Survival Of Follicular Lymphoma Patients Research Articles

Impact of positive CD4 cells on event-free survival in follicular lymphoma patients.

Previous results about prognostic value of CD4+ T cells in follicular lymphoma (FL) remain controversial. Immunohistochemistry was used to examine expression of positive CD4 cells in 103 patients with FL 1-3A. Early failure was described as failing to achieve event-free survival (EFS) at 12 or 24 months. There were 49 (47.6%) male and 54 (52.4%) females, with a median age of 54 years. Compared to patients with <20% of positive CD4 cells, patients with ≥20% of positive CD4 cells exhibited a significant lower risk of early failure (2-year EFS rate: 56.7% vs 73.5%, p = 0.047). When patients were stratified based on positive CD4 cell combined with FLIPI, the median EFS (p = 0.002) and median OS (p = 0.007) were significantly different. This study demonstrated that higher expression of positive CD4 cells predicts lower risk of early failure in follicular lymphoma, and combination analysis of CD4 and FLIPI could better predict disease relapse and survival outcome.

End of induction [18F]FDG PET is prognostic for progression-free survival and overall survival in follicular lymphoma patients enrolled in the FOLL12 trial.

To evaluate the reliability of the Deauville score (DS) in therapy response assessment and to define the prognostic value of the metabolic response of end of induction (EOI) [18F]FDG PET (PET) in follicular lymphoma patients. Adult patients with untreated grade 1-3a FL/ stage II-IV enrolled in the multicentre, prospective, phase III FOLL12 trial (NCT02063685) were randomized to receive standard immunochemotherapy followed by rituximab maintenance (standard arm) versus standard immunochemotherapy followed by response-adapted post-induction management (experimental arm). Baseline and EOI PET were mandatory for the study. All PET scans were centralized on the WIDEN® platform and classified according to DS in a blind independent central review. DS1-3 was considered negative (CMR), whereas DS4-5 was considered positive (not CMR). The primary endpoint was PFS. The main secondary endpoint was overall survival (OS). Overall, 807 follicular lymphoma patients-52% women, 89% stage III-IV disease, 40% with a high-risk FLIPI-2 score (3-5)-were enrolled in the study; 729 (90.4%) baseline and EOI PET were available for the analysis. EOI PET was positive (DS4-5) in 88/729 (12.1%) cases. Overall inter-reviewer agreement on PET pos/neg result was 0.92, while agreement on positive and negative cases was 0.77 and 0.94, respectively. The median follow-up was 69months; 247 events were registered in the 5-yr follow-up, with a 5-yr PFS of 67% (95%CI: 63%-70%). The 5-yr PFS rate for PET neg (DS1-3) and PET pos (DS4-5) patients was 71% (95%CI: 67%-75%) and 36% (95%CI: 25%-46%), respectively, with HR 3.49 (95%CI: 2.57-4.72). Five-year PFS was worse as DS increased, with 74% (70%-78%), 58% (48%-67%; HR 1.71; p = 0.001)] and 36% (25%-46%; HR 3.88; p < 0.001) in DS1-2, DS3 and DS4-5, respectively. EOI PET maintained its prognostic value in both the standard and experimental arms. In the whole population, 5-yr OS was 94% (95%CI: 92%-96%), with 96% (95%CI: 94-97) and 82% (95%CI: 72%-89%) in EOI PET negative (DS1-3) and positive (DS4-5), respectively (HR 4.48; p < 0.001). When DS was associated with FLIPI-2, patients with DS3 or DS1-2 with high FLIPI-2 (3-5) experienced worse OS than patients with DS1-2 and low FLIPI-2 (1-2) (p = 0.003). This study shows that DS is a reliable prognostic tool to evaluate EOI PET in follicular lymphoma patients, with prognostic value maintained both in the standard and experimental arms, making metabolic imaging a robust tool to assess response in FL. Moreover, although preliminary, this study provides further information on DS3 patients, who are considered as CMR but show a less favourable PFS than DS1-2 patients.

