Diagnosed Follicular Lymphoma Patients Research Articles

Baseline 18F-FDG PET/CT may contribute to the determination of initial treatment strategy for newly diagnosed follicular lymphoma

Background“Watch-and-wait” approach is an important management option in asymptomatic follicular lymphoma (FL) patients with low tumor burden. Since most FL lesions are FDG-avid, we wonder if 18F-FDG PET/CT at baseline can help to better choose the patients who can benefit from early chemotherapy. This study aimed to investigate the prognostic value of baseline 18F-FDG PET/CT in newly diagnosed FL patients treated with either watch-and-wait approach or chemotherapy. ResultsPatients received chemotherapy as initial treatment had higher Ann Arbor stage, higher incidence of extranodal involvement and bulky disease, more involved lymph nodes larger than 3 cm, and higher SUVmax, MTV, and TLG than those managed with watch-and-wait approach (p < 0.05). The median PFS and TTNT in patients received chemotherapy and under watch-and-wait did not show significant difference, however patients with MTV<111.66 mL or TLG<141.50 SUVbw*mL had significantly longer PFS and TTNT than those patients with MTV≥111.66 mL or TLG≥141.50 SUVbw*mL (p < 0.05). Further analysis revealed that for patients with TLG≥141.50 SUVbw*mL or MTV≥111.66 mL, those who received chemotherapy as initial treatment had a significantly longer PFS and TTNT than those managed with initial watch-and-wait approach (p < 0.05). However, for patients with MTV<111.66 mL or TLG<141.50 SUVbw*mL in baseline PET/CT, there was no significant difference in PFS or TTNT between patients who received chemotherapy and those under watch-and-wait. ConclusionBaseline 18F-FDG PET/CT may provide prognostic value and help to improve the decision-making of initial treatment plans for newly diagnosed FL patients.

Clinical features and outcomes of patients with follicular lymphoma grade 3A: A real-world study in single center.

e19058 Background: Follicular lymphoma (FL) was classified into three grades based on the number of centroblasts (FL1-2, FL3A, and FL3B). Guidelines suggest that FL1-2 should be treated according to the treatment recommendations for classical FL. FL3B is usually treated as diffuse large B-cell lymphoma (DLBCL).There is no consensus yet on the management of FL3A. In order to explore the relationship between clinical features and outcomes of FL3A, we conducted this study. Methods: We conducted a retrospective study of newly diagnosed FL patients who were admitted to our hospital from January 2013 to December 2022. The data were collected from the hospital electronic medical record system, including but not limited to: demographic characteristics, pathological information, clinical features at diagnosis, treatment, and efficacy evaluation. The survival curve was calculated through Kaplan-Meier method and compared with Log Rank test.The prognostic factors of PFS was compared by COX regression analysis. Results: There were 253 FL3A patients admitted, accounting for 27.55% of all FL patients. After screening, a total of 223 FL3A patients were included in this study. Among 223 patients, the male to female ratio was close to 1:1; The median age is 57 years old. At diagnosed, 33 patients in early stage and 190 in advanced stage. Among advanced patients, 144 had no treatment indications according to the GELF criteria. 86.1% (192/223) of patients received systemic treatment, with the majority of rituximab contained regimens. The overall response rate (ORR) was 96%, and 62.9% of patients who responded to chemotherapy received maintenance therapy with CD20 monoclonal antibody. A median follow-up of 41 months, with an estimated 5-year OS of 91.3% and 5-year PFS of 73%. The PFS of advanced FL patients treated with RCHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) was significantly longer than that of non-RCHOP regimen patients (P&lt;0.05). The PFS of patients receiving maintenance treatment was better than that of those not (P&lt;0.05). Conduct prognostic analysis on advanced FL3A patients. Univariate analysis showed that treatment plan selection, maintenance of treatment, PET scan of FDG metabolic maximum uptake value (SUVmax), Ki-67, lactate dehydrogenase (LDH), white blood cell count (WBC), IgA, IgM, all significantly affected PFS; Multivariate analysis shows SUVmax ≥ 15 and platelet count&lt;100 × 109/L and LDH&gt;210U/L are all correlated with poor PFS. Conclusions: This study found that FL3A accounts for 27.55% of all FLs, with a median age of 57 years old and mostly in the advanced stage. FL3A has a long survival period, with a 5-year PFS of 73%. COX regression analysis showed that SUVmax, platelet count, and LDH were all associated with PFS in advanced FL3A patients.Those may explore new clinical prognosis prediction models.

The clinical features, survival analysis, and geriatric assessment of 85 patients with follicular lymphoma: a single-center study

