High Tumor Burden Follicular Lymphoma Research Articles

Impact and utility of follicular lymphoma GELF criteria in routine care: an Australasian Lymphoma Alliance study.

Follicular lymphoma (FL) treatment initiation is largely determined by tumor burden and symptoms. In the pre-rituximab era, the Group d'Etude des Lymphomes Folliculaires (GELF) developed widely adopted criteria to identify high tumor burden FL patients to harmonize clinical trial populations. The utilization of GELF criteria (GELFc) in routine therapeutic decision- making is poorly described. This multicenter retrospective study evaluated patterns of GELFc at presentation and GELFc utilization in therapeutic decision-making in newly diagnosed, advanced-stage rituximab-era FL. Associations between GELFc, treatment given, and patient survival were analyzed in 300 eligible cases identified between 2002-2019. One hundred and sixty-three (54%) had ≥1 GELFc at diagnosis. The presence or cumulative number of GELFc did not predict progression-free survival in patients undergoing watch-and-wait (W&W) or those receiving systemic treatment. Of interest, in patients with ≥1 GELFc, 16 of 163 (10%) underwent initial W&W (comprising 22% of the W&W cohort). In those receiving systemic therapy +/- radiotherapy, 74 of 215 (34%) met no GELFc. Our data suggest clinicians are using adjunctive measures to make decisions regarding treatment initiation in a significant proportion of patients. By restricting FL clinical trial eligibility only to those meeting GELFc, reported outcomes may not be applicable to a significant proportion of patients treated in routine care settings.

Potent CD8+ T-Cell Proliferation and Effector Differentiation Following Subcutaneous (SC) Mosunetuzumab Administration in Patients with Untreated, High Tumor-Burden Follicular Lymphoma (FL)

Introduction: Bispecific antibodies (BsAb) have emerged as a potent therapeutic option for patients with B-cell non-Hodgkin lymphoma, including FL. These drugs leverage endogenous CD3+ T-cells to enable cytotoxic tumor cell killing. While their mode of action has been hypothesized in in vitro and animal models, the mechanisms by which these drugs promote both initial and long-term immune-dependent disease control remains unknown. We recently initiated a multicenter phase 2 trial of the CD20xCD3 BsAb mosunetuzumab (mosun) as first-line therapy for patients with high-burden FL (NCT05389293). As part of this study, we performed serial sampling of both blood and lymph node tissues in order to elucidate T-cell changes associated with response and outcome. Here we present the first analysis of peripheral blood immune profiling. Methods: Patients with untreated, high-burden stage 2-4 FL in need of treatment received SC mosun at the dose of 5 mg on D1 and 45 mg on D8 and D15 of C1, and 45 mg on D1 of each subsequent 21-day cycle. Peripheral blood samples were obtained on C1D1, C1D8, C1D15, C2D1, C3D1, C5D1, and end of treatment (EOT, 24w from C1D1). Peripheral blood mononuclear cells (PBMCs) and plasma were isolated and cryopreserved. Samples were later thawed in batches and processed as follows: CITE-Seq + single-cell TCR sequencing was performed on viable CD11b-/CD19-/CD56-/CD3+ T-cells using the 10x Genomics Single Cell Immune Profiling Platform. RNA was extracted from 1 x 10 6 viable PBMCs using TriZol, followed by phenol/chloroform-based extraction, followed by bulk TCR sequencing using an in-house platform developed by MSKCC's Integrated Genomics Operation. The remaining cells were stained with antibodies targeting CD45RA, CD8, CD45, CD45RO, CD38, CD27, CD28, CXCR3, LAG-3, CD3, CD4, HLA-DR, CXCR5, CCR6, CD56, CD11b, CD19, CD39, PD-1, OX40, Tim-3, CCR4, Granzyme B, T-bet, FoxP3, Ki-67, and CTLA-4 and analyzed using a Cytek Aurora Spectral Cytometer. Flow cytometry analysis was performed using OMIQ. Statistical analyses were performed using a paired t-test. Results: A total of 45 samples obtained from 8 patients were analyzed, including samples from C1D1 (8), C1D8 (6), C1D15 (3), C2D1 (7), C3D1 (8), C5D1 (6), and EOT (7). High dimensional clustering of spectral cytometry data using the FlowSOM algorithm revealed 9 clusters of CD8+ T-cells corresponding to known CD8+ T-cell subsets. Among these subsets, we observed two distinct temporal patterns of CD8+ T-cells within the blood. On C1D8 there was a profound drop in circulating effector CD8+ T-cells as well as terminally differentiated CD8+ Temra cells (Figure 1), with a corresponding enrichment of naïve CD8+ T-cells (Figure). We also observed significant proliferation of newly activated T-cells on C1D8, followed by expansion of CD8+ T-cells expressing several activation and exhaustion markers including PD-1, Tim-3, and CD39, peaking on C2D1 (Figure 2). CD4+ T-cell responses were more modest with a small early increase in CD28+OX40+PD-1+ CD4+ T-cells on C1D8 and a drop in circulating GzmB+OX40+ CD4+ T-cells on C1D15. Conclusion: SC mosun therapy for newly diagnosed FL was associated with a unique peripheral blood immune profile, with early mobilization of pre-differentiated CD8+ T-cell effector cells and subsequent activation and expansion of newly primed CD8+ T-cells. Further immune phenotyping, including scRNA-seq and TCR clonal dynamics in the peripheral blood over time, as well as TCR clonality of distinct CD8+ and CD4+ T-cell populations are currently being analyzed on these and additional samples, and will be presented in detail.