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

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

Efficacy of Autologous Hematopoietic Stem Cell Transplantation versus Chemotherapy or Allogeneic Hematopoietic Stem Cell Transplantation for Follicular Lymphoma: Systematic Review and Meta-Analysis

Background: The effect of autologous hematopoietic stem cell transplantation (auto-HSCT) versus conventional chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT) on the survival of patients with advanced follicular lymphoma (FL) is uncertain. Objectives: To elucidate this, FL and HSCT were used as keywords to search in PubMed, Embase, Web of Science, and Cochrane Library databases. Method: After data extraction and quality evaluation, a total of 13 studies were included, seven of which compared auto-HSCT with conventional chemotherapy and the other six compared allo-HSCT with auto-HSCT to the survival of FL patients. Results: The results showed that auto-HSCT improved overall survival (OS), progression-free survival, and event-free survival of FL patients compared with conventional chemotherapy without auto-HSCT. Compared with allo-HSCT, the patients receiving auto-HSCT had longer OS and lower non-recurrent mortality. Conclusions: Auto-HSCT can provide a survival advantage for patients with FL compared with conventional chemotherapy and allo-HSCT did not result in a survival benefit.

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.

Tumor-Tissue Expression of the Hyaluronic Acid Receptor RHAMM Predicts Histological Transformation in Follicular Lymphoma Patients.

Simple SummaryHistological transformation remains the leading cause of death in patients diagnosed with follicular lymphoma (FL). To date, no clinical nor biological biomarkers have been identified to unequivocally predict patients in high risk of transformation. In this study, we investigated the predictive value of the hyaluronic acid receptors RHAMM and CD44. Expression levels of RHAMM were higher in patients with subsequent transformation and were associated with poorer outcome.Histological transformation (HT) remains the leading cause of mortality in follicular lymphoma (FL), underlining the need to identify reliable transformation predictors. The hyaluronic acid receptors CD44 and the receptor for hyaluronan mediated motility (RHAMM, also known as HMMR and CD168), have been shown to be involved in the pathogeneses of both solid tumors and hematological malignancies. In an attempt to improve risk stratification, expression of RHAMM and CD44 were evaluated by immunohistochemistry and digital image analysis in pre-therapeutic tumor-tissue biopsies from FL patients, either without (nt-FL, n = 34), or with (st-FL, n = 31) subsequent transformation, and in paired biopsies from the transformed lymphomas (tFL, n = 31). At the time of initial diagnosis, samples from st-FL patients had a higher expression of RHAMM compared with samples from nt-FL patients (p < 0.001). RHAMM expression further increased in tFL samples following transformation (p < 0.001). Evaluation of CD44 expression showed no differences in expression comparing nt-FL, st-FL, and tFL samples. Shorter transformation-free survival was associated with high tumoral and intrafollicular RHAMM expression, as well as with low intrafollicular CD44 expression (p = 0.002, p < 0.001, and p = 0.034, respectively). Our data suggest that high tumor-tissue RHAMM expression predicts the risk of shorter transformation-free survival in FL patients already at initial diagnosis.

IBCL-114: Clinical and Biological Prognostic Factors in Follicular Lymphoma Patients During Treatment

Introduction Follicular lymphoma (FL) is an indolent yet heterogeneous B-cell lymphoproliferative disorder. Most people respond to treatment well. However, a particular group of patients has a poor prognosis, and these patients are difficult to define. Patients and Methods We retrospectively analyzed 143 FL patients treated at the University of Debrecen since 2009. We investigated the prognostic factors that may influence the survival of FL patients. Results We found a standardized uptake value (SUV)max cut-off of 9.85 at the staging PET/CT to significantly separate FL patients’ progression-free survival (PFS) (p=0.0001, HR: 0.2535, 95%CI: 0.1118-0.4878). Lymphocyte/monocyte (Ly/Mo) ratio of 3.41 drawn at diagnosis also significantly predicted PFS (p=0.0027, HR: 2.997, 95% CI: 1.463-6.142). Combining patients with staging SUVmax >9.85 and Ly/Mo 9.85 and interim SUVmax >3.15, a high-risk group of FL patients can be identified (p Discussion Biological prognostic factors, such as the Ly/Mo ratio, may improve the prognostic assessment of staging PET/CT. Nevertheless, PFS difference is translated into OS when using a combination of staging and interim SUVmax. We consider investigating additional biological prognostic factors while currently highlighting PET/CT’s role in FL.

