Rituximab Maintenance Benefits Less for Follicular Lymphoma Patients with Low Risk of the Follicular Lymphoma International Index

Background Follicular lymphoma (FL) is an incurable indolent disease with a heterogeneous course. The Follicular Lymphoma International Prognostic Index (FLIPI) is the most commonly used prognostic system to predict survival. Rituximab-based immunochemotherapy is now the standard choice for the first-line therapy of FL, followed by rituximab maintenance (RM) in patients with response, which prolongs the progression-free survival (PFS). However, the role of RM in different FLIPI risk groups has never been studied as we know. In this study, we aimed to illustrate the effect of RM in FLIPI risk groups. Methods Newly diagnosed FL patients at our center were enrolled in this analysis. All the patients received the rituximab-based chemoimmunotherapy induction regimens. Response assessments were determined according to Lugano's 2014 criteria. Patients who didn't respond to induction were excluded. Categorical variables were compared using Fisher's exact test. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared with the log-rank test. Results From May 2003 to September 2020, 203 newly diagnosed FL were included. 192 patients (95.0%) achieved remission (complete response, CR/partial response, PR) after immunochemotherapy induction, of whom 96 patients continued rituximab maintenance therapies every 3 months for 1-2 years (RM group) (median 7 times，range 4 to 12). 96 patients received no maintenance or fewer than 4 times (control group) (median 0 times, range 0-3). There were no significant differences in baseline characteristics other than the Ann Arbor stage and pathological grade. The RM group patients were more likely to be at low grade (71.8% vs 54.9%, P = 0.042) and advanced stage (90.6% vs 78.7% , P = 0.027) (Table 1). After a median follow-up of 36.4 months (95% confidence interval [CI], 32.2 to 40.6), median OS and PFS were not reached. The 5-year OS rates and PFS rates were 95.1% (95%CI, 90.2%-100%) and 83.0% (95%CI, 75%-91%)(Fig 1). And RM significantly prolonged the PFS, with 5-year PFS rates 92.2% (95%CI, 85.1%-99.3%) and 70.3%(95%CI, 55%-85.6%) (P = 0.0003) (Fig 2). According to FLIPI risk stratification, patients were classified into low-risk, intermediate-risk, and high-risk groups. The 5-year PFS rates were 97.7% (95%CI, 93.2%-100%), 84.7% (95%CI, 70.4%-99%), and 67.8% (95%CI, 49%-86.6%), respectively (Fig 3). For low-risk patients, there was no significant difference in PFS for the RM group vs the control group. However, for both intermediate risk and high-risk patients, PFS was significantly longer in the RM group compared to the control group (P < 0.0001). The PFS rates at 5 years in intermediate-risk patients were 100% and 77.8% (95%CI, 40.8%-92.6%), for the RM group vs control group, high risk 76.4% (95%CI, 54.3%-98.5%), and 54.9% (95%CI, 21.6%-88.2%), respectively (Fig 4). Conclusion Standard rituximab maintenance significantly prolongs progression-free survival in FLIPI intermediate risk and high-risk patients with FL, but not in the FLIPI low risk group. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

Lenalidomide Consolidation Added to Rituximab Maintenance Therapy in Patients Remaining PET Positive after Treatment for Relapsed Follicular Lymphoma: Phase 2 Australasian Leukaemia & Lymphoma Group NHL26 Study

