% for R2 vs 18% for control (P = 0.001). Median DOR was 36.6 and 21.7 months for R2 and control arms, respectively. TTNLT was improved for R2 vs control with HR = 0.54 (95% CI, 0.38 - 0.78; P = 0.0007). OS data were not mature with 16 deaths reported in the R2 arm vs 26 deaths in control (HR = 0.61 [95% CI, 0.33 - 1.13]). Selected all-grade treatment-emergent adverse events (TEAEs) of interest more common in the R2 vs control arm (≥ 10% difference) were infections (63% vs 49%), cutaneous reactions (32% vs 12%), constipation (26% vs 14%), thrombocytopenia (15% vs 4%), and tumor flare reaction (11% vs 1%). Grade 3/4 TEAEs were reported in 69% R2 and 32% control patients. More frequent grade 3/4 TEAEs in the R2 vs control arm were primarily attributable to increased neutropenia (50% vs 13%) and leukopenia (7% vs 2%). Grade 5 TEAEs were reported in 2 patients in each arm. TEAEs leading to discontinuation of lenalidomide occurred in 9% of patients vs 5% for rituximab + placebo. Neutropenia was the only TEAE leading to discontinuation of lenalidomide in > 1 patient (n = 5). Seventy-one percent of R2 patients completed all 12 cycles of planned treatment vs 61% of control. Disease progression was the leading reason for discontinuation of lenalidomide/placebo (n = 21 R2, n = 54 control). Conclusions: R2 demonstrated superior efficacy over rituximab monotherapy (plus placebo) as measured by the primary endpoint of progression-free survival as well as secondary endpoints of ORR, CR, DOR, and TTNLT in patients with R/R FL grade 1-3a and MZL. At this early analysis, fewer deaths have been observed in the R2 arm. Despite additional hematologic toxicity, greater efficacy of the R2 regimen (and fewer early progressions) allowed more patients to complete the planned therapy and delayed the need for subsequent treatment. R2 represents an important new treatment option in patients with previously treated FL/MZL, with meaningful advantages over single-agent rituximab. Disclosures Leonard: Celgene: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; MEI Pharma: Consultancy; Juno: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Sutro: Consultancy; Biotest: Consultancy; United Therapeutics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy; BMS: Consultancy. Trněný:F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria. Izutsu:Otsuka: Honoraria; Bristol- Myers Squibb: Honoraria; Nihon Medi-Physics: Honoraria; Novartis: Honoraria; Mundhi: Honoraria; HUYA Bioscience International: Research Funding; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Gilead Sciences: Honoraria; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Zenyaku: Research Funding; Celltrion: Research Funding; MSD: Honoraria; Ono: Honoraria, Research Funding; Symbio: Research Funding; Celgene: Consultancy, Research Funding; Solasia: Research Funding; Sanofi: Research Funding; Meiji Seika: Honoraria; Shionogi: Honoraria; Asahi Kasei: Honoraria. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Zhu:Beijing Cancer Hospital (Peking University Cancer Hospital): Employment. Scheliga:INCA - Instituto Nacional Do Cancer, Brazil: Employment. Pinto:Servier: Consultancy; BMS: Honoraria, Research Funding; MSD: Honoraria; Roche: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Gilead: Honoraria. Scheinberg:Novartis: Consultancy, Speakers Bureau; Janssen: Honoraria, Research Funding; Pfizer: Speakers Bureau. Flinn:Trillium: Research Funding; Takeda: Research Funding; Calithera: Research Funding; Incyte: Research Funding; Verastem: Research Funding; ArQule: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Agios: Research Funding; BeiGene: Research Funding; Kite: Research Funding; Portola: Research Funding; Verastem: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Forma: Research Funding; Merck: Research Funding; Novartis: Research Funding; Constellation: Research Funding; Curis: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding; Gilead: Research Funding. Moreira:Instituto Português de Oncologia do Porto FG, EPE, Porto, Portugal: Employment. Liu:Celgene: Employment, Equity Ownership. Kalambakas:Celgene: Employment, Equity Ownership. Fustier:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Gribben:Cancer Research UK: Research Funding; Unum: Equity Ownership; Novartis: Honoraria; Abbvie: Honoraria; Wellcome Trust: Research Funding; Acerta Pharma: Honoraria, Research Funding; Kite: Honoraria; NIH: Research Funding; Roche: Honoraria; Janssen: Honoraria, Research Funding; Medical Research Council: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; TG Therapeutics: Honoraria; Pharmacyclics: Honoraria.

