Risk Of Histological Transformation Research Articles

Generation and External Validation of a Histologic Transformation Risk Model for Patients with Follicular Lymphoma

Follicular lymphoma (FL) is the most frequent indolent lymphoma. Some patients (10%-15%) experience histologic transformation (HT) to a more aggressive lymphoma, usually diffuse large B-cell lymphoma (DLBCL). This study aimed to validate and improve a genetic risk model to predict HT at diagnosis.We collected mutational data from diagnosis biopsies of 64 FL patients. We combined them with the data from a previously published cohort (total n = 104; 62 from nontransformed and 42 from patients who did transform to DLBCL). This combined cohort was used to develop a nomogram to estimate the risk of HT. Prognostic mutated genes and clinical variables were assessed using Cox regression analysis to generate a risk model. The model was internally validated by bootstrapping and externally validated in an independent cohort. Its performance was evaluated using a concordance index and a calibration curve.The clinicogenetic nomogram included the mutational status of 3 genes (HIST1HE1, KMT2D, and TNFSR14) and high-risk Follicular Lymphoma International Prognostic Index and predicted HT with a concordance index of 0.746. Patients were classified as being at low or high risk of transformation. The probability HT function at 24 months was 0.90 in the low-risk group vs 0.51 in the high-risk group and, at 60 months, 0.71 vs 0.15, respectively. In the external validation cohort, the probability HT function in the low-risk group was 0.86 vs 0.54 in the high-risk group at 24 months, and 0.71 vs 0.32 at 60 months. The concordance index in the external cohort was 0.552. In conclusion, we propose a clinicogenetic risk model to predict FL HT to DLBLC, combining genetic alterations in HIST1H1E, KMT2D, and TNFRSF14 genes and clinical features (Follicular Lymphoma International Prognostic Index) at diagnosis. This model could improve the management of FL patients and allow treatment strategies that would prevent or delay transformation.

Impact of Early Histological Transformation on Survival in Patients with Follicular Lymphoma

Introduction: FL represents the second most common NHL with an indolent natural history and a median OS exceeding 20 y. Histologic transformation (HT) to an aggressive lymphoma is historically linked to poor outcomes with a median post-transformation survival of 2-5 y. EFS24 and POD24 are established adverse events indicating a poor overall survival. POD24 is associated with a higher incidence of HT following immunochemotherapy. However, the impact of HT within POD24 (HT24) remains unknown. Objective: Given the rarity of HT and the limited resources dedicated to this patient population, we aimed to assess and characterize the risk of HT and its outcomes, including the impact of HT24 on survival. Methods: This was a single-center retrospective observational study from the FL MSKCC database. Eligible pts were diagnosed between 01/1998-01/2022 and had a biopsy-proven grade 1-3A FL at diagnosis, with a subsequent biopsy eventually showing HT. Pts with any component of aggressive lymphoma defined as FL3B, DLBCL, or HGBCL within 3 months of diagnosis were excluded, as well as those with clinically suspected HT but not biopsy-proven. HT24 was defined as HT from 3-24 months from the initial FL diagnosis. POD24 was defined as progression within 24 months of initial diagnosis, irrespective of whether the patient underwent active surveillance or received therapeutic intervention. OS was defined as survival from the day of diagnosis. OS post-HT was defined as survival interval from HT biopsy. OS from a risk-defining event (Casulo, JCO 2015) was defined as survival from HT for HT24 or from 2 y after diagnosis for the reference group (all pts from the cohort without HT at any time). Results: 3,678 pts were identified as eligible for this analysis. At a median follow-up of 7.5 y (CI 95% 7.1,7.8), 415 pts (11%) had experienced HT. The risk of HT was associated with multiple high-burden disease features at diagnosis (i.e. advanced stage, 3 nodes above 3 cm, spleen involvement, higher FLIPI score, elevated LDH, Ki67, and higher SUVmax). In the entire cohort, the median time from initial diagnosis to HT was 4 y (CI95% 3.5; 4.7). The cumulative hazard of HT at 2, 5, and 10 y was 3%, 7%, and 10%, respectively, with an estimated rate of 1%/year over the first 10 y. During follow-up, 695 pts (19%) had died. As expected, median OS was significantly inferior for pts having experienced HT vs. non-HT pts (16 vs 22 y, p<0.001, HR 1.8). Median OS post-HT was 9.8 y (95% CI 7.2;12.5) with 2-, 5-, and 10-years OS of 73%, 61%, and 49%, respectively. Of the 415 pts with HT, 111 (27%) had experienced HT24, and those with HT24 had significantly more adverse initial characteristics ( Table) such as advanced stage, bulk, serous effusion, spleen involvement, high LDH and FLIPI score, anemia, grade 3A, and higher SUVmax. Interestingly, there were no significant risk factors specifically associated with HT>24 months. OS from a risk-defining event in HT24 was significantly inferior compared to the reference group (5-year estimate 66% vs 90%, p<0.001, HR 3.2). OS post-HT did not significantly differ between pts with HT24 vs HT>24 months (5-year estimates 66% vs. 58%, p=0.22). Similar results (51% vs. 55%, p=0.64) were observed when restricted to pts who received initial systemic therapy. POD24 from diagnosis was observed in 303 pts; of them, 192 (63%) maintained FL histology at progression (POD24 +/HT24 -). Pts with HT24 experienced a significantly lower 5-year OS compared to those POD24 +/HT24 - (66% vs. 75%, p=0.0023, HR 1.9), figure. Conclusions: Our study highlights the distinction between HT24 and HT occurring later. High-burden features at diagnosis may predict HT24, suggesting occult HT at diagnosis. We did not identify any predictors for later HT, suggesting it may represent a random event in FL history. In this sizeable single-center cohort of pts with FL, we observed a better outcome for pts with HT than previously described. Furthermore, while HT negatively impacted OS, post-HT survival outcomes were similar in pts with HT24 and those with HT after 24 mo. Strict selection criteria (excluding pts with FL 3B and those with HT documented within 3 months of diagnosis), recent progress in therapy, and tertiary center recruitment biases may account for these data. Patients with HT24 had a poorer outcome than those with POD24 without HT. Further analysis to delineate the pattern of first-line therapy and outcome of pts with HT and POD24 is in progress.

