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Supplementary material. Studies considered but not selected for this review of recent landmark studies in follicular lymphomaCategoryAuthorsTitle and referenceBiology/Prognostic factors/Risk stratificationMottok A, et al.FOXP1 expression is a prognostic biomarker in follicular lymphoma treated with rituximab and chemotherapy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1182/blood-2017-08-799080","ISSN":"1528-0020","PMID":"29122756","abstract":"Follicular lymphoma (FL) is a clinically and molecularly highly heterogeneous disease, yet prognostication relies predominantly on clinical tools. We recently demonstrated that integration of mutation status of 7 genes, including EZH2 and MEF2B, improves risk stratification. We mined gene expression data to uncover genes that are differentially expressed in EZH2- and MEF2B-mutated cases. We focused on FOXP1 and assessed its protein expression by immunohistochemistry (IHC) in 763 tissue biopsies. For outcome correlation, a population-based training cohort of 142 patients with FL treated with rituximab, cyclophosphamide, vincristine, and prednisone, and a clinical trial validation cohort comprising 395 patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) ± rituximab were used. We found FOXP1 to be significantly downregulated in both EZH2- and MEF2B-mutated cases. By IHC, 76 specimens in the training cohort (54%) had high FOXP1 expression (>10%), which was associated with reduced 5-year failure-free survival (FFS) rates (55% vs 70%). In the validation cohort, high FOXP1 expression status was observed in 248 patients (63%) and correlated with significantly shorter FFS in patients treated with R-CHOP (hazard ratio [HR], 1.95; P = .017) but not in patients treated with CHOP (HR, 1.15; P = .44). The impact of high FOXP1 expression on FFS in immunochemotherapy-treated patients was additional to the Follicular Lymphoma International Prognostic Index. High FOXP1 expression was associated with distinct molecular features such as TP53 mutations, expression of IRF4, and gene expression signatures reminiscent of dark zone germinal center or activated B cells. In summary, FOXP1 is a downstream phenotypic commonality of gene mutations and predicts outcome following rituximab-containing regimens.","author":[{"dropping-particle":"","family":"Mottok","given":"Anja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jurinovic","given":"Vindi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Farinha","given":"Pedro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenwald","given":"Andreas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leich","given":"Ellen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ott","given":"German","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horn","given":"Heike","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klapper","given":"Wolfram","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boesl","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hiddemann","given":"Wolfgang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steidl","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connors","given":"Joseph M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sehn","given":"Laurie H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gascoyne","given":"Randy D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoster","given":"Eva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weigert","given":"Oliver","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kridel","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2018","1","11"]]},"page":"226-235","title":"FOXP1 expression is a prognostic biomarker in follicular lymphoma treated with rituximab and chemotherapy.","type":"article-journal","volume":"131"},"uris":[""]}],"mendeley":{"formattedCitation":"[1]","plainTextFormattedCitation":"[1]","previouslyFormattedCitation":"[1]"},"properties":{"noteIndex":0},"schema":""}[1].Alig S, et alImpact of age on genetics and treatment efficacy in follicular lymphoma ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3324/haematol.2018.187773","ISSN":"1592-8721","PMID":"29545350","abstract":"Defining the impact of age on treatment outcome in patients with follicular lymphoma (FL) is challenging. Age >60 years is used as a risk factor in commonly applied risk scores.[1][1],[2][2] However, older patients are, per se, at an increased risk of death due to the natural limits of human","author":[{"dropping-particle":"","family":"Alig","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jurinovic","given":"Vindi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pastore","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bararia","given":"Deepak","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"H?be","given":"Sarah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hellmuth","given":"Johannes 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of age on genetics and treatment efficacy in follicular lymphoma.","type":"article-journal","volume":"103"},"uris":[""]}],"mendeley":{"formattedCitation":"[2]","plainTextFormattedCitation":"[2]","previouslyFormattedCitation":"[2]"},"properties":{"noteIndex":0},"schema":""}[2].Araf S, et alGenomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41375-018-0043-y","ISSN":"1476-5551","PMID":"29568095","author":[{"dropping-particle":"","family":"Araf","given":"Shamzah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Jun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Korfi","given":"Koorosh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pangault","given":"Celine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kotsiou","given":"Eleni","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rio-Machin","given":"Ana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rahim","given":"Tahrima","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heward","given":"James","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Clear","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iqbal","given":"Sameena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davies","given":"Jeff 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{"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1182/blood-2018-07-865428","ISSN":"1528-0020","PMID":"30446494","abstract":"Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy number aberrations (CNAs) and copy neutral loss of heterozygosity (cnLOH) identified by chromosome genomic array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in SWOG S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression free survival (PFS), and overall survival (OS). We showed that increased genomic complexity (i.e., the total number of aberration calls) was associated with poor outcome in FL. Certain chromosome arms were critical for clinical outcome. Prognostic CNAs/cnLOH were identified: while early progression was correlated with 2p gain [P=0.007, OR=2.55 (1.29, 5.03)] and 2p cnLOH [P=0.005, OR=10.9 (2.08, 57.2)], 2p gain specifically encompassing VRK2 and FANCL predicted PFS [P=0.01, HR=1.80 (1.14, 2.68)] as well as OS [P=0.005, 2.40 (1.30, 4.40)]; CDKN2A/B (9p) deletion correlated with worse PFS [P=0.004, 3.50 (1.51, 8.28)]; whereas CREBBP (16p) [P<0.001, 6.70 (2.52, 17.58)] and TP53 (17p) [P<0.001, 3.90 (1.85, 8.31)] deletion predicted worse OS. An independent cohort from the m7-FLIPI study was explored, and the prognostic significance of aberration count, and TP53 and CDKN2A/B deletion were further validated. In conclusion, assessing genomic aberrations at FL diagnosis with CGAT improves risk stratification independent of known clinical parameters, and provides a framework for development of future rational targeted therapies.","author":[{"dropping-particle":"","family":"Qu","given":"Xiaoyu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Hongli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Braziel","given":"Rita M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Passerini","given":"Verena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rimsza","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hsi","given":"Eric D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leonard","given":"John P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Sonali M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kridel","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Press","given":"Oliver","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weigert","given":"Oliver","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"LeBlanc","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Friedberg","given":"Jonathan W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fang","given":"Min","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood","id":"ITEM-1","issued":{"date-parts":[["2018","11","16"]]},"page":"blood-2018-07-865428","publisher":"American Society of Hematology","title":"Genomic alterations important for the prognosis in patients with follicular lymphoma treated on SWOG study S0016.","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"[4]","plainTextFormattedCitation":"[4]","previouslyFormattedCitation":"[4]"},"properties":{"noteIndex":0},"schema":""}[4].Trotman J, et alPrognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1470-2045(18)30618-1","ISSN":"1474-5488","PMID":"30309758","abstract":"BACKGROUND Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study. METHODS GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at , number NCT01332968. FINDINGS 1202 patients were enr…","author":[{"dropping-particle":"","family":"Trotman","given":"Judith","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barrington","given":"Sally 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An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (～3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.","author":[{"dropping-particle":"","family":"Musilova","given":"Katerina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Devan","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cerna","given":"Katerina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seda","given":"Vaclav","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pavlasova","given":"Gabriela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sharma","given":"Sonali","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oppelt","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pytlik","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Prochazka","given":"Vit","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Prouzova","given":"Zuzana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trbusek","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zlamalikova","given":"Lenka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liskova","given":"Kvetoslava","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kruzova","given":"Lenka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jarosova","given":"Marie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mareckova","given":"Andrea","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kornauth","given":"Christoph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Simonitsch-Klupp","given":"Ingrid","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schiefer","given":"Ana-Iris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Merkel","given":"Olaf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mocikova","given":"Heidi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burda","given":"Pavel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Machova Polakova","given":"Katerina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kren","given":"Leos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mayer","given":"Jiri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zent","given":"Clive S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trneny","given":"Marek","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Evans","given":"Andrew G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Janikova","given":"Andrea","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mraz","given":"Marek","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood","id":"ITEM-1","issue":"22","issued":{"date-parts":[["2018","9","13"]]},"page":"blood-2018-06-855502","title":"<i>miR-150</i> downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels","type":"article-journal","volume":"132"},"uris":[""]}],"mendeley":{"formattedCitation":"[6]","plainTextFormattedCitation":"[6]","previouslyFormattedCitation":"[6]"},"properties":{"noteIndex":0},"schema":""}[6].Cottereau AS, et alPrognostic model for high-tumor-burden follicular lymphoma integrating baseline and end-induction PET: a LYSA/FIL study ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1182/blood-2017-11-816298","ISSN":"0006-4971","PMID":"29559480","abstract":"Both total metabolic tumor volume (TMTV), computed on baseline positron emission tomography (PET), and end of induction (EOI) PET are imaging biomarkers showing promise for early risk stratification in patients with high-tumor-burden follicular lymphoma. A model was built incorporating these 2 factors in 159 patients from three prospective trials: 2 Lymphoma Study Association (LYSA) studies and 1 Fondazione Italiana Linfomi (FIL) trial. Median follow up was 64 months. High TMTV (>510 cm3) and positive EOI PET were independent, significant risk factors for progression. Their combination stratified the population into 3 risk groups: patients with no risk factors (n = 102; 64%) had a 5-year progression-free survival (PFS) of 67% vs 33% (hazard ratio [HR], 2.9; 95% confidence interval [CI], 1.8-4.9) for patients with 1 risk factor (n = 44; 27%) and only 23% (HR, 4.6; 95% CI, 2.3-9.2) for patients with both risk factors (n = 13; 8%). 