Follicular Lymphoma International Prognostic Index Score Research Articles

Characteristics and prognostic value of gut microbiota in follicular lymphoma.

The pathogenesis and progression of follicular lymphoma (FL) depends on immune evasion mechanisms. The gut microbiota has been reported to be associated with the development and outcome of several human diseases by modulating host immunity. Thus, the present study investigated the characteristics and prognostic value of the gut microbiota in FL. Fecal samples from treatment-naïve patients with FL (n=28) and healthy controls (n=18) were prospectively collected. The gut microbiota diversity and composition were examined by 16S ribosomal RNA sequencing. The results demonstrated that patients with FL had distinct microbiota compositions. The relative abundance of the Ruminococcaceae family was significantly increased in patients with FL (P=0.01). Furthermore, a high level of Ruminococcus was identified as a strong indicator of tumor burden (P=0.001), and was related to the FL International Prognostic Index score and serum lactate dehydrogenase levels. The present results indicated an association between the gut microbiota and FL prognosis. Findings from the present study may provide a rational foundation for further investigation of the role of gut microbiota in lymphoma management.

Real-World Response Rates across Lines of Therapy Among Patients with Relapsed/Refractory Follicular Lymphoma

Background: Follicular lymphoma (FL) is the most common indolent subtype of non-Hodgkin lymphoma. Despite the generally indolent nature of the condition, there are subgroups of FL patients who may not have an indolent experience, with their disease not responding to multiple lines of therapy. Thus, optimization of novel therapy could improve patient outcomes. This analysis examined treatment patterns, overall response rates (ORR), and complete response (CR) rates by line of therapy (LOT) in relapsed/refractory (R/R) FL in third-line or later (3L+) therapy. Methods: This retrospective observational study was conducted using the COTA database, comprising electronic health records (EHR) from academic (50%) and community (50%) practices in the US. Adults with a confirmed diagnosis of FL, with 3L+ therapy initiation in 2010 or later, at least 3 months of follow-up, and any response assessment after 3L initiation were included. LOTs eligible for inclusion met the following conditions: treatment with an anti-CD20, alkylating agent, or lenalidomide, and no investigational drug in the selected LOT. In addition, patients with only 3L had that line selected; patients with more than 1 eligible LOT had only 1 LOT randomly selected for the analysis. Outcomes were assessed by FL International Prognostic Index (FLIPI), double refractory (DR) status, and type of therapy. DR status was defined as being refractory (disease progression or initiation of a new LOT in <6 months) to an anti-CD20 monoclonal antibody therapy and an alkylating agent. Chemoimmunotherapy (CIT) regimens included obinutuzumab/rituximab + bendamustine (OB/BR), rituximab/obinutuzumab+cyclophosphamide, doxorubicin, vincristine, and prednisolone (R/O+CHOP), R/O+CVP, R/O+other alkylating agent, and R/O+fludarabine and cyclophosphamide (FC). Novel therapies included lenalidomide + rituximab (R 2), phosphatidylinositol-3-kinase (PI3K) inhibitors, and chimeric antigen receptor T-cell therapy (CAR T). The proportion of patients with CR (as retrieved from clinician documentation in EHR) as the physician-reported response within each LOT was calculated. ORR was calculated as the proportion of patients with a CR or PR. Response rates were reported by LOT (3L, 4L, 5L+) and stratified by patient age (<65 vs ≥65 years), FLIPI score (low/intermediate vs high), and DR (not DR vs DR). Results: Overall, 240 patients with R/R 3L+ FL were included: 3L (n=140), 4L (n=55), and 5L+ (n=45). At 3L initiation, median age was 66 years and most patients were male (58.8%), White (89.6%), and had FL grade 1/2 (72.5%); 47.9% of patients were DR, 22.9% had novel therapy use, and 51.3% had CIT use. A total of 152 patients had FLIPI scores available, 38.2% of whom had high-risk scores at 3L initiation. Among all R/R 3L+ FL patients, ORR was 67.9%, with CR in 30.4% ( Figure 1). Response rates decreased across LOTs for both ORR (3L: 72.9%; 4L: 65.5%; 5L+: 55.6%) and CR (3L: 35.0%; 4L: 30.9%; 5L+: 15.6%) ( Figure 2). ORR was higher among all R/R 3L+ FL patients <65 years vs ≥65 years (75.5% vs 62.3%), as was CR rate (36.3% vs 26.1%). Among the subset of R/R 3L+ FL patients with a FLIPI score, those with low/intermediate risk vs high risk had a greater ORR (78.7% vs 58.6%) and CR rate (36.2% vs 20.7%). ORR was also higher for R/R 3L+ patients without DR status vs with DR status (73.0% vs 63.2%), as was CR rate (37.4% vs 24.0%). Patients receiving novel therapy 3L+ had an ORR of 70.9% and a CR rate of 27.3%. Among R/R 3L+ FL patients, more LOTs of CIT were associated with decreased response rates; patients with CIT in 1 LOT vs CIT in >2 LOTs had greater ORR (76.4% vs 69.2%) and CR rate (37.4% vs 26.9%). Conclusions: This analysis provides granular details on patients with R/R FL with poor prognosis. Patients with FL who progress to later LOTs have worsening response rates. This analysis included more patients with later LOTs than previously published reports, providing additional insight into response rates as treatment progresses. Lower response rates were observed among patients ≥65 years, those with a high-risk FLIPI score, and those with DR status. The high utilization of CIT in later LOTs, despite suboptimal response rates, especially among subgroups of patients with FL who may not have indolent experience of the disease, underlines the need for efficacious alternative therapies in patients with R/R 3L+ FL.

