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Follicular lymphoma (FL) is a clinically heterogeneous disease. The need for treatment, treatment sequencing, number of treatment lines, and its association with survival have not been described in a population-based setting. We identified all patients diagnosed with FL in the Swedish Lymphoma register from 2007 to 2014, followed until 2020, with detailed data on progression/relapse, transformation, and 2nd and further lines of therapy. During a median follow-up of 6.8 years, 1226 patients (69%) received 1st systemic treatment, 358 patients (20%) were managed with watch-and-wait (WaW) only, and 188 (10%) patients were treated with radiotherapy and did not require additional therapy during the study period. Among patients starting systemic treatment, 496 (40%), 224 (18%), and 88 (7%) received 2nd-, 3rd-, or 4th-line therapy, respectively. The 10-year cause-specific cumulative incidence of transformation was 13%. Among patients managed with 1 st line R-single, R-CHOP, or BR, 54%, 33%, and 29% required 2nd line, respectively. The cumulative probability of starting subsequent treatment within 2 years was 26% after 1st line and 35% after 2nd line treatment. Two-year OS following 1st, 2nd, 3rd, and 4th line systemic treatment was 84%, 70%, 52%, and 36%, respectively, and remained similar when excluding transformations. We conclude that a substantial proportion of FL patients can be managed with WaW for a long period of time, while patients who require multiple treatment lines constitute a group with a large clinical unmet need. These results constitute valuable real-world reference data for FL., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Tumor-infiltrating regulatory T cells (Tregs) contribute to an immunosuppressive tumor microenvironment. Despite extensive studies, the prognostic impact of tumor-infiltrating Tregs in B-cell non-Hodgkin lymphomas (B-NHLs) remains unclear. Emerging studies suggest substantial heterogeneity in the phenotypes and suppressive capacities of Tregs, emphasizing the importance of understanding Treg diversity and the need for additional markers to identify highly suppressive Tregs. Here, we applied single-cell RNA sequencing and T-cell receptor sequencing combined with high-dimensional cytometry to decipher the heterogeneity of intratumoral Tregs in diffuse large B-cell lymphoma and follicular lymphoma (FL), compared with that in nonmalignant tonsillar tissue. We identified 3 distinct transcriptional states of Tregs: resting, activated, and unconventional LAG3+FOXP3- Tregs. Activated Tregs were enriched in B-NHL tumors, coexpressed several checkpoint receptors, and had stronger immunosuppressive activity compared with resting Tregs. In FL, activated Tregs were found in closer proximity to CD4+ and CD8+ T cells than other cell types. Furthermore, we used a computational approach to develop unique gene signature matrices, which were used to enumerate each Treg subset in cohorts with bulk gene expression data. In 2 independent FL cohorts, activated Tregs was the major subset, and high abundance was associated with adverse outcome. This study demonstrates that Tregs infiltrating B-NHL tumors are transcriptionally and functionally diverse. Highly immunosuppressive activated Tregs were enriched in tumor tissue but absent in the peripheral blood. Our data suggest that a deeper understanding of Treg heterogeneity in B-NHL could open new paths for rational drug design, facilitating selective targeting to improve antitumor immunity., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Follicular lymphoma is the most common indolent lymphoma accounting for approximately 20%-25% of all new non-Hodgkin lymphoma diagnoses in western countries. Whilst outcomes are mostly favorable, the spectrum of clinical phenotypes includes high-risk groups with significantly inferior outcomes. This review discusses recent updates in risk stratification and treatment approaches from upfront treatment for limited and advanced stage follicular lymphoma to the growing options for relapsed, refractory disease with perspectives on how to approach this from a personalized lens. Notable gaps remain on how one can precisely and prospectively select optimal treatment for patients based on varying risks, with an anticipation that an increased understanding of the biology of these different phenotypes and increasing refinement of imaging- and biomarker-based tools will, in time, allow these gaps to be closed., (© 2023 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Aims: Subclassification of large B cell lymphoma (LBCL) is challenging due to the overlap in histopathological, immunophenotypical and genetic data. In particular, the criteria to separate diffuse large B cell lymphoma (DLBCL) and high-grade B cell lymphoma (HGBL) are difficult to apply in practice. The Lunenburg Lymphoma Biomarker Consortium previously reported a cohort of over 5000 LBCL that included fluorescence in-situ hybridisation (FISH) data. This cohort contained 209 cases with MYC rearrangement that were available for a validation study by a panel of eight expert haematopathologists of how various histopathological features are used., Methods and Results: Digital whole slide images of haematoxylin and eosin-stained sections allowed the pathologists to visually score cases independently as well as participate in virtual joint review conferences. Standardised consensus guidelines were formulated for scoring histopathological features and included overall architecture/growth pattern, presence or absence of a starry-sky pattern, cell size, nuclear pleomorphism, nucleolar prominence and a range of cytological characteristics. Despite the use of consensus guidelines, the results show a high degree of discordance among the eight expert pathologists. Approximately 50% of the cases lacked a majority score, and this discordance spanned all six histopathological features. Moreover, none of the histological variables aided in prediction of MYC single versus double/triple-hit or immunoglobulin-partner FISH-based designations or clinical outcome measures., Conclusions: Our findings indicate that there are no specific conventional morphological parameters that help to subclassify MYC-rearranged LBCL or select cases for FISH analysis, and that incorporation of FISH data is essential for accurate classification and prognostication., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Purpose: Rituximab/chemotherapy is a cornerstone of treatment for Waldenström's macroglobulinemia (WM). In addition, bortezomib has shown significant activity in WM. This study evaluated the efficacy and safety of dexamethasone, rituximab, and cyclophosphamide (DRC) as first-line treatment in WM., Methods: In this European study, treatment-naïve patients were randomly assigned to DRC or bortezomib-DRC B-DRC for six cycles. The primary end point was progression-free survival. Secondary end points included response rates, overall survival, and safety., Results: Two hundred four patients were registered. After a median follow-up of 27.5 months, the estimated 24-month progression-free survival was 80.6% (95% CI, 69.5 to 88.0) for B-DRC and 72.8% (95% CI, 61.3 to 81.3) for DRC ( P = .32). At the end of treatment, B-DRC and DRC induced major responses in 80.6% versus 69.9% and a complete response/very good partial response in 17.2% versus 9.6% of patients, respectively. The median time to first response was shorter for B-DRC with 3.0 (95% CI, 2.8 to 3.2) versus 5.5 (95% CI, 2.9 to 5.8) months for DRC. This resulted in higher major response rates (57.0% v 32.5%; P < .01) after three cycles of B-DRC compared with DRC. At best response, the complete response/very good partial response increased to 32.6% for B-DRC. Both treatments were well tolerated: grade ≥ 3 adverse events occurred in 49.2% of all patients (B-DRC, 49.5%; DRC, 49.0%). Peripheral sensory neuropathy grade 3 occurred in two patients treated with B-DRC and in none with DRC., Conclusion: This large randomized study illustrates that B-DRC is highly effective and well tolerated in WM. The data demonstrate that fixed duration immunochemotherapy remains an important pillar in the clinical management of WM.