2-year PFS was respectively 90% vs 61% (HR, 4.8; 95% CI, 2.2-10.4) and 46% (HR, 8.1; 95%CI, 3.1-21.3). This model enhances the prognostic value of PET staging and response assessment, identifying a subset of patients with a very high risk of progression and early treatment failure at 2 years.","author":[{"dropping-particle":"","family":"Cottereau","given":"Anne Ségolène","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Versari","given":"Annibale","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Luminari","given":"Stefano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dupuis","given":"Jehan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chartier","given":"Lo?c","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casasnovas","given":"René-Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriolo-Riedinger","given":"Alina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Menga","given":"Massimo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haioun","given":"Corinne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tilly","given":"Hervé","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tarantino","given":"Vittoria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Federico","given":"Massimo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Salles","given":"Gilles","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trotman","given":"Judith","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meignan","given":"Michel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood","id":"ITEM-1","issue":"22","issued":{"date-parts":[["2018","5","31"]]},"page":"2449-2453","title":"Prognostic model for high-tumor-burden follicular lymphoma integrating baseline and end-induction PET: a LYSA/FIL study","type":"article-journal","volume":"131"},"uris":[""]}],"mendeley":{"formattedCitation":"[7]","plainTextFormattedCitation":"[7]","previouslyFormattedCitation":"[7]"},"properties":{"noteIndex":0},"schema":""}[7].Delfau-Larue MH, et al.Total metabolic tumor volume, circulating tumor cells, cell-free DNA: distinct prognostic value in follicular lymphoma ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1182/bloodadvances.2017015164","ISSN":"2473-9529","PMID":"29636326","abstract":"Outcomes for follicular lymphoma (FL) have greatly improved, but most patients will ultimately relapse. High total metabolic tumor volume (TMTV), computed from baseline 18F-fluorodeoxyglucose-positron emission tomography (PET), is associated with shorter progression-free survival (PFS), but circulating tumor cells (CTCs) and cell-free DNA (cfDNA) may also reflect tumor burden and be of prognostic value. The aim of our study was to correlate CTCs and cfDNA with TMTV in FL at diagnosis and to determine their prognostic values. We retrospectively analyzed 133 patients (with previously untreated FL and a baseline PET) from 2 cohorts with either a baseline plasma sample (n = 61) or a bcl2-JH-informative peripheral blood (PB) sample (n = 68). Quantification of circulating bcl2-JH+ cells and cfDNA was performed by droplet digital polymerase chain reaction. A significant correlation was found between TMTV and both CTCs (P < .0001) and cfDNA (P < .0001). With a median 48-month follow-up, 4-year PFS was lower in patients with TMTV > 510 cm3 (P = .0004), CTCs >0.0018 PB cells (P = .03), or cfDNA >2550 equivalent-genome/mL (P = .04). In comparison with TMTV alone, no additional prognostic information was obtained by measuring CTCs. In contrast, Cox multivariate analysis, including cfDNA and TMTV, showed that both cfDNA and TMTV remained predictive of outcome. In conclusion, CTCs and cfDNA correlate with TMTV in FL, and all 3 influence patient outcome. PFS was shorter for patients with high cfDNA and TMTV, suggesting that these parameters provide relevant information for tumor-tailored therapy.","author":[{"dropping-particle":"","family":"Delfau-Larue","given":"Marie-Hélène","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gucht","given":"Axel","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dupuis","given":"Jehan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jais","given":"Jean-Philippe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nel","given":"Isabelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beldi-Ferchiou","given":"Asma","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hamdane","given":"Salma","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Benmaad","given":"Ichrafe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laboure","given":"Gaelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verret","given":"Benjamin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haioun","given":"Corinne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Copie-Bergman","given":"Christiane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriolo-Riedinger","given":"Alina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robert","given":"Philippine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casasnovas","given":"René-Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Itti","given":"Emmanuel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood Advances","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2018","4","10"]]},"page":"807-816","title":"Total metabolic tumor volume, circulating tumor cells, cell-free DNA: distinct prognostic value in follicular lymphoma","type":"article-journal","volume":"2"},"uris":[""]}],"mendeley":{"formattedCitation":"[8]","plainTextFormattedCitation":"[8]","previouslyFormattedCitation":"[8]"},"properties":{"noteIndex":0},"schema":""}[8].TreatmentSarkozy C, et alCause of Death in Follicular Lymphoma in the First Decade of the Rituximab Era: A Pooled Analysis of French and US Cohorts ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.18.00400","ISSN":"1527-7755","PMID":"30481079","abstract":"PURPOSE Although the life expectancy of patients with follicular lymphoma (FL) has increased, little is known of their causes of death (CODs) in the rituximab era. PATIENTS AND METHODS We pooled two cohorts of newly diagnosed patients with FL grade 1-3A. Patients were enrolled between 2001 and 2013 in two French referral institutions (N = 734; median follow-up 89 months) and 2002 and 2012 in the University of Iowa and Mayo Clinic Specialized Program of Research Excellence (SPORE; N = 920; median follow-up 84 months). COD was classified as being a result of lymphoma, other malignancy, treatment related, or all other causes. RESULTS Ten-year overall survival was comparable in the French (80%) and US (77%) cohorts. We were able to classify COD in 248 (88%) of 283 decedents. In the overall cohort, lymphoma was the most common COD, with a cumulative incidence of 10.3% at 10 years, followed by treatment-related mortality (3.0%), other malignancy (2.9%), other causes (2.2%), and unknown (3.0%). The 10-year cumulative incidence of death as a result of lymphoma or treatment was higher than death as a result of all other causes for each age group (including patients ≥ 70 years of age at diagnosis [25.4% v 16.6%]) Follicular Lymphoma International Prognostic Index score 3 to 5 (27.4% v 5.2%), but not Follicular Lymphoma International Prognostic Index score 0 to 1 (4.0% v 3.7%); for patients who failed to achieve event-free survival within 24 months from diagnosis (36.1% v 7.0%), but not for patients who achieved event-free survival within 24 months of diagnosis (6.7% v 5.7%); and for patients with a history of transformed FL (45.9% v 4.7%), but not among patients without (8.1% v 6.2%). Overall, 77 of 140 deaths as a result of lymphoma occurred in patients whose FL transformed after diagnosis. CONCLUSION Despite the improvement in overall survival in patients with FL in the rituximab era, their leading COD remains lymphoma, especially after disease transformation. Treatment-related mortality also represents a concern, which supports the need for less-toxic therapies.","author":[{"dropping-particle":"","family":"Sarkozy","given":"Clémentine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maurer","given":"Matthew J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Link","given":"Brian K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ghesquieres","given":"Hervé","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nicolas","given":"Emmanuelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thompson","given":"Carrie A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Traverse-Glehen","given":"Alexandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feldman","given":"Andrew L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Allmer","given":"Cristine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Slager","given":"Susan L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ansell","given":"Stephen M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Habermann","given":"Thomas M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachy","given":"Emmanuel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cerhan","given":"James R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Salles","given":"Gilles","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2019","1","10"]]},"page":"144-152","title":"Cause of Death in Follicular Lymphoma in the First Decade of the Rituximab Era: A Pooled Analysis of French and US Cohorts.","type":"article-journal","volume":"37"},"uris":[""]}],"mendeley":{"formattedCitation":"[9]","plainTextFormattedCitation":"[9]","previouslyFormattedCitation":"[9]"},"properties":{"noteIndex":0},"schema":""}[9].Watanabe T, et alOutcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S2352-3026(18)30155-8","ISSN":"2352-3026","PMID":"30389034","abstract":"BACKGROUND 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. METHODS 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 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Haematology","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2018","11"]]},"page":"e520-e531","title":"Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial.","type":"article-journal","volume":"5"},"uris":[""]}],"mendeley":{"formattedCitation":"[10]","plainTextFormattedCitation":"[10]","previouslyFormattedCitation":"[10]"},"properties":{"noteIndex":0},"schema":""}[10].Lockmer S, et alChemotherapy-Free Initial Treatment of Advanced Indolent Lymphoma Has Durable Effect With Low Toxicity: Results From Two Nordic Lymphoma Group Trials With More Than 10 Years of Follow-Up ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.18.00262","ISSN":"1527-7755","PMID":"30285560","abstract":"PURPOSE For indolent lymphoma, the optimal timing, sequence, and choice of therapeutic regimens remain a matter of debate. In two Nordic Lymphoma Group randomized trials, symptomatic or clearly progressing patients were treated first line with a rituximab-containing regimen without chemotherapy. The purpose of this study was to assess long-term survival, risk of transformation, and need of new therapies. METHODS Data were collected at cross-sectional follow-up for 321 patients with indolent lymphoma (84% with follicular lymphomas [FL]) included in one of two Nordic Lymphoma Group trials (accrual 1998 to 1999 and 2002 to 2008). All patients received first-line therapy with one or two cycles of four weekly infusions of rituximab 375 mg/m2, and 148 were randomly allocated to the addition of interferon alfa-2a. Follow-up data were retrieved from initial trial databases and medical records on repeated clinical evaluations. RESULTS At the end of follow-up, 73% of patients were alive, with a median follow-up after random assignment of 10.6 years. Among all, 36% (38% with FL) had never needed chemotherapy. For patients with FL who required new therapy within 24 months because of early disease progression, the 10-year survival rate was 59% versus 81% for those with longer remission. Interferon was not shown to improve long-term outcome. Transformation was diagnosed in 20% of all patients (2.4% per person-year) and in 18% with FL. An additional malignancy was found in 12%. CONCLUSION Approximately one third of patients with symptomatic indolent lymphoma (30% with FL, 23% without