Impact of Large Cells and Ki-67% on Outcomes in Patients with Newly Diagnosed Marginal Zone Lymphoma - Results from a Multicenter Cohort Study

Introduction Marginal zone lymphoma (MZL) is an indolent B-cell lymphoma primarily composed of small/medium cells with low proliferation. However, there are cases where large B-cells (LC) are increased on the biopsy or Ki-67 expression is higher. The significance of LC content and Ki-67 in MZL is uncertain compared to other lymphomas (e.g., follicular or mantle cell). Previous studies evaluating prognostic indices in MZL or the risk of histologic transformation (HT) to diffuse large B-cell lymphoma did not assess these factors. Clinicians and patients often have concerns about the meaning and implications of increased LC or Ki-67 expression. We analyzed a large dataset of US MZL patients to evaluate the impact of LC and Ki-67 on outcomes. Methods This retrospective, multicenter study involved adults with MZL treated at 10 US medical centers on or after 1/1/2010. We included patients with splenic (SMZL), nodal (NMZL), and extranodal MZL (EMZL) of the mucosa-associated lymphatic tissue (MALT). Cases with information on LC or Ki-67+ cell percentages determined by immunohistochemistry on the diagnostic biopsy were included. Patients with HT at or within 60 days after MZL diagnosis were excluded. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS) and cumulative incidence of HT. We assessed PFS and OS from diagnosis and the start of first-line treatment for patients receiving systemic therapy. Cox models were adjusted for age, sex, performance status, MZL subtype, stage, hemoglobin, albumin, and lactate dehydrogenase (LDH), and used multiple imputation for missing data. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) are reported. Results The study included 783 MZL patients (median age: 63 years; 53% women; 60% EMZL, 20% NMZL, 20% SMZL). Of these, 91 (12%) had LC reported in the biopsy, and 44 (6%) had >10% LC content ( Fig. 1A). Ki-67 staining was performed on biopsies from 438 MZL patients. Of those, 235 (54%) had low Ki-67 expression (≤10%), and 98 (22%) had Ki-67 >20%, which we determined to be the best prognostic cutoff for high Ki-67 in MZL. Ki-67 >20% correlated with increased LDH (34% versus 20%, P=.017), but not with other clinical parameters or with the use of first-line RCHOP chemotherapy ( P=.07). The Ki-67 >20% group had significantly worse PFS (aHR=1.69, 95%CI=1.12-2.55, Fig. 1B) with a trend for worse OS from diagnosis (aHR=2.00; 95%CI = 0.97-4.15). These associations were statistically significant for survival outcomes measured from the start of first-line systemic therapy: both PFS (aHR = 1.84, 95%CI = 1.15-2.94) and OS (aHR = 2.71, 95%CI = 1.11-6.60). There were no significant differences in PFS or OS within the Ki-67 >20% group based on first-line therapy (R-CHOP vs. BR/RCVP). The cumulative incidence of HT was significantly higher in the high Ki-67 group (5-year risk, 9.8% versus 3.8%, p=0.013). LC presence was associated with higher Ki-67 but not other clinical characteristics. Patients with LC-containing MZL received R-CHOP as first-line chemotherapy (18%) more frequently than those without LC (5%; P=.004). Presence of LC was linked to shorter PFS from diagnosis (aHR = 1.56, 95%CI = 1.08-2.26), but not OS (aHR = 1.07; 95%CI = 0.53-2.18). Presence of LC did not affect PFS or OS from the start of first-line systemic therapy (n=523). Among patients with LC, there was no significant difference in PFS or OS according to the type of first-line therapy (R-CHOP vs. BR/RCVP). The cumulative incidence of HT (31 events, 5-year risk 3.7% [95%CI, 2.4-5.3%]), was higher in the group with LC (5-year risk 9.4% versus 2.9%, P=0.04). Comparing patients with >10% LC to others yielded similar associations without statistical significance for any endpoint (possibly due to few patients with >10% LC). Discussion In this large retrospective cohort of newly diagnosed MZL patients, Ki-67 staining >20% was an independent prognostic factor for worse PFS and OS. LC content in the tumor was not significantly associated with most outcomes. Anthracycline-based chemotherapy did not impact PFS or OS in the presence of high Ki-67 or LC. These findings, along with the increased risk of HT, suggest that MZL with Ki-67 >20% may represent a higher-risk subset to prioritize for experimental approaches. Patients with LC or high Ki-67 at diagnosis should undergo a repeat biopsy at relapse to assess for HT.