Prognostic impact of nutritional and inflammation-based risk scores in follicular lymphoma in the era of anti-CD20 targeted treatment strategies

BackgroundThe composition of the tumor microenvironment (TME) is conditioned by immunity and the inflammatory response. Nutritional and inflammation-based risk scores have emerged as relevant predictors of survival outcome across a variety of hematological malignancies.MethodsIn this retrospective multicenter trial, we ascertained the prognostic impact of established nutritional and inflammation-based risk scores [Glasgow Prognostic Score (GPS), C-reactive–protein/albumin ratio (CAR), neutrophil–lymphocyte ratio (NLR), prognostic nutritional index (PNI), and prognostic index (PI)] in 209 eligible patients with histologically confirmed CD20+ follicular lymphoma (FL) of WHO grade 1 (37.3%), 1–2 (16.3%), 2 (26.8%) or 3A (19.8%) admitted to the participating centers between January 2000 and December 2019. Characteristics significantly associated with overall or progression-free survival (OS, PFS) upon univariate analysis were subsequently included in a Cox proportional hazard model.ResultsIn the study cohort, the median age was 63 (range 22–90 years). The median follow-up period covered 99 months. The GPS and the CAR were identified to predict survival in FL patients. The GPS was the only independent predictor of OS (p < 0.0001; HR 2.773; 95% CI 1.630–4.719) and PFS (p = 0.001; HR 1.995; 95% CI 1.352–2.944) upon multivariate analysis. Additionally, there was frequent occurrence of progression of disease within 24 months (POD24) in FL patients with a calculated GPS of 2.ConclusionThe current results indicate that the GPS predicts especially OS in FL patients. Moreover, GPS was found to display disease-specific effects in regard to FL progression. These findings and potential combinations with additional established prognosticators should be further validated within prospective clinical trials.

Hepatitis B surface antigen positivity is associated with progression of disease within 24months in follicular lymphoma.

Studies have reported a positive association between hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection and follicular lymphoma (FL). Nevertheless, clinical information concerning chronic HBV infection in FL is sparse. This retrospective cohort study investigated the prognostic impact of HBsAg in immunocompetent patients with FL treated with frontline rituximab-containing chemoimmunotherapy in an HBV-endemic area between 2006 and 2016. Among the 149 analyzed patients, 32 (21.5%) were HBsAg-positive. HBsAg positivity was positively associated with symptomatic splenomegaly, significant serous effusions, and peritreatment hepatic dysfunction. HBsAg-positive patients had a trend of lower complete remission rate (59.4% vs. 76.9%, P = 0.07), significantly poorer overall survival (hazard ratio for death, 2.68; 95% confidence interval, 1.21-5.92), and shorter progression-free survival than had HBsAg-negative patients. Multivariate analysis revealed that HBsAg is an independent adverse prognostic factor for overall survival. Intriguingly, HBsAg-positive patients had a higher incidence of progression of disease within 24months (POD24) than had HBsAg-negative patients (cumulative incidence rate, 25.8% vs. 12.4%, P = 0.045). This study revealed that patients with FL and chronic HBV infection represent a distinct subgroup with a markedly poor prognosis. HBsAg was positively associated with POD24 and might serve as a new prognostic predictor of the survival of FL patients in endemic regions for HBV infection.

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.

An integrative microenvironment approach for follicular lymphoma: roles of inflammatory cell subsets and immune-response polymorphisms on disease clinical course.

