Histologic Transformation Of Follicular Lymphoma Research Articles

Early histological transformation of follicular lymphoma to diffuse large B-cell lymphoma indicating adverse survival: A population-based analysis and validation.

The histological transformation (HT) of follicular lymphoma (FL) is a crucial biological event. The study aimed to evaluate the incidence, clinicial characteristics, prognosis and impact of HT time on survival of FL transforming to diffuse large B-cell lymphoma in population-based large-scale cohorts. A retrospective cohort study of FL with HT was performed in the Surveillance, Epidemiology, and End Results database. The Hematological Malignancy Research Network FL cohort and Aristotle study FL cohort were used to assess the external validity. Among 44,127 FL cases from the Surveillance, Epidemiology, and End Results database, 1311 cases were pathology-proven recorded to transform to diffuse large B-cell lymphoma. The cumulative rates of HT at 5, 10, and 15 years after FL diagnosis were estimated to be 1.19%, 2.93%, and 5.01%, respectively. Significantly worse overall survival and cancer-specific survival were exhibited in patients with HT than those without HT. Early HT (transformation of FL within 48 months after FL diagnosis [TOD48]) was an independent predictor for adverse overall survival of HT patients, regardless of treatment modalities before transformation. The adverse prognostic effect of TOD48 was validated in the Hematological Malignancy Research Network cohort and Aristotle study cohort. Older age (>75 years) and B symptoms within FL at diagnosis were the independent risk factors of TOD48. Furthermore, a novel prognostic model combining TOD48 with Follicular Lymphoma International Prognostic Index (TOD48-FLIPI) was constructed and validated for risk stratification. TOD48 was a risk indicator of HT, and the novel prognostic model "TOD48-FLIPI" for HT patients was proposed.

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.

Diffuse large b-cell lymphoma of the ocular adnexa with flow cytometry analysis and review of the literature.

The aim of this study was to evaluate the clinicopathological features and flow cytometry (FCM) of tumor tissues in ocular adnexal diffuse large B-cell lymphoma (DLBCL). This retrospective, multicenter case study was designed to evaluate the clinical and immunohistochemical features of tumors. DLBCL was diagnosed based on histopathology, immunoglobulin (Ig) heavy chain gene rearrangement, and FCM in all surgically removed periocular tumor tissues. This study involved assessing percentages (%) of B-cell/T-cell markers, a natural killer cell marker, and cell-surface Ig kappa/lambda (κ/λ) expression measured by FCM analysis in tumor tissues. Eleven DLBCL patients (4 men and 7 women) with 11 tumors were enrolled in this study. The median age at the time of initial presentation was 73 years. The tumor cells were immunohistochemically positive for cluster of differentiation (CD) 20, while CD5 was negative in all 8 cases tested. At the time of ophthalmic diagnosis, two cases already showed systemic dissemination of DLBCL throughout the body. FCM of tumor tissues detected a high percentage of B-cell markers including CD19 and CD20 in all 11 tumors. One case with high CD10 levels in FCM was histologic transformation from follicular lymphoma. One case with a relatively low CD20 population involved a history of systemic treatments including intravenous rituximab. Although caution should be exercised when interpreting the data, FCM is useful for not only supportive diagnosis complementary to immunohistochemistry, but also facilitates a better understanding of immunopathology including histologic transformation of follicular lymphoma to DLBCL in the ocular adnexa.

Diagnostic utility and prognostic significance of the Ki-67 labeling index in diffuse large B-cell lymphoma transformed from follicular lymphoma: a study of 76 patients.

The diagnosis of histological transformation of follicular lymphoma can be challenging and ambiguous. We investigated the distribution of the Ki-67 labeling index of histological transformation of follicular lymphoma and determined its cutoff value to predict poor outcomes. The diagnostic criteria for histological transformation were a diffuse pattern of proliferation and a proportion of large lymphoma cells ≥20%. Of the 1121 patients with follicular lymphoma, 171 (15%) showed histological transformation to diffuse large B-cell lymphoma. Of these, 76 patients, whose biopsies were obtained from the sites with the highest maximum standardized uptake values, according to the positron emission tomography findings, were included. The Ki-67 index ranged from 16.8% to 98.4% (median, 60.6%). In patients with histological transformation, the most significant differences were found in progression-free survival (p = 0.087, 58% vs. 87% at 2 years) and overall survival (p = 0.024, 53% vs. 85% at 5 years) when a 70% cutoff was used. Additionally, overall survival was significantly shorter in patients with histological transformation with maximum standardized uptake values of ≥20 (p < 0.0001) and absence of a follicular lymphoma component (p = 0.004). A Ki-67 index of ≥70% was a significant adverse factor for overall survival in patients with histological transformation of follicular lymphoma and may predict poor outcomes.

