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Background: Results of randomized clinical trials may not be entirely applicable to clinical practice. The present manuscript aims to explore the pragmatism and robustness of the evidence that supports the European Society for Medical Oncology (ESMO) follicular lymphoma (FL) guidelines. Methods & design: Analysis of all trials used to support positive, therapeutic, oncological recommendations in the 2020 ESMO FL guidelines. Predefined data points were extracted from each trial. Pragmatism was assessed by means of the PRECIS-2 tool, the difference in overall survival in the interventions compared and the source of funding. Robustness was assessed by means of the fragility index and the p value. Results: 28 trials were included. The full protocol or a protocol summary was provided for 12 (43%). Based on the PRECIS-2 domains, trials were considered pragmatic in organization, analysis and flexibility and explanatory in eligibility. Robustness was high, with 4/24 (17%) trials with p values between 0.05 and 0.005 and a median fragility index of 18. Conclusions: Results of trials to support ESMO recommendations in FL were robust. Pragmatism was high in some domains but modest to low in others and the pattern was similar across trials. Transparency in the publication of trial protocols was suboptimal.

The clinical relevance of flow cytometry (FC)-based bone marrow involvement (BMI) in B cell non-Hodgkin lymphoma (B-NHL) is not well established. We conducted a systematic review of MEDLINE regarding the use of FC to establish BMI in B-NHL to determine the prevalence of BMI by FC, to understand the interrelation between FC and bone marrow biopsy (BMB), and to explore the prognostic impact of BMI by FC. Relevant exclusion criteria included publication before 2010. Eleven publications (of 18 screened) were included, with 2803 patients involved. Relevant methodological details were often unreported. The prevalence of BMI by FC varied based on histological subtypes included. The median kappa agreement between BMB and FC was 0.68 and the type of discordance (FC+/BMB- vs. FC-/BMB+) was highly variable across studies. Only 4 studies (all in diffuse large B cell lymphoma) assessed the prognostic impact of BMI by FC. Two found a worse prognosis for patients with FC+/BMB- than those without BMI. To conclude, studies assessing BMI by FC are retrospective, of low methodological quality and with heterogeneous findings.

The use of non-pegylated liposomal doxorubicin (Myocet(R)) in diffuse large B-cell lymphoma (DLBCL) has been investigated in retrospective and single-arm prospective studies. This was a prospective phase 2 trial of DLBCL patients >= 60 years old with left ventricular ejection fraction (LVEF) >= 55% randomized to standard R-CHOP or investigational R-COMP (with Myocet(R) instead of conventional doxorubicin). The primary end point was to evaluate the differences in subclinical cardiotoxicity, defined as decrease in LVEF to = 3) and in four R-COMP patients (five episodes, all grade 1-2). No significant differences in efficacy were observed. In conclusion, R-COMP is a feasible immunochemotherapy schedule for DLBCL patients >= 60 years, with similar efficacy to R-CHOP. However, the use of non-pegylated doxorubicin instead of conventional doxorubicin was not associated with less early cardiotoxicity, although some reduced cardiac safety signals were observed.

The role of CD200 in the differential diagnosis of chronic lymphocytic leukemia (CLL) and classical mantle cell lymphoma (MCL) is well established. Its role in the differential diagnosis of CLL and other lymphoproliferative disorders (LPD) is less clear, in particular its positive predictive value (PPV).

Atrial fibrillation and cancer are common comorbidities. Given an increased risk of arterial thrombosis caused by the former and an increased risk of bleeding in patients with the latter, the management of anticoagulation in patients in whom they coexist is complex. On the basis of generally low-quality evidence, numerous documents have been published in the past 3 years providing practice points for physicians to offer the best treatment plan to their patients. The present review begins with a summary of these recommendations and then proceeds to outline 9 practical challenges that fit into the larger questions of when and in whom anticoagulation is indicated, and what is the best agent in patients with atrial fibrillation and active cancer. For each of these 9 challenges, the evidence available is presented, the author's personal practical advice is given and the most pressing need to move the field forward is stated. I conclude by emphasizing the need for high-quality evidence and, more practically, by stressing 1) the importance of patient preference and values in the decision on whether and how to anticoagulate, and 2) the need for periodic reassessment of the benefits of anticoagulation with changes in cancer status and treatment plan.