Subcutaneous (SC) Mosunetuzumab (mosun) As First-Line Therapy for Patients (pts) with High Tumor-Burden Follicular Lymphoma (FL): First Results of a Multicenter Phase 2 Study

Introduction: Cytotoxic chemotherapy plus anti-CD20 antibodies is the current standard of care for pts with newly diagnosed high-burden FL. While effective, this approach is burdened by toxicities, including infections and second cancers, and up to 20% of pts progress within 2 years and have poor outcomes. Intravenous (IV) mosun is a CD20xCD3 bispecific antibody recently approved for the treatment of pts with relapsed or refractory FL based on remarkable efficacy data, and its activity may be even greater in chemotherapy-naïve patients. Furthermore, SC mosun proved as effective as, and possibly better tolerated than, the IV formulation while increasing administration efficiency and convenience. Here, we present the first results of a phase 2 multicenter trial of SC mosun in patients with untreated high-burden FL. Methods: Key eligibility criteria included: Age ≥18 years, stage 2-4 FL in need of therapy per GELF criteria, being fit for chemoimmunotherapy, adequate bone marrow and organ function. SC mosun was administered at the dose of 5 mg on D1 and 45 mg on D8 and D15 of C1, and 45 mg on D1 of each subsequent 21-day cycle. Premedication consisted of dexamethasone, diphenhydramine, and acetaminophen before each mosun dose during C1 and on C2D1 if cytokine release syndrome (CRS) occurred in C1. Subjects with ≥3 CRS risk factors (stage 3-4, bulky disease, bone marrow (BM) involvement, elevated LDH) received dexamethasone 10 mg for 3 days with each mosun dose in C1 and C2. Prophylactic hospitalization was not required. Treatment lasted 8 cycles in pts who achieved complete response (CR), and up to 17 in those with partial response. Response was assessed per the Lugano 2014 and LYRIC 2016 criteria. BM evaluation was mandated in pts with baseline BM involvement who achieved radiographic CR. CRS and neurotoxicity were graded per the 2019 ASTCT criteria. Results: Between July 2022 and July 2023, 43 pts were enrolled. Median age was 55 years (range 26-77), 40% of pts had bulky disease (≥7 cm), 25% had grade 3A FL, and 27% had a FLIPI score ≥3. The median SUV max was 11.5 (range 3.7-41.1)(Table). At the cutoff date of 07/21/2023, 4 pts were in screening, 22 were on treatment, and 13 completed treatment. Four pts discontinued therapy early due to progressive disease (1), or adverse events (AE) (3, one related to study drug). Out of 230 patient-cycles administered, 9 (4%) were delayed due to AEs, by a median of 13 days (range 7-17). Among 39 safety-evaluable pts, the most common treatment-emergent AE were injection site reaction (72%, all G1), CRS (51%), fatigue (33%), dry skin (33%), skin rash (26%), ALT elevation (23%), and AST elevation (21%). G≥3 neutropenia occurred in 4 pts (10%), while infections occurred in 10 pts (26%), and were G1-2 in 8 cases and G3 in 2 cases. One pt died of cardiac arrhythmia in the setting of COVID19-associated pneumonia. CRS occurred most commonly after C1D1 and was G1 in 18 pts (90%) and G2 in 2 (10%). Median time to onset of the first CRS episode was 31h (2-91). Hospitalization and tocilizumab were only required in the two pts who experienced G2 CRS. Twenty-six pts were evaluable for response (1 had concurrent neoplasm at first response assessment, 1 had indeterminate response (IR)3 per LYRIC criteria, and 15 are yet to be evaluated). The best overall response rate was 96% and the CR rate was 81%. All 22 CR were seen at the first response assessment (Figure). Similar response rates were observed among higher-risk subgroups, including pts with high-risk FLIPI (figure), grade 3A FL (ORR 100%, CR 75%), bulky disease (ORR 100%, CR 82%), or SUVmax ≥13 (ORR 83%, CR 83%)). At a median follow-up for response-evaluable pts of 6.0 months, 2 pts have experienced progression, one with CD20-negative FL at the end of therapy, the other with DLBCL diagnosed 6 weeks after treatment initiation on a left axillary lymph node with baseline SUV 41 and not previously biopsied. Conclusion: SC mosun demonstrated a manageable safety profile and highly encouraging efficacy in pts with newly diagnosed high-burden FL, including those with higher-risk disease. Assessment of durability of responses will require additional follow-up. Enrollment continues and updated data will be presented.