FL) did not need new therapy in the long term after first-line rituximab without chemotherapy. In the entire cohort, 10-year survival was excellent with no major safety issues, which suggests that chemotherapy can be delayed safely in the majority of patients.","author":[{"dropping-particle":"","family":"Lockmer","given":"Sandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"?stenstad","given":"Bj?rn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hagberg","given":"Hans","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holte","given":"Harald","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Ann-Sofie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wahlin","given":"Bj?rn Engelbrekt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wader","given":"Karin Fahl","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steen","given":"Chloé Beate","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meyer","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maisenh?lder","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smedby","given":"Karin Ekstr?m","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brown","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kimby","given":"Eva","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","id":"ITEM-1","issue":"33","issued":{"date-parts":[["2018","10","4"]]},"page":"JCO1800262","title":"Chemotherapy-Free Initial Treatment of Advanced Indolent Lymphoma Has Durable Effect With Low Toxicity: Results From Two Nordic Lymphoma Group Trials With More Than 10 Years of Follow-Up.","type":"article-journal","volume":"36"},"uris":[""]}],"mendeley":{"formattedCitation":"[11]","plainTextFormattedCitation":"[11]","previouslyFormattedCitation":"[11]"},"properties":{"noteIndex":0},"schema":""}[11].Jurinovic V, et al.Autologous Stem Cell Transplantation for Patients with Early Progression of Follicular Lymphoma: A Follow-Up Study of 2 Randomized Trials from the German Low Grade Lymphoma Study Group ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.bbmt.2018.03.022","ISSN":"10838791","PMID":"29605716","abstract":"Patients with follicular lymphoma (FL) and progression of disease (POD) within 24 months after frontline treatment (POD24) have poor overall survival (OS). The optimal salvage treatment for these patients is unknown. We assessed the role of high-dose therapy and autologous stem cell transplantation (ASCT) in transplant-eligible patients. We analyzed 162 patients with advanced-stage FL who had received frontline treatment within the GLSG1996 or GLSG2000 trials. All patients had POD at age ≤ 65 years and had not received a prior transplant. Second-line treatment was not specified by study protocols. Survival was calculated from time of second-line treatment. Eighteen patients (11%) progressed (n?=?16) or died (n?=?2) during cytoreductive second-line treatment (considered \"cytoreduction failure\"); none received ASCT, and their median second-line OS was <1 year. A total of 113 patients had POD24 (70%), whereas 49 had POD after 24 months (30%). Sixty-three patients without cytoreduction failure received ASCT (39%), and 81 received no transplant (50%). In patients with POD24, a significant survival benefit was associated with ASCT with a 5-year second-line progression-free survival for ASCT versus no transplant of 51% versus 19% (hazard ratio, .38; 95% confidence interval, .24 to .62; P?<?.0001) and a 5-year second-line OS of 77% versus 59% (hazard ratio, .54, 95% confidence interval, .30 to .95; P=?.031). Thus, ASCT is an effective treatment option for transplant-eligible patients with high-risk FL as identified by POD24 and should be evaluated in prospective clinical trials.","author":[{"dropping-particle":"","family":"Jurinovic","given":"Vindi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Metzner","given":"Bernd","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pfreundschuh","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schmitz","given":"Norbert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wandt","given":"Hannes","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Keller","given":"Ulrich","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dreger","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dreyling","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hiddemann","given":"Wolfgang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Unterhalt","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoster","given":"Eva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weigert","given":"Oliver","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Biology of Blood and Marrow Transplantation","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2018","6"]]},"page":"1172-1179","title":"Autologous Stem Cell Transplantation for Patients with Early Progression of Follicular Lymphoma: A Follow-Up Study of 2 Randomized Trials from the German Low Grade Lymphoma Study Group","type":"article-journal","volume":"24"},"uris":[""]}],"mendeley":{"formattedCitation":"[12]","plainTextFormattedCitation":"[12]","previouslyFormattedCitation":"[12]"},"properties":{"noteIndex":0},"schema":""}[12].Luminari S, et alLong-Term Results of the FOLL05 Trial Comparing R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Symptomatic Follicular Lymphoma ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2017.74.1652","ISSN":"1527-7755","PMID":"29095677","abstract":"Purpose The FOLL05 trial compared R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-FM (rituximab plus fludarabine and mitoxantrone) regimens without rituximab maintenance as initial therapy for patients with advanced-stage follicular lymphoma (FL). A previous analysis with a median follow-up of 34 months showed a superior 3-year time to treatment failure, the primary study end point, with R-CHOP and R-FM versus R-CVP and showed R-CHOP to have a better risk-benefit ratio in terms of toxicity than R-FM. We report a post hoc analysis of this trial after a median follow-up of 7 years. Patients and Methods Of the 534 enrolled patients, 504 were evaluable. At the time of analysis, the median follow-up was 84 months (range, 1 to 119 months). Results The 8-year time to treatment failure and progression-free survival rates were 44% (95% CI, 39% to 49%) and 48% (95% CI, 43% to 53%), respectively. The hazard ratio for progression-free survival adjusted by FL International Prognostic Index 2 versus R-CVP was 0.73 for R-CHOP (95% CI, 0.54 to 0.98; P = .037) and 0.67 for R-FM (95% CI, 0.50 to 0.91; P = .009). The 8-year overall survival (OS) rate was 83% (95% CI, 79% to 87%), with no significant differences among study arms. Overall, we observed a higher risk of dying as a result of causes unrelated to lymphoma progression with R-FM versus R-CVP. Conclusion With an 83% 8-year OS rate, long-term follow-up of the FOLL05 trial confirms the favorable outcome of patients with advanced-stage FL treated with immunochemotherapy. The three study arms had similar OS but different activity and toxicity profiles. Patients initially treated with R-CVP had a higher risk of lymphoma progression compared with those receiving R-CHOP, as well as a higher risk of requiring additional therapy.","author":[{"dropping-particle":"","family":"Luminari","given":"Stefano","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ferrari","given":"Angela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manni","given":"Martina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dondi","given":"Alessandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chiarenza","given":"Annalisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Merli","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rusconi","given":"Chiara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tarantino","given":"Vittoria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tucci","given":"Alessandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vitolo","given":"Umberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kovalchuk","given":"Sofia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Angelucci","given":"Emanuele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pulsoni","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arcaini","given":"Luca","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Angrilli","given":"Francesco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gaidano","given":"Gianluca","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stelitano","given":"Caterina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bertoldero","given":"Giovanni","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cascavilla","given":"Nicola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Salvi","given":"Flavia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ferreri","given":"Andrés J M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vallisa","given":"Daniele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marcheselli","given":"Luigi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Federico","given":"Massimo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2018","3","1"]]},"page":"689-696","title":"Long-Term Results of the FOLL05 Trial Comparing R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Symptomatic Follicular Lymphoma.","type":"article-journal","volume":"36"},"uris":[""]}],"mendeley":{"formattedCitation":"[13]","plainTextFormattedCitation":"[13]","previouslyFormattedCitation":"[13]"},"properties":{"noteIndex":0},"schema":""}[13].Shadman M, et al.Continued Excellent Outcomes in Previously Untreated Patients With Follicular Lymphoma After Treatment With CHOP Plus Rituximab or CHOP Plus 131I-Tositumomab: Long-Term Follow-Up of Phase III Randomized Study SWOG-S0016 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2017.74.5083","ISSN":"1527-7755","PMID":"29356608","abstract":"Purpose SWOG S0016 was a phase III randomized study that compared the safety and efficacy of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) with CHOP-RIT (CHOP followed by consolidation with iodine-133-tositumomab radioimmunotherapy) for previously untreated patients with follicular lymphoma. Understanding the long-term outcome of patients provides a benchmark for novel treatment regimens for FL. Patients and Methods Between 2001 and 2008, 531 previously untreated patients with FL were randomly assigned to receive either six cycles of R-CHOP or six cycles of CHOP-RIT. Patients with advanced-stage disease (bulky stage II, III, or IV) of any pathologic grade (1, 2, or 3) were eligible. Results After a median follow-up of 10.3 years, 10-year estimates of progression-free and overall survival were 49% and 78% among all patients, respectively. Patients in the CHOP-RIT arm had significantly better 10-year progression-free survival compared with patients in the R-CHOP arm (56% v 42%; P = .01), but 10-year overall survival was not different between the two arms (75% v 81%; P = .13). There was no significant difference between the CHOP-RIT and R-CHOP arms in regard to incidence of second malignancies (15.1% v 16.1%; P = .81) or myelodysplastic syndrome or acute myeloid leukemia (4.9% v 1.8%; P = .058). The estimated 10-year cumulative incidences of death resulting from second malignancies were not different (7.1% v 3.2%; P = .16), but cumulative incidence of death resulting from myelodysplastic syndrome or acute myeloid leukemia was higher in the CHOP-RIT arm compared with the R-CHOP arm (4% v 0.9%; P = .02). Conclusion Given these outstanding outcomes, immunochemotherapy should remain the standard induction approach for patients with high-risk FL until long-term follow-up of alternative approaches demonstrates superiority.","author":[{"dropping-particle":"","family":"Shadman","given":"Mazyar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Hongli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rimsza","given":"Lisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leonard","given":"John P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaminski","given":"Mark S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Braziel","given":"Rita M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spier","given":"Catherine M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gopal","given":"Ajay K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maloney","given":"David G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cheson","given":"Bruce D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dakhil","given":"Shaker","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"LeBlanc","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Sonali M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fisher","given":"Richard I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Friedberg","given":"Jonathan W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Press","given":"Oliver W","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2018","3","1"]]},"page":"697-703","title":"Continued