Background: Patients with chronic lymphocytic leukemia (CLL) show an immune dysfunction with increased risk of infections and poor response to vaccination. Streptococcus pneumoniae is a common cause of morbidity and mortality in CLL patients. In a previous randomized clinical trial, we found a superior immune response in CLL patients receiving conjugated pneumococcal vaccine compared to non-conjugated vaccine. The response to revaccination in CLL patients is scarcely studied. In this study, early humoral response to repeated revaccinations with pneumococcal vaccines was evaluated, by determination of B cell subsets and plasmablast dynamics in peripheral blood., Method: CLL patients (n = 14) and immunocompetent controls (n = 31) were revaccinated with a 13-valent pneumococcal conjugate vaccine (PCV13) after previous primary immunization (3-6 years ago) with PCV13 or a 23-valent pneumococcal polysaccharide vaccine (PPSV23). Eight weeks after the first revaccination, all CLL patients received a second revaccination with PCV13 or PPSV23. B cell subsets including plasmablasts were analyzed in peripheral blood by flow cytometry, before and after the first and the second revaccination., Results: None of the CLL patients, but all controls, had detectable plasmablasts at baseline (p < 0.001). After the first revaccination with PCV13, the plasmablast proportions did not increase in CLL patients (p = 0.13), while increases were seen in controls (p < 0.001). However, after a second revaccination with PCV13 or PPSV23, plasmablasts increased compared to baseline also in CLL patients (p < 0.01). If no response was evident after first revaccination, only a second revaccination with PCV13 increased plasmablasts in contrast to PPSV23 revaccination. Patients with hypogammaglobulinemia and ongoing/previous CLL specific treatment responded poorly, also to a second revaccination., Conclusion: In CLL patients, pneumococcal revaccination induced minor early plasmablast response compared to controls, but the response improved using a strategy of repeated doses with of conjugated T cell dependent pneumococcal vaccine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Competing Interests: The authors have no conflicts of interest to disclose.

Consensus Panel 4 (CP4) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with reviewing the current criteria for diagnosis and response assessment. Since the initial consensus reports of the 2nd International Workshop, there have been updates in the understanding of the mutational landscape of IgM related diseases, including the discovery and prevalence of MYD88 and CXCR4 mutations; an improved recognition of disease related morbidities attributed to monoclonal IgM and tumor infiltration; and a better understanding of response assessment based on multiple, prospective trials that have evaluated diverse agents in Waldenstrom's macroglobulinemia. The key recommendations from IWWM-11 CP4 included: (1) reaffirmation of IWWM-2 consensus panel recommendations that arbitrary values for laboratory parameters such as minimal IgM level or bone marrow infiltration should not be used to distinguish Waldenstrom's macroglobulinemia from IgM MGUS; (2) delineation of IgM MGUS into 2 subclasses including a subtype characterized by clonal plasma cells and MYD88 wild-type, and the other by presence of monotypic or monoclonal B cells which may carry the MYD88 mutation; and (3) recognition of "simplified" response assessments that use serum IgM only for determining partial and very good partial responses (simplified IWWM-6/new IWWM-11 response criteria). Guidance on response determination for suspected IgM flare and IgM rebound related to treatment, as well as extramedullary disease assessment was also updated and included in this report., (Copyright © 2023. Published by Elsevier Inc.)

In follicular lymphoma (FL), progression of disease ≤24 months (POD24) has emerged as an important prognostic marker for overall survival (OS). We aimed to investigate survival more broadly by timing of progression and treatment in a national population-based setting. We identified 948 stage II-IV indolent FL patients in the Swedish Lymphoma Register diagnosed 2007-2014 who received first-line systemic therapy, followed through 2020. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by first POD at any time during follow-up using Cox regression. OS was predicted by POD using an illness-death model. During a median follow-up of 6.1 years (IQR: 3.5-8.4), 414 patients experienced POD (44%), of which 270 (65%) occurred ≤24 months. POD was represented by a transformation in 15% of cases. Compared to progression-free patients, POD increased all-cause mortality across treatments, but less so among patients treated with rituximab(R)-single (HR = 4.54, 95% CI: 2.76-7.47) than R-chemotherapy (HR = 8.17, 95% CI: 6.09-10.94). The effect of POD was similar following R-CHOP (HR = 8.97, 95% CI: 6.14-13.10) and BR (HR = 10.29, 95% CI: 5.60-18.91). The negative impact of POD on survival remained for progressions up to 5 years after R-chemotherapy, but was restricted to 2 years after R-single. After R-chemotherapy, the 5-year OS conditional on POD occurring at 12, 24, and 60 months was 34%, 46%, and 57% respectively, versus 78%, 82%, and 83% if progression-free. To conclude, POD before but also beyond 24 months is associated with worse survival, illustrating the need for individualized management for optimal care of FL patients., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

The aims of this study are to describe health-related quality of life (HRQoL, SF-36) and fatigue in long-term indolent lymphoma survivors, compared to normative data, and to examine factors related to impaired HRQoL among the survivors. The participants ( N  = 136, median follow-up after first line therapy 9.8 years) were included from a follow-up study of two clinical trials, with chemo-free first-line therapy. The present survey included questionnaire based data. Compared to the normative data, the mean total fatigue score were higher, and HRQoL lower in 4 of 8 domains among the lymphoma survivors. Among the survivors, somatic comorbidities, not being in paid work and chronic fatigue were significantly associated with reduced physical HRQoL. Anxiety and depressive symptoms were associated with reduced mental HRQoL. Our findings highlight the need for awareness of HRQoL and fatigue in long term follow up in lymphoma survivors, as there are treatments and rehabilitation options.