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.

Non–diffuse large B-cell lymphoma transformation from follicular lymphoma: a single-institution study of 19 cases

Diffuse large B-cell lymphoma (DLBCL) is the most common histological transformation (HT) of follicular lymphoma (FL). Other types of HT are very rare, and their incidence, histopathology, and patient outcomes have not been sufficiently described. Here, we assessed the clinicopathological characteristics of 19 cases of non-DLBCL HT of FL in a single institution in Japanto advance the understanding of the disease. Among 889 consecutive patients diagnosed with FL between 2000 and 2018, 191 suffered HT (21%). The median follow-up period was 94 months (range = 3-225). A total of 172 patients (90%) had DLBCL transformation, whereas the remaining 19 patients (10%) exhibited non-DLBCL transformation. In the latter cases, the following diagnoses were made based on morphology, immunohistochemistry, flow cytometry, and fluorescence in situ hybridization analyses: classic Hodgkin lymphoma (7 patients; 4%); high-grade B-cell lymphoma (HGBL) with MYC and BCL2 rearrangements (4 patients; 2%); HGBL, not otherwise specified (4 patients; 2%); B-cell lymphoblastic leukemia/lymphoma (2 patients; 1%); anaplastic large-cell lymphoma-like lymphoma (1 patient; 0.5%); and plasmablastic lymphoma (1 patient; 0.5%). Epstein-Barr virus-encoded RNA-1 did not associate with HT in any of the cases tested (n=8). Patients with non-DLBCL transformation showed poor outcomes, with a median overall survival of 13 months (range = 2 days-107 months); 10 of the patients (53%) died of HT. In conclusions, non-DLBCL transformation was observed in 10% of patients with HT from FL. Our data show that timely, accurate, and comprehensive histopathological diagnosis is needed to ensure optimal treatment and improve the outcome of these 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.

NCCN Guidelines Insights: B-Cell Lymphomas, Version 3.2019.

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin's lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.

Systematic analysis of the frequently amplified 2p15-p16.1 locus reveals PAPOLG as a potential proto-oncogene in follicular and transformed follicular lymphoma.

Transformed follicular lymphoma (tFL) originates from histological transformation of follicular lymphoma (FL), which is the most common indolent non-Hodgkin lymphoma. High-resolution genomic copy-number analysis previously identified frequent amplification of the 2p15-p16.1 locus in FL and tFL cases. The genes (i.e. BCL11A, PAPOLG, PUS10, and USP34) in this amplified locus have not been systematically investigated to date in terms of their role in FL pathogenesis or transformation to tFL. Here we investigated the relationship between amplification and expression of genes in 2p15-p16.1 as well as their expression after histological transformation. NCBI GEO SNP array and gene expression profile (GEP) data of tFL cases were analyzed to evaluate the relationship between amplification and mRNA expression. Moreover, transcript levels of these four genes in FL cases were compared with those of patient-matched tFL cases and normal B-cells. Amplification of the 2p15-p16.1 locus is associated with increased transcription of BCL11A and PAPOLG in tFL cases, of which the latter showed increased expression after histological transformation. Compared with the level in normal B-cells, PAPOLG was significantly overexpressed in FL cases, but expression levels of the other three genes did not show any significant difference. Altogether these results suggest that PAPOLG may be the most critical gene in terms of transformation to tFL.

Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial

Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial. In the phase 2-3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1-3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m2], given on day 1, plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], vincristine [1·4 mg/m2, capped at 2·0 mg] given intravenously on day 3, and oral prednisone [100 mg once daily on days 3-7]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121. Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25-41; R-CHOP-14 39%, 31-47; hazard ratio 0·89, 95% CI 0·67-1·17). In 248 patients with grade 1-3a follicular lymphoma, progression-free survival was 39% (33-45) at 8 years and 36% (30-42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5-6·0) at 5 years, 8·5% (5·4-12·4) at 8 years, and 9·3% (6·1-13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1-12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3-5·5). R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up-both of which could lead to death. National Cancer Center and Ministry of Health, Labour and Welfare of Japan.