Excellent Outcomes in Previously Untreated Patients With Follicular Lymphoma After Treatment With CHOP Plus Rituximab or CHOP Plus 131I-Tositumomab: Long-Term Follow-Up of Phase III Randomized Study SWOG-S0016.","type":"article-journal","volume":"36"},"uris":[""]}],"mendeley":{"formattedCitation":"[14]","plainTextFormattedCitation":"[14]","previouslyFormattedCitation":"[14]"},"properties":{"noteIndex":0},"schema":""}[14].Supplementary material. Ongoing and future trialsBiologyBased on the promising, yet ultimately suboptimal, results of gene sequencing and gene expression studies, multi-level biological testing, including not only these two, but also less explored areas of transcriptomics ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.immuni.2014.12.021","ISSN":"1097-4180","PMID":"25607463","abstract":"Most B-cell lymphomas arise in the germinal center (GC), where humoral immune responses evolve from potentially oncogenic cycles of mutation, proliferation, and clonal selection. Although lymphoma gene expression diverges significantly from GC B cells, underlying mechanisms that alter the activities of corresponding regulatory elements (REs) remain elusive. Here we define the complete pathogenic circuitry of human follicular lymphoma (FL), which activates or decommissions REs from normal GC B?cells and commandeers enhancers from other lineages. Moreover, independent sets of transcription factors, whose expression was deregulated in?FL, targeted commandeered versus decommissioned REs. Our approach revealed two distinct subtypes of low-grade FL, whose pathogenic circuitries resembled GC B or activated B cells. FL-altered enhancers also were enriched for sequence variants, including somatic mutations, which disrupt transcription-factor?binding and expression of circuit-linked genes. Thus, the pathogenic regulatory circuitry of FL reveals distinct genetic and epigenetic etiologies for GC B-cell transformation.","author":[{"dropping-particle":"","family":"Koues","given":"Olivia I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kowalewski","given":"Rodney A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Li-Wei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pyfrom","given":"Sarah C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schmidt","given":"Jennifer A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Luo","given":"Hong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sandoval","given":"Luis E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hughes","given":"Tyler B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bednarski","given":"Jeffrey J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cashen","given":"Amanda F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Payton","given":"Jacqueline E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oltz","given":"Eugene M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Immunity","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2015","1","20"]]},"page":"186-98","title":"Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma.","type":"article-journal","volume":"42"},"uris":[""]}],"mendeley":{"formattedCitation":"[15]","plainTextFormattedCitation":"[15]","previouslyFormattedCitation":"[15]"},"properties":{"noteIndex":0},"schema":""}[15] and methylation analysis ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ng.3413","ISSN":"1061-4036","PMID":"26437030","abstract":"Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas.","author":[{"dropping-particle":"","family":"Kretzmer","given":"Helene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bernhart","given":"Stephan H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Wei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haake","given":"Andrea","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weniger","given":"Marc A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergmann","given":"Anke 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differentially methylated regions linked to somatic mutation and transcriptional control","type":"article-journal","volume":"47"},"uris":[""]}],"mendeley":{"formattedCitation":"[16]","plainTextFormattedCitation":"[16]","previouslyFormattedCitation":"[16]"},"properties":{"noteIndex":0},"schema":""}[16] will be key to further our understanding of the disease and will be required for accurate risk-guided therapeutic interventions. In order to obtain the best model, all these levels will need to be explored in the same cohort to find out which findings are of independent value and which are redundant. Specific biological subgroups (such as EZH2-mutated FLADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1470-2045(15)00169-2","ISSN":"1474-5488","PMID":"26256760","abstract":"BACKGROUND Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. METHODS We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). FINDINGS We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31-57·95) versus 77·21% (95% CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%,…","author":[{"dropping-particle":"","family":"Pastore","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jurinovic","given":"Vindi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kridel","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoster","given":"Eva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Staiger","given":"Annette M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szczepanowski","given":"Monika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pott","given":"Christiane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kopp","given":"Nadja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murakami","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horn","given":"Heike","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leich","given":"Ellen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moccia","given":"Alden A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottok","given":"Anja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sunkavalli","given":"Ashwini","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hummelen","given":"Paul","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ducar","given":"Matthew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ennishi","given":"Daisuke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shulha","given":"Hennady P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hother","given":"Christoffer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connors","given":"Joseph M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sehn","given":"Laurie H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dreyling","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neuberg","given":"Donna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"M?ller","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feller","given":"Alfred C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hansmann","given":"Martin L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stein","given":"Harald","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenwald","given":"Andreas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ott","given":"German","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klapper","given":"Wolfram","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Unterhalt","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hiddemann","given":"Wolfgang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gascoyne","given":"Randy D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weinstock","given":"David M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weigert","given":"Oliver","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet. Oncology","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2015","9"]]},"page":"1111-1122","title":"Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry.","type":"article-journal","volume":"16"},"uris":[""]}],"mendeley":{"formattedCitation":"[17]","plainTextFormattedCitation":"[17]","previouslyFormattedCitation":"[17]"},"properties":{"noteIndex":0},"schema":""}[17]) must also be studied to rule out a potentially predictive role for biomarkers within these subgroups ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.immuni.2014.12.021","ISSN":"1097-4180","PMID":"25607463","abstract":"Most B-cell lymphomas arise in the germinal center (GC), where humoral immune responses evolve from potentially oncogenic cycles of mutation, proliferation, and clonal selection. Although lymphoma gene expression diverges significantly from GC B cells, underlying mechanisms that alter the activities of corresponding regulatory elements (REs) remain elusive. Here we define the complete pathogenic circuitry of human follicular lymphoma (FL), which activates or decommissions REs from normal GC B?cells and commandeers enhancers from other lineages. Moreover, independent sets of transcription factors, whose expression was deregulated in?FL, targeted commandeered versus decommissioned REs. Our approach revealed two distinct subtypes of low-grade FL, whose pathogenic circuitries resembled GC B or activated B cells. FL-altered enhancers also were enriched for sequence variants, including somatic mutations, which disrupt transcription-factor?binding and expression of circuit-linked genes. Thus, the pathogenic regulatory circuitry of FL reveals distinct genetic and epigenetic etiologies for GC B-cell transformation.","author":[{"dropping-particle":"","family":"Koues","given":"Olivia I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kowalewski","given":"Rodney A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Li-Wei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pyfrom","given":"Sarah C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schmidt","given":"Jennifer A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Luo","given":"Hong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sandoval","given":"Luis E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hughes","given":"Tyler B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bednarski","given":"Jeffrey J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cashen","given":"Amanda F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Payton","given":"Jacqueline E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oltz","given":"Eugene M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Immunity","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2015","1","20"]]},"page":"186-98","title":"Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma.","type":"article-journal","volume":"42"},"uris":[""]}],"mendeley":{"formattedCitation":"[15]","plainTextFormattedCitation":"[15]","previouslyFormattedCitation":"[15]"},"properties":{"noteIndex":0},"schema":""}[15]. These studies should pick out, and ground studies to find out, which markers are prognostic (their value is retained across all therapeutic interventions) and which ones are predictive (their prognostic impact is dependent on the specific agents or strategies (predictive), as the latter are more likely to have a role in risk-guided interventions ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2015.63.3651","ISSN":"0732-183X","PMID":"26392104","abstract":"To demonstrate that a biomarker is predictive of treatment benefit, the study requires biomarker status on all patients as well as patients who were treated with the agent of interest and patients not so treated, preferably in the context of a randomized study. A formal statistical test of the treatment-by-biomarker interaction should be significant. To establish whether a marker is purely prognostic, it needs to be demonstrated that there is a significant association between the biomarker and outcome, regardless of treatment, and that treatment effects do not depend on the biomarker. Finally, a biomarker may have both predictive and prognostic implications. These concepts are summarized in Figure 2.","author":[{"dropping-particle":"V.","family":"Ballman","given":"Karla","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"33","issued":{"date-parts":[["2015","11","20"]]},"page":"3968-3971","title":"Biomarker: Predictive or Prognostic?","type":"article-journal","volume":"33"},"uris":[""]}],"mendeley":{"formattedCitation":"[18]","plainTextFormattedCitation":"[18]","previouslyFormattedCitation":"[18]"},"properties":{"noteIndex":0},"schema":""}[18]. The results will need validation not only in a different cohort but also preferably by different teams given the methodological, analytical and interpretative complexities of these tests.TreatmentNumerous clinical trials in all areas of FL are ongoing. Table 6 shows a personal selection from which a few are worth underscoring: The use of anti-CD20 maintenance offers a PFS but no OS benefit. Two trials will attempt to pick out patients who benefit from maintenance either by randomizing patients after restaging (EudraCT number: 2016-004010-10) or by randomizing patients to a standard maintenance