Preliminary Findings of a Phase Ib/II Trial Indicate Manageable Safety and Promising Efficacy for Mosunetuzumab in Combination with Lenalidomide (M+Len) in Previously Untreated (1L) Follicular Lymphoma (FL)

Background: First-line FL treatments typically include an anti-CD20 monoclonal antibody with alkylator-based chemotherapy. Despite encouraging efficacy, most patients (pts) eventually relapse; novel therapies that improve outcomes and prolong remission in 1L FL are needed. Also, chemotherapy-containing regimens may have substantial toxicities, emphasizing the need for new therapies with improved safety. Mosunetuzumab (M), a CD20xCD3 bispecific antibody that redirects T cells to eliminate malignant B cells, has shown manageable safety with high complete remission rates in pts with relapsed/refractory (R/R) FL after ≥2 prior lines of therapy (Budde et al. Lancet Oncol 2022). Lenalidomide (Len), a potent immunomodulatory agent, may have synergistic effects with M. Initial results from the CO41942 Phase Ib/II trial (NCT04246086) showed that M (intravenous) combined with Len had a manageable safety profile and encouraging chemotherapy-free anti-lymphoma activity in pts with R/R FL who had ≥1 prior line of therapy (Morschhauser et al. ASH 2021). We present preliminary safety, efficacy, and biomarker data from this ongoing trial of M (subcutaneous [SC]) combined with oral Len in pts with 1L FL who require systemic therapy. Methods: Pts with 1L FL requiring systemic therapy (investigator-assessed using GELF criteria) with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 are included; target enrollment is 40 pts. Pts received 12 cycles of M+Len (cycle [C] 1, 21 days; C2-12, 28 days); in C1, 5mg of M was given on Day (D) 1, with the target dose (45mg) given on C1D8, C1D15, and on D1 of C2-12; Len (20mg) was given on D1-21 of C2-12 ( Figure A). Cytokine release syndrome (CRS) was reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Responses by PET-CT were investigator-assessed using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). Flow cytometry (fluorescence-activated cell sorting) on whole blood was used to assess peripheral biomarkers. Results: At clinical cutoff date (CCOD; May 2, 2023), 37 pts were enrolled: 21 (56.8%) had been on the study for 0-3 months, 12 (32.4%) for 3-6 months, and 4 (10.8%) for 6-9 months. Median age was 62.0 (range 28-83) years and 20 (54.1%) pts were male. All pts had a baseline ECOG PS of ≤1; 32 (86.5%) had Ann Arbor stage III-IV; and 7 (18.9%), 13 (35.1%), and 17 (45.9%) had a FL International Prognostic Index score of 0-1 (low), 2 (intermediate), and 3-5 (high risk), respectively. All pts reported ≥1 treatment-emergent adverse event (TEAE); 12 (32.4%) had ≥1 serious TEAE. Two pts discontinued study treatment after the C1D15 dose, one pt due to uveitis and one pt due to tumor flare. TEAEs related to M or Len occurred in 36 (97.3%) and 29 (78.4%) pts, respectively. At least one Grade (Gr) 3-4 TEAE occurred in 16 (43.2%) pts, the most common being neutropenia (seven pts). No pts reported Gr 5 AEs. CRS occurred in 20 (54.1%) pts; all were Gr 1, except for one pt with Gr 2 CRS, and all events resolved (median CRS duration: 2 days [range 1-26]). CRS frequency was highest after C1D1 (32.4%), and steadily declined over subsequent days and cycles. No immune effector cell-associated neurotoxicity syndrome events were observed. To date, 27 pts were efficacy evaluable ( Figure B). Of 24 (88.9%) responders, 22 (81.5%) had a complete metabolic response (21 achieved by the first response assessment at end of C3), and two (7.4%) had a partial metabolic response. One pt (3.7%) had no response assessment by CCOD, and two (7.4%) had progressive disease but were recognized to have biopsy-proven transformed FL during C1 and C2. All responses were maintained at CCOD. Preliminary biomarker analyses of pt blood samples showed: increased CD69 and sustained HLA-DR expression in CD8 T cells, with modulation of CD8 subsets favoring central/effector memory phenotypes; sustained natural killer-cell activity; and minimal effects on CD4 T cells (except for lower PD-1 expression). Conclusions: This fixed-duration, chemotherapy-free M+Len regimen offers a convenient means for outpatient SC administration, and has a manageable early safety profile with promising anti-lymphoma activity in pts with 1L FL requiring systemic therapy, based on the preliminary data. Advancing M+Len into the first-line setting offers potential benefits in chemotherapy-naïve pts. Safety, efficacy, biomarker, and pharmacokinetic data from the complete cohort (40 pts) will be presented.

High Ki67 Index Is Associated with Shorter Progression Free Survival in Follicular Lymphoma Patients Treated with Frontline Immunochemotherapy

Introduction The Follicular Lymphoma International Prognostic Index (FLIPI) is a commonly used prognostic tool in follicular lymphoma (FL). However, there is a need for better risk stratification to predict risk of progression after frontline chemoimmunotherapy. Ki67 proliferation index has prognostic value in many lymphomas and is widely available in clinical laboratories. However, the impact of Ki67 on outcomes in FL have not been conclusive. Studies have been limited by the method of quantifying Ki67 (entire specimen or intrafollicular [IF]), heterogeneous treatments, or small single institution studies. Moreover, the impact of Ki67 on predicting disease progression at 24 months (POD24) is unknown. We sought to study the predictive value of Ki67 on PFS in FL treated with Bendamustine Rituximab (BR) or RCHOP with or without Rituximab maintenance (RM) as first line therapy at 2 tertiary care centers. Methods This study was conducted with approval by the Wake Forest University Health Sciences IRB. We retrospectively analyzed 122 patients with FL (grade 1-3A) from 2010 to 2021 at Atrium Health (AH) Levine Cancer Institute (n=72) and AH Wake Forest Baptist Medical Center (n=50) who underwent first line therapy with BR or RCHOP and had tissue/slides available for analysis. Clinical data was collected through electronic medical record review. Archival slides and paraffin-embedded blocks were retrieved. Ki67 immunohistochemistry (IHC) (SP6, Cell Marque, Rocklin, CA), was performed if it was not available from the original work-up (8 cases). CD21 IHC (1F8, Dako, Denmark) was performed in select cases to confirm the presence of follicles in order to assess IF Ki67. Diagnosis, grade, and Ki67 stains were evaluated by 2 hematopathologists. The IF Ki67 index was determined by visual estimate to the nearest 10%. All cases with scores between 20-40% were re-reviewed to achieve a consensus score. Ki67 controls were exchanged between the two centers to ensure equivalent staining. Comparisons of patient characteristics were done by Kruskal-Wallis test for continuous variables (age) or Chi-square tests (categorical variables). Survival analysis was performed using Kaplan-Meier estimation and log-rank testing. Cox proportional hazards modeling was used for multivariable progression free survival (PFS) analysis. Results The clinical and pathologic characteristics are shown in Table 1. No differences in demographics [age, stage, cytologic grade, FLIPI, IF Ki67 status (<30 or ≥30) and treatment selection] were seen between the two centers. 100 cases were grade 1-2 (82.0%) and 22 were grade 3A (18.0%). Consistent with expected treatment patterns in FL, more patients were treated with BR (70.5%) compared to RCHOP (29.5%) and RCHOP was more frequently used in grade 3A compared to grade 1-2 FL patients. As expected, low FLIPI score (0-1) was associated with favorable PFS (P=0.02, Figure 1A), but not OS. However, treatment regimen (BR vs RCHOP), use of RM, and cytologic grade (grade 1-2 vs 3A) were not associated with PFS or OS. The IF Ki67 index was elevated (≥30%) in 46 cases (38%) and high IF Ki67 was associated with shorter PFS (P=0.002, Figure 1B), but was not associated with OS (P=0.11). When stratified by treatment regimen and IF Ki67, these results were maintained ( Figure 1C). There was no association between FLIPI and IF Ki67 (P=0.10). In a multivariable regression analysis, IF Ki67 ≥30 was associated with a significantly higher risk of progression (HR= 2.3, 95% CI 1.3 to 4, P=0.005) after accounting for the effect of FLIPI. In an exploratory analysis, a FLIPI/Ki67 (FKi) score was devised in which one point was given for either FLIPI ≥ 2 or IF Ki67 ≥ 30% giving a possible score of 0, 1 or 2. The FKi score was associated with PFS (P=0.0005, Figure 1D). Moreover, IF Ki67 ≥ 30 was associated with a higher risk of POD 24 (P=0.037). FLIPI ≥2 was also associated with POD24 (P=0.005). Conclusion Intrafollicular Ki67 ≥ 30% predicts for increased risk of progression independent of FLIPI in patients with FL treated with frontline immunochemotherapy. Addition of Ki67 to FLIPI is strongly associated with PFS in FL. Ki67 stains were done over an 11 year period in different laboratories, demonstrating the wide applicability and robustness of the Ki67 IHC technique. Larger studies incorporating IF Ki67 in risk stratification models are warranted in FL.