Rituximab and the risk of transformation of follicular lymphoma: a retrospective pooled analysis

Histological transformation of follicular lymphoma to aggressive lymphoma is a serious event with a substantial effect on patient outcome. The aim of the Aristotle study was to assess the effect of rituximab on the risk of histological transformation and its outcome. 11 cooperative groups or institutions across Europe contributed data to this study. Eligible patients (≥18 years) had histologically confirmed follicular lymphoma grade 1, 2, or 3a, diagnosed between Jan 2, 1997, and Dec 20, 2013. Histological transformation was defined as a biopsy-proven aggressive lymphoma that occurred as a first event after first-line therapy. The primary endpoints were the cumulative hazard of histological transformation and survival after transformation. Information was available for 10 001 patients with follicular lymphoma, 8116 of whom were eligible for analysis. 509 histological transformations were reported. After a median follow-up of 87 months (range 1-221; 2·5-97·5th percentile 5-160), the 10-year cumulative hazard of histological transformation was 7·7% (95% CI 6·9-8·5). The 10-year cumulative hazard of histological transformation was 5·2% (95% CI 4·5-6·2) in patients who received rituximab and 8·7% (7·2-10·6) in those who did not (hazard ratio [HR] 0·73, 95% CI 0·58-0·90; p=0·004). The 10-year cumulative hazard of histological transformation was 5·9% (95% CI 5·0-7·0) for patients who received induction rituximab only and 3·6% (95% CI 2·3-5·5) for those treated with induction and maintenance rituximab (HR 0·55, 95% CI 0·37-0·81; p=0·003). This finding was confirmed in a multivariate analysis (p=0·016). 287 deaths were recorded in 509 patients with histological transformation, resulting in a 10-year survival after transformation of 32% (95% CI 26-38). Survival after transformation did not differ between patients not exposed to rituximab and those who received rituximab in induction only (HR 0·94, 95% CI 0·69-1·28; p=0·70), and those who received rituximab in induction and maintenance (0·96, 0·58-1·61; p=0·88). The risk of histological transformation as a first event can be significantly reduced by the use of rituximab. These findings support the need to inform patients using rituximab nowadays that the risk of transformation is lower than it was before the introduction of rituxumab. Associazione Angela Serra per la Ricerca sul Cancro, European Lymphoma Institute, European Hematology Association Lymphoma Group, Fondazione Italiana Linfomi, Spanish Group of Lymphoma and Bone Marrow Transplantation.

Theraputic Approaches to High Grade B-Cell Lymphoma Double-Hit and Follicular Lymphoma with C -MYC, BCL2 and/or BCL6 rearrangements. Single Center Expirience