Survival of Patients with Transformed Marginal Zone Lymphoma in the United States: A Population-Based Cohort Study

Background: Marginal zone lymphomas (MZLs) are a heterogenous group of indolent non-Hodgkin lymphomas that include extranodal MZL of mucosa-associated lymphoid tissue (EMZL or MALT lymphoma), nodal MZL (NMZL), and splenic (SMZL). All three subtypes can transform to diffuse large B-cell lymphoma (DLBCL). However, the cumulative incidence of histologic transformation (HT) and survival of patients with transformed MZL (t-MZL) in the US population have not been reported to date. Hence, we sought to estimate the risk of HT and relative survival (RS) in patients diagnosed with MZL in USA using a population-based study. Method: We conducted a population-based cohort study of t-MZL using the Surveillance, Epidemiology, and End Results-17 database. We included adults diagnosed with MZL in the US between 2011-2015. This time period was selected to provide a contemporary estimate of survival and allow for adequate follow-up. We identified patients with t-MZL by following patients with MZL and identifying those patients with subsequent diagnoses of DLBCL. All patients with t-MZL had biopsy-proven HT. We estimated the post-transformation RS of patients with t-MZL using flexible parametric survival models with 5 degrees of freedom for the baseline cumulative hazard. We compared the survival of the different MZL subtypes using multivariable modeling after adjusting for age, year, race, Ann Arbor stage, B symptoms, and geographic location. P values less than 0.05 were considered statistically significant. Results: A total of 5372 patients with MZL were included in the study. There were 3446 (64.2%) patients with EMZL, 1485 (27.6%) with NMZL, and 441 with SMZL (8.2%). Among the 5372 patients, 121 (2.3%) had biopsy-proven HT after a median follow-up of 6.2 years (95% confidence interval (CI), 6.1-6.3). HT was associated with decreased survival for patients with MZL ( Figure 1A). Among the MZL subtypes, SMZL was the most likely to develop HT (24/441, 5.4%), followed by NMZL (49/1436, 3.3%) and EMZL (48/3398, 1.4%) ( P < 0.001) despite similar follow-up between groups. The 5-year post-transformation RS was highest for t-EMZL (61%) followed by t-NMZL (51%) and t-SMZL (46%) (Figure 1B). On multivariable analysis, however, the subtype of MZL was not a significant predictor of RS. In addition, there were no significant predictors of RS identified among the study covariates. Conclusion: This is the first population-based study to date reporting outcomes associated with t-MZL in the USA. The risk of HT in MZL may vary depending on the subtype of MZL with cumulative incidence of 1.4-5.4% observed after 6 years of follow-up in the contemporary era. HT was associated with increased mortality irrespective of MZL subtype. Among the MZL subtypes, SMZL was most likely to develop HT and had the lowest estimated 5-year RS. Additional studies are needed to better understand factors associated with prognosis in t-MZL.