Long-Term Efficacy of a 6-Month Regimen of Rituximab and Lenalidomide in Follicular Lymphoma Patients in Need of First Therapy: Updated Analysis of the SAKK 35/10 Randomized Trial

Background:The Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) conducted the SAKK 35/10 randomized phase-2 trial (NCT0137605) to compare the effectiveness of rituximab (R) alone versus R combined with lenalidomide (L) as the initial treatment for symptomatic follicular lymphoma (FL). The primary endpoint analysis, which demonstrated higher complete remission (CR) rates with the combination therapy, was previously reported (Zucca et al. Blood 2019). This report provides a long-term analysis of time-to-event endpoints with a median follow-up of approximately 10 years. Methods:A total of 154 eligible patients with untreated grade 1 to 3a FL requiring systemic therapy were centrally randomized to receive either R monotherapy (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 for responding patients) or R+L. In the combination arm, R was administered at the same schedule as the monotherapy, while L was taken orally at a daily dose of 15 mg, starting 14 days before the first R administration, and continued until 14 days after the last R administration, for a total of 18 weeks. Random assignment to treatment arms was stratified based on histological grade (1-2 vs 3a), bulky disease (<6 vs ≥6 cm), Follicular Lymphoma International Prognostic Index (FLIPI) score (1-2 vs ≥3), and centre, using the minimization method. The sample size was determined to detect a 20% increase in the CR/CRu rate with 90% power, using a one-sided Z-test with a false positive rate of 10% to compare the two treatment arms. The assessed endpoints, including progression-free survival (PFS), time to next anti-lymphoma treatment (TTNT), duration of CR/CRu (DoR), and overall survival (OS), were defined according to NCI international standardized criteria (Cheson et al. J Clin Oncol 1999). Results:Seventy-seven patients (median age 63 years, 52% with stage IV and 47% with poor-risk FLIPI score) were assigned to the single-agent rituximab arm, and 77 patients (median age 61 years, 48% with stage IV and 47% with poor-risk FLIPI score) were assigned to the combination arm. The results for the primary endpoint were consistent with the positive initial analysis. At a median follow-up of 9.5 years, the overall survival was similar in both arms (77% vs. 78% at 10 years, p=0.881). However, significant, and sustained improvements were seen in all other time-to-event endpoints. Patients in the R+L arm had a longer PFS (median, 9.3 vs. 2.3 years; HR=0.58, 95% CI: 0.37-0.89; p=0.013) and TTNT (median, not reached vs. 2.1 years; HR=0.43, 95% CI: 0.27-0.67; p<0.001). DoR with R+L was also longer (median not reached vs 3.2 years with R only; HR=0.42, 95% CI: 0.21-0.86; p=0.014) and with over 60% of responders still in first remission at 10 years. The improved outcomes with R+L were not associated with unexpected toxicity. Grade ≥3 adverse events were more common with the combination regimen (56% vs. 22% of patients), with grade 3-4 neutropenia in 23% of patients receiving R+L and in 7% of those receiving R alone. Fatigue, diarrhea, and skin rash were more frequent with R+L, but mostly of grade 1-2 (grade 3 occurred in ≤ 5% in both arms, and no grade 4 was reported). The side effects were manageable, and there were no treatment-related deaths in either arm. Two cases of biopsy-proven into diffuse large B-cell lymphoma were reported in the R+L arm, and two cases of Hodgkin lymphoma were described in the R arm. Although their causal relationship with treatment is not completely clear, the number of second solid cancers was significantly higher in the R+L arm. Two cases of prostate cancer, two lung adenocarcinomas (one in situ), one small cell lung carcinoma, one rectal cancer, and four skin cancers (three squamous cell and one basal cell), were observed in the R+L arm, while only one solid tumor (prostate cancer) occurred in the R arm (p=0.09). Only one patient died of a second solid cancer (small cell lung carcinoma in the R+L arm). The rate of POD24 was 29% in the R+L arm vs. 34% in the R-arm (p=0.483). Conclusions:The long-term results of the SAKK 35/10 trial demonstrated a durable benefit for the R+L combination compared to R alone. Notably, the adopted R+L schedule is considerably shorter than the standard R2 regimen (18 vs. 120 weeks). This provides a promising alternative when treatment is required but durable immunosuppression is undesirable.

External Validation of the FLIPI Risk Score Measured at Diagnosis and POD24 Among Individuals With Follicular Lymphoma at the Time of Subsequent Relapse

BackgroundThe Follicular lymphoma international prognostic index (FLIPI) risk score and POD24 have previously been shown to have prognostic value in follicular lymphoma (FL), but the extent to which they can inform prognosis at the time of subsequent relapse is uncertain. Patients and MethodsWe conducted a longitudinal cohort study of individuals diagnosed with FL between 2004 and 2010 in Alberta, Canada who received front-line therapy and subsequently relapsed. FLIPI covariates were measured prior to the initiation of front-line therapy. Median overall survival (OS), progression-free survival (PFS2), and time to next treatment (TTNT2) were estimated from the time of relapse. ResultsA total of 216 individuals were included. The FLIPI risk score was highly prognostic at the time of relapse for OS (c-statistic = 0.70; HR[High vs. Low] = 7.38; 95% CI: 3.05-17.88), PFS2 (c-statistic = 0.68; HR[High vs. Low] = 5.84; 95% CI: 2.93-11.62) and TTNT2 (c-statistic = 0.68; HR[High vs. Low] = 5.72; 95% CI: 2.87-11.41). POD24 was not prognostic at the time of relapse for either OS, PFS2, or TTNT2 (c-statistic = 0.55). ConclusionThe FLIPI score measured at diagnosis may help with the risk stratification of individuals with relapsed FL.