Introduction/background: Leveraging the Follicular Lymphoma Analysis of Surrogacy Hypothesis database of individual patient data from first-line clinical trials, we studied the clinical course of follicular lymphoma (FL) and investigated clinical factors associated with FL outcomes., Patients and Methods: We examined 2428 patients from 8 randomized trials using multistate survival models with 4 states: induction treatment, progression, death from FL, and death from other causes. We utilized Aalen-Johansen estimator and Cox models to assess the likelihood of FL outcomes and quantify predictors' effects., Results: Two-year progression, FL-related death, and death from other causes estimates were 26.5%, 3.4% and 1.4%, respectively. FL-associated deaths were the primary cause of mortality within 10 years of follow-up. Male sex (hazard ratio: 1.25; 95% confidence interval: 1.05-1.47), > 4 involved nodal areas (1.51; 1.23-1.86), elevated LDH (1.20; 1.01-1.43), low hemoglobin (1.44; 1.15-1.81), and elevated β-2 levels (1.23; 1.02-1.47) increased risk of progression. CD20-targeting agents reduced risks for progression (0.29; 0.22-0.39), death from FL (0.05; 0.01-0.20), and death from other causes without progression (0.13; 0.05-0.33) and following progression (0.52; 0.30-0.92). Estimated 2-year progression rates were 22.3% and 43.5% with or without CD20-targeting agents, respectively. Two-year FL-associated mortality rate was 8.3% among patients without CD20-targeting agents, 5.4% with B-symptoms, 4.9% with elevated LDH, and 9.1% with low hemoglobin., Conclusion: This study identified independent contributions of baseline clinical factors to distinct outcomes for patients with FL following first-line therapy on a clinical trial. Similar analytical approaches are needed to increase understanding of factors that influence FL outcomes in other settings., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Although the genomic and immune microenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known about the potential biological differences between stage I and stage III/IV disease. Using next-generation sequencing and immunohistochemistry, 82 FL nodal stage I cases were analyzed and compared with 139 FL stage III/IV nodal cases. Many similarities in mutations, chromosomal copy number aberrations, and microenvironmental cell populations were detected. However, there were also significant differences in microenvironmental and genomic features. CD8+ T cells (P = .02) and STAT6 mutations (false discovery rate [FDR] <0.001) were more frequent in stage I FL. In contrast, programmed cell death protein 1-positive T cells, CD68+/CD163+ macrophages (P < .001), BCL2 translocation (BCL2trl+) (P < .0001), and KMT2D (FDR = 0.003) and CREBBP (FDR = 0.04) mutations were found more frequently in stage III/IV FL. Using clustering, we identified 3 clusters within stage I, and 2 clusters within stage III/IV. The BLC2trl+ stage I cluster was comparable to the BCL2trl+ cluster in stage III/IV. The two BCL2trl- stage I clusters were unique for stage I. One was enriched for CREBBP (95%) and STAT6 (64%) mutations, without BLC6 translocation (BCL6trl), whereas the BCL2trl- stage III/IV cluster contained BCL6trl (64%) with fewer CREBBP (45%) and STAT6 (9%) mutations. The other BCL2trl- stage I cluster was relatively heterogeneous with more copy number aberrations and linker histone mutations. This exploratory study shows that stage I FL is genetically heterogeneous with different underlying oncogenic pathways. Stage I FL BCL2trl- is likely STAT6 driven, whereas BCL2trl- stage III/IV appears to be more BCL6trl driven., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Hepatitis B virus (HBV) infection has been associated with an increased risk for B-cell lymphomas. We previously showed that 20% of diffuse large B-cell lymphoma (DLBCL) patients from China, an endemic area of HBV infection, have chronic HBV infection (surface antigen-positive, HBsAg+) and are characterized by distinct clinical and genetic features. Here, we showed that 24% of follicular lymphoma (FL) Chinese patients are HBsAg+. Compared with the HBsAg- FL patients, HBsAg+ patients are younger, have a higher histological grade at diagnosis, and have a higher incidence of disease progression within 24 months. Moreover, by sequencing the genomes of 109 FL tumors, we observed enhanced mutagenesis and distinct genetic profile in HBsAg+ FLs, with a unique set of preferentially mutated genes (TNFAIP3, FAS, HIST1H1C, KLF2, TP53, PIM1, TMSB4X, DUSP2, TAGAP, LYN, and SETD2) but lack of the hallmark of HBsAg- FLs (ie, IGH/BCL2 translocations and CREBBP mutations). Transcriptomic analyses further showed that HBsAg+ FLs displayed gene-expression signatures resembling the activated B-cell-like subtype of diffuse large B-cell lymphoma, involving IRF4-targeted genes and NF-κB/MYD88 signaling pathways. Finally, we identified an increased infiltration of CD8+ memory T cells, CD4+ Th1 cells, and M1 macrophages and higher T-cell exhaustion gene signature in HBsAg+ FL samples. Taken together, we present new genetic/epigenetic evidence that links chronic HBV infection to B-cell lymphomagenesis, and HBV-associated FL is likely to have a distinct cell-of-origin and represent as a separate subtype of FL. Targetable genetic/epigenetic alterations identified in tumors and their associated tumor microenvironment may provide potential novel therapeutic approaches for this subgroup of patients., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Observational studies and stand-alone trials indicate that patients with follicular lymphoma (FL) who experience disease progression within 24 months of front-line chemoimmunotherapy (POD24), have poor outcomes. We performed a pooled analysis of 13 randomized clinical trials of patients with FL in the pre- and postrituximab eras to identify clinical factors that predict POD24. Logistic regression models evaluated the association between clinical factors and POD24. Cox regression evaluated the association between POD24 as a time-dependent factor and subsequent overall survival (OS). A landmark analysis evaluated the association of POD24 with OS for the subset of patients who were alive at 24 months after trial registration. Patients without progression at 24 months at baseline had favorable performance status (PS), limited-stage (I/II) disease, low-risk FL International Prognostic Index (FLIPI) score, normal baseline hemoglobin, and normal baseline β2 microglobulin (B2M) level. In a multivariable logistic regression model, male sex (odds ratio [OR], 1.30), PS ≥2 (OR, 1.63), B2M (≥3 mg/L; OR, 1.43), and high-risk FLIPI score (3-5; OR, 3.14) were associated with increased risk of progression before 24 months. In the time-dependent Cox model and the 24-month landmark analysis, POD24 was associated with poor subsequent OS (hazard ratio, 4.85 and 3.06, respectively). This is the largest pooled analysis of clinical trials data validating POD24 as a robust indicator of poor FL survival and identified clinical predictors of early death and progression that can aid in building comprehensive prognostic models incorporating clinical and molecular predictors of POD24., (© 2022 by The American Society of Hematology.)