Proteomics identifies apoptotic markers as predictors of histological transformation in patients with follicular lymphoma

AbstractFollicular lymphoma (FL) is an indolent lymphoma with a generally favorable prognosis. However, histological transformation (HT) to a more aggressive disease leads to markedly inferior outcomes. This study aims to identify biological differences predictive of HT at the time of initial FL diagnosis. We show differential protein expression between diagnostic lymphoma samples from patients with subsequent HT (subsequently-transforming FL [st-FL]; n = 20) and patients without HT (nontransforming FL [nt-FL]; n = 34) by label-free quantification nano liquid chromatography-tandem mass spectrometry analysis. Protein profiles identified patients with high risk of HT. This was accompanied by disturbances in cellular pathways influencing apoptosis, the cytoskeleton, cell cycle, and immune processes. Comparisons between diagnostic st-FL samples and paired transformed FL (n = 20) samples demonstrated differential protein profiles and disrupted cellular pathways, indicating striking biological differences from the time of diagnosis up to HT. Immunohistochemical analysis of apoptotic proteins, CASP3, MCL1, BAX, BCL-xL, and BCL-rambo, confirmed higher expression levels in st-FL than in nt-FL samples (P < .001, P = .015, P = .003, P = .025, and P = .057, respectively). Moreover, all 5 markers were associated with shorter transformation-free survival (TFS; P < .001, P = .002, P < .001, P = .069, and P = .010, respectively). Notably, combining the expression of these proteins in a risk score revealed increasingly inferior TFS with an increasing number of positive markers. In conclusion, proteomics identified altered protein expression profiles (particularly apoptotic proteins) at the time of FL diagnosis, which predicted later transformation.

Genetic subdivisions of follicular lymphoma defined by distinct coding and noncoding mutation patterns

AbstractFollicular lymphoma (FL) accounts for ∼20% of all new lymphoma cases. Increases in cytological grade are a feature of the clinical progression of this malignancy, and eventual histologic transformation (HT) to the aggressive diffuse large B-cell lymphoma (DLBCL) occurs in up to 15% of patients. Clinical or genetic features to predict the risk and timing of HT have not been described comprehensively. In this study, we analyzed whole-genome sequencing data from 423 patients to compare the protein coding and noncoding mutation landscapes of untransformed FL, transformed FL, and de novo DLBCL. This revealed 2 genetically distinct subgroups of FL, which we have named DLBCL-like (dFL) and constrained FL (cFL). Each subgroup has distinguishing mutational patterns, aberrant somatic hypermutation rates, and biological and clinical characteristics. We implemented a machine learning–derived classification approach to stratify patients with FL into cFL and dFL subgroups based on their genomic features. Using separate validation cohorts, we demonstrate that cFL status, whether assigned with this full classifier or a single-gene approximation, is associated with a reduced rate of HT. This implies distinct biological features of cFL that constrain its evolution, and we highlight the potential for this classification to predict HT from genetic features present at diagnosis.

A Rare B-Myeloid Conversion of Follicular Lymphoma into Clonally Related Acute Myeloid Leukemia: A Case Report

Follicular lymphoma (FL) is a highly prevalent indolent lymphoma, and the risk of histological transformation is approximately 2-3% per year. Transformation of FL generally occurs in the same lineage (B cell lineage). Another rare form of disease progression is the transformation of neoplastic B-cells to another cell lineage such as acute myeloid leukemia (AML). The low incidence of B-myeloid transformation associated with poor prognosis hinders the establishment of model systems to identify molecular mechanisms. A 64-year-old woman was diagnosed with FL and achieved a satisfactory response after six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Approximately one month after treatment terminated, the disease progressed to AML with an increased white blood cell count and abnormal coagulation. Interestingly, nucleotide sequence analysis of the genomic region encoding the immunoglobulin heavy-chain variable domain showed the possibility of homologous transformation from lymphoma to leukemia cells. Although the patient experienced transient improvement after undergoing treatment with one cycle of idarubicin and cytarabine combined with etoposide, she relapsed and died 8 days after venetoclax salvage therapy. Patient with B-myeloid transformation was associated with an aggressive clinical course and poor prognosis. Conventional strategies for treating histologically transformed AML were ineffective. However, treatment with a Bcl-2 inhibitor could serve as an option. Here we review the literature relevant to this rare histological transformation of FL.

Analysis of Histologic Transformation and Prognosis for Follicular Lymphoma

To investigate the related factors of invasive transformation and prognosis for follicular lymphoma. A total of 168 patients with follicular lymphoma at First Affiliated Hospital of Zhengzhou University from August 2015 to January 2021 were collected, and the significance of each index in histological transformation (HT) and prognosis were analyzed. Pathology grade3, Ki-67 index ≥40%, β2MG＞3 mg/L, LDH＞245 U/L, POD24 and non-invasion of bone marrow were associated with HT. Univariate analysis showed that the high risk of FLIPI-2, pathological grade 3, Ki-67≥40%, anemia, β2MG＞3 mg/L, LDH＞245 U/L and HT had significant adverse effects on PFS; β2MG＞3 mg/L, LDH＞245 U/L, POD24 and HT had significant adverse effects on OS. Cox multivariate analysis showed that the β2MG >3 mg/L and HT were independent risk factors of PFS, HT was independent risk factor of OS. The pathological grade, Ki-67, β2MG, LDH, POD24 and bone marrow invasion of FL can predict the risk of HT. Meanwhile, β2MG >3 mg/L and HT are significantly related to poor prognosis of FL.