Background:Lenalidomide plus rituximab (R2) has established efficacy and a tolerable safety profile in patients with previously untreated and relapsed/refractory (R/R) indolent NHL. This includes patients with marginal zone lymphoma (MZL) who are generally treated in a similar manner to follicular lymphoma (FL).Aims:Primary results for the AUGMENT study in R/R FL grade 1–3a and MZL showed significantly improved progression‐free survival (PFS) for R2 over R/placebo in the overall population and in the subgroup analyses, with the exception of the MZL subgroup. Given the small sample size for MZL patients, post hoc analyses of baseline characteristics and univariate/multivariate analyses of PFS were conducted to examine possible explanations for these results.Methods:The phase III AUGMENT study randomized patients 1:1 to R2 (lenalidomide PO 20 mg/day (d), d1–21/28 X12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2–5) or rituximab‐placebo (R/placebo; same dosing schedule). PFS by 2007 IWG (without PET) was the primary endpoint. Post hoc Cox regression models were used for univariate analysis of one risk factor and multivariate analyses including treatment arm and significant risk factors (P < 0.05) from the univariate analyses.Results:A total of 63/358 (18%) MZL patients were part of the overall study population, including n = 14/16 MALT, n = 9/6 splenic, and n = 8/10 nodal MZL subtypes for respective R2 and R/placebo arms. Numerical differences between treatment arms for baseline demographics and disease characteristics for MZL patients favoring the R/placebo arm were: fewer R2 patients had an ECOG score of 0 (55% R2 vs 72% R/placebo), and more R2 (vs R/placebo) patients were older (≥65 y: 68% vs 59%; ≥70 y: 42% vs 38%), were refractory to the last prior regimen (13% vs 3%), had Ann Arbor stage IV disease at enrollment (65% vs 41%), high‐risk MALT‐IPI score (50% vs 19%), elevated LDH (29% vs 19%), B symptoms (13% vs 3%), and high tumor burden per GELF criteria (65% vs 56%). The most common grade 3/4 AEs for MZL patients receiving R2 vs R/placebo, respectively, were neutropenia (47% vs 16%), pneumonia (3% vs 13%), and leukopenia (10% vs 0). A total of 5 deaths occurred in the R2 arm (most associated with progression of disease; 2 deaths occurred early at 3 and 13 days after randomization [one prior to receiving R2 and one 2 days after treatment initiation]) and 2 in the R/placebo arm. Despite worse prognostic features, best response was improved with R2 (vs R/placebo) with ORR = 65% vs 44% (P = 0.13) and CR = 29% vs 13% (P = 0.13), although neither were statistically significant. Improved response rates did not translate into a survival advantage for R2. Median PFS for MZL patients was 20.2 mo R2 vs 25.2 mo R/placebo (HR = 1.00; 95% CI, 0.47–2.13; P = 1.0). Univariate analyses showed that several baseline factors were prognostic for MZL patients (P < 0.05): Ann Arbor stage IV, elevated LDH, and unfit for chemotherapy (Table). Multivariate analyses adjusting for the imbalance in these 3 significant prognostic factors showed an adjusted PFS HR of 0.51 (95% CI, 0.20–1.28) favoring the R2 arm, similar to the PFS HR in the overall population (HR = 0.46; 95% CI, 0.34–0.63). The univariate and multivariate analyses suggested that the imbalance in baseline prognostic factors impacted PFS results for MZL patients.Summary/Conclusion:Overall, these findings suggest that the PFS results in MZL patients were negatively impacted by the imbalance in baseline prognostic factors and more aggressive disease in the R2 over the R/placebo arm.image

PURPOSEPatients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab.METHODSA phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.RESULTSA total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.CONCLUSIONLenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.