strategy vs. a response-guided one that does not offer antiCD20 maintenance to patients in CR and MRD-negative (NCT02063685). In early treatment failure, a three arm randomized trial (NCT03269669) will attempt to determine what is the best approach to these patients. Obinutuzumab will be given to all patients, who will otherwise be randomized to umbralisib (a PI3K inhibitor), lenalidomide or standard chemotherapy (CHOP or bendamustine based on the front-line regimen. Among targeted agents, tazemetostat (an EZH2 inhibitor) has shown promising early results ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Ribrag, Vincent; Morschhauser, F; McKay, P; Salles, GA; Batlevi, CL; Schmitt, A; TIlly","given":"H;","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood","id":"ITEM-1","issued":{"date-parts":[["2018","12","3"]]},"page":"4196","publisher":"ASH","title":"Interim Results from an Ongoing Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients with Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)","type":"article-journal","volume":"130"},"uris":[""]}],"mendeley":{"formattedCitation":"[19]","plainTextFormattedCitation":"[19]","previouslyFormattedCitation":"[19]"},"properties":{"noteIndex":0},"schema":""}[19]. Predictably, responses seem dependent on EZH2 mutational status. EZH2-mutated FL has a distinct gene expression profile and is correlated with a better prognosis than EZH2-wild type FL ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S1470-2045(15)00169-2","ISSN":"1474-5488","PMID":"26256760","abstract":"BACKGROUND Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. METHODS We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). FINDINGS We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31-57·95) versus 77·21% (95% CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%,…","author":[{"dropping-particle":"","family":"Pastore","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jurinovic","given":"Vindi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kridel","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoster","given":"Eva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Staiger","given":"Annette M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szczepanowski","given":"Monika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pott","given":"Christiane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kopp","given":"Nadja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murakami","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horn","given":"Heike","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leich","given":"Ellen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moccia","given":"Alden A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottok","given":"Anja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sunkavalli","given":"Ashwini","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hummelen","given":"Paul","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ducar","given":"Matthew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ennishi","given":"Daisuke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shulha","given":"Hennady P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hother","given":"Christoffer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connors","given":"Joseph M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sehn","given":"Laurie H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dreyling","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neuberg","given":"Donna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"M?ller","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feller","given":"Alfred C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hansmann","given":"Martin L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stein","given":"Harald","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenwald","given":"Andreas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ott","given":"German","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klapper","given":"Wolfram","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Unterhalt","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hiddemann","given":"Wolfgang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gascoyne","given":"Randy D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weinstock","given":"David M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weigert","given":"Oliver","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Lancet. Oncology","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2015","9"]]},"page":"1111-1122","title":"Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry.","type":"article-journal","volume":"16"},"uris":[""]}],"mendeley":{"formattedCitation":"[17]","plainTextFormattedCitation":"[17]","previouslyFormattedCitation":"[17]"},"properties":{"noteIndex":0},"schema":""}[17]. A retrospective study showed that FL with either EZH2 mutations or copy gains seem to benefit less from rituximab maintenance than those without these alterations, seemingly indicating a predictive biomarker status for EZH2 in regards to rituximab maintenance treatment ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/bcj.2017.32","ISSN":"2044-5385","PMID":"28430172","abstract":"The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n=55) and H3K27 methylation (n=63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n=46, gain n=23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36-0.93, P=0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies.","author":[{"dropping-particle":"","family":"Huet","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xerri","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tesson","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mareschal","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taix","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mescam-Mancini","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sohier","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carrère","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lazarovici","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casasnovas","given":"O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tonon","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boyault","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hayette","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haioun","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fabiani","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viari","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jardin","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Salles","given":"G","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood cancer journal","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017","4","21"]]},"page":"e555","title":"EZH2 alterations in follicular lymphoma: biological and clinical correlations.","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"[20]","plainTextFormattedCitation":"[20]","previouslyFormattedCitation":"[20]"},"properties":{"noteIndex":0},"schema":""}[20]. This may also be the case for tazemetostat, making EZH2 mutational status (and number of copies) an essential part of any risk-stratification strategy.While data are still very limited, CAR T-cells are a promising approach to refractory patients. Phase 2 studies will provide the data needed to determine their place in the treatment algorithms of FL and suggest relevant phase 3 trials.Potential trialsCurrent data lead to questions that suggest clinical trials that are not ongoing. Although some of these trials seem unfeasible for several reasons, they would nevertheless answer scientifically relevant questions. Indeed, lack of feasibility is an important hurdle for current clinical research in FL. Most importantly, phase 3 trials in unselected patients with FL would now require prohibitively large numbers of patients and a very long follow-up, leading to questions being answered when they are no longer as relevant as when the trial was designed ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2018.79.3083","ISSN":"0732-183X","PMID":"29856695","author":[{"dropping-particle":"","family":"Friedberg","given":"Jonathan W.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"23","issued":{"date-parts":[["2018","8","10"]]},"page":"2363-2365","title":"Progress in Advanced-Stage Follicular Lymphoma","type":"article-journal","volume":"36"},"uris":[""]}],"mendeley":{"formattedCitation":"[21]","plainTextFormattedCitation":"[21]","previouslyFormattedCitation":"[21]"},"properties":{"noteIndex":0},"schema":""}[21]. Other trials appear unfeasible because of the constant availability of competitive trials, often industry funded, including more novel and seemingly more appealing alternatives. Some of these unfeasable trials would include: In localized FL, PET-staged patients still relapse despite radiotherapy (with or without chemotherapy) suggesting that PET is not a sensitive enough staging technique (a large recent retrospective study showed a 5-yr probability of freedom from progression of 69% ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1182/blood-2018-04-843540","ISSN":"1528-0020","PMID":"30446493","abstract":"Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40-50%. As 18F-FDG PET-CT upstages 10-60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study. Inclusion criteria were: RT alone for untreated stage I-II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow up ≥3 months. Endpoints were freedom from progression (FFP), local control, and overall survival (OS). FFP and OS were estimated with Kaplan-Meier, and uni- and multivariable analyses of prognostic factors performed with Cox Regression. 512 patients treated from 2000-2017 at 16 centres were eligible for analysis. Median age was 58 years (range 20-90). 410 patients (80.1%) had stage I disease. Median RT dose was 30 Gy (24-52). Median follow up was 52 months (3.2-174.6). 5y-FFP and OS were 68.9% and 95.7%. For stage I, 5y-FFP was 74.1%, vs 49.1% for stage II (p<0.0001). 8 patients relapsed infield (1.6%).4 had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (HR=2.11, 95%CI=1.44-3.10) and BCL2 expression (HR =1.62, 95%CI 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated.","author":[{"dropping-particle":"","family":"Brady","given":"Jessica L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Binkley","given":"Michael S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hajj","given":"Carla","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chelius","given":"Monica","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chau","given":"Karen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Balogh","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Levis","given":"Mario","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Filippi","given":"Andrea Riccardo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jones","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manus","given":"Michael","non-dropping-particle":"Mac","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wirth","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oguchi","given":"Masahiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Krog Vistisen","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andraos","given":"Therese Youssef","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ng","given":"Andrea K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aleman","given":"Berthe M P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choi","given":"Seo Hee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kirova","given":"Youlia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hardy","given":"Sara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reinartz","given":"Gabriele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eich","given":"Hans T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Bratman","given":"Scott","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Constine","given":"Louis S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Suh","given":"Chang-Ok","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dabaja","given":"Bouthaina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"El-Galaly","given":"Tarec C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hodgson","given":"David C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ricardi","given":"Umberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yahalom","given":"Joachim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoppe","given":"Richard T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mikhaeel","given":"N George","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood","id":"ITEM-1","issued":{"date-parts":[["2018","11","16"]]},"page":"blood-2018-04-843540","title":"Definitive radiotherapy for localized follicular lymphoma staged by 18F-FDG PET-CT: a collaborative study by