Lymphoplasmacytic lymphoma (LPL) not fulfilling the WHO diagnostic criteria (2017) for Waldenstrom's macroglobulinemia (WM) (named non-WM LPL) is a rare disease and only a few systematic studies have been published. Here, we present a population-based study of non-WM LPL focusing on diagnostic difficulties, patient characteristics, and outcome. From 1511 patients included in the Swedish Lymphoma Registry 1 Jan 2000 - 31 Dec 2014 with a diagnosis of WM/LPL, we could confirm the diagnosis of non-WM LP in only 33 patients. The median age at diagnosis was 69 years. A paraprotein was found in most (IgG in 54%, IgA in 15%) and 12% of the cases were non-secretory. Compared with the WM patients, the non-WM LPL patients were younger, had more adverse prognostic factors such as elevated LDH, anaemia, and lymphocytosis at diagnosis. In addition, the non-WM LPL patients more often were symptomatic and received treatment at diagnosis. The overall survival (OS) did not significantly differ between the non-WM LPL and WM groups (P = 0.247), with a median survival time of 71 and 96 months, respectively. To conclude, we found differences in clinical features between WM and non-WM LPL, but no difference in survival., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Mechanisms for late-onset neutropenia (LON) after rituximab treatment are poorly defined both for non-Hodgkin lymphoma (NHL) and for autoimmune disorders. We performed a case-control analysis of a prospective cohort of 169 evaluable consecutive rituximab-treated NHL patients to assess cytokines involved in neutro- and lymphopoiesis (G-CSF, SDF1, BAFF, APRIL) and inflammation (CRP) as possible LON mechanisms. Fifteen patients (9%) developed LON (peripheral blood /PB/ absolute neutrophil counts /ANC/ < 0.5 G/L, all with marked depletion of CD20 + B-lymphocytes in bone marrows); they were compared with 20 matched NHL controls without LON. At start of LON, significantly higher PB G-CSF and BAFF levels (P = 0.0004 and 0.006, respectively), as well as CRP rises were noted compared to controls; these G-CSF and BAFF and most CRP values returned to levels of the controls in post-LON samples. G-CSF (but not BAFF) changes correlated to CRP rises (but not to ANC levels). BAFF levels correlated significantly to absolute monocyte counts and PB large granular lymphocyte counts (but not to ANC, C-CSF or CRP values). No changes of SDF1 or APRIL levels were noted. Neither LON cases nor controls displayed anti-neutrophil autoantibodies. Collectively, LON in NHL patients was timewise related to transient bursts of blood G-CSF and BAFF concentrations, suggesting that these neutro- and lymphopoiesis growth factors play a role in emergence of rituximab-induced LON, and that inflammation may be a trigger for G-CSF production during LON.

Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs >70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (>70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age >70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin <12 g/dL, ECOG PS ≥2, and elevated β2-microglobulin. Median follow-up was 5.6 years. Patients >70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients >70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P < .001). Age >70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients >70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs., (© 2021 by The American Society of Hematology.)

The relapse of follicular lymphoma (FL) within 24 months (POD24) of chemoimmunotherapy has been associated with poor survival. We analyzed a pooled dataset of three randomized trials including FL patients with advanced disease, conducted by the Swiss Group for Clinical Cancer Research (SAKK). Overall, POD24 was observed in 27% of 318 patients, but rate variance among studies suggested that the rituximab schedule might affect POD24 rate. POD24 was associated with lower 10-year overall survival rates than in the reference group (69% vs. 77%; hazard ratio, 3·12; 95% confidence interval, 1·73-5·65). POD24 retains its prognostic validity in patients treated without chemotherapy and may represent a useful end-point for future studies., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Follicular lymphoma (FL) is a heterogeneous disease; therefore, reliable prognostic tools are needed to plan treatment strategies. The FL International Prognostic Index (FLIPI) was developed before the rituximab era, while the PRIMA-PI was built on rituximab chemotherapy. Our objective was to evaluate these two prognostic tools in a cohort of 291 patients with FL treated in two prospective randomised Nordic Lymphoma Group trials with rituximab ± interferon. All patients had symptomatic/progressive disease and were previously untreated. The PRIMA-PI was prognostic for both time to treatment failure (TTF) and overall survival (OS) (log-rank P = 0·003 and P < 0·001, respectively). The PRIMA-PI high-risk identified a small group of patients with a very short TTF and OS compared to the low-risk group, with a hazard ratio (HR) of 1·90 (95% confidence interval [CI] 1·30-2·78, P = 0·001) and HR of 3·19 (95% CI 1·75-5·83, P < 0·001), respectively. The FLIPI risk groups were prognostic only for OS (log-rank P = 0·018). The simplified PRIMA-PI was valid in our FL cohort with first-line rituximab-containing chemo-free therapy and shows an improved risk stratification compared to the FLIPI, especially in patients aged >60 years. Patients in the PRIMA-PI high-risk group should be considered for alternative therapies., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Competing Interests: The authors declare no conflict of interest related to this work.

Rituximab monotherapy is widely used for follicular lymphoma. However, there are no established predictors for response or response duration. We analyzed the long-term prognostic relevance of pre-treatment absolute blood counts of lymphocytes with subsets and monocytes in 265 follicular lymphoma patients, uniformly treated with rituximab without chemotherapy, in two Nordic Lymphoma Group trials. There were 265 previously untreated, stage II-IV follicular lymphoma patients with a median follow-up of over 10 years. Absolute B cell counts ≥ median (0.09 × 10 9 /L) were an independent predictor for shorter time to next treatment or death (multivariable analysis P = 0.010). In univariate analysis, absolute monocyte counts ≥ median (0.5 × 10 9 /L) did not correlate with time to next treatment or death, but with inferior overall survival (P = 0.034). Absolute T cell or T cell subset counts were not predictive for outcome. High absolute B cell counts, possibly reflecting circulating lymphoma cells, have an unfavorable impact on time to next treatment or death in patients treated with rituximab without chemotherapy.