Clinical Characterization, Prognosis and Therapeutic Management of 181 Patients with Splenic Marginal Zone Lymphoma (SMZL): Real World Experience of the Geltamo Group

Introduction: Splenic Marginal Zone Lymphoma (SMZL) is an uncommon subtype of non-Hodgkin Lymphoma, therefore, the data concerning the diagnosis, prognosis and treatment are scare and mostly based on a limited number of retrospective series. In 2014, GELTAMO group launched a guidelines for practical management of SMZL to be used in the everyday practice in this nation-wide network of collaborative hospitals. (GEL-LZME-2014-14). These Guidelines proposed/suggested different treatment strategies according to the HPLLs/ABC score (Montalban et al, 2012). Therapeutic recommendations were observation (W&W) in group A, rituximab in group B and rituximab in combination with chemotherapy (R-Chemotherapy) in group C. The primary endpoint was to analyze compliance with the guidelines and to evaluate the outcome according to the HPLLs/ABC-adapted therapeutic strategy in the real life. Methods: Observational multicenter study of patients with diagnostic of SMZL between 2014 and 2019 included prospectively and consecutively in the RELINF registry by Spanish GELTAMO centers. Clinical data at diagnosis, HPLLs/ABC prognostic index, treatment, response and follow up were obtained from the medical records and entered into a database. Lymphoma Specific Survival (LSS) and response rates according to treatment received were assessed in this study. Composite event free survival (CEFS) defined as death, histological transformation (HT), recurrence/progression under treatment, and need for treatment under observation, was also analyzed. HT was considered as a time-dependent event. Results: A total of 181 patients (84M/97F; median age 71 years) from 22 centers were included. The main initial characteristics of the patients are shown in Table 1. Splenectomy was performed in 17 cases (9%). 57% of the patients followed the recommendation of the GELTAMO Guidelines. 13 cases were excluded for response and survival analyses (i.e., 3 with HT at diagnosis, 5 treated for hepatitis C virus and 5 managed with palliative care). At diagnosis 77 patients (45%) received some therapy while 96 (55%) remained on W&W (Table 1). The overall response rate was higher in the R-Chemotherapy arm and in the Rituximab arm compared to splenectomy (p<0.001), with no significant differences between Rituximab and R-Chemotherapy. With a median follow up of 41.2 months, the 5-year overall survival (OS) of the whole series was 77%, and the 5-year LSS of 93%, with 32 patients (18%) dying, but only 13 (40%) due to the lymphoma or its treatment. 5-year LSS was 98% and 87% for score A and B, respectively (p=0.048), but unexpectedly, there were no deaths among the 9 patients of score C (5-year LSS: 100%). There were no differences in the 5-year LSS according to the treatment received in the overall series (p=0.68) (Figure 1), nor when scores A and B were analyzed separately. The 5-year CEFS in the overall series was 46%. Analyzing the composed event according to score, there were significant differences in terms of the 5-year CEFS between scores A and B (p=0.044). When comparing LSS and progression-free survival (PFS) in patients treated with Rituximab or R-Chemotherapy at diagnosis or after the W&W period, there were no significant differences between the two groups. Patients on score C had a higher risk of HT than the remaining groups (HT at 5 years: 1.3%, 6.6% and 36% for scores A, B and C, respectively; p<0.001). HT was associated with significantly lower OS (Cox-time dependent: HR 7.816, 95% CI 3.179-19.217; p<0.001). Conclusions: Herein we describe the everyday practice for diagnosis, stratification, and treatment of SMZL in Spain. Overall, 57% of the patients were managed according to the Guidelines. Our data support that Rituximab is the best treatment, when needed. Patients with score A who do not need immediate treatment after diagnosis and are followed with W&W policy have a very good outcome. In patients with scores A and B who were observed after initial diagnosis, the response to Rituximab at the time of need of therapy was not hampered when compared to patients receiving Rituximab immediately after diagnosis. HT is associated with reduced survival. The low number of cases in score C prevents us from drawing conclusions in this group at this time. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P1132: PET INTERIM RESULTS PREDICT PROGRESSION-FREE-SURVIVAL IN FOLLICULAR LYMPHOMA PATIENTS WITH ADVANCED STAGE