Final Analysis of JCOG0203 for Advanced-Stage Indolent B-Cell Lymphoma 15 Years after the End of Enrollment: Pooled Analysis of Arms a and B for Follicular Lymphoma

Optimal immunochemotherapy as first-line treatment for patients with follicular lymphoma (FL) remains undetermined. FL frequently relapses after frontline treatment; thus, fatal secondary malignancies (SMs) and treatment-related death, including death due to infection, which will be accumulated by subsequent treatments, should be avoided. To evaluate the cumulative incidence of SMs as well as histologic transformation (HT), a follow-up of more than 15 years is necessary. However, such data are available only in the pre-rituximab era by retrospective and single-institute studies. In addition, the real incidence of HT was probably underestimated in the studies that estimated only biopsy-proven cases. In JCOG0203, previously untreated patients with stage III/IV indolent B-cell lymphoma were randomly assigned to receive six cycles of R-CHOP (Arm A) or R-CHOP-14 (every 2 weeks with G-CSF, Arm B) without rituximab maintenance. All histopathological specimens were centrally reviewed by three hematopathologists. To evaluate long term follow-up data, analyses for overall survival (OS), progression-free survival (PFS), HT, SMs, and progression of disease within 24 months after treatment initiation (POD24) were performed. OS and PFS were calculated using Kaplan-Meier method. Hazard ratios (HRs) were estimated by proportional hazards model. Cumulative incidence function of HT and SM were estimated. Exploration of risk factors for frequency of HT and POD24 were conducted by logistic regression model. Between Sep 1, 2002 and Feb 28, 2007, 300 patients, including 248 with grade (G)1-3A FL, were enrolled from 44 centers. Nineteen (6.3%) patients were lost to follow-up. The 10- and 15-year OS of patients with FL in Arm A vs. Arm B was 83.8% vs. 85.3% and 76.4% vs. 75.9%, respectively. No protocol treatment-related death or fatal late infection was reported. Multivariable analysis for the 299 patients eligible for OS revealed that significant adverse prognostic factors were age ≥61 (HR=2.54, p<0.0001), male sex (HR=2.06, p=0.002), and ECOG PS ≥1 (HR=1.71, p=0.044). As both arms revealed similar outcomes, pooled analyses of Arms A and B were performed for FL. The incidence of HT, including biopsy-proven and clinically diagnosed HT, was 9.8% and 14.4% at 10 and 15 years after enrollment, respectively, and increased thereafter. Seventy-seven of 245 (31.4%) patients, excluding two who died and one lost to follow-up patients without POD24, experienced POD24. HT occurred in 19 of 76 (25.0%) patients. Multivariable analysis for POD24 identified high Follicular Lymphoma International Prognostic Index (FLIPI) score (Odds ratio (OR)=4.40) and G3A histology (OR=2.63) as risk factors for HT and intermediate (OR=2.53) and high (OR=2.24) FLIPI score, B symptoms (OR=2.09), and G3A (OR=1.83) as risk factors for POD24. Additional analysis suggested that, restricted to within a 10-year period, high FLIPI (OR=3.24, p=0.046) and G3A (OR=3.30, p=0.054) were more related to HT than in the whole study period in univariable analysis. The cumulative incidence of SMs increased after the 10-year follow-up. The incidence of solid tumors was 12.8% {10.6% (fatal [f], n=3/17 events) in Arm A vs. 15.0% (f, n=10/23 events) in Arm B} at 15 years, whereas that of hematologic malignancies was 3.7% {4.1% (f, n=2/5) in Arm A vs. 3.3% (f, n= 1/4) in Arm B}. These results are the longest follow-up data of more than 200 patients with FL homogeneously treated in a multicenter prospective trial. R-CHOP was safe and efficacious, reducing HT, without increasing fatal hematologic malignancies in the long-term and may, therefore, be a reasonable option as frontline therapy for advanced-stage FL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

External Validation of the FLIPI Risk Score Measured at Initial Diagnosis and POD24 Among Previously Treated Individuals with Progressed Follicular Lymphoma in Alberta, Canada