Outpatient administration of mosunetuzumab in US community practice settings: perspectives and learnings from the Phase II MorningSun study

Outpatient administration of mosunetuzumab in US community practice settings: perspectives and learnings from the Phase II MorningSun study

A Phase II Investigator Initiated Study of Acalabrutinib, Lenalidomide and Rituximab (aR2) in Patients with Previously Untreated High Tumor Burden Follicular Lymphoma

Background: The efficacy of lenalidomide and rituximab (R2) is comparable to chemoimmunotherapy in patients with previously untreated follicular lymphoma (FL). We previously reported pro-tumoral macrophage enrichment may be associated with resistance to R2. As pre-clinical studies show that BTK inhibition can mitigate the crosstalk between macrophages and FL B cells, we hypothesized that acalabrutinib, a specific BTK inhibitor, may synergize with R2 without increasing toxicity. In agreement with this, the combination of acalabrutinib and R2 (aR2) was shown to be safe and effective in patients with relapsed FL. Methods: This phase 2 single arm study (NCT04404088) was conducted between 09/2020 and 09/2021 (data cutoff 02/2023). Adult patients with previously untreated FL, grade 1 to 3A, stage 3–4, and with high tumor burden (per GELF criteria) were included. Dosing included acalabrutinib 100 mg PO twice a day in a 28-day cycle for 13 cycles, lenalidomide 20 mg PO daily on days 1–21, starting from cycle 2, and rituximab 375 mg/m2 IV weekly during cycle 2, and on day 1 of subsequent cycles. Response was assessed per Lugano 2014 criteria. The primary endpoint was best complete response (CR) rate, and an exact binomial test was used for sample size calculation (N = 24; H0 50%, HA 80%, power 80%, 2-sided alpha level 0.05). Results: Twenty-four patients were enrolled. Median age was 62 years (range, 40–82), 18 (75%) were male; median largest lymph node size was 6.2 cm (range, 1.9–15), median SUVmax was 14 (range, 6–36), and 17 (61%) patients had an intermediate-high FLIPI. Median number of cycles was 13 (range, 6–13) and 15 (62.5%) patients experienced a cycle delay, due to COVID-19 in 11 (46%) cases; 6 (25%) patients required dose reduction of lenalidomide, but none discontinued, and 2 (8%) required dose reduction of acalabrutinib and 1 discontinued. The most common (>5% of patients) grade 3–4 adverse events were neutropenia (58%), liver function test elevation (17%), infection (12.5%; 2 out of 3 related to COVID-19), anemia (8%) and skin rash (8%). Best ORR was 100% and best CR rate was 92%, as early as after 6 cycles (Figure). After a median follow-up of 22 months (95% CI: 20–24 months), 4 patients had disease progression, including 2 who transformed at 5 and 7 months, while in partial response (both with pre-treatment bulky disease and SUVmax >17), and 1 who transformed at end of treatment, after initial CR. The 2-year PFS rate was estimated at 79% (95% CI, 56%–91%). At data cutoff, 2 patients have died, 1 due to COVID-19 (while in CR, at 14 months) and 1 due to transformed lymphoma (at 10 months), both 4 months after study discontinuation. The 2-year OS rate was estimated at 92% (95% CI, 71%–98%) (Figure). Encore Abstract - previously submitted to EHA 2023 The research was funded by: Astrazeneca Keyword: Targeting the Tumor Microenvironment Conflicts of interests pertinent to the abstract. P. Strati Consultant or advisory role: PS served on advisory boards for Astrazeneca Research funding: PS received research funding from Astrazeneca for this study

COMBINING BASELINE TOTAL METABOLIC TUMOR VOLUME AND BETA‐2‐MICROGLOBULIN LEVELS PREDICTS OUTCOMES IN HIGH BURDEN FOLLICULAR LYMPHOMA