Follicular lymphoma (FL) constitutes a significant proportion of lymphomas and shows frequent relapses. Beyond conventional chemotherapy, new therapeutic approaches have emerged, focussing on the interplay between lymphoma cells and the microenvironment. Here we report the immunophenotypic investigation of the microenvironment of a clinically well-characterized prospective cohort (study SAKK35/10, NCT01307605) of 154 treatment-naïve FL patients in need of therapy, who have been treated with rituximab only or a combination of rituximab and the immunomodulatory drug lenalidomide/Revlimid® A high ratio of CD4- to CD8-positive T cells (P = 0·009) and increased amounts of PD1 + tumour-infiltrating T cells (P = 0·007) were associated with inferior progression-free survival in the whole cohort. Interestingly, the prognostic impact of PD1 + T cells and the CD4/CD8 ratio lost its significance in the subgroup treated with R 2 . In the latter group, high amounts of GATA3 + T helper (Th2) equivalents were associated with better progression-free survival (P < 0·001). We identified tumour microenvironmental features that allow prognostic stratification with respect to immuno- and combined immuno- and immunomodulatory therapy. Our analysis indicates that lenalidomide may compensate the adverse prognostic implication of higher amounts of CD4 + and, particularly, PD1 + T cells and that it has favourable effects mainly in cases with higher amounts of Th2 equivalents. [Correction added on 11 February 2020, after online publication: The NCT-trial number was previously incorrect and has been updated in this version]., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

The clinical course of follicular lymphoma (FL) is highly variable. Recently the m7-FL international prognostic index (FLIPI) integrating performance status, FLIPI score and the mutational status of seven genes, was shown to stratify patients into "low-risk" and "high-risk" with respect to 5-year failure-free survival after first-line immunochemotherapy. Our aim was to evaluate the model after rituximab without chemotherapy. The Nordic Lymphoma Group performed two randomized clinical trials on indolent lymphoma patients receiving single rituximab and rituximab with interferon-α2a. In total, 95 FL patients had sufficient fresh-frozen diagnostic material for sequencing. A targeted panel for the genes EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11 was utilized for m7-FLIPI score calculation. With a median follow-up of 10·6 years, 76% of patients were alive. No difference in time to treatment failure (TTF), defined as the interval between start of trial therapy and initiation of new therapy or death, nor overall survival (OS) was found between the m7-FLIPI risk groups (log-rank P = 0·94 and 0·99, respectively). EZH2 mutations were associated with longer TTF (log-rank P = 0·04) and in EP300 mutations were associated with shorter TTF (log-rank P = 0·01). We conclude that the prognostic value of the m7-FLIPI clinicogenetic model seems dependent on therapeutic regimen., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: MYC rearrangement ( MYC -R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of MYC- R on prognosis may be influenced by the MYC partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of MYC-R (single-, double-, and triple-hit status) in DLBCL within the context of the MYC partner gene., Methods: The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the MYC , BCL2 , BCL6 , and IG heavy and light chain loci was used, and results were correlated with clinical outcomes., Results: A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for MYC -R. MYC -R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of MYC- R was only evident in patients with a concurrent rearrangement of BCL2 and/or BCL6 and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; P < .001)., Conclusion: The negative prognostic impact of MYC -R in DLBCL is largely observed in patients with MYC double hit/triple-hit disease in which MYC is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.

The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m 2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥90%). Toxicity grade ≥3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.gov as #NCT01307605., (© 2019 by The American Society of Hematology.)

The aim of this study was to investigate long-term outcome following first-line therapy in consecutive chronic lymphocytic leukemia (CLL) patients in a well-defined geographic area: Sweden. All patients diagnosed with CLL (2007-2013) (n=3672) were identified from national registries, screening of patient files identified all (100%) treated first line (n=1053) and for those, an in-depth analysis was performed. End points were overall response rate, progression-free survival (PFS), overall survival (OS), and safety. Median age was 71 years; 53% had Rai stage III-IV and 97% had performance status grade 0-2. Fluorescence in situ hybridization (FISH) was performed in 57% of patients: 15% had del(17p). Chlorambucil + prednisone was used in 39% (5% also received rituximab). Fludarabine+cyclophosphamide+rituximab or fludarabine+cyclophosphamide was used in 43% and bendamustine + rituximab in 6%. Overall response rate was 64%; chlorambucil 43%, fludarabine+cyclophosphamide+rituximab 84%, fludarabine+cyclophosphamide 75% and bendamustine + rituximab 75%. Median PFS and OS was 24 and 58 months, respectively, both were significantly associated (multivariate analysis) with type of treatment, del(17p), performance status, gender, age and geographical region (OS only). Chlorambucil-treated patients had a median PFS and OS of only 9 and 33 months, respectively. Chlorambucil usage declined gradually throughout the study period, but one-third of patients still received chlorambucil + rituximab in 2013. Infections ≥grade III were significantly associated with treatment; chlorambucil 19% versus fludarabine+cyclophosphamide+rituximab 30%. Richter transformation occurred in 5.5% of the patients, equally distributed across therapies. This is the largest retrospective, real-world cohort of consecutive first-line treated CLL patients with a complete follow up. In elderly patients, an unmet need for more effective, well-tolerated therapies was identified., (Copyright© 2019 Ferrata Storti Foundation.)

Checkpoint blockade can reverse T-cell exhaustion and promote antitumor responses. Although blocking the PD-1 pathway has been successful in Hodgkin lymphoma, response rates have been modest in B-cell non-Hodgkin lymphoma (NHL). Coblockade of checkpoint receptors may therefore be necessary to optimize antitumor T-cell responses. Here, characterization of coinhibitory receptor expression in intratumoral T cells from different NHL types identified TIGIT and PD-1 as frequently expressed coinhibitory receptors. Tumors from NHL patients were enriched in CD8 + and CD4 + T effector memory cells that displayed high coexpression of TIGIT and PD-1, and coexpression of these checkpoint receptors identified T cells with reduced production of IFNγ, TNFα, and IL2. The suppressed cytokine production could be improved upon in vitro culture in the absence of ligands. Whereas PD-L1 was expressed by macrophages, the TIGIT ligands CD155 and CD112 were expressed by lymphoma cells in 39% and 50% of DLBCL cases and in some mantle cell lymphoma cases, as well as by endothelium and follicular dendritic cells in all NHLs investigated. Collectively, our results show that TIGIT and PD-1 mark dysfunctional T cells and suggest that TIGIT and PD-1 coblockade should be further explored to elicit potent antitumor responses in patients with NHL., (©2019 American Association for Cancer Research.)

We present a nationwide prospective Swedish registry-based study of Waldenström macroglobulinaemia (WM), that focuses on incidence and survival in relation to clinical prognostic factors and primary systemic therapies. A total of 1511 patients with WM and lymphoplasmocytic lymphoma (LPL) were registered in the Swedish Lymphoma Registry (SLR) between 1 January 2000 and 31 December 2014. The age-adjusted incidence of WM/LPL was 11·5 per million persons per year, three times higher than the reported incidence worldwide. Medical records were retrieved for 1135 patients (75%). A retrospective review showed that 981 (86·1%) of these patients fulfilled the World Health Organization diagnostic criteria for WM and these patients were analysed further. The overall survival (OS) improved between two periods - 2000-2006 and 2007-2014 - with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS, evaluated at the time of diagnosis, were age, elevated lactate dehydrogenase level and haemoglobin ≤115 g/l for patients receiving therapy 0-3 months after diagnosis, and age, poor performance status, haemoglobin ≤115 g/l, and female sex in "watch and wait" patients (multivariable analysis). The level of the IgM monoclonal immunoglobulin had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

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/m 2 , 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.