Introduction: A number of variables have been shown to predict survival outcomes in follicular lymphoma (FL), including the Follicular Lymphoma International Prognostic Index (FLIPI) score measured at initial diagnosis and progression of disease within 24 months (POD24). However, there exists little research aimed at informing prognosis in a cohort comprised exclusively of FL patients whose disease has relapsed after prior therapy. To address this gap, we assessed the FLIPI score measured at diagnosis and POD24 with respect to their ability to stratify survival outcomes measured from the time of first progression in a group of individuals with FL who experienced disease progression after initial treatment. Methods: An external validation of the FLIPI score measured at diagnosis and POD24 was conducted using population-level data from Alberta, Canada. The study cohort was comprised of individuals diagnosed with FL between 2004-2010 who received either systemic therapy and/or radiation within 180 days of diagnosis and who subsequently had disease progression. Individuals were followed until death or last-known contact with the healthcare system. Relevant data were identified through record linkage of the provincial cancer registry and electronic medical records along with a manual chart review conducted by trained medical doctors. Outcomes were examined from the time of first progression and included time to death (OS), time to death after first progression or second progression (PFS2), and time to death or initiation of third line treatment (TTNT2). For each outcome, Kaplan-Meier curves were estimated stratified by FLIPI and by POD24. To quantify the degree of separation of the Kaplan-Meier curves, we estimated hazard ratios (HRs) using a Cox proportional hazards model and Harrell's concordance statistic (c-statistic) for both the FLIPI index and POD24. Results: 910 individuals were diagnosed with FL between 2004-2010, of which 584 received systemic or radiation therapy. 527 individuals initiated front-line therapy within 180 days of diagnosis, of which 216 experienced progression during the follow-up period and were included in these analyses. Among the 216 individuals, 162 (75%) received front-line systemic therapy which was primarily R-CVP (n=57; 35%) or R-CHOP (n=78; 48.1%). From the time of disease progression, median OS was 11.7 years (95% CI: 8.9-NA). POD24 status was available for all 216 individuals, with 90 (42%) individuals having evidence of progression of disease within 24 months of initiating front-line therapy (POD24+). Overall, 129 of the 216 (60%) individuals had complete information required to derive the FLIPI risk score with 43 (33%) being classified as high-risk, 46 (36%) intermediate-risk, and 40 (31%) low-risk. OS estimates stratified by FLIPI score and by POD24 are presented in Table 1. POD24 was not highly predictive of OS from the time of disease progression (c-statistic: 0.55; HR [POD24+ vs. POD24-]: 1.42; 95% CI: 0.93 to 2.15; p = 0.10). Conversely, the FLIPI score measured at diagnosis was highly predictive of OS from the time of disease progression (c-statistic 0.70; HR [High vs. Low]: 7.38; 95% CI: 3.05 to 17.88, p < 0.01; HR [Int. vs. Low]: 3.70; 95% CI: 1.51 to 9.10, p < 0.01; ; HR [High vs. Int.]: 1.99; 95% CI: 1.15 to 3.47, p = 0.01; Figure 1). These findings were similar when examining PFS2 and TTNT2. In sensitivity analysis, findings were similar when restricting to individuals who received front-line systemic therapy. In addition, the classification of individuals by both POD24 and FLIPI did not meaningfully improve discrimination over FLIPI alone. Conclusions: The FLIPI score measured at initial diagnosis can be used for risk stratification at the time of disease progression among previously treated FL patients. In contrast, POD24 was not highly predictive of survival outcomes from the time of disease progression within this population of FL patients who all had disease progression. Future research is needed to determine if the prognostic utility of the FLIPI risk score measured at initial diagnosis can be improved upon by incorporating variables assessed at the time of relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) monotherapy in patients (pts) with relapsed or refractory (R/R) follicular lymphoma (FL): Primary analysis of the phase 2 randomized ROSEWOOD trial.

7510 Background: FL is the most common type of indolent non-Hodgkin lymphoma. Approved treatment options are limited for pts with R/R FL. In a phase 1b trial ( Blood Adv. 2020;4(19):4802-4811), ZO was found to be tolerable and associated with early signal of efficacy. ROSEWOOD (BGB-3111-212) is a phase 2, randomized study designed to assess efficacy and safety of ZO vs O in pts with R/R FL. Methods: Pts with R/R FL who received ≥2 lines of therapy, including an anti-CD20 antibody and an alkylating agent, were randomized 2:1 to receive either ZO or O. O was given in both arms on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycles 2-6, and then every 8 weeks up to 20 doses maximum. Z (160 mg twice daily) was given until progressive disease (PD) or unacceptable toxicity; Pts with confirmed PD in the O arm were allowed to crossover to ZO. Primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoint included ORR by investigator after crossover. Primary analysis cutoff was October 8, 2021. Results: A total of 217 pts were randomized to ZO (n = 145) or O (n = 72). Median study follow-up was 12.5 mo; median age was 64 yrs. Incidence of high FL International Prognostic Index score was 53% (ZO) and 51% (O). Pts received a median of 3 prior lines of therapy, with 28% (ZO) and 25% (O) of pts receiving &gt; 3 lines. Proportion of pts refractory to rituximab, refractory to the most recent line of therapy, or with PD within 24 mo of initiation of first-line immunochemotherapy was 54%, 32% and 28% with ZO and 50%, 40% and 32% with O, respectively. The study met its primary endpoint: ORR was 68.3% with ZO vs 45.8% with O ( p= 0.0017). CRR was 37.2% (ZO) vs 19.4% (O); 18-mo DOR rate was 70.9% (ZO) vs 54.6% (O); and median PFS was 27.4 mo (ZO) vs 11.2 mo (O; hazard ratio [HR], 0.51 [95% CI, 0.32-0.81], p= 0.0040). Median time to new anti-lymphoma therapy or crossover was not evaluable (NE; ZO) vs 12.1 mo (O; HR, 0.37 [95% CI, 0.23-0.60], p&lt; 0.0001). ORR for 29 pts who crossed over to ZO was 24.1%. Median OS was NE; 18-mo OS probability was 85.4% (ZO) vs 72.6% (O). Most common any grade AEs in the ZO arm were thrombocytopenia (34.3%), neutropenia (27.3%), diarrhea (16.1%), fatigue (14.0%), constipation (13.3%), cough (11.9%), pyrexia (11.2%), and dyspnea (10.5%). Grade ≥3 AEs with incidence &gt; 5% with ZO were neutropenia (22.4%) and thrombocytopenia (14.0%); incidence of atrial fibrillation was 0.7% and major bleeding was 1.4%. Incidence of treatment-emergent AEs leading to death was 5.6% (ZO) and 9.9% (O). Conclusions: ZO demonstrated superior efficacy to O in treatment of pts with R/R FL. ZO had a favorable benefit-risk profile and represents a potential combination therapy for pts with R/R FL. Clinical trial information: NCT03332017.

High inter-follicular spatial co-localization of CD8+FOXP3+ with CD4+CD8+ cells predicts favorable outcome in follicular lymphoma.

The spatial architecture of the lymphoid tissue in follicular lymphoma (FL) presents unique challenges to studying its immune microenvironment. We investigated the spatial interplay of T cells, macrophages, myeloid cells and natural killer T cells using multispectral immunofluorescence images of diagnostic biopsies of 32 patients. A deep learning-based image analysis pipeline was tailored to the needs of follicular lymphoma spatial histology research, enabling the identification of different immune cells within and outside neoplastic follicles. We analyzed the density and spatial co-localization of immune cells in the inter-follicular and intra-follicular regions of follicular lymphoma. Low inter-follicular density of CD8+FOXP3+ cells and co-localization of CD8+FOXP3+ with CD4+CD8+ cells were significantly associated with relapse (p=0.0057 and p=0.0019, respectively) and shorter time to progression after first-line treatment (Logrank p=0.0097 and log-rank p=0.0093, respectively). A low inter-follicular density of CD8+FOXP3+ cells is associated with increased risk of relapse independent of follicular lymphoma international prognostic index (FLIPI) (p=0.038, Hazard ratio (HR)=0.42 [0.19, 0.95], but not independent of co-localization of CD8+FOXP3+ with CD4+CD8+ cells (p=0.43). Co-localization of CD8+FOXP3+ with CD4+CD8+ cells is predictors of time to relapse independent of the FLIPI score and density of CD8+FOXP3+ cells (p=0.027, HR=0.0019 [7.19×10-6 , 0.49], This suggests a potential role of inter-follicular CD8+FOXP3+ and CD4+CD8+ cells in the disease progression of FL, warranting further validation on larger patient cohorts.