Objective: To retrospectively analyze the clinical characteristics and prognosis of 85 newly diagnosed patients with follicular lymphoma (FL), as well as the prognostic value of comprehensive geriatric assessment (CGA) in patients with FL aged ≥ 60 years old. Methods: The clinical data and prognosis of 85 newly diagnosed FL patients admitted from August 2011 to June 2022 were collected. The clinical features, laboratory indicators, therapeutic efficacy, survival and prognostic factors of patients were statistically analyzed, and the prognosis of patients was stratified using various geriatric assessment tools. Results: ① The patients with FL were mostly middle-aged and older, with a median age of 59 (20-87) years, including 41 patients (48.2%) aged ≥60 years. The ratio of male to female was 1∶1.36. Overall, 77.6% of the patients were diagnosed with Ann Arbor stage Ⅲ-Ⅳ, and 17 cases (20.0%) were accompanied by B symptoms. Bone marrow involvement was the most common (34.1%). ②Overall, 71 patients received immunochemotherapy. The overall response rate was 86.6%, and the complete recovery rate was 47.1% of 68 evaluated patients. Disease progression or relapse in the first 2 years was observed in 23.9% of the patient. Overall, 14.1% of the patients died during follow-up. ③Of the 56 patients receiving R-CHOP-like therapies, the 3-year and 5-year progression-free survival (PFS) rates were 85.2% and 72.8%, respectively, and the 3-year and 5-year overall survival (OS) rates were 95.9% and 88.8%, respectively. The univariate analysis showed that age ≥60 years old (HR=3.430, 95% CI 1.256-9.371, P=0.016), B symptoms (HR=5.030, 95% CI 1.903-13.294, P=0.016), Prognostic Nutritional Index (PNI) <45.25 (HR=3.478, 95% CI 1.299-9.310, P=0.013), Follicular Lymphoma International Prognostic Index (FLIPI) high-risk (HR=2.918, 95% CI 1.074-7.928, P=0.036), and PRIMA-prognostic index (PRIMA-PI) high-risk (HR=2.745, 95% CI 1.057-7.129, P=0.038) significantly predicted PFS. Moreover, age ≥60 years old and B symptoms were independent risk factors for PFS. Progression of disease within 24 months (POD24) significantly predicted OS in the univariate analysis. Conclusions: FL is more common among middle-aged and older women. Age, B symptoms, PNI score, FLIPI high-risk, PRIMA-PI high-risk, and POD24 influenced PFS and OS. The CGA can be used for treatment selection and risk prognostication in older patients with FL.

Feasibility of Circulating Tumor DNA Analysis in Patients with Follicular Lymphoma.

The feasibility of sequencing circulating tumor DNA (ctDNA) in plasma as a biomarker to predict early relapse or poor prognosis in patients with follicular lymphoma (FL) receiving systemic immunochemotherapy is not clear. We sequenced DNA from cell-free plasma that was serially obtained from newly diagnosed FL patients undergoing systemic immunochemotherapy. The mutation profiles of ctDNA at the time of diagnosis and at response evaluation and relapse and/or progression were compared with clinical course and treatment outcomes. Forty samples from patients receiving rituximab-containing immunochemotherapy were analyzed. Baseline sequencing detected mutations in all cases, with the major detected mutations being KMT2C (50%), CREBBP (45%), and KMT2D (45%). The concentration of ctDNA and tumor mutation burden showed a significant association with survival outcome. In particular, the presence of mutations in CREBBP and TP53 showed poor prognosis compared with patients without them. Longitudinal analysis of ctDNA using serially collected plasma samples showed an association between persistence or reappearance of ctDNA mutations and disease relapse or progression. Analysis of ctDNA mutations in plasma at diagnosis might help predict outcome of disease, while analysis during follow-up may help to monitor disease status of patients with advanced FL. However, the feasibility of ctDNA measurement must be improved in order for it to become an appropriate and clinically relevant test in FL patients.

The Nature of High-Risk Defining Events in Follicular Lymphoma Determines Overall Survival

Background: A subset of follicular lymphoma (FL) patients will experience a ‘high-risk defining event’ (HRDE) that portends poor survival due to early progression of disease or transformation to diffuse large B cell lymphoma (TFL). Progression of disease within 24 months (POD24) from front-line immunochemotherapy (ICT) identifies patients with a subsequent five-year OS of 50% compared to a reference group of 90% (Casulo et al. JCO 2015). Although a robust surrogate endpoint for OS in clinical trials (Casulo et al. Blood 2022), it remains to be established if the OS of patents is influenced by the nature of the HRDE. In this study, we examined whether characteristics and clinical trajectory of those with relapsed/progressive FL is the same as that of patients experiencing TFL. Methods: We conducted an international retrospective analysis of newly diagnosed FL patients requiring treatment across 14 academic centres between 2002 and 2021 in the era of rituximab and PET-CT staging. Patients were included with grade 1-3A FL requiring first-line (1L) treatment (ICT, rituximab monotherapy or radiotherapy). We excluded patients with untreated FL, de novo TFL and those with &amp;lt;24 months follow up provided they did not experience a HRDE. Baseline clinical, imaging and laboratory values, treatment details and outcomes were collected. We defined HRDE groups as persistent (relapse or progression) FL within 24 months of 1L treatment (FL24), early TFL (&amp;lt;24 months of 1L treatment) or late TFL (&amp;gt;24 months of 1L treatment). Patients not experiencing a HRDE formed the FL reference group. Landmark overall survival (OS) analysis was performed by Cox regression using risk status as a time-varying covariate for time of HRDE. For the FL reference group, landmark was defined at 24 months after 1L treatment. Results: 501 patients met the inclusion criteria and were categorised as: reference FL (n=378), FL24 (n=50), early TFL (n=28), late TFL (n=15). 24 patients who died within 24 months of 1L treatment without documentation of preceding HRDE and were omitted. Median follow up for patients alive beyond 24 months was 5.1 years. Median age at diagnosis was 60 years, 91% had ECOG performance status 0-1 and 38% were high-risk (&amp;gt;3) FLIPI. 1L chemotherapy regimens included: bendamustine (59%), CHOP (24%), CVP (8%), other (9%); a majority received rituximab (80%) vs obinutuzumab (20%). Maintenance therapy was used in 54% of pts. Expectedly, those experiencing HRDE had an inferior OS compared to the reference group (HR 5.23, p&amp;lt;0.001)(Figure 1). However, among HRDE group, median OS significantly differed: early TFL patients (3.0 yrs) and FL24 (12.6yrs)(HR 2.27, p=0.02) (Table 1). There was no difference in OS after HRDE between early TFL and late TFL ( p=0.81). Biopsy was performed in 84% of TFL cases with no difference in OS between biopsy-proven vs clinically suspected cases ( p=0.23). Multivariate OS analysis assessing HRDE and treatment demonstrated no significant interaction between HRDE group and 1L chemotherapy ( p=0.52), monoclonal antibody ( p=0.29) or maintenance therapy ( p=0.27). Several established prognostic features at baseline were enriched in patients who went on to experience HRDE including: ECOG &amp;gt;1 ( p&amp;lt;0.001), raised LDH ( p&amp;lt;0.001), advanced-stage disease (( p&amp;lt;0.011) and high risk FLIPI ( p=0.005). Baseline FDG-PET was available in 259 patients. Adverse PET metrics were enriched in only early TFL, and not FL24 or late TFL patients, including high SUV max( p=0.009), total metabolic tumor volume ( p=0.015) and total lesional glycolysis ( p=0.01). Conclusions: HRDEs after 1L treatment are associated with inferior OS in FL compared with standard-risk patients. Unlike POD24, this study demonstrates disparate clinical outcomes between patients experiencing early progression with persistent FL and those experiencing TFL. Adverse metabolic characteristics on baseline FDG-PET also suggest biological distinction between HRDE subsets. These findings have important implications for epidemiological studies, biomarker development and clinical trials aiming to improve outcomes in this underserved high-risk FL cohort.