Background: Follicular lymphoma (FL) is the second most common NHL. It is generally associated with an indolent course, but a subgroup of patients has worse outcome, lower progression-free-survival (PFS) and higher risk of histological transformation (HT). Since Lugano classification, the Deauville criteria using the 5-point scale (D5PS) is validated as the interpretation method for response assessment PET scans in HL and NHL. Nevertheless, the prognostic value of D5PS in the interim evaluation in FL (PETINT) is not well stablished. Additionally, the quantitative value of SUVmax parameter in the response assessment is almost not studied. Aims: The aim of this study is to evaluate the prognostic value of PETINT evaluation and quantitative mid-induction SUVmax parameter in a cohort of FL patients followed and treated in a single, academic centre with chemo-immunotherapy. Methods: 179 consecutive FL patients were newly diagnosed between 2011 and 2020. 40 patients that did not require systemic treatment and 68 that did not have a PETINT evaluation were excluded. As well, patients with HT (9) and FL grade 3B (4) were excluded. From the 58 remaining patients, clinical, laboratory and PET examinations data was recorded. All patients were Ann-Arbor stage III-IV and were treated with chemo-immunotherapy. PET/CT examinations were acquired at baseline, mid-induction (after 4 cycles of treatment) and end of treatment (EOT). PET positive was considered when Deauville score (DS) was 4 or 5. Statistical analysis was performed with SPSS® using Cox regression, Kaplan-Meier survival curves and log-rank test. Results: The median age at diagnosis was 64 years (26-95) and 29 (50%) patients were female. 33/58 (57%) patients had a high risk FLIPI and 18/55 (33%) had a high risk PRIMA-PI. 37 (64%) patients were treated with R-CHOP and 21 with R-bendamustine. 44 (76%) patients received maintenance with rituximab. After a median follow-up of 43 months, 20 (34%) patients had progression. On PETINT, 19 (32%) patients were PET(+), and 10 of them remained PETEOT(+). Only one patient with PETINT(-), became PETEOT(+). PETINT(+) patients had a median PFS of 31 months compared with a median PFS of 88 months in PETINT(-) (p < 0.001), Figure 1. 38.2% PETINT(+) presented progression of disease in less than 24 months (POD24) vs 5.2% on those who were in PETINT(-), with a p<0.001. PETINT(-) presented a negative predictive value of 95%. No differences in OS was observed. 3/19 (16%) patients with PETINT(+) presented HT vs 1/39 (2%) with PETINT(-). Transformation-free survival was lower in patients with PETINT(+), with a trend towards significance (p= 0.057). Similar PFS results were obtained independently of prognostic index, treatment or maintenance received. Analysing the prognostic value of quantitative SUVmax, patients with SUVmax< 3,8 (28/58; 48%) presented better outcomes, with larger PFS (p < 0.001) and less HT (p= 0.004). Figure 2. Additionally, PET/CT findings at EOT were predictive of relapse, with a median PFS of 30 months in PETEOF (+) vs 88 months in PETEOT(-) (p = 0.005). PETEOT (+) presented a higher risk of HT (p= 0.004). Figure 3. Image:Summary/Conclusion: This study suggests that response assessment by PET at mid-induction is predictive of relapse in advanced stage FL patients treated with 1st line chemo-immunotherapy. With previous conflicting results, further studies are needed to confirm this preliminary data. Probably, new laboratory tests such as MRD monitored by liquid biopsy could improve the detection of this subgroup of high risk patients and help to develop a response-adapted precision therapy.

Prospects in the management of patients with follicular lymphoma beyond first-line therapy.

The management of patients with relapsed or refractory follicular lymphoma has evolved markedly in the last decade, with the availability of new classes of agents (phosphoinositide 3-kinase inhibitors, immunomodulators, epigenetic therapies, and chimeric antigen receptor T cells) supplementing the multiple approaches already available (cytotoxic agents, anti-CD20 antibodies, radiation therapy, radioimmunotherapy, and autologous and allogeneic transplants). The diversity of clinical scenarios, the flood of data derived from phase II studies, and the lack of randomized studies comparing treatment strategies preclude firm recommendations and require personalized decisions. Patients with early progression require specific attention given the risk of histological transformation and their lower response to standard therapies. In sequencing therapies, one must consider prior treatment regimens and the potential need for future lines of therapy. Careful evaluation of risks and expected benefits of available options, which vary depending on location and socioeconomics, should be undertaken, and should incorporate the patient’s goals. Preserving quality of life for these patients is essential, given the likelihood of years to decades of survival and the possibility of multiple lines of therapy. The current landscape is likely to continue evolving rapidly with other effective agents emerging (notably bispecific antibodies and other targeted therapies), and multiple combinations being evaluated. It is hoped that new treatments under development will achieve longer progression-free intervals and minimize toxicity. A better understanding of disease biology and the mechanisms of these different agents should provide further insights to select the optimal therapy at each stage of disease.

