Summary
The prognostic value of grading follicular lymphoma has been debated since the 1980s. There is consensus that World Health Organization (WHO) grades 1 and 2 are indolent, but not whether ...grades 3A or 3B are aggressive. We retrospectively reviewed the follicular lymphoma diagnoses according to the 2008 WHO classification in all diagnostic specimens from a population‐based cohort of 505 patients with a median follow‐up time of 10·0 years (range, 4·6–16·0). After excluding 43 patients with concomitant diffuse large B‐cell lymphoma, 345 remained with grade 1–2, 94 with grade 3A, and 23 with grade 3B follicular lymphoma. Grades 1–2 and 3A seemed equally indolent, with indistinguishable clinical courses, even in patients receiving anthracyclines. Compared with grades 1–3A and independently of clinical factors, grade 3B correlated with higher mortality (P = 0·008), but outcome was improved after upfront anthracycline‐containing therapy (P = 0·015). In contrast to grade 1–3A patients, grade 3B patients experienced no relapses or deaths beyond 5 years of follow‐up. Furthermore, patients with grade 3B were predominantly male and seldom presented with bone‐marrow involvement. We conclude that follicular lymphoma grade 1–3A is indolent and incurable with conventional therapy. Grade 3B appears to be an aggressive but curable disease.
We performed a national population-based study of all patients diagnosed with diffuse large B-cell lymphoma (DLBCL) in Sweden in 2007-2014 to assess treatment intent and risk of relapsed/refractory ...disease, including central nervous system (CNS) relapse, in the presence of competing risks. Overall, 84% of patients started treatment with curative intent (anthracycline-based) (n = 3550, median age 69 years), whereas 14% did not (n = 594, median age 84 years) (for 2% the intent was uncertain). Patients treated with curative intent had a 5-year OS of 65.3% (95% CI: 63.7-66.9). The median OS among non-curatively treated patients was 2.9 months. The 5-year cumulative incidence of relapsed/refractory disease in curative patients was 23.1% (95% CI: 21.7-24.6, n = 847). The 2-year cumulative incidence of CNS relapse was 3.0% (95% CI: 2.5-3.6, n = 118) overall, and 8.0% (95% CI: 6.0-10.6, n = 48) among patients with high CNS-IPI (4-6), when considering other relapse locations and death as competing events. The incidence of relapsed/refractory DLBCL overall and in the CNS was lower than in previous reports, still one in seven patients was not considered fit enough to start standard immunochemotherapy at diagnosis. These results are important for quantification of groups of DLBCL patients with poor prognosis requiring completely different types of interventions.
Plerixafor + granulocyte-colony stimulating factor (G-CSF) is administered to patients with lymphoma who are poor mobilizers of hematopoietic stem cells (HSCs) in Europe. This international, ...multicenter, non-interventional registry study (NCT01362972) evaluated long-term follow-up of patients with lymphoma who received plerixafor for HSC mobilization versus other mobilization methods. Propensity score matching was conducted to balance baseline characteristics between comparison groups. The following mobilization regimens were compared: G-CSF + plerixafor (G + P) versus G-CSF alone; G + P versus G-CSF + chemotherapy (G + C); and G-CSF + plerixafor + chemotherapy (G + P + C) versus G + C. The primary outcomes were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Overall, 313/3749 (8.3%) eligible patients were mobilized with plerixafor-containing regimens. After propensity score matching, 70 versus 36 patients were matched in the G + P versus G-CSF alone cohort, 124 versus 124 in the G + P versus G + C cohort, and 130 versus 130 in the G + P + C versus G + C cohort. For both PFS and OS, the upper bound of confidence interval for the hazard ratio was >1.3 for all comparisons, implying that non-inferiority was not demonstrated. No major differences in PFS, OS, and CIR were observed between the plerixafor and comparison groups.
Summary
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent CD20+ lymphoma. Its scarcity has made clinical trials difficult and there is no consensus on first‐line treatment. We ...conducted a population‐based study of all patients diagnosed with NLPHL in Sweden between 2000 and 2014 (N = 158; 41 women and 117 men), focusing on clinical features, therapy and overall survival. The median female and male age was 59 and 44 years, respectively (P = 0·002). In early‐stage disease, there was little mortality and no survival differences between therapies. In patients with advanced‐stage disease, mortality was relatively high in patients who did not receive first‐line rituximab but absent in those who did (10‐year survival, 55% vs. 100%; P = 0·033); there were no imbalances of prognostic factors between those two groups. In advanced stages, first‐line rituximab use increased markedly between 2000–2004 and 2005–2014 (7% vs. 67%; P < 0·00005), as did 10‐year survival, 53% vs. 72% (multivariate P = 0·027). Although all patients were diagnosed in the 2000s, this is the longest‐followed (and largest) population‐based cohort. We report a hitherto unreported 15‐year median age difference between sexes, increasing rituximab use and improved survival.