Abstract Introduction. An appearance of secondary c-MYC gene rearrangement in patients with follicular lymphoma (FL) can predispose to histologic transformation of FL and aggressive clinical course of disease. Approaches to follicular lymphoma with с -MYC, BCL2 and/or BCL6 rearrangements treatment are not clearly defined. Aim. To compare clinical characteristics and treatment efficacy in groups of patients with FL histologic transformation or blastoid variant of FL with c-MYC, BCL2 and/or BCL6 genes rearrangements and HGBL double-hit (DH). Patients and methods. We analyzed data (since 2004 to 2017 years) from a single-center observation of 12 pts with high grade B-cell lymphoma (HGBL) DH, and 5 FL pts with c-MYC, BCL2 and/or BCL6 rearrangements (2 with histologic transformation into DLBCL, 2 cases of FL grade 3A with blastoid morphology and 1 FL grade 3B). Median follow-up was 9,3 (from 0,6 to 71,1) months. These groups did not have significant differences in clinical parameters such as age, ratio between men and women. In both groups majority of patients had ECOG≥2, III-IV stage of disease according to Ann-Arbor classification, high frequency of extranodal involvement (over 80%), bone marrow involvement (40-55%), high activity of LDH. In pts with HGBL DH Ki-67 expression level was significantly higher (median 93% (from 80 to 100%)) than in FL pts (median 70% (from 35% to 80%)), p=0,0037. Three pts with HGBL DH underwent CHOP-21±R, 2 pts - R-(DA)-EPOCH with lenalidomide maintenance, 7 pts - BL-M-04+R. 4 pts with HGBL DH achieved complete remission (CR) (2 - after BL-M-04+R, 1 - after R-DA-EPOCH, 1 - after CHOP), 2 pts achieved partial remission (PR) (1 after R-EPOCH), 7 pts had progressive disease (PD) (6 - after BL-M-04+R, 1 - after R-CHOP). 4 patients underwent autologous stem cell transplantation (autosSCT) 2 - in CR, 2 - in PR. Two pts transplanted in PR had PD 1-3 months later. Three pts with anamnesis or current diagnosis of FL underwent R-(DA)-EPOCH (1 with transformed FL, 2 - with blastoid variant of FL), 2 - R-CHOP-21 (1 pt with transformed FL, 1 pt - with 3B FL). From 3 pts after R-DA-EPOCH - 1 pt with blastoid variant of FL had CR (Ki-67 was 40%), 1 pt with blastoid variant of FL had stable disease (SD) (Ki-67 was 70%), she achieved CR after 3 R-DHAP, autoSCT now is planning. 1 pt with transformed FL had PR after R-DA-EPOCH and after 2 R-DHAP had PD (Ki-67 was 80%), subsequently died at 12,4 months. One pt is alive taking R-CHOP-21 (FL3B), one pts died due to PD after 6 R-CHOP-21 (with transformed FL, Ki-67 was 80%). Median overall survival in pts with HGBL, DH, was 9,6 (0,6-71,1) months; in pts with diagnosis or history of FL - 7,0 (2,4-19) months, p=0,99. Median time to progression (TTP) was 5,8 (0,3-71,1) months in first group and 7,0 (2,4-19) months in second group, respectively (p=0,98). Conclusion. Pts with de novo HGBL DH have a similarly poor prognosis as pts with histologic transformation of FL with c-MYC, BCL2 and/or BCL6 rearrangements. Cases corresponding to morphological criteria of FL with c-MYC and BCL2 rearrangements can differ in clinical course from indolent to highly aggressive depending on proliferative potential of tumor cells. Majority of FL cases with c-MYC and BCL2 rearrangements are characterized by aggressive clinical behavior and require more intensive approach than R-CHOP-21. We suggest that FL pts with c-MYC, BCL2 and/or BCL6 rearrangements could have benefit from R-(DA)-EPOCH. It is reasonable to consider FL pts with c-MYC, BCL2 and/or BCL6 rearrangements as candidates for consequent high dose therapy following autosSCT, if partial remission or stable disease is achieved on the first line of treatment. Download : Download high-res image (82KB) Download : Download full-size image Figure . Disclosures No relevant conflicts of interest to declare.

Risk of, and survival following, histological transformation in follicular lymphoma in the rituximab era. A retrospective multicentre study by the Spanish GELTAMO group.

The diagnostic criteria for follicular lymphoma (FL) transformation vary among the largest series, which commonly exclude histologically-documented transformation (HT) mandatorily. The aims of this retrospective observational multicentre study by the Spanish Grupo Español de Linfoma y Transplante Autólogo de Médula Ósea, which recruited 1734 patients (800 males/934 females; median age 59years), diagnosed with FL grades 1-3A, were, (i) the cumulative incidence of HT (CI-HT); (ii) risk factors associated with HT; and (iii) the role of treatment and response on survival following transformation (SFT). With a median follow-up of 6·2years, 106 patients developed HT. Ten-year CI-HT was 8%. Considering these 106 patients who developed HT, median time to transformation was 2·5years. High-risk FL International Prognostic Index [Hazard ratio (HR) 2·6, 95% confidence interval (CI): 1·5-4·5] and non-response to first-line therapy (HR 2·9, 95% CI: 1·3-6·8) were associated with HT. Seventy out of the 106 patients died (5-year SFT, 26%). Response to HT first-line therapy (HR 5·3, 95% CI: 2·4-12·0), autologous stem cell transplantation (HR 3·9, 95% CI: 1·5-10·1), and revised International Prognostic Index (HR 2·2, 95% CI: 1·1-4·2) were significantly associated with SFT. Response to treatment and HT were the variables most significantly associated with survival in the rituximab era. Better therapies are needed to improve response. Inclusion of HT in clinical trials with new agents is mandatory.