Differences between follicular lymphoma (FL) and diffuse large B-cell lymphoma/high-grade B-cell lymphoma (DLBCL/HGBL) by flow cytometry are underexplored.

Current care for patients with follicular lymphoma (FL) offers most of them long-term survival. Improving it further will require careful patient selection. This review focuses on predictive biomarkers (ie, those whose outcome correlations depend on the treatment strategy) in FL, because awareness of what patient subsets benefit most or least from each therapy will help in this task. The first part of this review aims to summarize what biomarkers are predictive in FL, the magnitude of the effect and the quality of the evidence. We find predictive biomarkers in the setting of (a) indication of active treatment, (b) front-line induction (use of anthracyline-based regimens, CHOP vs bendamustine, addition of rituximab), (c) post-(front-line)induction (rituximab maintenance, radioimmunotherapy), and (d) relapse (hematopoietic stem cell transplant) and targeted agents. The second part of this review discusses the challenges of precision medicine in FL, including (a) cost, (b) clinical relevance considerations, and (c) difficulties over the broad implementation of biomarkers. We then provide our view on what biomarkers may become used in the next few years. We conclude by underscoring the importance of assessing the potential predictiveness of available biomarkers to improve patient care but also that there is a long road ahead before reaching their broad implementation due to remaining scientific, technological, and economic hurdles.

Background Within the hematopoietic compartment, fibromodulin (FMOD) is almost exclusively expressed in chronic lymphocytic leukemia (CLL) lymphocytes. We set out to determine whether FMOD could be of help in diagnosing borderline lymphoproliferative disorders (LPD). Methods We established 3 flow cytometry-defined groups (CLL [n= 65], borderline LPD [n= 28], broadly defined as those with CLLflow score between 35 and -20 or discordant CD43 and CLLflow, and non-CLL LPD [n= 40]). FMOD expression levels were determined by standard RT-PCR in whole-blood samples. Patients were included regardless of lymphocyte count but with tumor burden >= 40%. Results FMOD expression levels distinguished between CLL (median 98.5, interquartile range [IQR] 37.8-195.1) and non-CLL LPD (median 0.012, IQR 0.003-0.033) with a sensitivity and specificity of 1. Most borderline LPDs were CD5/CD23/CD200-positive with no loss of B-cell antigens and negative or partial expression of CD43. 16/22 patients with available cytogenetic analysis showed trisomy 12. In 25/28 (89%) of these patients, FMOD expression levels fell between CLL and non-CLL (median 3.58, IQR 1.06-6.21). Discussion This study could suggest that borderline LPDs may constitute a distinct group laying in the biological spectrum of chronic leukemic LPDs. Future studies will have to confirm these results with other biological data. Quantification of FMOD can potentially be of help in the diagnosis of phenotypically complex LPDs.

Venous thromboembolism (VTE) is a common complication of cancer. Its treatment is challenging because of the high risk for both VTE recurrence and bleeding. Evidence is particularly scarce for patients with hematological malignancies. This review aims to summarize new developments in anticoagulation for the prevention and treatment of VTE in patients with active cancer, largely derived from the formal introduction of direct anticoagulants (DOACs) in this population. We then offer our recommendations for the thromboprophylaxis and treatment of VTE in patients with hematological disorders (mature lymphoid disorders, plasma cell disorders, myeloproliferative neoplasms, myelodysplastic syndrome and acute leukemia/stem cell transplant). We conclude by emphasizing the lack of high-quality evidence in a majority of these settings, caution about the use of DOACs in clinical situations where evidence is lacking and, finally, note the importance of involving patients in the decision-making process.

Patients with follicular lymphoma (FL) refractory to front-line immunochemotherapy (ICT) have a poor overall survival (OS). Gene mutation analysis may be more accurate than classical risk factors to pick out these patients before treatment. This study aimed to describe the prevalence of selected genetic mutations in a cohort of patients with high-risk FL. Twenty-five patients with FL refractory to front-line ICT and 10 non-refractory patients matched for age, sex, and FLIPI score were included. We sequenced 18 genes (custom targeted sequencing panel) previously reported to potentially have prognostic impact, including the seven genes necessary to determine m7FLIPI risk. The 35 patients had a median age of 62. The FLIPI and FLIPI2 were high in 27 (84%) and 14 (48%), respectively. Three-year progression-free survival (PFS) and OS probabilities were 25% (95% CI, 13%-41%) and 53% (34%-69%), respectively. There were 73 variants in the 18 genes among the 35 patients. The median number of mutations per patient was 1 (interquartile range, 0-3). The most commonly mutated genes were CREBBP (11 of 35, 31%) and EP300 (10 of 35, 29%). EP300 mutations were associated with refractoriness to treatment (10 of 25 among refractory and 0 of 10 among non-refractory). In conclusion, in this study, patients with high-risk follicular lymphoma were genetically heterogeneous.