The prognostic index PRIMA-PI combined with Ki67 as a better predictor of progression of disease within 24 months in follicular lymphoma.

Progression of disease within 24 months (POD24) is a risk factor for poor survival in follicular lymphoma (FL), and there is currently no optimal prognostic model to accurately predict patients with early disease progression. How to combine traditional prognostic models with new indicators to establish a new prediction system, to predict the early progression of FL patients more accurately is a future research direction. This study retrospectively analyzed patients with newly diagnosed FL patients in Shanxi Provincial Cancer Hospital from January 2015 to December 2020. Data from patients undergoing immunohistochemical detection (IHC) were analyzed using χ2 test and multivariate Logistic regression. Also, we built a nomogram model based on the results of LASSO regression analysis of POD24, which was validated in both the training set and validation set, and additional external validation was performed using a dataset (n = 74) from another center, Tianjin Cancer Hospital. The multivariate Logistic regression results suggest that high-risk PRIMA-PI group, Ki-67 high expression represent risk factors for POD24 (P<0.05). Next, PRIMA-PI and Ki67 were combined to build a new model, namely, PRIMA-PIC to reclassify high and low-risk groups. The result showed that the new clinical prediction model constructed by PRIMA-PI with ki67 has a high sensitivity to the prediction of POD24. Compared to PRIMA-PI, PRIMA-PIC also has better discrimination in predicting patient's progression-free survival (PFS) and overall survival (OS). In addition, we built nomogram models based on the results of LASSO regression (histological grading, NK cell percentage, PRIMA-PIC risk group) in the training set, which were validated using internal validation set and external validation set, we found that C-index and calibration curve showed good performance. As such, the new predictive model-based nomogram established by PRIMA-PI and Ki67 could well predict the risk of POD24 in FL patients, which boasts clinical practical value.

FDG-PET/CT Provides Clues on Bone Marrow Involvement in Follicular Lymphoma and Carries Important Prognostic Information.

Objectives: To compare the diagnostic efficacy of PET-CT and bone marrow biopsy (BMB) in the detection of bone marrow involvement (BMI) in newly diagnosed patients with follicular lymphoma (FL), as well as their prognostic implications in such patients. Methods: Retrospective analysis was conducted on clinical data from 165 newly diagnosed FL patients. The benefits and drawbacks of PET-CT and BMB in assessing BMI in FL patients were compared and evaluated. Moreover, the prognostic outcomes and factors affecting the survival of FL patients were examined. Results: Among 165 patients, bone marrow involvement (BMI) was diagnosed by PET-CT (PET+) in 54 cases (32.7%), by bone marrow biopsy (BMB+) in 50 cases (30.3%), and by either PET+ or BMB+ in 80 cases (48.5%). PET-CT scans upgraded 32 patients (19.4%) to stage IV, including 1 stage I and 4 stage II cases. Four patients were elevated to stage IV by BMB, all of whom had a previous stage III diagnosis. No patients with previous stages I or II were elevated to stage IV by BMB. The median follow-up time was 6.6 years (range,0-11.0 years). The 5-year OS was 86.7%, and the 5-year PFS was 44.8%. Multivariate analysis revealed that BMI by PET-CT was the only independent predictor of PFS reduction. Regarding OS, grade 3a and BMI by PET-CT were independent predictors of decreased survival. Conclusion: PET-CT enables a thorough evaluation of bone marrow involvement in patients with FL, and BMI identified by PET-CT can have substantially implications for patient prognosis. PET-CT obtains vital data for the diagnosis, treatment, and prognosis of FL patients. By contrast, BMB seldom augments crucial data.