Introduction: Follicular lymphoma (FL) usually presents an indolent course with repeated events of disease progression but treatment-free time intervals and patients’ survival are reduced at each relapse. Many prognostic scores exist but few are used in practice due to their complexity. Total metabolic tumor volume (TMTV) has demonstrated a strong prognostic value in FL and its routine use is increasing in academic centers. We aim to explore the predictive value of a simple prognostic score based on TMTV and beta-2-microglobulin (B2M) levels at baseline in high tumor burden FL to identify patients with the highest unmet medical need. Methods: In this monocentric retrospective analysis, we enrolled adult patients admitted to our hospital between 2006 and 2018 and fulfilling the following inclusion criteria: grade 1 to 3A FL with at least one high tumor burden criteria defined by the Groupe d'Etude des Lymphomes Folliculaires (GELF), available PET-CT images collected before first-line standard immunochemotherapy start and suitable for TMTV assessment. Baseline TMTV was determined using the 41% SUVmax threshold method. B2M levels were routinely measured at diagnosis. Primary endpoints were progression-free survival (PFS) and overall survival (OS) according to a score combining TMTV and B2M. Results: We included 126 FL patients in this analysis. Median age at time of treatment was 61 years (55; 57). Patients displayed advanced-stage disease (n = 112, 88.9%), intermediate (n = 51, 40.8%) or high (n = 62, 49.6%) FLIPI and intermediate (n = 40, 33.3%) or high (n = 31, 25.8%) PRIMA-PI scores. Median baseline SUVmax and TMTV were 12.1 (10; 17) and 606 mm3 (268;1219), respectively. Baseline B2M levels were measured for 125 (97%) patients and >3 mg/L in 30 (24%). Treatment regimens used were mostly R-CHOP like (n = 109, 86.5%) and R-lenalidomide (n = 9, 7.1%). 80 patients (63.5%) received a maintenance therapy during 24 months. We defined three risk categories : (i) Low risk (n = 45, 36%): TMTV ≤510 mm3 and B2M ≤3 mg/L; (ii) Intermediate risk (n = 57, 45.6%) : TMTV >510 mm3 or B2M >3 mg/L ; (iii) High risk (n = 23, 18.4%) : TMTV >510 mm3 and B2M >3 mg/L. With a median follow-up of 83 (52; 116) months, the 5-year PFS was 81.7% (95% CI: 71–94), 53.7% (95% CI: 41.8–69) and 38.6% (95% CI: 23–65) in the low, intermediate and high risk groups, respectively (p < 0.0001). Five-year OS was based on 14 deaths and estimated at 96.1% (95% CI: 91–100), 89.1% (95% CI: 81.2–97.7) and 73.7% (95% CI: 57.6–94.2) in the low, intermediate and high risk groups, respectively (p = 0.003). Keywords: aggressive B-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, PET-CT No conflicts of interests pertinent to the abstract.

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

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

FLIPI-3: A New PET-Based Prognostic Index for Follicular Lymphoma Based on Results from a Validation Study with the ECOG-ACRIN E2408 Cohort