Introduction: Patients with follicular lymphoma (FL) have classically had a higher risk of solid cancers than the general population, but there is little data available in patients diagnosed and treated with modern day regimens. Material and methods: We conducted a retrospective multicenter study assessing the cumulative incidence of solid cancers other than nonmelanoma skin cancer in patients with FL between 1997 and 2016 and determined the standardized incidence ratio (SIR) to compare the incidence of solid cancers with that of the general population Results: Among 1002 FL patients with 7 years of median follow-up, we found 74 solid cancers (most common breast [n = 19], lung and colon [n = 9 each]). The cumulative incidence was 3.8% at 5 years (95%CI 2.6-5.2) from the time of diagnosis and 4.4% at 5 years (95%CI 3.1-5.9%) from the time of front-line treatment. Although a comparison of all front-line strategies did not reveal differences in the risk of solid cancers, patients treated with anthracycline-based regimens appeared to have a lower incidence than those treated with bendamustine-based strategies (2.8% vs. 6.9%). However, patients receiving the former regimen were younger than the latter. On multivariable analysis, older age was correlated with the incidence of solid cancer and bendamustine-based treatment was of borderline significance. SIR for any solid cancer was 1.22 (95%CI 0.91-1.64), indicating no increased risk of solid cancer in patients with FL over that of the general population. However, on subgroup analyses, female patients treated with bendamustine-based strategies appeared to have a greater risk (SIR 3.85 [95%CI 1.45-10.27]) Discussion: The incidence of solid cancer in this cohort of patients with FL was low and not greater than in the general population. However, the risk may be greater in female patients treated with bendamustine.

Follicular lymphoma (FL) is the most common indolent lymphoma. Therapeutic advances in the past decade have improved its prognosis, but some questions remain open, particularly over adapting therapy to each individual patient's disease risk. Several trials and large studies dealing with biological and therapeutic aspects of FL have been published in the past few months and may have immediate or near-future practice-changing implications. These studies include risk-assessment by gene expression profiling, the therapeutic strategy in localized FL, use of obinutuzumab or lenalidomide in the front-line setting, stem cell transplant in early treatment failure and phosphatidylinositol 3-kinase (PI3K) inhibition and chimeric antigen receptor (CAR) T-cells in multiply relapsed disease. This review aims to contextualize these studies, summarize their design and results, assess their impact, highlight related questions that remain unanswered and, finally, provide a personal view as to how they change our approach to non-transformed FL.

Follicular lymphoma (FL) is the most common indolent lymphoma. Currently there are many comparable treatment options available for FL. When selecting the most optimal therapy it is important to consider possible late effects of the treatment as well as survival. Secondary haematological malignancy (SHM) is a severe late effect of treatments, but the incidence of SHMs is still largely unknown. The goal of the present study was to determine the incidence of SHMs and how therapeutic decisions interfere with this risk. The study included 1028 FL patients with a median follow-up time of 5 center dot 6 years. The 5-year risk of SHM was 1 center dot 1% and the risk was associated with multiple lines of treatment (P = 0 center dot 016). The 5-year risk of SHM was 0 center dot 5% after the first-line treatment and 1 center dot 6% after the second-line. The standardized incidence ratio (SIR) was 6 center dot 2 (95% confidence interval 3 center dot 4-10 center dot 5) for SHM overall. This retrospective study found that the risk of SHM was low after first-line treatment in FL patients from the rituximab era. However, the risk of SHM increases with multiple lines of treatment. Therapeutic approaches should aim to achieve as long a remission as possible with first-line treatment, thereby postponing the added risk of SHM.