Clinical features and outcomes of newly diagnosed follicular lymphoma concurrent with diffuse large B-cell lymphoma component

Objective: To explore the clinical features and survival of newly diagnosed follicular lymphoma (FL) patients with diffuse large B-cell lymphoma (DLBCL) component. Methods: 1845 newly diagnosed FL patients aged ≥ 18 years with grades 1-3a in 11 medical centers in China from 2000 to 2020 were included, and patients with DLBCL component were screened. The clinical data and survival data of the patients were retrospectively analyzed, and the prognostic factors were screened by univariate and multivariate analysis. Results: 146 patients (7.9% ) with newly diagnosed FL had DLBCL component. The median age was 56 (25-83) years, 79 males (54.1% ) . The pathology of 127 patients showed the proportion of DLBCL component. Patients were divided into two groups according to whether the proportion of DLBCL component was ≥ 50% . The study found that patients with DLBCL component ≥ 50% had higher grade 3 ratio (94.3% vs 91.9% , P=0.010) , Ki-67 index ≥ 70% ratio (58.5% vs 32.9% , P=0.013) and PET-CT SUVmax ≥ 13 ratio (72.4% vs 46.3% , P=0.030) than patients with DLBCL component<50% . All patients received CHOP or CHOP like ± rituximab chemotherapy. The overall response rate (ORR) was 88.2% , and the complete response (CR) rate was 76.4% . In the groups with different proportions of DLBCL component, there was no significant difference in the remission rate after induction treatment and the incidence of disease progression within 2 years after initiation of treatment (POD24) (P<0.05) . The overall estimated 5-year progression free survival (PFS) rate was 58.9% , and the 5-year overall survival (OS) rate was 90.4% . The 5-year OS rate of POD24 patients was lower than that of non POD24 patients (70.3% vs 98.5% , P<0.001) . Compared with non maintenance treatment of rituximab, maintenance treatment of rituximab could not benefit the 5-year PFS rate (57.7% vs 58.8% , P=0.543) , and the 5-year OS rate had a benefit trend, but the difference was not statistically significant (100% vs 87.8% , P=0.082) . Multivariate analysis showed that failure to reach CR after induction treatment was an independent risk factor for PFS (P=0.006) , while LDH higher than normal was an independent risk factor for OS (P=0.031) . Conclusion: FL patients with DLBCL component ≥50% have more invasive clinical and pathological features. CHOP/CHOP like ± rituximab regimen can improve the clinical efficacy of patients. Rituximab maintenance therapy can not benefit the PFS and OS of patients. Failure to reach CR after induction therapy was the independent unfavorable factor for PFS.

Baseline [18F]FDG PET/CT may predict the outcome of newly diagnosed follicular lymphoma in patients managed with initial "watch-and-wait" approach.

To investigate if baseline [18F]FDG PET/CT can predict the outcome of follicular lymphoma (FL) in patients managed with an initial "watch-and-wait" approach. Thirty-eight newly diagnosed FL patients who were managed with an initial "watch-and-wait" approach and undergone baseline [18F]FDG PET/CT were retrospectively enrolled. The standard uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of FL lesions were measured on PET/CT. Patients were followed up for at least 24 months or until initiation of FL therapy. The endpoint was the time to initiation of lymphoma treatment (TLT). After a median follow-up of 28 months (range 3-94 months), lymphoma treatment was initiated in 21/38 (55.3%) patients (median 15 months, range 3-51 months). Patients with TLT < 24 months showed SUVmax and TLG values significantly higher than those with TLT ≥ 24 months (p < 0.05). Receiver operating characteristic analysis demonstrated cutoff values of SUVmax > 9.5, MTV > 90.62 ml, and TLG > 144.96 SUVbw*ml were optimal for predicting TLT < 24 months. Kaplan-Meier analysis showed SUVmax > 9.5, MTV > 90.62 ml, and TLG > 144.96 SUVbw*ml had statistically significant correlations with shorter TLT (p < 0.01). Lymph node regions ≥ 3 and lymph nodes > 3 cm had almost significance (p < 0.1). In multivariate analysis, SUVmax > 9.5 (HR 3.2 [95% CI 1.1-9.2], p = 0.033) and TLG > 144.96 SUVbw*ml (HR 9.3 [95% CI 1.8-47.7], p = 0.008) were demonstrated to be independent predictive factors for shorter TLT. Metabolic indices (SUVmax and TLG) of baseline [18F]FDG PET/CT could predict the outcome independently in FL patients under an initial "watch-and-wait" approach. • "Watch-and-wait" approach is part of the overall treatment plan in asymptomatic patients with low tumor burden FL. However, the time to initiation of active treatment varies from months to years. • In our retrospective study of 38 patients with FL managed with an initial "watch-and-wait" approach, the SUVmax and TLG were demonstrated to be independent predictive factors for time to initiation of FL treatment. • Baseline [18F]FDG PET/CT may help to better select patients with FL who are most likely to benefit from "watch-and-wait" management.

Diagnostic value of baseline 18FDG PET/CT skeletal textural features in follicular lymphoma