Follicular Lymphoma in China: Systematic Evaluation of Follicular Lymphoma Prognostic Models

ObjectsTo systematically evaluate the baseline characteristics, tumour microenvironment indicators such as the lymphocyte/monocyte ratio (LMR) and treatment response (POD24) as prognostic predictors of follicular lymphoma (FL) among Chinese patients.MethodsWe retrospectively analysed 112 FL patients from 2000 to 2017, whose pathology grading included 1–3a. Absolute lymphocyte and monocyte counts were determined by cell blood counting. The Kaplan–Meier method was used to analyse the influence of prognostic predictors on progression-free survival (PFS) and overall survival (OS). Multivariate analysis was conducted using the Cox proportional risk model.ResultsThe long-term survival of Chinese FL patients (median PFS, 74.8 months) was slightly better than that of patients in foreign countries. Among several prognostic models, the Follicular Lymphoma International Prognostic Index (FLIPI) score had a significant effect on both PFS and OS, while there were no independent prognostic predictors. Patients with LMR ≤3.6, ALC ≤0.6*109/L and AMC >0.6*109/L had worse OS, among which LMR was an independent indicator of OS. The POD24 subgroup had a higher frequency of high-risk patients according to FLIPI and FLIPI2 scores (63.0% vs 35.1%, P = 0.013 and 18.5% vs 3.9%, P = 0.003) and had an markedly shorter OS (P < 0.0001).ConclusionThis study is a systematic prognostic evaluation based on Chinese clinical data. We found a new factor, the LMR, that could independently predict prognosis compared with FLIPI or FLIPI2.

Validation of POD24 as a robust early clinical end point of poor survival in FL from 5225 patients on 13 clinical trials

AbstractObservational studies and stand-alone trials indicate that patients with follicular lymphoma (FL) who experience disease progression within 24 months of front-line chemoimmunotherapy (POD24), have poor outcomes. We performed a pooled analysis of 13 randomized clinical trials of patients with FL in the pre- and postrituximab eras to identify clinical factors that predict POD24. Logistic regression models evaluated the association between clinical factors and POD24. Cox regression evaluated the association between POD24 as a time-dependent factor and subsequent overall survival (OS). A landmark analysis evaluated the association of POD24 with OS for the subset of patients who were alive at 24 months after trial registration. Patients without progression at 24 months at baseline had favorable performance status (PS), limited-stage (I/II) disease, low-risk FL International Prognostic Index (FLIPI) score, normal baseline hemoglobin, and normal baseline β2 microglobulin (B2M) level. In a multivariable logistic regression model, male sex (odds ratio [OR], 1.30), PS ≥2 (OR, 1.63), B2M (≥3 mg/L; OR, 1.43), and high-risk FLIPI score (3-5; OR, 3.14) were associated with increased risk of progression before 24 months. In the time-dependent Cox model and the 24-month landmark analysis, POD24 was associated with poor subsequent OS (hazard ratio, 4.85 and 3.06, respectively). This is the largest pooled analysis of clinical trials data validating POD24 as a robust indicator of poor FL survival and identified clinical predictors of early death and progression that can aid in building comprehensive prognostic models incorporating clinical and molecular predictors of POD24.

High-Risk FLIPI Score at Diagnosis Is Associated with Early Relapse in the Rituximab Era for Patients with Follicular Lymphoma

High-Risk FLIPI Score at Diagnosis Is Associated with Early Relapse in the Rituximab Era for Patients with Follicular Lymphoma

Clinical Factors Impact on Pharmacokinetics of CT-P10 and Reference Rituximab in Patients with Advanced-Stage Follicular Lymphoma

Background: CT-P10 is the first biosimilar to the innovator rituximab (RTX), which was approved by the European Medicines Agency for all indications for which RTX is approved. Pharmacokinetic equivalence and comparable efficacy was demonstrated in advanced-stage follicular lymphoma patients (Kim WS et al. Lancet Haematol. 2017; S2352-3026(17)) as well as in rheumatoid arthritis (Yoo DH, et al. Arthritis Rheumatol. 2016; 68 (suppl 10)). It is known that there are several factors affecting on pharmacokinetics (PK) of rituximab. However, there are limited data on comparing PK data between a biosimilar of rituximab and RTX with different subgroups in advanced-stage follicular lymphoma (AFL) patients.Objective: This report is to investigate the PK of CT-P10 according to the several relevant clinical factors and to compare with RTX in the post-hoc analysis of randomized controlled trial to compare CT-P10 and RTX in advanced-stage follicular lymphoma (NCT02162771).Methods: A total of 121 patients of PK population were included in this analysis. Fifty nine patients in the CT-P10 group and 62 patients in the RTX group received CT-P10 or RTX (375 mg/m2 i.v) plus CVP (cyclophosphamide, vincristine and prednisone) for every 3 weeks over 8 cycles. Area Under the Concentration-time curve at steady state (AUCtau) and the maximum serum concentration at steady state (CmaxSS) at Cycle 4 and trough serum concentration (Ctrough) at Cycle 4 and Cycle 8 were calculated by standard non-compartmental methods using Phoenix WinNonlin. The parameters were analysed by subgroups of Gender (male vs. female), Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. ≥1), Follicular Lymphoma International Prognostic Index (FLIPI) Score (0-2 vs. 3-5) and its component (Age (≥60 vs. <60), Hemoglobin [Hb] (≥120g/L vs. <120g/L), Lactate dehydrogenase [LDH] (>UNL vs. ≤UNL), number of nodal sites (>4 vs. ≤4)), presence of bulky lesion at baseline (≥7cm vs. <7cm) and Complete response (CR)/Complete response unconfirmed (CRu) as best overall response assessed by International Working Group 1999 in the each and combined group of CT-P10 and RTX. Outliers which determined by robust regression outlier testing were excluded in this analysis. For AUCtau, 7 patients (5 in the CT-P10 group and 2 in the RTX group) and among them, 4 patients (2 patients in each group) for CmaxSS were defined as outliers.Result: Higher AUCtau and CmaxSS were observed in patients who are female, under 60 years old, good ECOG Performance Status, low FLIPI score, normal Hb and LDH levels, and non-bulky disease at baseline as shown in Table 1. In patients who achieved CR/CRu as their best overall response during 8 cycles showed higher AUCtau, CmaxSS and Ctrough than in patients who did not achieve CR/CRu response in both CT-P10 and RTX groups. At Cycle 4 and Cycle 8, mean Ctrough in the CR/CRu responder were 72 μg/mL, 108 μg/mL, respectively, and those concentrations are 56 μg/mL, 96 μg/mL in the CR/CRu non-responder. Importantly, there was no statistically significant difference between the CT-P10 and RTX in any of subgroup analyses; confidence interval of the ratio of geometric mean of CT-P10 to RTX contains 1 using Satterthwaite approximation for each comparison.Conclusion: Female gender, younger age (<60), better ECOG Performance Status, lower FLIPI score, LDH and Hb levels in normal range, absence of bulky disease at baseline and better response are factors associated with increased serum rituximab concentration in the combined treatment groups. No statistically significant differences were found between CT-P10 and RTX groups in PK at all subgroup analyses. Therefore, this result shows that the PK of CT-P10 is in accordance with the RTX from historical data and further supports the PK similarity between CT-P10 and RTX. [Display omitted] DisclosuresKim:Celltrion, Inc: Consultancy, Honoraria; Roche: Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Donga: Research Funding; J&J: Research Funding; Takeda: Research Funding. Coiffier:Celltrion, Inc: Consultancy, Honoraria. Buske:Hexal: Honoraria; Celltrion, Inc.: Consultancy, Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Ogura:SymBio: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Astrazeneca: Honoraria; Takeda: Consultancy, Honoraria; Mundipharma: Consultancy; MeijiSeika Pharma: Consultancy; Celltrion, Inc: Consultancy, Honoraria. Kwak:Celltrion, Inc: Consultancy; InnoLifes: Consultancy, Equity Ownership; Pepromene Bio: Consultancy, Equity Ownership. Lee:Celltrion, Inc: Employment. Bae:Celltrion, Inc: Employment. Kim:Celltrion, Inc: Employment. Kim:Celltrion, Inc: Employment. Lee:Celltrion, Inc: Employment. Kwak:Celltrion, Inc: Employment. Lee:Celltrion, Inc: Employment.