ILROG.","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"[22]","plainTextFormattedCitation":"[22]","previouslyFormattedCitation":"[22]"},"properties":{"noteIndex":0},"schema":""}[22]). Detection of bcl2 in bone marrow has been used, with unsatisfactory results ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1365-2141.2007.06545.x","ISSN":"0007-1048","PMID":"17408460","abstract":"Stage I/IIA follicular lymphoma (FL) is considered a localised disease that can be adequately treated with radiotherapy alone. Bone marrow (BM) and peripheral blood (PB) involvement in FL was investigated by polymerase chain reaction (PCR) in a series of 24 consecutive patients with histologically revised diagnosis and treated with involved field radiotherapy. Despite the limited stage, Bcl-2/IgH+ cells were found at diagnosis in PB and/or BM of 16 patients (66.6%). After treatment, in 9/15 Bcl-2/IgH positive evaluable patients, a disappearance of Bcl-2/IgH+ cells was observed, which persisted after a median follow-up of 43.5 months (range 11-70) in all but one patient. Quantitative PCR demonstrated the feasibility of clearing PB and BM Bcl-2+ cells after local irradiation of the primary site of the disease only when the basal number of lymphoma cells was <1:100 000. Patients with Bcl-2/IgH+ cells at diagnosis or after treatment had a higher likelihood of relapse. Thus, despite a negative BM biopsy, the majority of localised FL Bcl-2/IgH+ cells were found in the PB and BM. Lymphoma cells can reversibly spread from the affected lymph node to PB and BM and, in a proportion of cases, durably disappear after irradiation. The possibility of a persistent lymphoma cell clearance is proportional to the amount of cells detected at presentation by quantitative PCR.","author":[{"dropping-particle":"","family":"Pulsoni","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Della","family":"Starza","given":"Irene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frattarelli","given":"Natalia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ghia","given":"Emanuela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carlotti","given":"Emanuela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cavalieri","given":"Elena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matturro","given":"Angela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tempera","given":"Settimio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rambaldi","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Foà","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Journal of Haematology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2007","5"]]},"page":"216-220","title":"Stage I/II follicular lymphoma: spread of bcl-2/IgH+ cells in blood and bone marrow from primary site of disease and possibility of clearance after involved field radiotherapy","type":"article-journal","volume":"137"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1111/ejh.13093","ISSN":"1600-0609","PMID":"29754401","abstract":"Follicular lymphoma (FL) is the most common indolent lymphoma, and it most frequently presents in an advanced stage. Therapeutic considerations for advanced stage are different from those of localized-stage FL, in which radiotherapy (RT) is generally recommended. However, the available evidence suffers from shortcomings that are relatively specific to this clinical entity due to its rarity and long survival with all available treatment modalities, including that most of the existing evidence originated at a time when diagnostic classifications, staging procedures and radiotherapeutic standards were different from those available today and when anti-CD20 monoclonal antibodies were not available. Available treatment modalities include observation, systemic therapy only, RT only and RT in combination with systemic therapy. We review the evidence available with each of them and the data from present-day clinical practice studies as well as briefly discuss what diagnostic and therapeutic developments may take place in the next few years.","author":[{"dropping-particle":"","family":"Sorigue","given":"Marc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuset","given":"Victòria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sancho","given":"Juan-Manuel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European journal of haematology","id":"ITEM-2","issue":"2","issued":{"date-parts":[["2018","5","12"]]},"page":"245-256","title":"Treatment of localized-stage follicular lymphoma.","type":"article-journal","volume":"101"},"uris":[""]}],"mendeley":{"formattedCitation":"[23,24]","plainTextFormattedCitation":"[23,24]","previouslyFormattedCitation":"[23,24]"},"properties":{"noteIndex":0},"schema":""}[23,24]. Although still experimental, circulating tumor DNA (ctDNA) could eventually provide a more sensitive and reliable staging technique ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1080/10428194.2019.1573998","ISSN":"1042-8194","PMID":"30774000","abstract":"Although targeted deep sequencing of cell-free DNA (cfDNA) was recently used to investigate tumor somatic mutations in particular subtypes of non-Hodgkin lymphomas (NHLs), the immense genetic heterogeneity across subtypes poses a hurdle to design a universal gene panel applicable for diverse subtypes of NHLs. We designed a panel targeting 66 genes associated with NHLs and performed targeted deep sequencing to analyze plasma cfDNA from patients with various subtypes of NHLs. Genetic profiling in plasma cfDNA using the method resulted in 88.0% sensitivity and >99% specificity in detecting mutations present at a frequency greater than 20% in the tumor biopsies. Furthermore, the level of ctDNA significantly decreased and increased depending on designated clinical responses to therapy and disease progression. These results demonstrated that ctDNA sensitively indicated the presence of cancer and reliably correlated with tumor burden, suggesting potential utility of the method for patients with various subtypes of NHLs.","author":[{"dropping-particle":"","family":"Shin","given":"Seung-Ho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Yeon Jeong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Danbi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cho","given":"Duck","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ko","given":"Young Hyeh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cho","given":"Junhun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Woong-Yang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Park","given":"Donghyun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Seok Jin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Won Seog","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Leukemia & Lymphoma","id":"ITEM-1","issued":{"date-parts":[["2019","2","18"]]},"page":"1-10","title":"Analysis of circulating tumor DNA by targeted ultra-deep sequencing across various non-Hodgkin lymphoma subtypes","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1007/s11899-018-0468-4","ISSN":"1558-8211","PMID":"30136210","abstract":"PURPOSE OF REVIEW The use of circulating tumor DNA (ctDNA) for the purposes of diagnosis, prognosis, assessment of treatment response, and monitoring for relapse is a new and developing field in lymphoma. This review aims to summarize many of the most recent advances in ctDNA applications. RECENT FINDINGS Recent studies have demonstrated the use of ctDNA assessment across many lymphoma subtypes including diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, and T-cell lymphoma. In addition, many novel applications of ctDNA assessment have been described such as the development of new prognostic models, investigation of clonal evolution and heterogeneity, early assessment of treatment response, and prediction of response to targeted therapy as a form of personalized medicine. The use of ctDNA has been shown to be feasible across many lymphoma subtypes and has shown significant promise for several new applications. Additional studies will be needed to validate these findings prior to routine use in clinical practice.","author":[{"dropping-particle":"","family":"Darrah","given":"Justin M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herrera","given":"Alex F.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Current Hematologic Malignancy Reports","id":"ITEM-2","issue":"5","issued":{"date-parts":[["2018","10","23"]]},"page":"348-355","title":"Updates on Circulating Tumor DNA Assessment in Lymphoma","type":"article-journal","volume":"13"},"uris":[""]}],"mendeley":{"formattedCitation":"[25,26]","plainTextFormattedCitation":"[25,26]","previouslyFormattedCitation":"[25,26]"},"properties":{"noteIndex":0},"schema":""}[25,26]. Unfortunately, there is still no established threshold that defines what should be considered localized FL. Retrospective data on ctDNA levels of PET-staged localized FL patients who were cured and not cured with RT could provide the foundation for a randomized trial. Patients would be randomized to a standard strategy with PET staging and RT (with or without systemic treatment) vs. an experimental strategy with PET and ctDNA staging and the same treatment. Long-term cure (10-yr disease-free survival) would be the primary endpoint (Supplementary figure 1). A recent long-term report of two randomized trials including a short course of rituximab for patients with high-rumor burden FL showed long term outcomes similar to those seen with ICT ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.18.00262","ISSN":"1527-7755","PMID":"30285560","abstract":"PURPOSE For indolent lymphoma, the optimal timing, sequence, and choice of therapeutic regimens remain a matter of debate. In two Nordic Lymphoma Group randomized trials, symptomatic or clearly progressing patients were treated first line with a rituximab-containing regimen without chemotherapy. The purpose of this study was to assess long-term survival, risk of transformation, and need of new therapies. METHODS Data were collected at cross-sectional follow-up for 321 patients with indolent lymphoma (84% with follicular lymphomas [FL]) included in one of two Nordic Lymphoma Group trials (accrual 1998 to 1999 and 2002 to 2008). All patients received first-line therapy with one or two cycles of four weekly infusions of rituximab 375 mg/m2, and 148 were randomly allocated to the addition of interferon alfa-2a. Follow-up data were retrieved from initial trial databases and medical records on repeated clinical evaluations. RESULTS At the end of follow-up, 73% of patients were alive, with a median follow-up after random assignment of 10.6 years. Among all, 36% (38% with FL) had never needed chemotherapy. For patients with FL who required new therapy within 24 months because of early disease progression, the 10-year survival rate was 59% versus 81% for those with longer remission. Interferon was not shown to improve long-term outcome. Transformation was diagnosed in 20% of all patients (2.4% per person-year) and in 18% with FL. An additional malignancy was found in 12%. CONCLUSION Approximately one third of patients with symptomatic indolent lymphoma (30% with FL, 23% without FL) did not need new therapy in the long term after first-line rituximab without chemotherapy. In the entire cohort, 10-year survival was excellent with no major safety issues, which suggests that chemotherapy can be delayed safely in the majority of patients.","author":[{"dropping-particle":"","family":"Lockmer","given":"Sandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"?stenstad","given":"Bj?rn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hagberg","given":"Hans","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holte","given":"Harald","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Ann-Sofie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wahlin","given":"Bj?rn Engelbrekt","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wader","given":"Karin Fahl","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steen","given":"Chloé Beate","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meyer","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maisenh?lder","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smedby","given":"Karin Ekstr?m","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brown","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kimby","given":"Eva","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","id":"ITEM-1","issue":"33","issued":{"date-parts":[["2018","10","4"]]},"page":"JCO1800262","title":"Chemotherapy-Free Initial Treatment of Advanced Indolent Lymphoma Has Durable Effect With Low Toxicity: Results From Two Nordic Lymphoma Group Trials With More Than 10 Years of Follow-Up.","type":"article-journal","volume":"36"},"uris":[""]}],"mendeley":{"formattedCitation":"[11]","plainTextFormattedCitation":"[11]","previouslyFormattedCitation":"[11]"},"properties":{"noteIndex":0},"schema":""}[11]. A randomized trial of a 4-week course of weekly rituximab (with 4 