Background: Early recurrence after first line therapy in patients with untreated follicular lymphoma (FL) has been shown to correlate with worse overall survival (Casulo et al., JCO 2015). Numerous clinical and molecular models have attempted to predict outcome and guide therapy. Lymphoma involvement of extra-nodal (EN) sites is better detected by fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) than CT alone, but PET detected parameters are not part of the usual predictive indices. In a retrospective study of 613 cases of newly diagnosed FL grade 1-3a, we found that qualitative PET/CT abnormalities of spleen, skin/soft tissue, and bone, as well as involvement of ≥2 EN sites, predicted early clinical failure (St-Pierre et al., AJH 2019). We aimed to validate these findings with a separate cohort of patients with untreated high-tumor burden FL. Additionally, we aimed to evaluate the prognostic significance of a predictive index incorporating the PET factors that were validated in this study. Methods: PET/CT images from 258 patients with newly diagnosed grade 1-3a FL included in the ECOG-ACRIN E2408 randomized phase II trial (Evens et al., Clin Cancer Res. 2020) were reviewed. Of these, 9 patients were excluded due to poor image quality. This study included untreated high-tumor burden FL patients who were treated with a bendamustine/rituximab backbone for induction followed by 2 years of rituximab-based maintenance. Location, pattern, and number of EN sites, as well as splenic involvement, were recorded. The primary endpoint was progression-free survival (PFS) and overall survival (OS). Time to event measures were estimated using the Kaplan and Meier method, where differences between groups were assessed using log-rank statistics. Multivariate analyses were performed using Cox-proportional hazards regression models. PET factors that had a statistically significant (p≤0.05) impact on PFS and/or OS were combined with statistically significant FLIPI and FLIPI-2 factors in this cohort to create a PET-based prognostic index for newly diagnosed FL. Results: Presence of ≥2 EN sites and skin/soft tissue involvement on PET/CT were validated as univariate predictors of PFS and OS. In a multivariate analysis with FLIPI-2 factors, presence of ≥2 EN sites on PET/CT was validated as an independent predictor of PFS (HR 1.69, p=0.045) and OS (HR 2.52, p=0.009). 2-year OS was 83% in the group with ≥2 EN sites compared with 94% in the group with 0-1 EN sites, and 84% in the group with skin/soft tissue involvement compared with 96% in the group with no skin/soft tissue involvement. In subset analyses, these PET factors were predictive of PFS and OS across all E2408 treatment arms. Bone and spleen involvement, contrary to the prior study, did not predict outcomes. Results are outlined in Table 1. Other factors that impacted PFS and/or OS in this cohort included ages > 60 years, longest diameter of any lymph node > 6 cm, hemoglobin < 12, and elevated β2-microglobulin (FLIPI-2). These factors were combined with the number of EN sites involved (0-1 vs 2+) and presence of skin/soft tissue involvement on PET/CT to form the PET-based FLIPI score. Each factor represents one point on a 6-point scale. A high-risk score of 4-6 using this index was associated with a 2-year PFS of 70% vs 87% in the intermediate-risk group (score 2-3), and 91% in the low-risk group (score 0-1) (p=0.00033). The 2-year OS was 82% in the high-risk group, compared with 93% in the intermediate-risk group, and 97% in the low-risk group (p=0.00013). These results are outlined in Figure 1. Using the same score without the two PET factors, the 2-year OS was 88% in the high-risk group (score 3-4), 90% in the intermediate-risk group (score 1-2), and 100% in the low-risk group (score 0) (p=0.0099). Conclusions: In this validation study, we 1) confirm that involvement of ≥2 EN sites and skin/soft tissue involvement on qualitative PET/CT represent predictors of PFS and OS in newly diagnosed FL, while bone and spleen involvement were not validated. Furthermore, this was validated in a FL patient population treated with contemporary bendamustine-based induction therapy with rituximab maintenance. 2) The PET-FLIPI score combining these PET-derived factors with traditional FLIPI and FLIPI-2 provides a more robust prognostic index for PFS and OS in these patients. These results provide a readily available tool that may help guide future clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Obinutuzumab plus lenalidomide in advanced, previously untreated follicular lymphoma in need of systemic therapy: a LYSA study

AbstractObinutuzumab and lenalidomide (referred to as the GALEN combination) is an active immunomodulatory combination with a manageable safety profile in multiple types of lymphoma. We report efficacy and safety results for the phase 2 GALEN study in previously untreated patients with advanced follicular lymphoma (FL). Eligible patients aged ≥18 years had an Eastern Cooperative Oncology Group performance status ≤2 and high-tumor burden, grade 1 to 3a FL. Induction treatment was obinutuzumab (1000 mg IV, days 8, 15, and 22, cycle 1; day 1, cycles 2-6) plus lenalidomide (20 mg/d, days 1-21, cycle 1; days 2-22, cycles 2-6) for six 28-day cycles. Maintenance included obinutuzumab (1000 mg every 2 cycles) plus lenalidomide (10 mg, days 2-22) for ≤12 cycles (year 1) followed by obinutuzumab (1000 mg every 56 days) for 6 cycles (year 2). The primary end point was complete response rate (CRR) after induction per the 1999 International Working Group criteria. From October 2015 to February 2017, a total of 100 patients were enrolled. CRR after induction was 47%, and the overall response rate (ORR) was 92%. Post hoc analyses per the 2014 Lugano classification, including patients with missing bone marrow assessments, identified an additional 13 patients fulfilling CRR criteria, resulting in a complete metabolic response of 80% and an ORR of 94%. At a median follow-up of 3.7 years, 3-year progression-free survival and overall survival were 82% and 94%, respectively. The most common adverse event was neutropenia (48% any grade; 47% grade ≥3). Only 2% of patients presented with febrile neutropenia; others were mainly grade ≤2. No other specific grade ≥3 toxicity occurred at a frequency >3%. Overall, these results showed promising clinical efficacy for the chemotherapy-free GALEN backbone in previously untreated patients with high tumor burden FL. Except for neutropenia, the safety profile of the combination is remarkable. The study was registered at clinicaltrials.gov as #NCT01582776.

Follicular Lymphoma Treated with First-Line Immunochemotherapy: A Review of PET/CT in Patients Who Did Not Achieve a Complete Metabolic Response in the GALLIUM Study.