Summary
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.
Summary
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.
The cellular microenvironment in follicular lymphoma is of biological and clinical importance. Studies on the clinical significance of non-malignant cell populations have generated conflicting ...results, which may partly be influenced by poor reproducibility in immunohistochemical marker quantification. In this study, the reproducibility of manual scoring and automated microscopy based on a tissue microarray of 25 follicular lymphomas as compared to flow cytometry is evaluated. The agreement between manual scoring and flow cytometry was moderate for CD3, low for CD4, and moderate to high for CD8, with some laboratories scoring closer to the flow cytometry results. Agreement in manual quantification across the 7 laboratories was low to moderate for CD3, CD4, CD8 and FOXP3 frequencies, moderate for CD21, low for MIB1 and CD68, and high for CD10. Manual scoring of the architectural distribution resulted in moderate agreement for CD3, CD4 and CD8, and low agreement for FOXP3 and CD68. Comparing manual scoring to automated microscopy demonstrated that manual scoring increased the variability in the low and high frequency interval with some laboratories showing a better agreement with automated scores. Manual scoring reliably identified rare architectural patterns of T-cell infiltrates. Automated microscopy analyses for T-cell markers by two different instruments were highly reproducible and provided acceptable agreement with flow cytometry. These validation results provide explanations for the heterogeneous findings on the prognostic value of the microenvironment in follicular lymphoma. We recommend a more objective measurement, such as computer-assisted scoring, in future studies of the prognostic impact of microenvironment in follicular lymphoma patients.
The purpose of this study was to investigate the impact of T-cell subsets on pathologic and clinical features including disease outcome in mantle cell lymphoma (MCL).
Cell populations were ...investigated using flow cytometry in diagnostic MCL (n = 153) and reactive (n = 26) lymph node biopsies. Levels of tumor cells, T cells, T-cell subsets, and the CD4:CD8 ratio were assessed and related to pathologic and clinical parameters.
MCL cases with diffuse and nodular histologic subtypes showed lower levels of T cells, especially CD4(+) T cells, than those with mantle zone growth pattern. Both CD3 and CD4 levels were lower in the nodular subtype than in mantle zone (P = 0.007; P = 0.003) and in the diffuse compared with the nodular subtype (P = 0.022; P = 0.015). The CD4:CD8 ratios were inversely correlated to tumor cell proliferation (P = 0.003). Higher levels of CD3(+) and CD4(+) T cells and higher CD4:CD8 ratios were associated with indolent disease (P = 0.043, 0.021, and 0.003 respectively). In univariate analysis, a high CD4:CD8 ratio, but not the histologic subtype, was correlated to longer overall survival (OS). In multivariate analysis, the CD4:CD8 ratio correlated with OS independently of Mantle Cell Lymphoma International Prognostic Index (MIPI) and high p53 expression (P = 0.023).
CD3(+), CD8(+), and particularly CD4(+) T-cell levels are higher in indolent MCL and decrease with more aggressive histology as reflected by a diffuse growth pattern. High CD4:CD8 ratio correlated independently of other high-risk prognostic factors with longer OS, suggesting a prognostic role for T cells in MCL.
Summary
Diffuse large B‐cell lymphoma (DLBCL) incidence rises with increasing age. Rituximab‐anthracycline‐based regimens offer a potential cure but also risks of adverse events, especially in the ...elderly. Using Swedish registers, we conducted a nationwide, population‐based study of DLBCL in the very elderly. We obtained information on clinical characteristics, residence, comorbidity, therapy and survival for the 1194 patients aged ≥80 years diagnosed in Sweden 2007–2014. To address selection bias, we also investigated treatment differences between Sweden’s Healthcare Regions and whether there were survival differences between the Regions. The 2‐year overall and relative survivals were better in patients aged ≥80 years given treatment with curative intent (54%; 64%) than low‐intensity (26%; 33%), or palliative treatment (6%; 7%). The fraction of patients treated with curative intent varied between the Healthcare Regions (45–76%). Survival was significantly inferior in Regions with few patients treated with curative intent (multivariable hazard ratio 1.3, 95% confidence interval 1.1–1.6). When treatment intensity and Regions competed, Regions were no longer independent, suggesting that Regional survival differences are due to therapeutic differences. Furthermore, we found that the age‐adjusted International Prognostic Index was independently associated with survival. We conclude that patients aged ≥80 years with DLBCL appear to benefit from rituximab‐anthracycline‐based treatment given with curative intent.
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