In chronic lymphocytic leukaemia (CLL) patients, treatment with the Bruton tyrosine kinase inhibitor ibrutinib induces a rapid shift of tumour cells from lymph nodes (LN) to peripheral blood (PB). Here, we characterized in depth the dynamics of ibrutinib-induced inflammatory, transcriptional and cellular changes in different compartments immediately after treatment initiation in seven relapsed/refractory CLL patients. Serial PB and LN samples were taken before start and during the first 29 days of treatment. Changes in plasma inflammation-related biomarkers, CLL cell RNA expression, B-cell activation and migration markers expression, and PB mononuclear cell populations were assessed. A significant reduction of 10 plasma inflammation markers, the majority of which were chemokines and not CLL-derived, was observed within hours, and was paralleled by very early increase of CD19 + circulating cells. At the RNA level, significant and continuous changes in transcription factors and signalling molecules linked to B-cell receptor signalling and CLL biology was observed in both PB and LN CLL cells already after 2 days of treatment. In conclusion, ibrutinib seems to instantly shut off an ongoing inflammatory response and interfere with diverse sensitive pathways in the LN., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

High-risk chronic lymphocytic leukemia (CLL) has been defined by clinical and/or genetic resistance ( TP53 abnormalities) to treatment with chemoimmunotherapy (CIT). With the availability of pathway inhibitors (PIs), such as kinase inhibitors and BCL2 antagonists, the outlook of CIT-resistant patients has dramatically improved. Here, we propose a revision of the concept of high-risk CLL, driven by TP53 abnormalities and response to treatment with PI. CLL high-risk-I, CIT-resistant is defined by clinically CIT-resistant disease with TP53 aberrations, but fully responsive to PI. This category is largely the domain of PI-based therapy, and cellular therapy (ie, allogeneic hematopoietic cell transplantation) remains an option only in selected patients with low individual procedure-related risk. In CLL high-risk-II, CIT- and PI-resistant, characterized by increasing exhaustion of pharmacological treatment possibilities, cellular therapies (including chimeric antigen receptor-engineered T cells) should be considered in patients eligible for these procedures. Moreover, molecular and cellular therapies are not mutually exclusive and could be used synergistically to exploit their full potential., (© 2018 by The American Society of Hematology.)

Background: Histological transformation of follicular lymphoma to aggressive lymphoma is a serious event with a substantial effect on patient outcome. The aim of the Aristotle study was to assess the effect of rituximab on the risk of histological transformation and its outcome., Methods: 11 cooperative groups or institutions across Europe contributed data to this study. Eligible patients (≥18 years) had histologically confirmed follicular lymphoma grade 1, 2, or 3a, diagnosed between Jan 2, 1997, and Dec 20, 2013. Histological transformation was defined as a biopsy-proven aggressive lymphoma that occurred as a first event after first-line therapy. The primary endpoints were the cumulative hazard of histological transformation and survival after transformation., Findings: Information was available for 10 001 patients with follicular lymphoma, 8116 of whom were eligible for analysis. 509 histological transformations were reported. After a median follow-up of 87 months (range 1-221; 2·5-97·5th percentile 5-160), the 10-year cumulative hazard of histological transformation was 7·7% (95% CI 6·9-8·5). The 10-year cumulative hazard of histological transformation was 5·2% (95% CI 4·5-6·2) in patients who received rituximab and 8·7% (7·2-10·6) in those who did not (hazard ratio [HR] 0·73, 95% CI 0·58-0·90; p=0·004). The 10-year cumulative hazard of histological transformation was 5·9% (95% CI 5·0-7·0) for patients who received induction rituximab only and 3·6% (95% CI 2·3-5·5) for those treated with induction and maintenance rituximab (HR 0·55, 95% CI 0·37-0·81; p=0·003). This finding was confirmed in a multivariate analysis (p=0·016). 287 deaths were recorded in 509 patients with histological transformation, resulting in a 10-year survival after transformation of 32% (95% CI 26-38). Survival after transformation did not differ between patients not exposed to rituximab and those who received rituximab in induction only (HR 0·94, 95% CI 0·69-1·28; p=0·70), and those who received rituximab in induction and maintenance (0·96, 0·58-1·61; p=0·88)., Interpretation: The risk of histological transformation as a first event can be significantly reduced by the use of rituximab. These findings support the need to inform patients using rituximab nowadays that the risk of transformation is lower than it was before the introduction of rituxumab., Funding: Associazione Angela Serra per la Ricerca sul Cancro, European Lymphoma Institute, European Hematology Association Lymphoma Group, Fondazione Italiana Linfomi, Spanish Group of Lymphoma and Bone Marrow Transplantation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: To determine if patients with untreated chronic lymphocytic leukemia (CLL) benefit from vaccination with a 13-valent pneumococcal conjugated vaccine (PCV13), Prevenar13®, compared to a 23-valent pneumococcal polysaccharide vaccine (PPSV23), Pneumovax®, in terms of immune response., Background: Streptococcus pneumoniae causes substantial morbidity in patients with CLL, a group known to respond poorly to polysaccharide vaccines. Comparative studies with conjugated vaccines are lacking., Methods: 128 treatment naïve CLL patients from eight hematology clinics in Sweden were randomized to vaccination with PCV13 (n = 63) or PPSV23 (n = 65) after stratification by IgG level and CLL clinical stage (Rai). Blood samples for evaluation of immune response were obtained at baseline, and at one and six months after vaccination. Analyses for each of the 12 pneumococcal serotypes common for PCV13 and PPSV23 were performed by opsonophagocytic assay (OPA) and enzyme-linked immunosorbent assay (ELISA)., Results: PCV13 elicited a superior immune response than PPSV23 in 10/12 serotypes one month after vaccination and in 5/12 serotypes six months after vaccination, measured as OPA geometric mean titers (GMTs). Geometric mean concentrations of serotype-specific IgG antibodies elicited by PCV13 as measured by ELISA, were higher than those elicited by PPSV23 in half of the common serotypes, both after one and six months. PPSV23 did not trigger a better immune response than PCV13 for any of the serotypes, regardless of analysis method or time point of analysis. Negative predictive factors for vaccination response were hypogammaglobulinemia and long disease duration. Both vaccines were well tolerated., Conclusions: In patients with previously untreated CLL, the efficacy of PCV13 in terms of immune response is superior to PPSV23 for most serotypes common for the two vaccines. We therefore propose that PCV13 should be included in vaccination programs against Streptococcus pneumoniae for CLL patients and administered as early as possible during the course of the disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