Introduction The combination of rituximab & lenalidomide (R 2) is an established regimen for treatment of follicular lymphoma (FL), with efficacy reported in the first line and relapsed setting (Morchhauser NEJM 2018, Leonard JCO 2019). The inferior OS of patients who remain post-induction PET-CT positive (PET+ve) has also been demonstrated in both settings (Trotman Lancet Haem 2014, Lancet Oncol 2018, Ysebaert, ASH 2011). We sought to study the effect of R 2 in relapsed FL by examining its ability to convert to PET-negative (PET-ve) those patients who remain PET+ve after reinduction rituximab-chemotherapy. Methods This was a prospective, multicentre, Phase 2 study of patients with bulky Stage II, or Stage III-IV relapsed FL. Eligibility criteria were: at least stable disease on CT within 4-6 weeks of last cycle of re-induction rituximab-chemotherapy; ECOG ≤2; CrCL ³30mL/min; haemoglobin >80g/L, neutrophils >1.0 & platelets >75 x 10 9/L. Exclusion criteria were: histological transformation ≤12 months (mo); any interim-PET that was negative, and other malignancy ≤5 years. After enrolment pts underwent a centrally-reviewed PET within 8 weeks of D1 last cycle of re-induction rituximab-chemotherapy. Given the higher probability of further progression in the relapsed setting PET+ve was defined as a Deauville score (DS) 3-5. PET-ve patients were assigned rituximab maintenance q2mo for 2 years, and those remaining PET+ve were assigned R 2 to commence within 12 weeks. Lenalidomide schedule for R 2 pts was 10mg/d x 21 q28d, with dose modifications for tolerance, over a planned 2 years. Repeat PET scans were scheduled at 6 & 12 mo after starting R 2. The primary endpoint was the rate of conversion from postinduction PET+ve to PET-ve in evaluable patients 6 mo after commencing lenalidomide. Evaluable patients were defined as those receiving >63 days of Lenalidomide. Sample size calculations used a one-sided exact test for proportions, assuming a conversion rate of ³50% as worthy of further evaluation and ≤20% as unacceptable. Thus 16 evaluable patients were required to have 80% power with type I error of 5%. Secondary endpoints were PET conversion rates by baseline DS in the PET+ve, the toxicity & deliverability of R 2, and PFS & OS in both the PET+ve & PET-ve populations. Results Thirty-seven patients (pts) were recruited from Nov 2013 to Jan 2021 when the study was closed due to poor recruitment attributed to competing studies. Median (med) age was 67yrs (36-83); 58% male, med 2 (range 2-11) prior therapies incl. the recent rituximab-chemotherapy; FLIPI low risk (21%), intermediate risk (12%) high risk (67%). Eighteen of 37 (48.6%) pts were postinduction PET+ve. Med follow-up was 38 mo (0.8 - 76.4): 32 mo (0.8 - 76.4) in PET+ve and 42 mo (6.7 - 73.8) in PET-neg. Of the 18 PET+ve pts one was ineligible for R 2 due to reactivation of hepatitis B; 3 were not evaluable having not received >63 doses of lenalidomide due to progressive disease (PD). Thus 14/18 (78%) PET+ve pts were evaluable, of whom 5/14 (36%; 95% CI 11% - 61%) became PET-ve at 6-mo, thus not excluding a PET conversion rate of <20%, (p=0.14). If we had obtained full recruitment both additional pts would have had to convert to PET-neg to meet the primary endpoint. PET conversion occurred in 4/6 evaluable pts with DS 3 and 1/8 with DS 5. PD occurred in 14 pts: 11/17 PET+ve and 3/19 PET-ve. Med PFS was 30.8 mo (5.7-37.6) in the PET+ve and NR (95% CI 42.3-NR) in the PET-ve, p = 0.0001. Death occurred in 11/37 (30%): 7 from lymphoma (5 PET+ve), 1 other malignancy, 2 pneumonia, 1 aspergillosis. Med OS was 68.1 mo (9.6 - NR) in PET+ve and NR (95% CI 42.3 - NR) in PET-ve (p 0.059). Of the 17 PET+ve pts starting lenalidomide, deliverability was limited by both disease progression and AEs: 3 failed to receive 3 cycles, 6 pts received 4-6, and 8 pts 7-24 cycles. Mean number of lenalidomide doses was 213 (SD 188). At least one AE was reported in 16/17 (94%), most commonly neutropenia (n=10, 59%, Gd4 24%). At least one SAE occurred in 9/17 (53%): infections 2, malignancy 2, cardiac disorders 2, musculoskeletal 2, other causes 3 pts. Conclusion The high PET+ve rate of 49% (DS 3-5) after rituximab-chemotherapy for relapsed FL suggests the need for consolidation therapy. However, R 2 did not achieve a sufficiently high PET-conversion rate to justify further study. The inferior outcome of patients who remain PET+ve after treatment of relapse highlights the importance of investigating novel approaches in this setting. Figure 1 Figure 1. Disclosures Trotman: TAKEDA: Research Funding; beigene: Research Funding; roche: Research Funding; BMS: Research Funding; PCYC: Research Funding; JANSSEN: Research Funding. Gandhi: janssen: Research Funding; novartis: Honoraria. Butcher: WriteSource: Current Employment, Other: Medical writing for Pharma companies. Not pertinent to this abstract for which author is study Statisticiam.

Outcomes of Patients with Indolent Lymphoma Treated with Bendamustine Plus Rituximab Compared to Rituximab Plus CVP or CHOP Chemoimmunotherapy in Ontario