Constrained FL: A Genetically Distinct Subgroup of Follicular Lymphoma with Low Rates of Somatic Hypermutation and a Reduced Propensity for Histologic Transformation

Constrained FL: A Genetically Distinct Subgroup of Follicular Lymphoma with Low Rates of Somatic Hypermutation and a Reduced Propensity for Histologic Transformation

Primary refractory follicular lymphoma: a poor outcome entity with high risk of transformation to aggressive B cell lymphoma

BackgroundPrimary refractory (PREF) follicular lymphoma (FL) has a completely different clinical course from that of FL that responds to front-line treatments. In addition to having poor responses to salvage therapies, it seems that patients with PREF are at increased risk of histological transformation (HT). The Aristotle consortium presented the opportunity of investigating the risk of HT in a very large series of cases. Thus, we investigated the risk of HT in patients with PREF FL compared with that of responding patients or in stable disease and ultimately their outcome. MethodsSix thousand three hundred thirty-nine patients from the Aristotle database were included in the analysis. These patients had a histologically confirmed grade 1, 2 or 3a FL diagnosed between 1997 and 2013. The primary end-points were the cumulative incidence (CI) of HT at the first progression or relapse and the survival after transformation. Findings.The 5-year CI of HT among patients with PREF was 34% (95% confidence interval (CI): 27–43), whilst it was 7.1% (95% CI: 6.0–8.5) in the group of patients with partial response (PR) or stable disease (SD) (PR + SD) and 3.5% (95% CI: 3.0–4.2) in the group of patients achieving complete response (CR). The 5-year survival after relapse (SAR) was 33% (95% CI: 28–39) for the PREF group, 57% (95% CI 54–61) in patients with PR, 51% (95% CI 43–58) in the SD group after first-line therapy and 63% (95% CI: 66–72) in patients with CR after initial treatment (p-value <0.001). The 5-year SAR for those patients with PREF who developed HT was 21% (95% CI: 12–31), clearly diminished when compared with those patients with PREF who did not experience HT (38% [95% CI: 31–44]) (p-value = 0.001). Interpretation.Patients with PREF FL have a dismal outcome and an associated very high rate of HT that further worsens their poor prognosis.

CD5 expression in marginal zone lymphoma predicts differential response to rituximab or bendamustine/rituximab

We examined outcomes of 244 patients with marginal zone lymphoma (MZL) diagnosed in 2010–2020, of which 25 (10%) expressed CD5. CD5 expression was present in 22% of splenic, 8% of nodal, and 5% of extranodal MZL, and showed frequent blood/bone marrow involvement, elevated lactate dehydrogenase, and TP53 deletions. CD5 expression was not associated with progression-free or overall survival, but it conferred a significantly higher risk of histologic transformation (22% versus 4% at 5 years, p = 0.002). Among patients receiving first-line rituximab monotherapy, CD5 expression was associated with lower response rate (30% versus 77%, p = 0.006), PFS (25% versus 45% at 3 years, p = 0.003) and OS (44% versus 77%, p = 0.010), whereas CD5 status did not significantly affect outcomes of patients receiving bendamustine with rituximab (P for interaction = 0.012 for progression-free survival). CD5-positive MZL may have a propensity to leukemic dissemination, histologic transformation, and may derive benefit from first-line bendamustine/rituximab rather than rituximab alone.

R-CHOP Versus R-Bendamustine with or without Rituximab Maintenance in Newly Diagnosed Follicular Lymphoma Patients with High SUV at Baseline PET

R-CHOP Versus R-Bendamustine with or without Rituximab Maintenance in Newly Diagnosed Follicular Lymphoma Patients with High SUV at Baseline PET

A low lymphocyte-to-monocyte ratio is an independent predictor of poorer survival and higher risk of histological transformation in follicular lymphoma

The lymphocyte-to-monocyte ratio (LMR) is a prognostic factor in different neoplasms, but its potential importance in follicular lymphoma (FL) is not well defined. We studied 384 FL patients for which the LMR was available at diagnosis. Baseline features and outcomes were compared between patients with an LMR ≤/>2.5. The 76 patients (20%) who had an LMR ≤2.5 were older and had a higher tumor burden. A low LMR was predictive of a lower 10-y progression-free survival (32 vs. 55%, p = .001) and overall survival (35 vs. 78%, p < .0001; HR = 2.3, p = .003 in a 6-element multivariable model). A low LMR was also an independent risk factor for histological transformation (11 vs. 6% at 10 years, p = .01). Likewise, patients with a low LMR had a higher rate of second malignancies. The potential utility of this widely available parameter and its contribution to well-established prognostic scores need to be explored in independent, prospective series.