CD52 is a glycoprotein expressed on normal as well as leukemic immune cells and shed as soluble CD52 (sCD52). We studied sCD52 levels in three CLL cohorts: the 'early', the 'high-risk', and the 'ibrutinib-treated'. The 'high-risk' patients had significantly higher sCD52 levels than the 'early' patients. For the 'early' patients, high sCD52 levels were associated with a significantly shorter time to first treatment. Regarding prognostic factors, no clear correlations with stage, IGHV, or beta-2-microglobulin were found; in a cox multivariate analysis of the 'early' patients, sCD52 and IGHV both had independent prognostic value. Following chemo-immunotherapy, sCD52 decreased in parallel with leukocytes while during ibrutinib treatment and ibrutinib-induced ymphocytosis, sCD52 decreased along with lymph node reductions. In vitro IgM stimulation of CLL cells led to increased sCD52 levels in the medium. Our findings indicate that sCD52 reflects disease activity and potentially treatment efficacy in CLL.

In follicular lymphoma, studies addressing the prognostic value of microenvironment-related immunohistochemical markers and tumor cell-related genetic markers have yielded conflicting results, precluding implementation in practice. Therefore, the Lunenburg Lymphoma Biomarker Consortium performed a validation study evaluating published markers. To maximize sensitivity, an end of spectrum design was applied for 122 uniformly immunochemotherapy-treated follicular lymphoma patients retrieved from international trials and registries. The criteria were: early failure, progression or lymphoma-related death <2 years versus long remission, response duration of >5 years. Immunohistochemical staining for T cells and macrophages was performed on tissue microarrays from initial biopsies and scored with a validated computer-assisted protocol. Shallow whole-genome and deep targeted sequencing was performed on the same samples. The 96/122 cases with complete molecular and immunohistochemical data were included in the analysis. EZH2 wild-type ( P =0.006), gain of chromosome 18 ( P =0.002), low percentages of CD8+ cells ( P =0.011) and CD163+ areas ( P =0.038) were associated with early failure. No significant differences in other markers were observed, thereby refuting previous claims of their prognostic significance. Using an optimized study design, this Lunenburg Lymphoma Biomarker Consortium study substantiates wild-type EZH2 status, gain of chromosome 18, low percentages of CD8+ cells and CD163+ area as predictors of early failure to immunochemotherapy in follicular lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP [-like]), while refuting the prognostic impact of various other markers., (Copyright© 2017 Ferrata Storti Foundation.)

Background: Immunocompromised patients can experience significant morbidity and occasional mortality from complications associated with herpes zoster (HZ), but live attenuated HZ vaccine is contraindicated for these patients. Inactivated zoster vaccine (ZV IN ) is in development for prevention of HZ in immunocompromised patients. However, there are limited data in the literature regarding the effect of anti-CD20 monoclonal antibodies on vaccine-related cell-mediated immune response. This study evaluated safety and immunogenicity of ZV IN in patients with hematologic malignancies (HM) receiving anti-CD20 monoclonal antibodies (alone or in combination chemotherapy regimens) and not likely to undergo hematopoietic cell transplant (HCT) (n=80)., Methods: This was an open-label, single-arm, multicenter Phase I study (NCT01460719) of a 4-dose ZV IN regimen (∼30days between doses) in patients ⩾18years old. Blood samples were collected prior to dose 1 and 28days Postdose 4 to measure varicella zoster virus (VZV)-specific T-cell responses using interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT). The primary hypothesis was that ZV IN would elicit significant VZV-specific immune responses at ∼28days Postdose 4, with a geometric fold rise (GMFR) >1.0. All vaccinated patients were evaluated for adverse events (AE) through 28days Postdose 4., Results: ZV IN elicited a statistically significant VZV-specific immune response measured by IFN-γ ELISPOT at 28days Postdose 4 (GMFR=4.34 [90% CI:3.01, 6.24], p-value<0.001), meeting the pre-specified success criterion. Overall, 85% (68/80) of patients reported ⩾1 AE, 44% (35/80) reported ⩾1 injection-site AE, and 74% (59/80) reported ⩾1 systemic AE. The majority of systemic AEs were non-serious and considered unrelated to vaccination by the investigator. Frequencies of AEs did not increase with subsequent doses of vaccine. No recipient of ZV IN had rash polymerase chain reaction (PCR) positive for VZV vaccine strain., Conclusions: In adults with HM receiving anti-CD20 monoclonal antibodies, ZV IN was well-tolerated and elicited statistically significant VZV-specific T-cell responses ∼28days Postdose 4. CLINICALTRIALS.GOV identifier: NCT01460719., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In the HOVON68 CLL trial, patients 65 to 75 years of age had no survival benefit from the addition of low-dose alemtuzumab to fludarabine and cyclophosphamide (FC) in contrast to younger patients. The reasons are explored in this 5-year trial update using both survival analysis and competing risk analysis on non-CLL-related mortality. Elderly FCA patients died more frequently from causes not related to CLL, and more often related to comorbidity (mostly cardiovascular) than to infection. In a Cox multivariate analysis, del(17p), performance status >0, and comorbidity were associated with a higher non-CLL-related mortality in the elderly independent of the treatment modality. Thus, while the 'fit' elderly with no comorbidity or performance status of 0 might potentially benefit from chemo-immunotherapy with FC, caution is warranted, when considering alemtuzumab treatment in elderly patients with cardiovascular comorbidity.