Background For patients with symptomatic advanced stage indolent lymphoma, rituximab (R) was traditionally used alongside cyclophosphamide, vincristine, prednisone (CVP), or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Bendamustine plus rituximab (BR) has been found to increase progression-free survival compared to R-CVP/CHOP, albeit with possible increased toxicity. Since 2013, bendamustine has been approved for public reimbursement for treatment of indolent lymphomas in Ontario, Canada, and has become the preferred regimen. We aimed to assess survival and toxicity of patients with indolent lymphoma treated with BR compared with R-CVP/CHOP in Ontario. Methods We conducted a retrospective cohort population-based study using administrative healthcare databases from Ontario, Canada. Patients were included if they had a diagnosis of indolent lymphoma and were treated with R-CVP/CHOP from 2005-2012, or with BR from 2013-2018. Patients with mantle cell lymphoma were excluded. Treatment groups were propensity score matched based on lymphoma subtype, age, sex, prior cancer diagnosis, time since diagnosis and rural or urban residence. The primary outcome of the study was overall survival (OS) from time of first treatment to death or end of study period. Secondary outcomes included toxicities during the first nine months of treatment, such as infections and secondary malignancies, associated resource utilization, and outcomes of patients treated with rituximab maintenance therapy. Cox regression models were used to assess factors associated with mortality. Results A propensity-matched cohort of 2032 patients treated with BR and 2032 treated with R-CVP/CHOP (1473 patients treated with R-CVP, 559 patients treated with R-CHOP) were included. The median age of patients was 65 years and 48% were female. A majority of patients had a diagnosis of follicular lymphoma (58.9% of patients treated with BR, 59.7% of patients treated with R-CVP/CHOP, p=0.59). Median follow-up time was 41 and 87 months for patients treated with BR and R-CVP/CHOP, respectively. BR was associated with significantly lower mortality compared to R-CVP/CHOP (HR 0.77, 95% CI 0.67-0.89, p<0.01). Five-year OS was 80% and 75% for patients treated with BR and R-CVP/CHOP, respectively (Figure 1). A total of 969 patients died during a follow-up period of seven years - 331 (16.3%) treated with BR and 638 (31.4%) treated with R-CVP/CHOP. Causes of death were available in 861 patients (88.9%), shown in Table 1. Most patients in both groups died from lymphoma (66.9% treated with BR, 66.4% treated with R-CVP/CHOP, p=0.88). A Charlson comorbidity index greater than or equal to 2 was associated with increased mortality (HR 3.04, 95% CI 2.45-3.77). Treatment toxicities are listed in Table 2.Over a nine-month period after treatment initiation (induction), patients treated with BR had a mean of 0.85 emergency department visits compared to a mean of 1.01 for patients treated with R-CVP/CHOP (p<0.01). Admissions for febrile neutropenia were more common in patients treated with R-CVP/CHOP compared to BR (4.9% vs. 2.2%, p<0.01), whereas infections resulting in hospitalization were more common in patients treated with BR. (21.9% vs. 17.3%, p<0.01). A majority of patients in both cohorts received maintenance therapy (81% of patients treated with BR, 64.1% of patients treated with R-CVP/CHOP). The use of maintenance therapy with either regimen was associated with less mortality (HR 0.16, 95% CI 0.14-0.19). Among patients who received maintenance therapy, patients previously treated with BR had more hospital admissions for fever (21.5% vs. 18.3%, p=0.03) and infections (37.9% vs. 31.5%, p<0.01) over a three-year period. Conclusion In these well-matched cohorts of patients with indolent lymphoma, improved OS was seen with BR compared to R-CVP/CHOP. Patients treated with BR had more infectious complications, although more episodes of febrile neutropenia were seen in patients treated with R-CVP/CHOP. The use of maintenance therapy was associated with less mortality, although patients who received maintenance therapy may have been a more fit and selected population. Higher infectious toxicities were seen for patients who received maintenance rituximab after BR. This study supports BR as the standard of care, and future prospective studies should evaluate the survival and toxicity impact of rituximab maintenance. Figure 1 Figure 1. Disclosures Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria.

Invasive Field Radiotherapy Combined with Rituximab Versus Rituximab Alone for Consolidation Therapy in Stage III Follicular Lymphoma Patients Response to R-CHOP Chemotherapy: A Randomized Clinical Study

Background: Stage III follicular lymphoma (FL) is currently still considered incurable after RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy and rituximab maintenance. Radiotherapy plays a vital role in early-stage FL, but the value remains unclear in stage III FL. Here, we reported the results of invasive field radiotherapy (IFRT) combined with rituximab maintenance versus rituximab maintenance alone in patients with stage III FL who achieved complete remission (CR) or partial response (PR) after induction chemotherapy. Methods: From January 2015 and January 2020, patients aged 18-70 years with CR or PR after induction chemotherapy in stage III FL, grade 1, 2 or 3a and CD20 positive in immunohistochemical feature were randomly assigned (1:1) to receive IFRT combined rituximab maintenance or rituximab maintenance alone after induction chemotherapy in multicenter. The primary endpoint was progression-free survival at 5 years. This study is registered with Chinese ClinicalTrials.gov, number ChiCTR2000032550. Results: 63 patients were randomly assigned to IFRT combined rituximab maintenance (IFRT+R arm) and 66 patients to rituximab maintenance alone (R arm) after induction chemotherapy. The dose of IFRT was 30Gy. After a medium follow-up of 48 months (range 7-72 months), the 5-year progression free survival (PFS) were significantly improved in patients with IFRT +R, with 87.8% versus 67.1% (HR, 0.32; 95% CI, 0.14-0.72, P=0.006). Patients with IFRT +R also have a better overall survival (OS), OS was 96.6% versus 80% (HR, 0.28; 95% CI, 0.09-0.92, P=0.036). Thirty-six (57%) patients in IFRT+R arm and twenty-four (36%) patients in R arm suffered toxic effects (P=0.02). Grade 3 and 4 adverse events were recorded in 17 patients (27%) in IFRT+R arm and 11 (16%) in R arm (P=0.200). Conclusion: On the basis of rituximab maintenance, IFRT demonstrated promising efficacy and manageable toxicity in stage III FL, with longer PFS and OS compared with rituximab alone. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.