Real world data on histological transformation in patients with follicular lymphoma: incidence, clinico-pathological risk factors and outcome in a nationwide Danish cohort

We investigated incidence, risk factors and outcome for follicular lymphoma (FL) patients with histologic transformation (HT) found at primary diagnosis (discordant/composite, dc-tFL) or sequentially (s-tFL). Between 2000 and 2015, 2773 patients were identified. The majority of patients (2252, 81%) did not experience HT (nt-FL), while 224 (8%) had dc-tFL and 297 (11%) s-tFL. The risk of HT was 2.2% per year and 9.6% at 5 years. Age ≥60, a high FLIPI risk score and LDH-elevation were associated with increased risk of HT. Calculated from primary diagnosis and compared with nt-FL, 5-year overall survival (OS) was inferior in both s-tFL and dc-tFL (nt-FL: 82%, s-tFL: 68%, dc-tFL: 68%; p = .001), whereas 5-year progression-free survival (PFS) was worse only in s-tFL (s-tFL: 18%, dc-tFL: 58%, nt-FL: 60%). Calculated from time of HT, s-tFL had inferior outcome compared to dc-tFL for both OS (s-tFL: 47%, dc-tFL: 68%, p = .001) and PFS (s-tFL: 35%, dc-tFL: 58%, p = .001).

High serum levels of IL-2R, IL-6, and TNF-α are associated with higher tumor burden and poorer outcome of follicular lymphoma patients in the rituximab era

The clinical behavior of FL patients is heterogeneous. The levels of sIL-2R have been correlated with tumor burden and outcome in FL. However, the impact of IL-6 and TNF-α in this disease is unclear. We studied 253 patients diagnosed with grade 1-3a FL between 2002 and 2018, with available information on serum levels of sIL-2R, IL-6, and TNF-α at diagnosis. Patients with cytokine levels above the cutoff had features of a higher tumor burden and higher-risk disease. Levels of any of the studied cytokines above the cutoff and a higher number of cytokines above the cutoff impacted on a shorter PFS and OS. TNF-α levels were an independent predictor of a poorer PFS. No differences were observed in the risk of histological transformation or second malignancies. The determination of cytokine levels in FL patients is feasible in clinical practice, and elevated levels are associated with a higher tumor burden and poorer survival.

Patterns of change in treatment, response, and outcome in patients with follicular lymphoma over the last four decades: a single-center experience

Although the introduction of immunotherapy has improved outcomes for follicular lymphoma (FL) patients, histological transformation (HT) and early relapse still confer a poor prognosis. We sought to describe the patterns of change in treatment, response, and outcome of FL patients at our institution over the last four decades. Seven hundred and twenty-seven patients (389 F/338 M; median age, 57 years) consecutively diagnosed with grade 1-3a FL between 1980 and 2017, categorized into four decades according to the time of diagnosis, constituted the study population. Clinical characteristics, treatment, response, absolute and relative survival, HT, second malignancies (SM), and causes of death were assessed. Median OS for the entire cohort was 17.6 years. From decade 1 to 4, there was an increase in the complete response rate (48 to 70%), progression-free survival (40 to 56% at 5 years), OS (77 to 86% at 5 years), and relative survival ratio (0.83 to 0.94 at 5 years), with no significant differences in the risk of HT or SM. Lymphoma remained the most common cause of death in all four decades. These findings illustrate the overall improvement in outcome for FL patients, but support the need for further research into risk stratification and management.

Positron-emission tomography–based staging reduces the prognostic impact of early disease progression in patients with follicular lymphoma

BackgroundPrevious studies reported that early progression of disease (POD) after initial therapy predicted poor overall survival (OS) in patients with follicular lymphoma (FL). Here, we investigated whether pre-treatment imaging modality had an impact on prognostic significance of POD. MethodsIn this retrospective study, we identified 1088 patients with grade I–IIIA FL; of whom, 238 patients with stage II–IV disease were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), and 346 patients were treated with rituximab-based chemotherapy. Patients (N = 484) from the FOLL05 study served as an independent validation cohort. We risk-stratified patients based on pre-treatment radiographic imaging (positron-emission tomography [PET] versus computed tomography [CT]) and early POD status using event-defining and landmark analyses. A competing risk analysis evaluated the association between early POD and histologic transformation. ResultsIn the discovery cohort, patients with POD within 24 months (PFS24) of initiating R-CHOP therapy had a 5-year OS of 57.6% for CT-staged patients compared with 70.6% for PET-staged patients. In the validation cohort, the 5-year OS for patients with early POD was 53.9% and 100% in CT- and PET-staged patients, respectively. The risk of histologic transformation in patients whose disease progressed within one year of initiating therapy was higher in CT-staged patients than in PET-staged patients (16.7% versus 6.3%, respectively), which was associated with a 9.7-fold higher risk of death. ConclusionIn FL, pre-treatment PET staging reduced the prognostic impact of early POD compared with CT staging. Patients with early POD and no histologic transformation have an extended OS with standard therapy.