At present, 18F-fluorodesoxyglucose (18FDG) positron emission tomography (PET)/computed tomography (CT) cannot be used to omit a bone marrow biopsy (BMB) among initial staging procedures in follicular lymphoma (FL). The additional diagnostic value of skeletal textural features on baseline 18FDG-PET/CT in diffuse large B-cell lymphoma (DLBCL) patients has given promising results. The aim of this study is to evaluate the value of 18FDG-PET/CT radiomics for the diagnosis of bone marrow involvement (BMI) in FL patients. This retrospective bicentric study enrolled newly diagnosed FL patients addressed for baseline 18FDG PET/CT. For visual assessment, examinations were considered positive in cases of obvious bone focal uptakes. For textural analysis, the skeleton volumes of interest (VOIs) were automatically extracted from segmented CT images and analysed using LifeX software. BMB and visual assessment were taken as the gold standard: BMB −/PET − patients were considered as bone-NEGATIVE patients, whereas BMB +/PET −, BMB −/PET + and BMB +/PET + patients were considered bone-POSITIVE patients. A LASSO regression algorithm was used to select features of interest and to build a prediction model. Sixty-six consecutive patients were included: 36 bone-NEGATIVE (54.5%) and 30 bone-POSITIVE (45.5%). The LASSO regression found variance_GLCM, correlation_GLCM, joint entropy_GLCM and busyness_NGLDM to have nonzero regression coefficients. Based on ROC analysis, a cut-off equal to − 0.190 was found to be optimal for the diagnosis of BMI using PET pred.score. The corresponding sensitivity, specificity, PPV and NPV values were equal to 70.0%, 83.3%, 77.8% and 76.9%, respectively. When comparing the ROC AUCs with using BMB alone, visual PET assessment or PET pred.score, a significant difference was found between BMB versus visual PET assessments (p = 0.010) but not between BMB and PET pred.score assessments (p = 0.097). Skeleton texture analysis is worth exploring to improve the performance of 18FDG-PET/CT for the diagnosis of BMI at baseline in FL patients.

Trial-in-Progress: Randomized Phase II Trial in Early Relapsing or Refractory Follicular Lymphoma (NCT#03269669): SWOG S1608

Trial-in-Progress: Randomized Phase II Trial in Early Relapsing or Refractory Follicular Lymphoma (NCT#03269669): SWOG S1608

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. [Display omitted] DisclosuresWang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

Survival Outcomes after First-Line Therapy in Follicular Lymphoma Patients Treated with Bendamustine and Rituximab Vs Other Rituximab Combinations in the United States

Background: Follicular lymphoma (FL) is a heterogeneous disease, and clinical presentation is highly variable. The Follicular Lymphoma International Prognostic Index (FLIPI-2) identifies prognostic factors at diagnosis, but does not predict in whom and when to initiate first-line therapy (1LT) (Federico 2009). Recommended therapies for 1LT vary by stage, symptomatology, and tumor burden, but include monotherapy with rituximab (R) or in combination with other chemotherapies. Survival of FL patients in the R era has greatly improved, but few studies have evaluated survival outcomes in patients seen in routine clinical care. This study aimed to evaluate survival outcomes in a United States (US) population of newly diagnosed FL patients seen in routine clinical care.Methods: A retrospective study was conducted in which the presence of ≥1 inpatient record or ≥2 outpatient records with FL diagnosis codes were used to identified newly diagnosed FL patients from Humedica, a large US electronic medical record database, between 01/01/08 and 07/31/15. The study index date was the first FL record. Patients who subsequently initiated 1LT with bendamustine+R or other R-based combinations were followed from the date of treatment initiation until death, loss to follow-up, or end of study (09/30/15) for the evaluation of the survival outcomes. Median progression-free survival (PFS) (defined as initiation of second-line therapy, evidence of supportive care >30 days after the end of a line of therapy, or death), median overall survival (OS), and PFS and OS rates at 2 years following initiation of 1LT were evaluated using Kaplan-Meier analyses. Cox proportional hazard models were used to further assess the impact of bendamustine+R and other R-based combinations on OS and PFS at 2 years.Results: 1,346 newly diagnosed FL patients who initiated 1LT met the patient selection criteria; of these, 362 and 417 received bendamustine+R and other R-based combinations, respectively. The majority of the other R-based combinations were R-CHOP (48.7%) and R-CVP (25.4%). The mean age (bendamustine+R, 65.3 [SD: 11.5] and other R-based combinations, 65.0 [SD: 11.6]) and proportion of males (bendamustine+R, 48.9% and R-based combinations, 48.0%) were similar between the two treatment groups. At baseline, 19.3% of patients treated with bendamustine+R and 15.3% of patients treated with other R-based combinations had a Charlson Comorbidity Index of ≥2. Unadjusted Kaplan-Meier analysis revealed that for patients treated with bendamustine+R and R-based combinations, 2-year OS rates were 90.2% and 86.2% (P=0.0916), respectively, and 2-year PFS rates were 76.7% and 56.0% (P <0.0001), respectively. Median OS was not reached in both treatment groups, and median PFS was not reached in the bendamustine+R and was 36.4 months (95% CI: 24.3, 47.3) for patients treated with other R-based combinations. In the adjusted, no significant difference was observed between the two treatment groups for the 2-year OS; however, the bendamustine+R when compared to the other R-based combinations had a lower hazard for progression at 2 years (0.42; 95% CI: 0.31, 0.58).Conclusion: In routine clinical practice, patients treated with bendamustine+R in 1LT had significantly better 2-year PFS than patients treated with other R-based combination therapy, while OS was similar between the groups. These results are similar to that of the clinical trial comparing bendamustine plus rituximab and R-CHOP, where PFS was found to be significantly better with bendamustine plus rituximab and OS was similar (Rummel 2009). DisclosuresGalaznik:Takeda Pharmaceuticals: Employment, Equity Ownership. Bell:Takeda Pharmaceuticals: Employment, Equity Ownership. Hamilton:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; Xcenda: Employment. Ogbonnaya:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; Xcenda: Employment. Hennenfent:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; Xcenda: Employment. Eaddy:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; Xcenda: Employment. Shou:Takeda Pharmaceuticals: Employment, Equity Ownership.