The study of the tumor microenvironment (TME) in follicular lymphoma (FL) has produced conflicting results due to assessment of limited TME subpopulations, and because of heterogeneous treatments among different cohorts. Also, important genetic determinants of immune response, such as single-nucleotide polymorphisms (SNPs), remain underexplored in this disease.We performed a detailed study of the TME in 169 FL biopsies using immunohistochemistry, encompassing lymphocytes, macrophages, and cytokines. We also genotyped 16 SNPs within key immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, and IL17F) in 159 patients. We tested associations between SNPs, clinicopathological features and TME composition, and proposed survival models in R-CHOP/R-CVP-treated patients.Presence of the IL12A rs568408 “A” allele associated with the follicular pattern of FOXP3+ cells. The IL12A AA haplotype included rs583911 and rs568408 and was an independent predictor of worse survival, together with the follicular patterns of T-cells (FOXP3+ and CD8+) and high IL-17F tumor levels. The patterns of CD3+, CD4+ and CD8+ cells, displayed as a principal component, also associated with survival. Hierarchical clustering of the TME proteins demonstrated a cluster that was associated with worse prognosis (tumors enriched in IL-17A, IL-17F, CD8, PD1, and Ki-67).The survival of FL patients who were treated in the rituximab era shows a strong dependence on TME signals, especially the T-cell infiltration patterns and IL-17F tumor levels. The presence of the AA haplotype of IL12A in the genome of FL patients is an additional prognostic factor that may modulate the composition of T-reg cells in this disease.

The Impact of First Complete Remission by PET-CT and Time to Next Treatment on Survival of Follicular Lymphoma Patients

We retrospectively analyzed the impact of initial positron emission tomography and computed tomography (PET-CT) complete remission (CR) and time to next treatment (TTNT) on patient outcome in follicular lymphoma. Between 2002 and 2014, 150 patients could be evaluated for treatment response and long-term outcome. The CR after first line treatment with either rituximab-cyclophosphamide, oncovin, and prednisolone (R-COP) or rituximab-cyclophosphamide, doxorubicin, oncovin, and prednisolone (R-CHOP) was 89% and partial response (PR) was 7%. The 5- and 10-year survival rates were 86.0% and 62.6%, respectively. In five years, 11% of patients had died of lymphoma and 3% from other causes. Forty-seven patients (31%) underwent a second line of treatment comprising 19 (40%) with a TTNT shorter than 24 months and 28 (60%) longer than 24 months. There was no difference in overall survival (OS) between R-COP (86%) and R-CHOP (77%) at 5 years, but there were more next treatment events in the R-COP compared with the R-CHOP group on longer follow-up (60% versus 35% at 8 years). For PET-CT response, there was a significant OS difference between initial CR and PR patients (88% versus 70%, p < 0.01), and a longer TTNT was seen in initial CR patients. Patients with a TTNT longer than 24 months had better OS compared with patients with a shorter TTNT (93% versus 54% at 5 years, p < 0.01). In conclusion, patients with initial PET-CT CR and TTNT longer than 24 months had better OS compared with those achieving only PR and shorter TTNT. PET-CT CR should be considered the treatment goal during initial treatment, and more aggressive treatment should be considered for patients with a TTNT of less than 24 months.

A Tridimensional Model for NK Cell-Mediated ADCC of Follicular Lymphoma.

Follicular lymphoma (FL) is the second most frequent subtype of B non-Hodgkin's lymphomas (NHL) for which the treatment is based on the use of anti-CD20 mAbs. NK cells play a crucial role in their mechanism of action and the number of these cells mediating antibody-dependent cell cycotoxicity (ADCC) in the peripheral blood of FL patients predict the outcome. However, their presence in FL biopsies, their activation and their role have been poorly investigated. Moreover, in vitro studies have not deciphered the exact signaling cascades triggered by NK cells in presence of anti-CD20 mAbs on both effector and target cells in a relevant FL model. We performed in silico analyses and ex vivo functional assays to determine the presence and the activation status of NK cells in FL biopsies. We modelized ADCC phenomenon by developing a co-culture model composed by 3D-cultured FL cells and NK cells. Thus, we investigated the biological effect of anti-CD20 mAbs by fluorescent microscopy and the phosphorylation status of survival pathways by cell bar coding phosphoflow in target cells. In parallel, we measured the status of activation of downstream FcγRIIIa signaling pathways in effector cells and their activation (CD69, perforin, granzyme B, IFNγ) by flow cytometry. We determined by in vivo experiments the effects of anti-CD20 mAbs in presence of NK cells in SCID-Beige engrafted FL mice. Here, we show that functional NK cells infiltrate FL biopsies, and that their presence tends to correlate with the survival of FL patients. Using our 3D co-culture model, we show that rituximab and GA101 are able to promote degranulation, CD69 expression, IFNγ production and activate FcγRIIIa signaling cascade in NK cells, and inhibit survival pathways and induce apoptosis in FL cells. The effect of GA101 seems to be more pronounced as observed in vivo in a xenograft FL model. This study strongly supports the role of NK cells in FL and highlights the application of the 3D co-culture model for in vitro validation.