The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rearrangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (P < .0001). OS was 75% at 10 years and median not reached in the MRD-negative group, compared with only 35 months in the MRD-positive group (P < .0001). Of the 86 patients (47%) who remained in continuous molecular remission, 73% were still in clinical remission after 10 years. For all patients, the median time from ASCT to first molecular relapse was 55 months, with a continuous occurrence of late molecular relapses. Fifty-eight patients who experienced MRD relapse received rituximab as preemptive treatment on 1 or more occasions, and in this group, the median time from first molecular relapse to clinical relapse was 55 months. In most cases, rituximab converted patients to MRD negativity (87%), but many patients became MRD-positive again later during follow-up (69%). By multivariate analysis, high-risk Mantle Cell Lymphoma International Prognostic Index score and positive MRD status pre-ASCT predicted early molecular relapse. In conclusion, preemptive rituximab treatment converts patients to MRD negativity and likely postpones clinical relapse. Molecular monitoring offers an opportunity to select some patients for therapeutic intervention and to avoid unnecessary treatment in others. MRD-positive patients in the first analysis post-ASCT have a dismal prognosis and thus are in need of novel strategies., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, > 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R 2 WLS ) and bivariate copula (R 2 Copula ) models. Prespecified criteria for surrogacy required either R 2 WLS or R 2 Copula ≥ 0.80, with a lower-bound 95% CI > 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R 2 WLS of 0.88 (95% CI, 0.77 to 0.96) and an R 2 Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.

We present health-related quality of life (HRQoL) data from GADOLIN, comparing bendamustine (B) alone or combined with obinutuzumab (G-B) in rituximab-refractory indolent non-Hodgkin lymphoma patients. The Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) questionnaire was administered on day 1 of cycles 1, 3, and 5 during treatment, at end of induction (EOI), bi-monthly for 2 years during maintenance/follow-up, and annually during extended follow-up until progression/death. Time to first ≥6-point worsening from baseline in the FACT-Lym trial outcome index (TOI) was estimated. Minimally important differences at individual subscale and total score level were used to define the proportion of patients reporting improvement on the FACT-Lym lymphoma-specific subscale (≥3 points), FACT-Lym TOI (≥6 points), and FACT-Lym total score (≥7 points). Overall, 396 patients were randomized. Analysis was conducted when 175 Independent Review Committee-assessed progression-free survival (PFS) events were observed. Questionnaire completion rates were generally balanced between arms at baseline, EOI, and final follow-up. Median time to ≥6-point worsening from baseline on the FACT-Lym TOI was 8.0 months in the G-B arm and 4.6 months in the B arm (HR 0.74; 95% CI 0.56-0.98). More G-B patients reported meaningful improvements on the FACT-Lym questionnaire subscales. Results were similar when follicular lymphoma patients were analyzed separately. The delayed time to worsening and greater proportion of patients reporting meaningful improvement in HRQoL in the G-B arm suggest that benefit in PFS is not at the expense of an increase in treatment-related toxicity that could lead to reduced HRQoL., Competing Interests: Compliance with ethical standards The protocol was approved by the ethics committees of participating centers and is registered at ClinicalTrials.gov. Funding This study was sponsored by F. Hoffmann-La Roche Ltd. Conflict of interest BDC has performed in a consulting or advisory role for Celgene, Gilead, Pharmacyclics, Astra Zeneca, Spectrum, and Astellas, and his institution has received research funding from Pharmacyclics, Acerta, Seattle Genetics, and Gilead. PCT is an employee of Genentech, Inc. and owns stock in Roche/Genentech. JGG has received honoraria from Roche/Genentech, Celgene, Pharmacyclis, Janssen, Gilead, Mundipharma, TG Therapeutics, and Acerta. ND is an employee of Roche and owns stock in Roche and GSK. EK has received honoraria from Janssen, Gilead, Celgene, and AbbVie; has performed in a consulting or advisory role for Janssen, Baxalta, and AbbVie; and has received research funding and drug support from—and worked on transitional research with—Pfizer. PJL has performed in a consulting or advisory role for Celgene, Mundipharma, and Servier. CT has performed in a consulting or advisory role for Janssen, Gilead, and Roche and has received travel, accommodation, and expenses support from Janssen and Gilead. EW-F is an employee of F. Hoffmann-La Roche Ltd. AL is an employee of F. Hoffmann-La Roche Ltd., owns stock in Novartis, and has received travel, accommodation, and expenses support from Roche and Novartis. LHS has received honoraria from Roche/Genentech, Celgene, Seattle Genetics, AbbVie, Janssen, Gilead, Amgen, and TG Therapeutics and has performed in a consulting or advisory role for Roche/Genentech, Celgene, Gilead, Janssen, Pfizer, Amgen, Seattle Genetics, AbbVie, Lundbeck, and TG Therapeutics. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study.

Bing Neel syndrome is a rare disease manifestation of Waldenström's macroglobulinemia that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. In this guideline we describe the clinical symptoms, as well as the appropriate laboratory and radiological studies, that can aid in the diagnosis. The presentation of Bing Neel syndrome may be very diverse, and includes headaches, cognitive deficits, paresis, and psychiatric symptoms. The syndrome can present in patients with known Waldenström's macroglobulinemia, even in the absence of systemic progression, but also in previously undiagnosed patients. Diagnostic work-up should include cerebral spinal fluid analysis with multiparameter flow cytometry to establish B-cell clonality, protein electrophoresis and immunofixation for the detection and classification of a monoclonal protein as well as molecular diagnostic testing for immunoglobulin gene rearrangement and mutated MYD88. MRI of the brain and spinal cord is also essential. The second challenge is to expand our knowledge of prognosis and treatment outcome. Prospective clinical trials on Bing Neel syndrome patients that employ uniform treatment along with appropriate laboratory cerebral spinal fluid assessments and standardized MRI protocols will be invaluable, constituting a significant step forward in delineating treatment outcome for this intriguing disease manifestation., (Copyright© Ferrata Storti Foundation.)

In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first-line regimens containing cytarabine, rituximab and consolidation with high-dose-therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15-year updated results of the Nordic MCL2 study after a median follow-up of 11·4 years: For all patients on an intent-to-treat basis, the median overall and progression-free survival was 12·7 and 8·5 years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI-B) and the MIPI-B including mIR-18b expression (MIPI-B-miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12 years, we still see an excess disease-related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL., (© 2016 John Wiley & Sons Ltd.)

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of the International Workshop on Waldenström's Macroglobulinemia (IWWM). At IWWM-8, a task force for treatment recommendations was impanelled to review recently published and ongoing clinical trial data as well as the impact of new mutations (MYD88 and CXCR4) on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives for WM patients. The panel concluded that therapeutic strategies in WM should be based on individual patient and disease characteristics. Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients. Approval of the BTK inhibitor ibrutinib in the United States and Europe represents a novel and effective treatment option for both treatment-naive and relapsing patients. Other B-cell receptor inhibitors, second-generation proteasome inhibitors (eg, carfilzomib), and mammalian target of rapamycin inhibitors are promising and may increase future treatment options. Active enrollment in clinical trials whenever possible was endorsed by the panel for most patients with WM., (© 2016 by The American Society of Hematology.)