Complete metabolic response (CMR) on PET/CT was the sole independent predictor of overall survival in the PET substudy of the phase III GALLIUM trial (NCT01332968) in first-line treatment of high-tumor-burden follicular lymphoma. The aim of this analysis was to further investigate the outcome of patients not achieving CMR. Methods: Two international experts rereviewed PET/CT scans from patients failing to achieve CMR assessed by the Independent Review Committee masked otherwise to committee results. Metabolic response category and Deauville score were assigned. Progression-free survival (PFS) was investigator-assessed with contrast-enhanced CT. Kaplan-Meier methodology was used to estimate landmark PFS and time to next treatment from end of induction by Deauville score. Patients who experienced CT-based progressive disease at the end of induction were excluded. Results: Fifty-four patients were reviewed. Six had CMR, 37 had a partial metabolic response, 2 had no metabolic response, and 9 had progressive metabolic disease. Patients were reassigned to CMR because 18F-FDG uptake was considered inflammatory (n = 2), was considered incidental neoplasia (n = 2), or was visually close to liver uptake but quantitatively lower (n = 2). There was a trend for shorter PFS and time to next treatment for patients with a Deauville score of 5 than a score of 4. High-grade mesenteric uptake at the end of induction was common, occurring in 20 patients with non-CMR, 14 of whom achieved CMR at all other sites. Only 3 of 14 (21%) patients with mesenteric uptake as the only site of disease experienced progression or death within 24 mo, whereas 4 of 6 patients (67%) with mesenteric and additional sites of 18F-FDG-avid disease experienced progression or death within 24 mo. All patients with early progression had measurable disease on contrast-enhanced CT at 18F-FDG-avid sites at the end of induction. Conclusion: After induction immunochemotherapy, CMR was assigned after reassessment in some patients, in whom increased 18F-FDG uptake was considered due to inflammation or incidental neoplasia rather than to lymphoma. Quantitative assessment to confirm the visual impression of residual uptake in lesions is suggested. Isolated mesenteric 18F-FDG uptake is likely a common false-positive finding at the end of induction and does not warrant changes in clinical management or disease surveillance unless there is measurable disease on contrast-enhanced CT or clinical suspicion of active disease.

Impact of Immunochemotherapy with R-Bendamustine or R-CHOP in the Post-Induction Management of Treatment Naïve Advanced Stage Follicular Lymphoma Patients: A Subset Analysis of the FOLL12 Trial By the Fondazione Italiana Linfomi (FIL)

Impact of Immunochemotherapy with R-Bendamustine or R-CHOP in the Post-Induction Management of Treatment Naïve Advanced Stage Follicular Lymphoma Patients: A Subset Analysis of the FOLL12 Trial By the Fondazione Italiana Linfomi (FIL)

Sirpα and CSF1R Positive Tissue Macrophages Are Increased in Patients with Follicular Lymphoma Who Relapse after Frontline Lenalidomide and Rituximab

Sirpα and CSF1R Positive Tissue Macrophages Are Increased in Patients with Follicular Lymphoma Who Relapse after Frontline Lenalidomide and Rituximab

Phase II Study of Venetoclax in Combination with Obinutuzumab and Bendamustine in Patients with High Tumor Burden Follicular Lymphoma As Front Line Therapy (PrECOG 0403)

Phase II Study of Venetoclax in Combination with Obinutuzumab and Bendamustine in Patients with High Tumor Burden Follicular Lymphoma As Front Line Therapy (PrECOG 0403)

Ten Year Follow up of the MD Anderson Cancer Center Phase 2 Study of Rituximab in Combination with Lenalidomide (R2) for Patients with Low Tumor Burden Follicular Lymphoma

Ten Year Follow up of the MD Anderson Cancer Center Phase 2 Study of Rituximab in Combination with Lenalidomide (R2) for Patients with Low Tumor Burden Follicular Lymphoma

Discovery and Validation of a Simplified Scoring System (the PRIMA-Prognostic Index) in De Novo Follicular Lymphoma Treated Initially with Immunochemotherapy