Treatment Patterns in Newly Treated and Relapse/Refractory Patients with Follicular Lymphoma in Routine Clinical Care — a United States Electronic Medical Record Database Study

Background: Follicular lymphoma (FL) represents 70% of all indolent non-Hodgkin lymphomas and it is widely recognized that FL is a heterogeneous disease, with patients presenting with differing amounts of tumor burden and prognostic indicators. The NCCN guideline recommends using rituximab (R) as a single-agent or in combination with other chemotherapies as first-line therapy (1LT) or second-line therapy (2LT). No recommendations are provided beyond 2LT. The aim of our study was to evaluate first-, second-, and third-line treatment patterns and associated response in patients with newly diagnosed FL in routine care in the United States (US).Methods: Newly diagnosed FL patients aged ³18 years were selected from Humedica, a large, national US electronic medical record database between 01/01/08 and 07/31/15 if they had ≥1 inpatient record or ≥2 outpatient records with FL diagnosis codes. The date of the first FL record was the index date. Patients were followed from index date until end of continuous activity, progression to diffuse large B-cell lymphoma, death, or end of study period (09/30/15), and were evalauted for FL treatment patterns and treatment response. Possible remission was defined as no additional chemotherapy and no supportive care use or receipt of supportive care <30 days after end of line of therapy (LOT) for <30 days. Lack of remission was defined as receipt of supportive <30 days after end of LOT for >30 days. Progression was defined as initiation of another LOT, transition to DLBCL, or evidence of supportive care >30 days after end of LOT.Results: Of the3,756 patients selected into the study, 1,346 (35.8%) initiated 1LT and median (interquartile range [IQR]) time to therapy was 1.3 (0.5-5.9) months. Overall, treatment regimens were mainly R-based. In 1LT, more patients initiated combination chemotherapy (61.4%) vs single-agent chemotherapy (38.6%). Bendamustine+R (43.8%), R-CHOP (25.5%), R-CVP (12.8%) were the most common combination regimens and R (85.8%) was the most common single-agent. Median (IQR) duration of 1LT was 4.3 (1.7-10.4) months. At the end of the 1LT, 54.7% (n=736) had evidence of remission, 25.5% (n=344) progressed, and 1.6% (n=22) had no evidence of remission. 201 initiated 2LT; 34.3% received a single-agent and 65.7% received combination chemotherapy. 2LT regimens were similar to the 1LT, with R (55.1%) remaining the top single-agent, while bendamustine+R (39.4%), R-CHOP (9.8%), and R-CVP (12.8%) remained the top combinations. Median (IQR) duration of 2LT was 3.6 (1.4-6.1) months. Of patients receiving 2LT, 41.3% (n=83) had evidence of remission, 35.4% (n=71) progressed, and 1.5% (n=3) had no evidence of remission. 45 patients received third-line therapy (3LT); 35.6% received a single-agent, while 64.4% received combination chemotherapy. In 3LT, R (31.2%) was the most common single-agent; bendamustine+R (31.1%) was the most common combinations. Median (IQR) duration of 3LT was 2.8 (1.4-4.7) months. Following the 3LT, 26.7% (n=12) had evidence of remission, 39.9% (n=18) progressed, and 4.4% (n=2) had no evidence of remission.CONCLUSIONS: FL treatment in routine clinical care aligns with treatment guidelines in 1LT and 2LT, with most patients receiving R-based combination chemotherapy. Similar regimens were used in the 3LT setting. As expected, the rates of remission decreased with subsequent LOTs. With similar treatments being used in newly diagnosed and relapse/refractory patients, newer treatment options are needed to provide alternative options for patients who do not benefit from currently available treatments. DisclosuresGalaznik:Takeda Pharmaceuticals: Employment, Equity Ownership. Bell:Takeda Pharmaceuticals: Employment, Equity Ownership. Hamilton:Xcenda: Employment; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy. Ogbonnaya:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; Xcenda: Employment. Hennenfent:Xcenda: Employment; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy. Eaddy:Xcenda: Employment; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy. Shou:Takeda Pharmaceuticals: Employment, Equity Ownership.

Prognostic relevance of CD4+ T-cells in the microenvironment of newly diagnosed follicular lymphoma (FL) patients is independent of the tumor gene expression profile.

8052 Background: A significant proportion of patients with FL experience an early relapse and a subsequent poor outcome. While several prognostic indices have been developed, none were designed to predict early failure. Recently, we established that lack of intrafollicular CD4+ T-cell expression predicted risk of early failure, and integrating this microenvironment biomarker with the Follicular Lymphoma International Prognostic Index, termed BioFLIPI, further improved identification of FL patients at risk of early failure ( Blood 2019;134(suppl1):121). However, the microenvironment may be influenced by the genetic composition of tumor. We investigated whether the CD4 biomarker and BioFLIPI were impacted by genetic features of the tumor as assessed by a 23-gene expression prognostic score ( Lancet Oncol 2018;19:549-61). Methods: Of the 186 cases with FL grade 1-3A treated with immunochemotherapy (IC) in our prior study, 152 had digital expression quantification of 23 selected genes (23-GEP score), which used RNA from formalin-fixed, paraffin-embedded samples. Event-free survival (EFS) was defined as time from diagnosis to progression, relapse, retreatment, or death. Early failure was defined as failing to achieve EFS at 24 months. Risk of early failure was estimated using odds ratios (ORs) and 95% confidence intervals from logistic regression models. We also used Cox regression to assess associations with continuous EFS and overall survival (OS). Results: 28% of patients failed to achieve EFS24. Lack of CD4+ intrafollicular expression (38% of patients, OR = 2.33, p = 0.024) and high risk 23-GEP score (26% of patients, OR = 3.52, p = 0.001) each predicted early failure, and in a multivariable model that included FLIPI, both CD4+ (OR = 2.26, p = 0.046) and 23-GEP score (OR = 2.26, p = 0.0.057) remained predictors. Similarly, BioFLIPI modeled as a continuous score (1-4, OR per one point increase = 2.31, p &lt; 0.001) predicted early failure, and the association remained (OR = 2.14, p &lt; 0.001) when the high risk 23-GEP score (OR = 2.79, p = 0.013) was included in the model. When stratified on 23-GEP score, BioFLIPI was a stronger predictor of early failure in low risk (74%, OR = 2.51, p = 0.002) relative to high risk (26%, OR = 1.55, p = 0.27) patients. Similar patterns were observed for EFS and OS. Conclusions: CD4+ T-cell infiltrate and tumor gene expression appear to be independently predictive of early failure in newly diagnosed FL patients treated with IC. Future studies should integrate and validate these measures.