additional doses for patients in remission) could be compared to physician’s choice front-line. The main endpoint would be OS. This trial would offer relevant information regarding the ultimate value of PFS as an endpoint. It may be even more relevant (and likely to be carried out) when low-risk patients can be accurately selected at diagnosis based on biological testing (Supplementary figure 2).Retrospective studies have indicated that SCT (both autologous and allogeneic) may offer better survival outcomes than no SCT in patients with ETF ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/cncr.31264","ISSN":"0008543X","PMID":"29424927","abstract":"BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains the only potentially curative treatment option for relapsed follicular lymphoma (FL), yet questions remain about the optimal timing. This study analyzed long-term outcomes and associated factors among recipients of allo-HCT with FL. METHODS Patients with relapsed FL who underwent allo-HCT from 2001 to 2011 with a human leukocyte antigen (HLA)-matched donor were included. Outcome analyses for overall survival (OS), progression-free survival (PFS), transplant-related mortality (TRM), and disease relapse/progression were calculated. A multivariate analysis was performed to determine factors associated with outcomes, and a prognostic score for treatment failure was developed in a subset analysis of patients. RESULTS In all, 1567 patients with relapsed FL were included; the median follow-up was 55 months. The 5-year probabilities of OS and PFS were 61% and 52%, respectively. The 5-year cumulative incidences of disease progression/relapse and TRM were 29% and 19%, respectively. Chemoresistant disease, older age, heavy pretreatment, poor performance status (PS), and myeloablative protocols were predictors for worse survival. The prognostic score, using age, lines of prior therapy, disease status, and PS, stratified patients into 3 groups-low, intermediate, and high risk-with 5-year PFS rates of 68%, 53%, and 46%, respectively, and 5-year OS rates of 80%, 62%, and 50%, respectively. CONCLUSIONS Allo-HCT should be considered for patients with relapsed FL and available HLA-matched donors. Outcomes are better in earlier phases of the disease, and reduced-intensity conditioning should be preferred. The prognostic score presented here can assist in counseling patients and determining the time to proceed to transplantation. Cancer 2018;124:1733-42. ? 2018 American Cancer Society.","author":[{"dropping-particle":"","family":"Sureda","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Mei-Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dreger","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carreras","given":"Jeanette","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fenske","given":"Timothy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Finel","given":"Herve","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schouten","given":"Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Montoto","given":"Silvia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robinson","given":"Stephen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Sonali M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boumedil","given":"Ariane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hamadani","given":"Mehdi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pasquini","given":"Marcelo C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2018","4","15"]]},"page":"1733-1742","title":"Allogeneic hematopoietic stem cell transplantation for relapsed follicular lymphoma: A combined analysis on behalf of the Lymphoma Working Party of the EBMT and the Lymphoma Committee of the CIBMTR","type":"article-journal","volume":"124"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1002/cncr.31374","ISSN":"0008543X","PMID":"29645093","abstract":"BACKGROUND Early treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high-risk group of patients with an expected 5-year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated. METHODS This study compared autologous hematopoietic stem cell transplantation (auto-HCT) with either matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo-HCT) as the first transplantation approach for patients with ETF FL (age?≥?18 years) undergoing auto-HCT or allo-HCT between 2002 and 2014. The primary endpoint was OS. The secondary endpoints were progression-free survival, relapse, and nonrelapse mortality (NRM). RESULTS Four hundred forty FL patients had ETF (auto-HCT, 240; MSD hematopoietic stem cell transplantation [HCT], 105; and MUD HCT, 95). With a median follow-up of 69 to 73 months, the adjusted probability of 5-year OS was significantly higher after auto-HCT (70%) or MSD HCT (73%) versus MUD HCT (49%; P?=?.0008). The 5-year adjusted probability of NRM was significantly lower for auto-HCT (5%) versus MSD (17%) or MUD HCT (33%; P?<?.0001). The 5-year adjusted probability of disease relapse was lower with MSD (31%) or MUD HCT (23%) versus auto-HCT (58%; P?<?.0001). CONCLUSIONS Patients with high-risk FL, as defined by ETF, undergoing auto-HCT for FL have low NRM and a promising 5-year OS rate (70%). MSD HCT has lower relapse rates than auto-HCT but similar OS. Cancer 2018;124:2541-51. ? 2018 American Cancer Society.","author":[{"dropping-particle":"","family":"Smith","given":"Sonali M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Godfrey","given":"James","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahn","given":"Kwang Woo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"DiGilio","given":"Alyssa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahmed","given":"Sairah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Agrawal","given":"Vaibhav","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachanova","given":"Veronika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bacher","given":"Ulrike","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bashey","given":"Asad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bola?os-Meade","given":"Javier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cairo","given":"Mitchell","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Andy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chhabra","given":"Saurabh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Copelan","given":"Edward","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dahi","given":"Parastoo B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aljurf","given":"Mahmoud","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Farooq","given":"Umar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ganguly","given":"Siddhartha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hertzberg","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmberg","given":"Leona","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Inwards","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanate","given":"Abraham S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Karmali","given":"Reem","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kenkre","given":"Vaishalee P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kharfan-Dabaja","given":"Mohamed A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klein","given":"Andreas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lazarus","given":"Hillard M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mei","given":"Matthew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mussetti","given":"Alberto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nishihori","given":"Taiga","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramakrishnan Geethakumari","given":"Praveen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saad","given":"Ayman","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Savani","given":"Bipin N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schouten","given":"Harry C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shah","given":"Nirav","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Urbano-Ispizua","given":"Alvaro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vij","given":"Ravi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vose","given":"Julie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sureda","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hamadani","given":"Mehdi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer","id":"ITEM-2","issue":"12","issued":{"date-parts":[["2018","6","15"]]},"page":"2541-2551","title":"Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure","type":"article-journal","volume":"124"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.bbmt.2017.12.771","ISSN":"10838791","PMID":"29242111","abstract":"Patients with follicular lymphoma (FL) experiencing early therapy failure (ETF) within 2 years of frontline chemoimmunotherapy have poor overall survival (OS). We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National LymphoCare Study (NLCS) to determine whether autologous hematopoietic cell transplant (autoHCT) can improve outcomes in this high-risk FL subgroup. ETF was defined as failure to achieve at least partial response after frontline chemoimmunotherapy or lymphoma progression within 2 years of frontline chemoimmunotherapy. We identified 2 groups: the non-autoHCT cohort (patients from the NLCS with ETF not undergoing autoHCT) and the autoHCT cohort (CIBMTR patients with ETF undergoing autoHCT). All patients received rituximab-based chemotherapy as frontline treatment; 174 non-autoHCT patients and 175 autoHCT patients were identified and analyzed. There was no difference in 5-year OS between the 2 groups (60% versus 67%, respectively; P?=?.16). A planned subgroup analysis showed that patients with ETF receiving autoHCT soon after treatment failure (≤1 year of ETF; n?=?123) had higher 5-year OS than those without autoHCT (73% versus 60%, P?=?.05). On multivariate analysis, early use of autoHCT was associated with significantly reduced mortality (hazard ratio, .63; 95% confidence interval, .42 to .94; P?=?.02). Patients with FL experiencing ETF after frontline chemoimmunotherapy lack optimal therapy. We demonstrate improved OS when receiving autoHCT within 1 year of treatment failure. Results from this unique collaboration between the NLCS and CIBMTR support consideration of early consolidation with autoHCT in select FL patients experiencing ETF.","author":[{"dropping-particle":"","family":"Casulo","given":"Carla","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Friedberg","given":"Jonathan W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahn","given":"Kwang W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Flowers","given":"Christopher","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"DiGilio","given":"Alyssa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Sonali 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L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shah","given":"Nina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Solh","given":"Melham","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sureda","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"William","given":"Basem","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cumpston","given":"Aaron","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zelenetz","given":"Andrew D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Link","given":"Brian K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hamadani","given":"Mehdi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Biology of Blood and Marrow Transplantation","id":"ITEM-3","issue":"6","issued":{"date-parts":[["2018","6"]]},"page":"1163-1171","title":"Autologous Transplantation in Follicular Lymphoma with Early Therapy Failure: A National LymphoCare Study and Center for International Blood and Marrow Transplant Research Analysis","type":"article-journal","volume":"24"},"uris":[""]}],"mendeley":{"formattedCitation":"[27–29]","plainTextFormattedCitation":"[27–29]","previouslyFormattedCitation":"[27–29]"},"properties":{"noteIndex":0},"schema":""}[27–29]. Randomized trials including SCT after relapse have traditionally failed to accrue enough patients ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2003.10.023","ISSN":"0732-183X","PMID":"14517188","abstract":"PURPOSE To determine, in a randomized clinical trial, whether high-dose therapy (HDT) followed by autologous stem-cell transplantation is more effective than standard treatment with regard to progression-free survival (PFS) and overall survival (OS) in patients with relapsed follicular non-Hodgkin's lymphoma; and to assess the additional value of B-cell purging of the stem-cell graft with regards to PFS and OS. PATIENTS AND METHODS Patients received three cycles of chemotherapy. Responding patients with limited bone marrow infiltration were eligible for random assignment to three further cycles of chemotherapy (C), unpurged HDT (U), or purged HDT (P). RESULTS Between August 1993 and April 1997, 140 patients were registered from 36 centers internationally, and 89 were randomly assigned. Reasons for not randomizing included patient refusal, early progression, or death on induction therapy. With a 69-month median follow-up, the log-rank P value for PFS and OS were.0037 and.079, respectively. For PFS, the hazard ratios (95% CIs) for U versus C, P versus C, and P versus U were 0.33 (0.16 to 0.70), 0.38 (0.19 to 0.79), and 1.02 (0.51 to 2.05), respectively. The hazard ratio (95% CI) for C versus U + P was 0.30 (0.15 to 0.61). Hazard ratios (95% CIs) for OS were 0.43 (0.18 to 1.06), 0.43 (0.18 to 1.02), and 0.72 (0.32 to 1.63). For C versus U + P, the hazard ratio (95% CI) was 0.40 (0.18 to 0.89). Kaplan-Meier estimates (95% CIs) of 2-year PFS for C, U, and P were 26% (8% to 44%), 58% (37% to 79%), and 55% (34% to 75%), respectively. OS at 4 years for C, U, and P are 46% (25% to 67%), 71% (52% to 91%), and 77% (60% to 95%) respectively. CONCLUSION HDT significantly improves PFS and OS. There is no clear evidence of benefit through purging.","author":[{"dropping-particle":"","family":"Schouten","given":"Harry C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Qian","given":"Wendi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kvaloy","given":"Stein","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Porcellini","given":"Adolfo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hagberg","given":"Hans","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johnsen","given":"Hans Erik","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Doorduijn","given":"Jeanette K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sydes","given":"Matthew R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kvalheim","given":"Gunnar","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"21","issued":{"date-parts":[["2003","11","1"]]},"page":"3918-3927","title":"High-Dose Therapy Improves Progression-Free Survival and Survival in Relapsed Follicular Non-Hodgkin’s Lymphoma: Results From the Randomized European CUP Trial","type":"article-journal","volume":"21"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.bbmt.2010.11.004","ISSN":"1523-6536","PMID":"21073974","abstract":"Patients with follicular lymphoma (FL) typically experience an indolent course; however, the disease is rarely curable with conventional chemotherapy. Autologous hematopoietic cell transplantation (HCT) can extend progression-free survival (PFS) and overall survival (OS), but relapse is the primary cause of failure. Allogeneic HCT confers lower relapse rates due to a graft-versus-lymphoma effect. Reduced-intensity conditioning (RIC) allows the performance of allogeneic HCT with lower toxicity. The Blood and Marrow Transplant Clinical Trials Network conducted a prospective multicenter trial comparing these two strategies in patients with relapsed, chemotherapy-sensitive FL. Patients were assigned to a treatment arm based on the availability of an HLA-matched sibling donor (MSD). Those with an MSD underwent allogeneic HCT (n = 8) with the FCR preparative regimen (fludarabine, cyclophosphamide [Cy], rituximab [RTX]) and received tacrolimus and methotrexate for graft-versus-host disease (GVHD) prophylaxis. Those without an MSD (n = 22) underwent mobilization with Cy, RTX, and filgrastim and received a conditioning regimen of either CBV (Cy, carmustine, Etoposide [VP16]) or total body irradiation with Cy and VP16. Patients undergoing autologous HCT received 4 doses of weekly maintenance RTX (375 mg/m?) starting on day +42 post-HCT. Sixteen patients were in complete remission, 10 patients were in partial remission, and 1 patient had stable disease after salvage therapy and before HCT. Median follow-up was 36 months (range, 1-51 months). OS was 73% in autologous HCT versus 100% in allogeneic HCT, and PFS was 63% in autologous HCT versus 86% in allogeneic HCT. No patient had grade II-IV acute GVHD; two patients developed extensive chronic GVHD. Three autologous recipients died from nonrelapse causes. This trial closed early because of slow accrual. We show that the FCR regimen is well tolerated, and that both allogeneic and autologous HCT result in promising 3-year OS and PFS in patients with relapsed FL.","author":[{"dropping-particle":"","family":"Tomblyn","given":"Marcie R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ewell","given":"Marian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bredeson","given":"Christopher","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kahl","given":"Brad S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goodman","given":"Stacey A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Horowitz","given":"Mary M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vose","given":"Julie M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Negrin","given":"Robert S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laport","given":"Ginna G","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation","id":"ITEM-2","issue":"7","issued":{"date-parts":[["2011","7"]]},"page":"1051-7","publisher":"NIH Public Access","title":"Autologous versus reduced-intensity allogeneic hematopoietic cell transplantation for patients with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first partial response.","type":"article-journal","volume":"17"},"uris":[""]}],"mendeley":{"formattedCitation":"[30,31]","plainTextFormattedCitation":"[30,31]","previouslyFormattedCitation":"[30,31]"},"properties":{"noteIndex":0},"schema":""}[30,31], arguably based on the frontloaded risks of the treatment and the lack of interest of the pharmaceutical industry. The current awareness of the high-risk nature of ETF may raise renewed interest in a trial including such strategies. One could consider a response-based randomization, with patients in CR by PET after second-line treatment randomized to autologous SCT or standard treatment (with standard maintenance or targeted therapy until progression) and patients in PR by PET or any remission after more than 2 previous lines of therapy randomized to autologous SCT or allogeneic SCT (Supplementary figure 3). Sequencing of therapiesAnother relevant question, and one that may have a preliminary answer based on retrospective clinical analysis, is the optimal sequencing of treatments. Despite the availability of a number of drugs and strategies for each clinical situation, little is known about what the best sequence is ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1182/asheducation-2018.1.189","ISSN":"1520-4383","PMID":"30504309","abstract":"Follicular lymphoma (FL) is an incurable but treatable disease with vast treatment options. Despite the abundance of efficacious treatment modalities, there is no universally agreed upon standard approach to treatment, particularly in the relapsed/refractory setting. There is an increasing need for more robust and clinically available tools to risk-stratify patients and identify those likely to experience early relapse, which is currently recognized as the unmet need in FL. Additionally, the use of gene-expression profiling and next-generation sequencing techniques in recent years has led to a wealth of knowledge regarding the molecular drivers of lymphomagenesis. However, much of this knowledge is not currently available in the clinic to inform treatment decisions. Future studies are needed to generate clinically relevant predictive models adept at incorporating patient-specific and molecular features to inform management strategies along the entire disease continuum as treatment decisions should not be made in a vacuum with a one-size-fits-all approach. Sequencing of therapy in the management of relapsed FL should involve personalized decision-making for care plans that balance patient characteristics, preferences, and comorbidities with treatment-related factors such as efficacy, toxicity profile, and mechanisms of action to achieve a durable, quality remission.","author":[{"dropping-particle":"","family":"Nastoupil","given":"Loretta J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Flowers","given":"Christopher R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leonard","given":"John P","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Hematology. American Society of Hematology. Education Program","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2018"]]},"page":"189-193","title":"Sequencing of therapies in relapsed follicular lymphoma.","type":"article-journal","volume":"2018"},"uris":[""]}],"mendeley":{"formattedCitation":"[32]","plainTextFormattedCitation":"[32]","previouslyFormattedCitation":"[32]"},"properties":{"noteIndex":0},"schema":""}[32]. Patient preference and physician recommendation based on individual characteristics will always be a major consideration but the different mechanisms of action of the available agents raises the possibility that a particular sequence is less toxic or more efficacious than others. One can wonder about the risk of opportunistic infections with sequential bendamustine and PI3K inhibitors or about the sequential use of a T-cell depleting agent (e.g., bendamustine) and a subsequent strategy deriving efficacy from immune enhancement (e.g. lenalidomide). At present there is no solid data in that regard but the recent DYNAMO trial suggested that patients who had received previous bendamustine had a lower response rate to duvelisib ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.18.00915","ISSN":"1527-7755","PMID":"30742566","abstract":"PURPOSE Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy. PATIENTS AND METHODS Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma. RESULTS This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%). CONCLUSION In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.","author":[{"dropping-particle":"","family":"Flinn","given":"Ian W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Carole B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ardeshna","given":"Kirit M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tetreault","given":"Scott","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Assouline","given":"Sarit E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mayer","given":"Jiri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Merli","given":"Michele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lunin","given":"Scott D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pettitt","given":"Andrew R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagy","given":"Zoltan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tournilhac","given":"Olivier","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abou-Nassar","given":"Karem-Etienne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crump","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jacobsen","given":"Eric D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vos","given":"Sven","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kelly","given":"Virginia M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shi","given":"Weiliang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steelman","given":"Lori","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Le","given":"NgocDiep","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weaver","given":"David T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lustgarten","given":"Stephanie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wagner-Johnston","given":"Nina D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zinzani","given":"Pier Luigi","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","id":"ITEM-1","issued":{"date-parts":[["2019","2","11"]]},"page":"JCO1800915","title":"DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma.","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"[33]","plainTextFormattedCitation":"[33]","previouslyFormattedCitation":"[33]"},"properties":{"noteIndex":0},"schema":""}[33]. Studies examining the ideal sequencing of therapies will be reported in the next few years.REFERENCESADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY [1]Mottok A, Jurinovic V, Farinha P, Rosenwald A, Leich E, Ott G, et al. FOXP1 expression is a prognostic biomarker in follicular lymphoma treated with rituximab and chemotherapy. Blood 2018;131:226–35. doi:10.1182/blood-2017-08-799080.[2]Alig S, Jurinovic V, Pastore A, Bararia D, H?be S, Hellmuth JC, et al. Impact of age on genetics and treatment efficacy in follicular lymphoma. Haematologica 2018;103:e364–7. doi:10.3324/haematol.2018.187773.[3]Araf S, Wang J, Korfi K, Pangault C, Kotsiou E, Rio-Machin A, et al. Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma. Leukemia 2018;32:1258–63. doi:10.1038/s41375-018-0043-y.[4]Qu X, Li H, Braziel RM, Passerini V, Rimsza LM, Hsi ED, et al. Genomic alterations important for the prognosis in patients with follicular lymphoma treated on SWOG study S0016. 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