Risk of histological transformation and therapy-related myelodysplasia/acute myeloid leukaemia in patients receiving radioimmunotherapy for follicular lymphoma.

Histological transformation (HT) of follicular lymphoma (FL) to an aggressive lymphoma after chemotherapy remains a key issue. The incidence of HT after radioimmunotherapy (RIT) is unknown. This single institution study analysed the risk of HT in FL after treatment with yttrium-90 ibritumomab tiuxetan in 115 consecutive patients treated during 1987-2012. RIT was administered for progressive FL in 111 (97%) patients and as first-line therapy in the remaining 4. 28% (n=32) had HT, occurring at a median of 60months from diagnosis and 20months after RIT. 48% (12/25) of patients who received fludarabine developed HT. The estimated 10-year risk of HT in the fludarabine and non-fludarabine groups was 67% and 26% respectively (P=0·015). Only prior fludarabine was significantly associated with predicting the risk of HT after RIT. 8% (9/115) of patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (tMDS/AML) at a median of 41·4months (range, 5-89). The estimated 10-year risk of tMDS/AML in non-fludarabine treated patients (n=90) versus fludarabine treated (n=25) was 13% and 29%, respectively. The estimated overall risk of FL undergoing HT at 10years without fludarabine exposure appears similar to patients reported in the literature that have not received RIT. Patients with prior purine-analogue therapy are at significantly higher risk of HT.

Unmet needs in histological transformation of follicular lymphoma: a clinical and biological review

Histological transformation, with its profound diagnostic and therapeutic implications, is considered to be one of the most unfavorable events in the natural history of follicular lymphoma (FL). No optimal treatment of transformed follicular lymphoma (tFL) has been identified because of its rarity and heterogeneous presentation, and the lack of data from randomized clinical trials. Consequently, its treatment has been based on that used in de novo diffuse large B-cell lymphomas. However, patients with tFL present a different behavior, with a worse clinical course and poor response to treatment, although their prognosis seems to have improved significantly since the introduction of rituximab into therapeutic schemes. There is no consensus definition of tFL, which prevents the genuine identification of transformation when a biopsy is unavailable. There are no biomarkers at diagnosis that accurately identify patients who will transform. A better knowledge of the pathways leading to transformation would clearly help to identify patients at risk of transformation, and to distinguish them from patients who will relapse with FL and from those who will remain disease-free. This would also facilitate the identification of new drug targets, the design of clinical trials and the treatment of transformation when it arises. In the present review we provide a comprehensive overview of the current open questions in the field of transformation of FL. Large-scale international collaborative studies are required to address these gaps in our knowledge.

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.

Research progress on biological behavior and molecular mechanism of histological transformation in follicular lymphoma

A variety of inert non Hodgkin's lymphoma were converted into the risk of aggressive non Hodgkin's lymphoma, especially in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). The histological transformation is not an event driven by a single factor, but is the clonal evolution process of a variety of mechanisms. This article reviews the biological behavior of the transformation from the high risk factors, the evolution mode of cloning and the molecular mechanism of the occurrence of the transformation. Key words: Lymphoma, follicular; Cell transformation, neoplasms; Molecular mechanism

XIV. The pathology of transformation of indolent B cell lymphomas.

XIV. The pathology of transformation of indolent B cell lymphomas.

Incidence, risk factors and outcome of histological transformation in follicular lymphoma

Histological transformation (HT) into diffuse large B-cell lymphoma (DLBCL) was documented in 37 of the 281 (13%; 95% CI, 9-18) follicular lymphoma (FL) patients treated at our institute from 1979 to 2007. HT occurred at a median of 2·75years from initial FL diagnosis and HT rate was 15% at 10years and 26% at 14years, with a plateau from that point onward. Patients with bulky or extranodal disease, or those diagnosed before 1990 had a significantly higher risk of HT. When initial treatment strategies were taken into account, a reduced HT risk was seen in the patients initially managed with a 'watch and wait' policy, while the risk appeared significantly increased in the small subset of 18 patients initially managed with rituximab plus chemotherapy (P=0·0005). HT was associated with a significantly shorter cause-specific survival (P=0·0002). Predictors of survival after HT were the Follicular Lymphoma International Prognostic Index at diagnosis, as well as age and performance status at the time of HT. Our data confirm the adverse clinical outcome of FL after HT. In keeping with previous isolated reports, our findings suggest that there is a subgroup of patients in whom HT may not occur.