Intrafollicular CD4+ T-Cells As an Independent Predictor of Early Clinical Failure in Newly Diagnosed Follicular Lymphoma

Intrafollicular CD4+ T-Cells As an Independent Predictor of Early Clinical Failure in Newly Diagnosed Follicular Lymphoma

A Phase II Study of Lenalidomide Plus Rituximab in Patients with Newly Diagnosed Follicular Lymphoma: An Interim Analysis

A Phase II Study of Lenalidomide Plus Rituximab in Patients with Newly Diagnosed Follicular Lymphoma: An Interim Analysis Zhong Zheng1, Li Wang1,2, Shu Cheng1, Peng-Peng Xu1, Wei-Li Zhao1,2 1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China Abstract Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (iNHL). Rituximab plus chemotherapy for FL significantly improves the outcome of the patients, nevertheless, most patients ultimately relapse. Therefore, novel agents along with Rituximab have been applied to increase treatment efficacy in this subset of iNHL patients. Tumor immune eascape plays a crucial role in lymphoma progression. Through modulating tumor microenvironment, lenalidomide, are emerging as effective therapeutic approaches to affect tumor immunity and inhibit lymphoma cells proliferation. However, its anti-tumor activity activity has not yet been assessed in de-novo chinese FL patients. This prospective phase II study is to evaluate the efficacy and safety of lenalidomide in combination with Rituximab (R2) in newly diagnosed FL patients (NCT 03715309). Methods: Patients with newly diagnosed FL (grade 1 to 3a), aged 16 to 75 years, Eastern Cooperative Oncology Group performance status of 0 to 2 are enrolled. The doses and administration schedule are as follows: rituximab 375 mg/m2 on day 0, lenalidomide 25mg from day 1 to day 10 every 3 weeks for 6 cycles. The primary endpoint is complete response (CR) rate assessed by PET-CT, and secondary endpoints include progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and main adverse events (AEs). Results: To date, eighty-six patients have been enrolled, with median age of 48 years (range, 22-73). At diagnosis, Seventy-seven patients (89.5%) presented advanced Ann Arbor stage and 19 cases (22.0%) showed elevated serum LDH level. Twenty-nine patients (33.7%) had multiple extra-nodal sites involving bone marrow, bone, gastrointestinal, and spleen. Twenty-one patients (24.4%) had IPI scores ≥ 3. For Sixty-four patients available for response evaluation, the CR rate was 81.2% (52/64) and the ORR was 90.1% (58/64). Grade 3-4 neutropenia was found in 18 cases (20.9%). No grade 3-4 thrombocytopenia and grade 3-4 anemia were observed. For non-hematological AEs, cutaneous reactions and tumor flare reaction were observed in 12 cases (13.9%) and in 1 case (1.16%), respectively, while no grade 4 non-hematological AEs were presented. Conclusion: Lenalidomide Plus Rituximab as first-line therapy for de novo patients with FL showed encouraging response and good tolerability. Disclosures No relevant conflicts of interest to declare.

Indolent Lymphoma and Vitamin D (ILyAD): A Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Supplemental Effect of Vitamin D on Event-Free Survival in Patients with Low Tumor Burden Indolent Non-Hodgkin Lymphoma Treated with Rituximab

Indolent Lymphoma and Vitamin D (ILyAD): A Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Supplemental Effect of Vitamin D on Event-Free Survival in Patients with Low Tumor Burden Indolent Non-Hodgkin Lymphoma Treated with Rituximab

Identification of Patients with Follicular Lymphoma Patients at Risk of Failing Frontline Immunochemotherapy and Rituximab Maintenance

Introduction:Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma that represents 15-30% of all newly diagnosed lymphomas. It is characterized by a high rate of response followed by continuous relapses being considered incurable with standard immunochemotherapy regimens (Ardeshna et al. Lancet. 2003). The combination of immunochemotherapy and rituximab maintenance (Rm) improves progression free survival (PFS) when compared with a cohort without Rm (51% vs 35%) (Salles G. et al. ASH, 2017), being the standard for many centers. This improvement may have changed the risk assessment in FL. However, there is a need for identifying those patients with a poor prognosis with standard Rm-based therapy and candidates to receive alternative approaches using new drugs such as obinutuzumab with better reported results in this frontline setting (Gallium trial) (Marcus et al., 2017).Methods:From February-2002 to October-2016, all newly diagnosed FL patients with the intention to treat with immunochemotherapy and Rm where included. The participant centers were Son Espases University Hospital and Hospital del Mar of Barcelona. Clinical data were retrospectively collected from clinical histories and standard prognostic variables were evaluated at diagnosis including FLIPI and FLIPI-2. Another prognostic markers were defined: POD12 (progression of disease at 12 months), POD24 (progression of disease at 24 months) and POD30 (progression of disease at 30 months). The regimen effectiveness was evaluated based on the CT or PET/CT findings. Overall survival (OS) and PFS were determined from the date of the first cycle and they were estimated through Kaplan-Meier.Results:A total of 96 patients were included in the study with a median follow-up of 68 months. Main characteristics of the sample are shown in Tables 1. Briefly, median age was 61 years old, 88% where diagnosed in an advanced stage (III-IV), 36% and 38% presented with high risk (3-5) FLIPI and FLIPI2. Five-year OS and PFS was of 94% and 78% respectively. Univariate survival analysis proved that ECOG and response rate affected PFS and that stage and response influenced OS. In this analysis, no significant relation was found between the studied variables and POD12, POD24 or POD30 except beta2-microglobuline in POD30.Conclusions:•Frontline Rm significantly improves outcomes of FL patients.•It seems that it is not possible to predict only with clinical variables which patients are in high risk of failure to a standard approach with immunochemotherapy followed by Rm.•Additional prognostic factors such as molecular markers may help to identify these patients at risk of failure at the beginning of a first line of immunochemotherapy followed by Rm, and candidates for alternative approaches. DisclosuresNo relevant conflicts of interest to declare.