CXCR5+CD8+ T cells are a distinct functional subset with an antitumor activity.

CXCR5 mediates homing of both B and follicular helper T (TFH) cells into follicles of secondary lymphoid organs. We found that CXCR5+CD8+ T cells are present in human tonsils and follicular lymphoma, inhibit TFH-mediated B-cell differentiation, and exhibit strong cytotoxic activity. Consistent with these findings, adoptive transfer of CXCR5+CD8+ T cells into an animal model of lymphoma resulted in significantly greater antitumor activity than CXCR5−CD8+ T cells. Furthermore, RNA-Seq-based transcriptional profiling revealed a 77-gene signature unique to CXCR5+CD8+ T cells. The upregulated 33 genes among the 77-gene signature correlated with improved survival in follicular lymphoma patients. We also showed that CXCR5+CD8+ T cells could be induced and expanded ex vivo using IL-23 plus TGF-β, suggesting a possible strategy to generate these cells for clinical application. In summary, our study identified CXCR5+CD8+ T cells as a distinct T-cell subset with ability to suppress TFH-mediated B-cell differentiation, exert strong antitumor activity, and confer favorable prognosis in follicular lymphoma patients.

Progress and Challenges in the Treatment of Follicular Lymphoma

Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma. The disease is characterized by a very heterogeneous natural history ranging from an indolent course not requiring therapeutic interventions at the time of diagnosis to a more aggressive clinical behavior with poor or only brief and transient response to therapy. Transformation to aggressive lymphoma may occur. Recent advances in supportive measures and novel therapeutic approaches have markedly improved survival of FL patients. While the disease is still considered incurable, some patients exhibit prolonged failure free survival (>10 years). In this presentation, the progress and challenges in managing patients with FL will be discussed.

COMPARISON IMMUNOCHEMOTHERAPY AND CHEMOTHERAPY EFFICASY IN FOLLICULAR LYMPHOMA

Introduction. Immunochemotherapy is an obligate component in treatment of follicular lymphoma (FL). Monoclonal antibodies to CD20 antigen is the most well studied and frequently used drug. Chemotherapy department of Russian Cancer Research Center has a very good experience in FL treatment using rituximab. In the article we characterize and compare two methods of treatment of FL - polychemotherapy vs chemotherapy. Materials and methods. 286 patients with FL were included into analysis. In 125 (44 %) from 286 patients polychemotherapy was used as a first line of FL treatment. In 161 (56 %) patients rituximab was added to chemothrepy regimens. Analysis of survival and disease-free survival was done according to Kaplan-Meier. Analysis of treatment results has been done according to international criteria of treatment response in non-Hodgkin’s lymphomas. In statistical calculations SPSS program for Windows was used. Results. Responses to treatment were significantly better in immunochemotherapy group of patients, p = 0,002. In unifactorial analysis rituximab significantly improved both overall and disease-free sirvival. Taking in mind that groups of patients receiving chemotherapy and immunochemotherapy were not completely identical we performed multifactorial analysis, Coxs regression analysis. In that case (Cox regression analysis) significant advantages of immunochemotherapy were noted in improving disease-free survival in FL patients (р = 0,000); significant influence on overall survival was not noted (p = 0,44). Addition of rituximab did not improved overall and disease-free survival in a group (n = 88; 31 %) of refractory and early relapsing FL. Conclusion. Addition of rituximab to polychemotherapy in FL patients significantly improved treatment results. In multifactorial analysis immunochemotherapy was the most important prognostic factors of favourable prognosis of disease-free survival. In that analysis rituximab did not influenced on overall survival and on survival in refractory and early relapsing FL.