Evaluation of the Different Stratification Models for POD24 Prediction in Patients with Follicular Lymphoma

Evaluation of the Different Stratification Models for POD24 Prediction in Patients with Follicular Lymphoma

Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups

Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1–3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.

Relevance of bone marrow biopsies for response assessment in NCTN follicular lymphoma clinical trials.

8038 Background: Bone marrow biopsies (BMB) are performed pre/post therapy to confirm complete response (CR) in patients (pts) with lymphoma on clinical trials. We evaluated 2 prior data sets and concluded that BMB impact response assessment in a minority of pts with follicular lymphoma (FL) (Rutherford BJH 2017; Rutherford ASH abstract 1605, 2018). We sought to establish if BMB add value in assessing response or identify distinct progression free (PFS) or overall survival (OS) outcomes in a large, multicenter, multi-trial cohort. Methods: Data were pooled from 7 trials of 580 pts with untreated FL conducted through the Alliance for Clinical Trials in Oncology and SWOG from 2002-2016. The proportion of pts with positive (+) baseline BMB, CR on imaging after treatment, and (+) repeat BMB was calculated using total pts enrolled as the denominator. We tested against the null hypothesis that the proportion was = 10%, the threshold below which BMB would be considered irrelevant for response assessment, versus (vs) the alternative hypothesis that this proportion was &lt; 10%, using 1-sided exact binomial test. Response criteria were CT-based. Imaging was not used to assess BM involvement. Because confirmatory BMB were not completed in all indicated pts, landmark survival analyses compared PFS/OS of pts with CR on imaging and negative (-) BMB vs pts with CR on imaging without repeat BMB. Pts with CR on imaging were categorized as having (-) repeat BMB or no repeat BMB within 60 days of first CR on imaging. PFS and OS were calculated from time of first CR and estimated using Kaplan-Meier and Cox models adjusting for age, sex, stage, Follicular Lymphoma International Prognostic Index (FLIPI) score, and treatment type (targeted vs chemotherapy plus targeted therapy), and stratified by treatment arm. Results: Median age was 55 with 51% male, 96% stage III-IV, and 88% grade I-II. FLIPI scores were 113 low, 265 intermediate, and 199 high risk. 67% received chemotherapy-based regimens. Baseline BMB was (+) in 321 (55%). Only 5/580 (0.8%) had (+) baseline BMB, CR on imaging, and subsequent (+) BMB (p &lt; 0.0001). Of pts with CR on imaging, PFS and OS were not different among pts with (-) BMB vs pts without repeat BMB (PFS: HR = 1.08, 95%CI 0.61-1.93, p = 0.783; OS: HR = 0.52, 95%CI 0.20-1.40, p = 0.199). Conclusions: BMB requirements may discourage pt participation in trials and add pain, expense and time without providing necessary information. We recommend eliminating BMB for response assessment from FL clinical trials. Clinical trial information: NCT00553501, NCT01145495, NCT01190449, NCT01286272, NCT01829568, NCT00822120, and NCT00770224 .

Pretreatment SUVmax may influence the clinical benefit of BR over R-CHOP in patients with previously untreated FL

In 2 randomized phase 3 trials BR resulted in longer progression-free survival (PFS) than frontline R-CHOP in patients with indolent and mantle cell lymphoma. However, in subset analyses of follicular lymphoma (FL), the results were incongruent. We conducted a retrospective matched-pair analysis to compare the outcome of patients with advanced stage FL, receiving frontline BR (N = 73) or R-CHOP (N = 73), matched by age, gender, stage, and FL International Prognostic Index score. On multivariable analysis, baseline maximum standardized uptake value (SUVmax) >13 was associated with use of R-CHOP (p = .001). After a median follow-up of 69 months for the BR arm and 126 months for the R-CHOP arm, 5-year PFS was 80% and 70%, respectively (p = .07). After adjusting for SUVmax >13, the trend for better PFS in BR was not maintained. Prospective studies are needed to validate the role of pretreatment SUVmax as a stratification factor in future randomized therapeutic trials in FL.

PB2020 EARLY RELAPSED FOLLICULAR LYMPHOMA‐ IS IT NEW ENTITY WITH DIFFERENT TREATMENT APPROACH?