Quantitative Analysis of AID Expression and Somatic Hypermutation Identifies Isotype-Switched and Non-Switched Follicular Lymphomas As Distinct Biological Subgroups,

Abstract 3666 Introduction:Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation (SHM) and class switch recombination (CSR) in B cells. Deamination of cytosine residues by AID leads to double-strand breaks and point mutations in immunoglobulin (Ig) genes by subsequent mechanisms. Physiological AID expression is tightly regulated and restricted to germinal center (GC) B cells. AID acts not exclusively on Ig loci but effects aberrant SHM (ASHM) throughout the genome (Liu et al., 2008). High-fidelity mutation repair mechanisms protect most non-Ig AID target genes against mutation accumulation. Some genes including BCL6, the most highly mutated non-Ig gene, also undergo error-prone repair and consequently accumulate aberrant somatic mutations (Liu et al., 2009). In contrast to normal B cells, AID is constitutively expressed in follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) (Greeve et al., 2003; Lossos et al., 2004). These lymphoma entities are derived from GC B cells and continue to accumulate somatic mutations in the immunoglobulin heavy variable region (IGHV) through ongoing SHM (Kosmas et al., 1998). In FL, the 5` noncoding region of BCL6 is altered by aberrant somatic mutations. Histological transformation of FL to DLBCL is associated with ASHM of this gene segment (Pasqualucci et al., 2001; Lossos et al., 2000). To further elucidate the role of AID in FL pathogenesis, we performed precise quantitative correlations between AID expression, frequency of ongoing SHM of IGHV and ASHM of BCL6 in 16 isotype-switched (IgG-expressing) and 23 non-switched (IgM-expressing) FL. Methods:AID expression was measured by quantitative real-time PCR. SHM of IGHV and ASHM of the 5` noncoding region of BCL6 were determined by PCR-based cloning and sequencing, followed by alignment with their consensus and germ-line sequences, respectively. Detected mutations were further categorized into consensus mutations, defined by their presence in the majority of clones, and sporadic mutations, defined by their presence in the minority of clones. Consensus and sporadic mutations are taken to represent previous and current AID activity, respectively. Results:All FL had readily detectable AID transcripts, albeit at highly variable levels. Overall, AID expression levels did not differ between isotype-switched and non-switched FL (p=0.99). Sporadic IGHV mutations were slightly more prevalent in switched FL (p=0.026). Consensus IGHV mutations (p=0.99) and both sporadic and consensus mutations in BCL6 did not differ between the FL subgroups (p=0.91 and p=0.77, respectively). In non-switched FL, AID expression levels were positively correlated with sporadic (r=0.44, p=0.041) and consensus IGHV mutations (r=0.42, p=0.049) and sporadic BCL6 mutations (r=0.51, p=0.016). Consensus mutations in BCL6 were independent of AID levels (r=0.23, p=0.30). In switched FL, AID expression was inversely correlated with consensus IGHV mutations (r= -0.71, p=0.004). There was no correlation between AID expression and sporadic IGHV mutations (r= -0.055, p=0.85), nor with sporadic or consensus BCL6 mutations (r=0.056, p=0.84 and r= -0.058, p=0.82, respectively). Conclusions:Only in non-switched FL, AID expression levels determine its enzymatic activity with respect to expected mutations in its physiological and unphysiological target genes IGHV and BCL6 in a manner that appears to be quantitatively independent from AID cofactors or repair mechanisms. In contrast, the rates of ongoing IGHV mutations and of ASHM in isotype-switched FL are not directly dependent on AID expression levels. The unexpected inverse correlation to consensus IGHV mutations points to efficient high-fidelity mutation repair or alternative mechanisms that suppress AID activity in isotype-switched FL. Therefore, our data demonstrate hitherto unrecognized biological differences between isotype-switched and non-switched FL. These results predict that the combination of IgM isotype with high AID expression define an FL subgroup that is genetically less stable over time than their IgG-expressing or AID low-expressing counterparts. As a consequence, we postulate that continuous AID activity and the resulting ASHM of BCL6 and perhaps other proto-oncogenes cause a more aggressive clinical behaviour and an inferior prognosis in this FL subgroup, including a predisposition to histological transformation. Disclosures:No relevant conflicts of interest to declare.