BONE MARROW IN FOLLICULAR LYMPHOMA PROGNOSIS

Background. Bone marrow is the mostfrequent metastatic site in follicular lymphoma, 40-70 % cases. It’s unfovourable prognostic role is stated in the index FLIPI-2 (Follicular Lymphoma International Prognostic Index-2). Objective. To study both prognostic role of bone marrow involvement and it’s relation to erythropoiesis peculiarities in follicular lymphoma was the purpose of this research. Materials and methods. Histological study was performed in 269 follicular lymphoma patients. Erythropoiesis peculiarities were studied in that patients according to standard myelogram analysis. Results. Bone marrow involvement was noted according to trephine biopsy section staining in 37,9 % of follicular lymphoma case (102 from 269). Bone marrow involvement did not influenced the prognosis (overall survival) in all period of observation (p = 0,18). Longterm survival (more than 48 months) was negatively influenced by bone marrow involvement (p = 0,04). Intertrabecular pattern of follicular lymphoma growth in bone marrow was negative prognostic factor (p = 0,02). We noted negative correlation between bone marrow involvement and the elevation of orthochromic normoblasts in bone marrow of patients with follicular lymphoma. In cause of bone marrow such elevation was noted in 67 %, and in the absense of involvement - in 78 % (p = 0,043). Elevation of orthochromic normoblasts did not influenced the overall survival of follicular lymphoma patients (p = 0,89). Conclusion. Bone marrow involvement in follicular lymphoma plays prognostically unfavourable role in long-time observation periods (later than 48 months). The most unfavourable are the intertrabecular patchy lesions. Involvement of bone marrow is in opposite relations to elevation of orthochromic normoblast, but the latter sign is of no prognostic significance.

The tumour microenvironment influences survival and time to transformation in follicular lymphoma in the rituximab era.

The tumour microenvironment influences outcome in patients with follicular lymphoma (FL), but its impact on transformation is less studied. We investigated the prognostic significance of the tumour microenvironment on transformation and survival in FL patients treated in the rituximab era. We examined diagnostic and transformed biopsies from 52 FL patients using antibodies against CD3, CD4, CD8, CD21 (CR2), CD57 (B3GAT1), CD68, FOXP3, TIA1, PD-1 (PDCD1), PD-L1 (CD274) and PAX5. Results were compared with a second cohort of 40 FL patients without signs of transformation during a minimum of five years observation time. Cell numbers and localization were semi-quantitatively assessed. Better developed CD21+ follicular dendritic cell (FDC) meshworks at diagnosis was a negative prognostic factor for overall survival (OS), progression-free survival (PFS) and time to transformation (TTT) in patients with subsequently transformed FL. Remnants of FDC meshworks at transformation were associated with shorter OS and PFS from transformation. High degrees of intrafollicular CD68+ and PD-L1+ macrophage infiltration, high total area scores and an extrafollicular/diffuse pattern of FOXP3+ T cells and high intrafollicular scores of CD4+ T cells at diagnosis were associated with shorter TTT. Scores of several T-cell subset markers from the combined patient cohorts were predictive for transformation, especially CD4 and CD57.

Follicular Lymphoma: The Role of the Tumor Microenvironment in Prognosis.