Responses and Cardiotoxicity with R-CDOP and R-CHOP Observed in Frontline Therapy for Patients with Primary Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL): A Randomized Phase-IV Study from Multiple Centers in China

Introduction: Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most common types of B-cell non-Hodgkin's lymphoma (B-NHL). R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is the frontline treatment for primary DLBCL and FL. Pegylated liposomal doxorubicin (PLD) is the liposome formulation of doxorubicin. R-CDOP, in which PLD was used to substitute for doxorubicin, has been recommended for patients with poor cardiac function. This study was aimed to elucidate the therapy responses and cardiotoxicity with R-CDOP and R-CHOP observed in frontline treatment of patients with primary DLBCL and FL.Methods: From January 2015 to January 2018, 77 newly diagnosed DLBCL and 25 newly diagnosed FL patients were treated with R-CDOP or R-CHOP regimen randomly. Among the 102 patients, 67 cases were treated with R-CDOP and 35 cases received R-CHOP therapy. The regimen of R-CDOP or R-CHOP consisted of Rituximab 375 mg/m2 on cycle day 0, and along with Cyclophosphamide 750 mg/m2, PLD 35 mg/ m2 or Epirubicin 70 mg/m2 (substituting for Doxorubicin), Vindesine 3.0 mg/m2 on cycle day 1 and Prednisone 100mg/d from day1 to day5 of each cycle. This regimen was implemented every 21 days approximately. After 3 cycles, tumor response were assessed and classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to the Cheson criteria. Cardiac function was also evaluated, including N-terminal pro B-type natriuretic peptide (NT-proBNP), left ventricular ejection fractions (LVEF) and myocardial enzymes. Patients with a therapeutic assessment of CR/PR received another 3 cycles of R-CDOP or R-CHOP regimen. Patients whose responses were evaluated for SD/PD were withdrawn from our study. After 6 cycles, tumor responses and cardiac functions were assessed again. Then the patients were followed up every three months up to 9 months or till PD. The analyses of data were performed using SAS (statistical analysis system) 9.3. Repeated measurement of variance analysis was used to determine the statistical significances of rate differences between R-CDOP group and R-CHOP group. Other statistical data analyses were performed using the two-tailed Student's t test. All differences were considered to be statistically significant when the P value was less than 0.05.Results: The clinical characteristics were summarized in Table 1. All the patients were randomized to one of the two treatment arms. Baseline characteristics had no significant difference between the two groups. The follow up time was range from 3 to 9 months. In R-CDOP group, the CR/PR ratio was higher than that in R-CHOP group (P<0.05, Table 2). For DLBCL patients, CR/PR ratio in R-CDOP group was also higher that in R-CHOP group (P<0.05, Table 3.1). However, for FL patients, only CR ratio in R-CDOP group was higher than that in R-CHOP group (P<0.05, Table 3.1). For young patients (age≤60 years) and patients whose stage was I/II, CR/PR ratio in R-CDOP group was also higher than that in R-CHOP group (P<0.05, Table 3.2 and 3.3). However, for old patients (age> 60years) and patients whose stage was III/IV, the CR/PR ratio in R-CDOP group and R-CHOP group showed no statistical difference (Table 3.2 and 3.3).NT-proBNP, LVEF and myocardial enzymes were measured to evaluate cardiac function. Our study showed that NT-proBNP levels had significant difference after 3 and 6 cycles treatment between R-CDOP group and R-CHOP group (62.7±44.8 pg/ml, n=29 vs. 101.0±65.0 pg/ml, n=26 and 55.6±35.6 pg/ml, n=25 vs. 103.20±57.7 pg/ml, n=25, P<0.05). Surprisingly, the difference between these two groups disappeared in follow-up period. LVEF (0.66±0.02, n=18 vs. 0.64±0.01, n=12) and myocardial enzymes, including creatine kinase (CK, 65.1±25.1 U/L, n=27 vs. 127.6±64.1 U/L, n=20) and creatine kinase isoenzyme CKMB (8.0±2.5 ng/ml, n=24 vs. 14.9±9.3 ng/ml, n=17), were found to have significant differences in R-CDOP group and R-CHOP group at 9 months after the last cycle (P<0.05).Conclusions: Our findings in this study indicated that the R-CDOP regimen offers superior oncologic efficiency when compared to standard R-CHOP regimen in primary DLBCL and FL patients. This study also showed that the substitution of conventional doxorubicin by PLD was a safer therapeutic option for patients' cardiac function. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.