Introduction. In follicular lymphoma (FL), no prognostic index has been built based on a cohort of patients treated only with initial immunochemotherapy. Given the emergence of new biomolecular and metabolic prognostic factors in FL, an easy-to-compute and reliable scoring system utilizing such variables could aid in trial stratification and routine clinical evaluation. Methods. The primary endpoint for model building was progression-free survival (PFS). For discovery, we used the large prospective PRIMA trial cohort of 1,135 patients treated with initial R-chemotherapy +/- R-maintenance. Variables considered for model building included age, sex, performance status, B symptoms, stage, number of nodal and extranodal sites involved, LDH, hemoglobin, longest diameter of the largest lymph node, presence of effusion and compression syndrome, circulating lymphoma cells, platelet count, serum albumin, bone marrow involvement, and s2m. For validation, we combined 175 patients with high tumor burden FL from the R-CHVP+interferon arm of treatment from the FL2000 trial and 304 patients prospectively enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE) who were treated upfront with immunochemotherapy. Event-free survival (EFS) was the endpoint available in the validation cohort. For model building, we used a two-step approach based on resample Cox regression and conditional inference trees analyses to identify 3 patient groups of approximately equal size and experiencing differential outcome in terms of PFS. For comparison with the FLIPI, model9s discrimination was computed using theConcordance Probability Estimates (CPE) based upon Harrell9s c-index. All statistical tests were 2-sided. A P value Results. The final simplified score based on the discovery set was called the PRIMA-PI (PRIMA-prognostic index) and comprised 3 risk categories: high (s2m > 3 mg/L), low (s2m ≤ 3 mg/L without bone marrow involvement) and intermediate (≤ 3 mg/L with bone marrow involvement). In the discovery cohort, the PRIMA-PI was highly discriminatory with 5-year PFS of 69% (95%CI: 64-73%), 55% (49-60%) and 37% (32-42%) in the low-, intermediate- and high-risk groups respectively (P In the validation cohort, the PRIMA-PI remained highly discriminatory: 5-year EFS was 77% (69-83%), 57% (48-66%) and 44% (35-52%) in the low-, intermediate- and high-risk groups respectively (P Conclusion. We developed and validated a new prognostic tool comprising only 2 parameters (bone marrow involvement and s2m) which are easily measured clinically. The PRIMA-PI is a new and easy-to-compute prognostic index for patients treated upfront with immunochemotherapy. This could serve as a basis for building more sophisticated and integrated biomolecular scores. Disclosures Bachy: Amgen: Honoraria; Sandoz: Consultancy, Honoraria; Mundipharma: Research Funding; Roche/Genentech: Consultancy, Honoraria, Research Funding. Estell: Janssen: Membership on an entity9s Board of Directors or advisory committees. Delmer: Abbvie: Consultancy, Honoraria; Janssen: Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Belada: Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Travel grants , Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Travel grants , Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Travel grants , Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau. Ansell: Celldex: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Affimed: Research Funding. Lamy: Roche: Consultancy, Honoraria. Cerhan: Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering . Salles: Gilead: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Bayesian Network Modelling As a New Tool in Predicting of the Early Progression of Disease in Follicular Lymphoma Patients

Bayesian Network Modelling As a New Tool in Predicting of the Early Progression of Disease in Follicular Lymphoma Patients

Baseline SUVmax did not predict histological transformation in follicular lymphoma in the phase 3 GALLIUM study

AbstractA minority of patients with follicular lymphoma (FL) undergo histological transformation (HT). This retrospective analysis of 549 patients from the phase 3 GALLIUM study (NCT01332968) assessed the relationship between maximum standardized uptake value (SUVmax) at baseline on positron emission tomography (PET) and HT risk. Previously untreated patients with high tumor burden grade 1-3a FL received obinutuzumab- or rituximab-based chemotherapy induction. The relationship between baseline SUVmax (bSUVmax) and HT risk was assessed using cutoff values for SUVmax >10 and >20. Overall, 15 of 549 (2.7%) patients with baseline PET scans experienced biopsy-confirmed HT (median follow-up, 59 months). More than 65% of patients had bSUVmax > 10, with 3.3% of these experiencing HT. Only 1 of 74 (1.4%) patients with bSUVmax > 20 underwent HT. Median bSUVmax in patients with HT vs without HT was 12.4 (range, 8.1-28.0) vs 11.8 (range, 3.1-64.4), respectively; median bSUVrange (the difference between bSUVmax of the most and least 18F-fluorodeoxyglucose–avid lymphoma sites) was 8.0 (range, 1.1-23.9) vs 7.1 (range, 0.0-59.8), respectively. There was no temporal relationship between bSUVmax and HT. Neither bSUVmax nor bSUVrange predicted HT in GALLIUM, suggesting that there may be little benefit in rebiopsy of lesions to exclude HT based on SUVmax alone before initiating therapy in patients with high tumor burden FL.

Results of a Phase II Study of Obinutuzumab in Combination with Lenalidomide in Previously Untreated, High Tumor Burden Follicular Lymphoma (FL)

Results of a Phase II Study of Obinutuzumab in Combination with Lenalidomide in Previously Untreated, High Tumor Burden Follicular Lymphoma (FL)

Lenalidomide in combination with R-CHOP (R2-CHOP) as first-line treatment of patients with high tumour burden follicular lymphoma: a single-arm, open-label, phase 2 study

Immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard front-line treatment for follicular lymphoma. The combination of lenalidomide and rituximab has shown high efficacy in relapsed or refractory and untreated follicular lymphoma. We aimed to evaluate the safety and activity of the combination of lenalidomide and R-CHOP (R2-CHOP) in previously untreated patients with high burden follicular lymphoma. This single-arm, open-label, multicentre, phase 2 trial was done in 16 hospitals in France, all of which were Lymphoma Study Association (LYSA) sites. Eligible patients were aged 18-70 years and had previously untreated CD20-positive follicular lymphoma of grade 1, 2, or 3a; at least one high tumour burden criterion according to Groupe d'Etude des Lymphomes Folliculaires criteria; an Eastern Cooperative Oncology Group performance status score of 2 or less; and a minimum life expectancy of more than 3 months. Patients received induction therapy with six cycles of R2-CHOP every 3 weeks (one cycle involved standard R-CHOP on days 1-5, and 25 mg oral lenalidomide per day on days 1-14), followed by two rituximab infusions at 3-week intervals. The total treatment schedule was 24 weeks. Patients who achieved a complete or partial response to induction therapy received maintenance therapy consisting of one rituximab infusion every 8 weeks for 2 years. The primary outcome was the proportion of patients who achieved a complete response (complete response and complete response unconfirmed), according to International Workshop to Standardize Response Criteria, at the end of induction treatment. Safety was assessed in all patients who completed treatment. This trial is registered with ClinicalTrials.gov, number NCT01393756, and is closed to accrual. Between Dec 21, 2010, and Jan 25, 2012, 80 patients were enrolled, and 68 (85%) completed six cycles of R2-CHOP. At the end of the induction phase, 59 patients achieved a complete response (74%, 95% CI 63-83). 55 patients achieved a complete response at 30 months from enrolment (69%, 57-78). The most frequent adverse event was grade 4 neutropenia in 52 (65%) patients. The most frequent non-haematological side-effects included grade 1-2 sensory neuropathy in 28 (35%) patients and grade 1-2 transient rash in 27 (34%) patients. Four patients died during the study period; none of these deaths were judged to be related to treatment. Lenalidomide in combination with R-CHOP had an acceptable safety profile and showed anti-cancer activity in patients with previously untreated high burden follicular lymphoma. A future comparative study showing evidence of a survival advantage would be necessary for this combination to be proposed as a treatment for follicular lymphoma. French Ministry of Health, Celgene Corporation, and Amgen France.

Abstract 5616: Rituximab chemotherapy induces a partial recovery from T-cell exhaustion in follicular lymphoma patients

Abstract For many years, the clinical responses observed in cancer patients treated with antitumor antibodies have been viewed only as a consequence of the recruitment and activation of innate immune cells. Several preclinical studies have indicated that anti-tumor antibodies can also induce a potent anti-tumor adaptive T-cell response capable of protecting animals from tumor challenge. Our studies have shown that CD4+ Th1 cells play a central role in the response to anti-CD20 tumor therapy by opposing Treg expansion and that CD20-specific memory T cells are responsible for anti-tumor protection observed in surviving animals subjected to tumor rechallenge. Whether an adaptive T-cell response is elicited in patients with Follicular Lymphoma (FL) receiving anti-CD20-based treatment is not known. In the present work, we analyzed peripheral T cells before and during anti-CD20-chemotherapy treatment of FL patients (R-CHOP) with high tumor burden. We first examined in ELISPOT assays the IFN-γ production by PBMC from 20 patients against human CD20-derived peptides previously selected by combining in silico and in vivo screening using transgenic human HLA-DR mice. Both FL patients before treatment and patients undergoing R-CHOP treatment exhibited peripheral T-cell responses to the selected CD20-derived peptides. However, these responses were markedly lower than those observed in healthy donors. Similar results were also obtained when T cell responses against viruses commonly infecting large numbers of individuals (CMV, EBV, influenza) were assessed, suggesting that high tumor burden FL patients exhibit an immune exhaustion of T cells. Multiparametric flow cytometry analyses suggested that their poor ability to respond to viral and CD20-derived peptides is related to the presence of an immunocompromised and exhausted blood T-cell peripheral compartment with higher percentages of TIGIT- and PD-1-expressing T cells, of peripheral Treg, and terminally differentiated CD8+ TEMRA. R-CHOP therapy induced a shift of CD4+ and CD8+ T cells toward a central memory phenotype (TCM), an additional shift of CD8+ T cells to a naive phenotype, and a decrease in the number of PD-1+ and TIGIT+ T cells, making these cells evolving toward a lesser degree of exhaustion. However, it did not restore a level of specific responses similar to those observed in healthy donors. These results support the use of anti-PD-1 and anti-TIGIT antibodies in combination with anti-CD20 in FL patients with high-tumor burden. Citation Format: Benoit Milcent, Pauline Brice, Catherine Thieblemont, Jean-Luc Teillaud, Sophie Siberil. Rituximab chemotherapy induces a partial recovery from T-cell exhaustion in follicular lymphoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5616.