The microenvironment of follicular lymphoma (FL) is composed of tumor-infiltrating CD8(+) T cells, follicular regulatory T cells, lymphoma-associated macrophages and mast cells, follicular helper T cells, follicular dendritic cells, and follicular reticular cells, all of which have been reported to have relevance in the prognosis of FL patients. In addition, some of these cells play a role in the histologic transformation of FL. Macrophages contribute to a poor prognosis in FL patients treated in the pre-rituximab era, but are associated with good prognosis in those treated in the rituximab era. T-cell immunoglobulin and mucin domain protein (TIM) 3 are markers of T-cell exhaustion, and T cells co-expressing programed death 1 (PD1) in peripheral blood and lymph nodes secrete interleukin (IL)-12 in the serum. Serum CXCL9, IL-2 receptor, and IL-1 receptor agonist are associated with shorter survival of FL patients. Agents for manipulation of the microenvironment surrounding FL cells include the immunomodulatory drug lenalidomide, immune check-point inhibitors, and cyclophosphamide prior to rituximab. To battle FL and to improve the outcomes of FL patients, understanding the relationship between neoplastic cells and the various microenvironmental cellular components is crucial for developing therapeutics against the microenvironment.

Progression-Free Survival at 24 Months (PFS24) and Complete Response at 30 Months (CR30) from Autologous Stem Cell Transplantation (ASCT) Should be Used As Surrogates for OS in Follicular Lymphoma (FL) Patients

Introduction: At present, determining OS (Overall Survival) remains the gold standard in clinical trial endpoints which evaluate the role of ASCT in FL. However, in the context of a disease characterized by very long median survivals with a continuous pattern of relapse, and still more with the advent of novel treatments, OS assessments seem elusive. In fact, PFS (Progression Free Survival) is the standard endpoint for new drug approvals in first-line FL, and some other earlier endpoints such 2-year PFS (Casulo et al , JCO 2015) or CR30 (Sargent, 2015) have been recently proposed as potential surrogates and as alternatives to PFS or OS as primary end-points in FL patients treated with 1st line chemoinmunoterapy. Objective: To assess if 2-year PFS and CR30 are feasible surrogates of OS in the setting of a very long follow-up series of FL patients treated with ASCT. Material and Methods: A total of 626 chemosensitive FL patients (mean age 47 years, male 49%) reported to the Spanish GELTAMO registry and intensified with ASCT between 1989 and 2007 were analyzed. The status of the disease at the moment of ASCT was either in 1st response [203 in 1st CR, 43% of them needing more than one therapy line to reach the CR, and 140 in 1st Partial Response (PR)] or in response after salvage therapy (174 in 2nd CR, 28 in 3rd CR and 81 in 2nd or 3rd PR). In 615 patients the status of the disease was evaluable after ASCT: 569 cases (92%) in CR, 27 cases (4%) in PR and 19 cases (3%) progressed or died. To assess 2-year PFS, two groups were defined: patients with progression of disease (POD) within 2 years from ASCT (early POD) and patients without progression within 2 years from ASCT. Cox model analysis was used to evaluate the association between early POD and OS from a risk - defining event, which is survival from time of POD for early progressors or from 2 years after ASCT for the reference group (Casulo et al, JCO 2015.Appendix). To asses CR30, two groups were defined: patients with and patients without CR at 30 months from ASCT. Cox model analysis was used to evaluate the association between being or not in CR at 30 months from ASCT. Results: Median follow-up is 12.2 years from ASCT and 14.2 years from diagnosis. Of the assessable patients, 31% were in the high-risk FLIPI group and 40% in the high-risk FLIPI 2 group. 30% of patients received rituximab prior to ASCT. Globally median PFS and median OS are 11 and 21 years, respectively. Patients transplanted in PR (n=221; 35%) had a worse OS than those transplanted in CR (n=405, 65%): HR 2.45 (95% CI, 2.2-2.7; P 10-5), fig. 3. Conclusion: 2-year PFS and CR30 could be used as subrogates for OS and as primary end points, not only in FL patients treated with 1st line chemoinmunoterapy, but also in FL intensified with an ASCT. To our knowledge this is the first study to establish that early relapse after ASCT is predictive of poor survival in FL patients; in both, patients treated or not with rituximab previously to the ASCT. This finding is even more evident in patients transplanted in CR. Likewise, best response achieved before ASCT is a robust prognostic factor for OS in FL patients. ![Figure 1.][1] Figure 1. ![Figure 2.][1] Figure 2. ![Figure 3.][1] Figure 3. Disclosures No relevant conflicts of interest to declare. [1]: pending:yes