Background:Although most patients with follicular lymphoma (FL) follow an indolent course with long‐lasting remissions, surviving more than 20 years after diagnosis, a small proportion of patients (20‐25%) has worse outcome due to early relapse or transformation to an aggressive form of lymphoma. The current risk prognosticators are based on the Follicular Lymphoma International Prognostic Index (FLIPI). There is not a perfect marker to predict those at higher risk of disease progression. FL with short remission duration has been established as a poor prognostic marker for survival and the optimal therapy for these patients is really not known.Aims:To analyze the clinicopathological features of refractory and early relapsed FL, the role of aggressive regimens and correlation between the treatment modality and outcome.Methods:In total, 9 patients with the primary refractory and early relapsed FL were diagnosed in Institute for radiology and oncology of Serbia during the period 2014‐2016. The treatment modality, the response, and follow‐up were registered for all the patients.Results:The median age of patients was 64 years (range, 48‐69). There were 5 male and 4 female patients. All patients were diagnosed with FL (grades 1‐3). There were 3 patients within each histologic grade. All patients presented with Ann Arbor stage III or IV disease and high FLIPI score. The bulky disease was present in 8 patients. Only three patients had normal serum LDH. All patients were treated with immunochemotherapy, R‐CVP or R‐CHOP. The median follow‐up was 33 months (range, 6‐57). Primary refractory disease was registered in 3 patients that had bulky disease, splenomegaly, and elevated serum LDH, who received non‐anthracycline, based regimen and progressed during induction therapy. One patient with primary refractory lymphoma died during induction therapy. Six patients were treated with an anthracycline‐based regimen. The overall response rate (ORR) for all R‐CHOP treated patients was 100% (50% PR and 50% CR after induction therapy). Relapse was documented during Rituximab maintenance within the first 8 months after the induction therapy in non‐refractory patients. Eight patients received Fludarabine‐based second‐line regimen with ORR of 89%. One patient died due to Richter's transformation during Fludarabine treatment. One patient who was transplant‐eligible experienced severe infectious complications following high dose therapy but later responded on local radiotherapy (RT) combined with low dose corticosteroid therapy. The second relapse was registered in three patients. They were treated with involved field RT with good response. Seven patients were still alive at the time of the last follow‐up and all of them remained in achieved response.Summary/Conclusion:The major needs are to upfront identify FL patients, for whom existing immunochemotherapeutic strategies are suboptimal and to find the best second‐line options for these patients. ASCT should be introduced within ≤1 year of treatment failure, early in the course of disease in order to preserve bone marrow capacity. Patients that are not candidates for ASCT can benefit from a less aggressive approach like RT, so there is a potential role of immunomodulators and PI3K inhibitors in overcoming the chemoresistance and establishing durable disease control.

The PRIMA-Prognostic Index (PI) Is Valid in Follicular Lymphoma (FL) Patients with Rituximab Chemo-Free First-Line Treatment

Background: Follicular lymphoma (FL) is a heterogenous disease. The optimal timing, sequence and choice of therapy remain matters of debate and there is no optimal prognostic tool. The FLIPI (Follicular Lymphoma International Prognostic Index) is based on five bio-clinical parameters and is widely used, but not as guide for choice of treatment. Recently a new prognostic score (PRIMA-PI), based solely on two parameters, bone marrow involvement and serum beta2 microglobulin (ß2m) was proposed for patients treated with immunochemotherapy (Bachy E., Blood 2018).The Nordic Lymphoma Group (NLG) performed two randomized trials including patients with symptomatic/progressive indolent CD20+ lymphoma, with rituximab monotherapy or rituximab in combination with interferon (IFN)-α2a as primary treatment, without maintenance (Kimby E., 2008, 2015). The 10 years follow-up of these patients showed a good survival with no major safety issues and no need for later chemotherapy in 38% of FL patients (Lockmer S, JCO 2018).Aim/Purpose: To evaluate two different prognostic systems (the new PRIMA-PI and the FLIPI), for overall survival (OS) and time to treatment failure (TTF) in a cohort of symptomatic/progressive FL patients treated with a rituximab-containing first-line regimen without chemotherapy.Methods: Previously untreated patients with a confirmed FL diagnosis (n=269) or indolent lymphoma not otherwise specified (n=22, most FLs with insufficient material for grading), treated in the NLG randomized trials with two cycles rituximab (375 mg/m2 x 4 weeks), with or without IFN-α2a, were classified into the three PRIMA-PI categories: high-risk: ß2m> 3mg / L, intermediate-risk: ß2m ≤ 3 mg / L with bone marrow involvement and low-risk: ß2m ≤ 3 mg / without bone marrow involvement. The FLIPI scores were also assessed. TTF, defined as the interval between randomization and either initiation of new lymphoma therapy due to relapse or intolerance, or death from any cause, as well as OS were estimated using the Kaplan Meier method. The log-rank test was used for comparison between risk groups.Results: Out of 291 patients, 252 had complete data on PRIMA-PI and FLIPI (at the time of randomization in the original trials) and were available for analyses of TTF and OS. Patient characteristics are shown in Table 1. PRIMA-PI seemed to identify a true high-risk group of 47 patients, 32 of them being high risk also according to FLIPI, while a larger patient group (n=117) was classified as FLIPI high-risk.After a long follow-up time, median 9.9 years (0.4 -18.8) from randomization, median 10.6 years for the 214 patients (74%) still alive, 76 patients (26%) were failure-free and 108 (37%) without need of any chemotherapy, Patients with PRIMA-PI high showed a shorter TTF compared to PRIMA-PI intermediate and low (Fig 1a), whereas the FLIPI risk-groups were not significantly separated (Fig 1b). Evidence of transformation to aggressive disease was seen in 55 patients, with no significant difference in frequency between the PRIMA-PI groups, nor between FLIPI groups.Both PRIMA-PI and FLIPI were of significant value for predicting OS, most evident after a long follow-up time (Fig 1c and d). In 41 patients the cause of death was progressive disease or therapy complications, regarded as lymphoma-related death, whereas 21 died of other causes. The lymphoma-specific survival was related to the PRIMA-PI (log-rank p=0.03), but not to the FLIPI (n.s). Prognosis was worse for the PRIMA-PI high-risk group than the for the low-risk, also when adjusted for sex, high age (>60 years), diagnosis, stage, ECOG and FLIPI risk-group; TTF HR 1.82 (95% CI 1.16-2.85, p=0.01) and OS HR 2.3 (95% CI 1.00-5.38, p=0.05).Conclusion: FL patients included in two NLG trials with complete clinical data and a median follow-up of >10 years after randomization have been assessed for validation of different prognostic indices. In these patients, all with chemo-free first-line therapy, the PRIMA-PI was shown a valid predictor of both TTF and OS and seemed more useful than the FLIPI. The PRIMA-PI high risk identified a group of patients (19% of all) with true poor prognosis. [Display omitted] DisclosuresKimby:Roche: Honoraria; Roche: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees. Holte:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Roche, Norway: Research Funding. Wahlin:Roche: Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Hagberg:Roche: Honoraria.