Lenalidomide has been associated with an increased risk of venous thromboembolism (VTE) in multiple myeloma. It is unclear whether patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are also at such risk. We conducted a systematic review of the incidence of VTE in prospective trials of lenalidomide-treated patients with NHL or CLL. Sixty-eight unique reports were assessed for inclusion. For grade >= 3 VTE, 98 events were reported in 3043 patients (60 studies) (crude incidence: 3.22% [95% confidence interval: 2.6-3.9%]). For any grade VTE, 97 events were reported in 2244 patients (46 studies) (crude incidence: 4.32% [3.5-5.2%]). Subgroup analysis showed no difference based on histological subtype or use of prophylaxis. The study is at risk of bias, largely due to insufficient data from the individual studies. Within the limitations of this systematic review, we found a low risk of VTE in patients with NHL treated with lenalidomide.

Follicular lymphoma (FL) is generally considered an indolent disorder. With modern day treatments, long remissions are often achieved both in the front-line and relapsed setting. However, a subset of patients has a more aggressive course and a worse outcome. Their identification is the main purpose of modern day prognostic tools. In this review, we attempt to summarize the evidence concerning prognostic and predictive factors in FL, including (1) pre-treatment factors, from baseline clinical characteristics and imaging tests to histological grade, the microenvironment and genomic abnormalities; (2) post-treatment factors, i.e., depth of response, measured both by imaging tests and minimal residual disease; (3) factors at relapse and duration of response; and (4) prognostic factors in histological transformation. We conclude that, despite the existence of numerous tools, the availability of some of them is still limited; they generally suffer from notable downsides, and most have unproven predictive value, thus having scarce bearing on the choice of regimen at present. However, with the technological and scientific developments of the last few years, the potential for these prognostic factors is promising, particularly in combination, which will probably, in time, help guide therapeutic decisions.

BACKGROUND: CD43 has been used on histological samples for the differential diagnosis of lymphoproliferative disorders but there is scarce data on its use by flow cytometry (FC). We set out to characterize the expression of CD43 by FC in B-cell lymphoproliferative disorders and to determine its possible role in the differential diagnosis of these malignancies. METHODS: We analyzed the expression of CD43 in clonal B-cell lymphoproliferative disorders with exclusive peripheral blood and/or bone marrow involvement based on their Moreau chronic lymphocytic leukemia (CLL) score with particular emphasis on Moreau CLL score 3 (MS3) cases, which often present a diagnostic challenge. The cohort included 433 CLL (score 4-5), 34 MS3 and 166 lymphoproliferative disorders with lower scores. RESULTS: Generally, the higher the Moreau CLL score, the higher CD43-positivity (425/443 [96%] for CLL, 23/34 [67%] for MS3 and 18/166 [11%] for cases with lower scores). MS3 cases constituted 5.4% of all cases and were more frequently CD5, CD200, CD43-positive and had del(q13) than score 0-2 cases. Among MS3 cases, del(13q) cases were predominantly CD43-positive (12/13). CONCLUSIONS: The frequency of CD43-positivity increases sharply with the Moreau score. MS3 cases seem to include both CLL and non-CLL lymphoproliferative disorders and CD43 could aid in the differential diagnosis between the two. However, studies analyzing the correlation between CD43 expression and the underlying biologic changes of these cases are warranted. © 2017 International Clinical Cytometry Society.

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.

BackgroundTrisomy 12 chronic lymphocytic leukemia (CLL) is phenotypically different from the rest of CLL cytogenetic subgroups. However, it is unknown whether this is also the case for trisomy 12 CLL-phenotype monoclonal B-cell lymphocytosis (MBL). MethodsWe analyzed the expression of several markers in a series of 89 cytogenetically characterized MBL (including 17 trisomy 12 cases). Additionally, we compared the expression of these markers between trisomy 12 MBL, trisomy 12 CLL and a series of cases with trisomy 12 but fulfilling only 3 of the 5 Moreau CLL diagnostic criteria. ResultsCD20, CD22 and CD79b were expressed more intensely in trisomy 12 MBL than in non-trisomy 12 MBL and there was a trend towards a dimmer expression of CD43 in trisomy 12 MBL. There were no differences between trisomy 12 CLL and trisomy 12 MBL. Expression of CD20 was dimmer and that of CD43 brighter in trisomy 12 MBL than in cases with trisomy 12 and 3 Moreau criteria. ConclusionsIn this study, trisomy 12 and non-trisomy 12 MBL were phenotypically different, but the differences are similar to those described between trisomy 12 and non-trisomy 12 CLL, suggesting that they are a distinct subgroup within CLL, given that the differences can already be found at its precursor stage. (c) 2017 International Clinical Cytometry Society