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.
Purpose: Follicular lymphoma is a heterogeneous disease with variable prognosis and clinical course. We hypothesized that the presence
of nonmalignant T cells in the microenvironment of the tumor may ...affect the outcome.
Experimental Design: Using flow cytometry, we evaluated the T-cell subsets in the lymph node microenvironment of follicular lymphoma. All patients
in South Stockholm County with indolent follicular lymphoma and with flow cytometry done on a diagnostic lymph node between
1994 and 2004 were included ( N = 139). Diagnosis and grade (1, 2, and 3a) were confirmed by re-review. Flow cytometry results were reanalyzed. Lymphocyte
subsets, the Follicular Lymphoma International Prognostic Index, grade, and clinical characteristics were evaluated in univariable
and multivariable Cox analysis with respect to overall survival (OS) and disease-specific survival (DSS).
Results: Higher CD8+ T-cell levels correlated with longer OS and DSS, independently of the Follicular Lymphoma International Prognostic
Index (OS, P = 0.017; DSS, P = 0.020) and independently of all other prognostic factors (OS, P = 0.001; DSS, P = 0.004). Median OS was not reached for patients in the upper quarter of CD8+ T-cell levels (>8.6%), 10.4 years for patients
in the middle half (4.2-8.6%), and 6.0 years for patients in the lower quarter (<4.2%). Furthermore, patients who had not
required treatment within 6 months from diagnosis had more CD8+ T cells ( P = 0.011).
Conclusions: Higher levels of CD8+ T cells predict a better prognosis, and these data support an important role for nonmalignant immune
cells in the biology of follicular lymphoma. Evaluating the CD8+ T cells by flow cytometry at diagnosis may provide prognostic
information.
In lymphomas of B-cell origin, cancer cells orchestrate an inflammatory microenvironment of immune and stromal cells that sustain the tumor cell survival and growth, known as a tumor microenvironment ...(TME). The features of the TME differ between the different lymphoma types, ranging from extremely inflammatory, such as in Hodgkin lymphoma, to anergic, leading to immune deficiency and susceptibility to infections, such as in chronic lymphocytic leukemia. Understanding the characteristic features of the TME as well as the interactions between cancer and TME cells has given insight into the pathogenesis of most lymphomas and contributed to identify novel therapeutic targets. Here, we summarize the preclinical data that contributed to clarifying the role of the immune cells in the TME of different types of lymphomas of B-cell origin, and explain how the understanding of the biological background has led to new clinical applications. Moreover, we provide an overview of the clinical results of trials that assessed the safety and efficacy of drugs directly targeting TME immune cells in lymphoma patients.
Chimeric antigen-receptor T-cell and bispecific antibody therapies will likely necessitate a reconsideration of the role of autologous stem-cell transplantation (ASCT) in lymphoma. Patients who are ...likely to profit from ASCT need to be better identified.
Here, we investigated the value of positron emission tomography/computerized tomography (PET/CT) before ASCT. All 521 patients transplanted for lymphoma 1994-2019 at Karolinska (497 conditioned with BEAM) were included.
Outcome improved over three calendar periods 1994-2004, 2005-2014, 2015-2019 (2-year overall survival OS: 66, 73, 83%; P = 0.018). Non-relapse mortality (NRM) at 100 days over the three periods were 9.8, 3.9, 2.9%, respectively. The OS improvement between 1994 and 2004 and 2005-2014 was due to lower NRM (P = 0.027), but the large OS advance from 2015 was not accompanied by a significant reduction in NRM (P = 0.6). The fraction of PET/CT as pre-ASCT assessment also increased over time: 1994-2004, 2%; 2005-2014, 24%; 2015-2019, 60% (P < 0.00005). Complete responses (PET/CT-CR) were observed in 77% and metabolically active partial responses (PET/CT-PR) in 23%. PET/CT-CR was a predictor for survival in the entire population (P = 0.0003), also in the subpopulations of aggressive B-cell (P = 0.004) and peripheral T-cell (P = 0.024) lymphomas. Two-year OS and progression-free survival (OS/PFS) for patients in PET/CT-CR were in relapsed/refractory aggressive B-cell lymphoma 87%/75% and peripheral T-cell lymphoma 91%/78%. The corresponding figures in PET/CT-PR were 43%/44 and 33%/33%. Patients with solitary PET/CT-positive lesions showed acceptable outcome with ASCT followed by local irradiation (2-year OS/PFS 80%/60%). CT was less discriminative: 2-year OS/PFS: CT-CR, 76%/66%; CT-PR, 62%/51%. Outcome was inferior after BEAC compared with BEAM conditioning.
We conclude that the improved outcome reflects better, PET/CT-informed, identification of patients who should proceed to ASCT. The excellent survival of patients in PET/CT-CR indicates that ASCT should remain part of standard therapy for lymphoma.
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.
The phase III ASPEN study demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM). Here, we report long-term ...follow-up outcomes from ASPEN. The primary end point was the sum of very good partial response (VGPR) + complete response (CR) rates; secondary and exploratory end points were also reported. Cohort 1 comprised 201 patients (myeloid differentiation primary response 88-mutant WM: 102 receiving zanubrutinib; 99 receiving ibrutinib); cohort 2 comprised 28 patients (myeloid differentiation primary response 88 wild-type WM: 28 zanubrutinib; 26 efficacy evaluable). At 44.4-month median follow-up, VGPR + CR rates were 36.3% with zanubrutinib versus 25.3% with ibrutinib in cohort 1 and 30.8% with one CR in cohort 2. In patients with CXC motif chemokine receptor 4 mutation, VGPR + CR rates were 21.2% with zanubrutinib versus 10.0% with ibrutinib (cohort 1). Median progression-free survival and overall survival were not reached. Any-grade adverse events (AEs) of diarrhea (34.7%
22.8%), muscle spasms (28.6%
11.9%), hypertension (25.5%
14.9%), atrial fibrillation/flutter (23.5%
7.9%), and pneumonia (18.4%
5.0%) were more common with ibrutinib versus zanubrutinib; neutropenia (20.4%
34.7%) was less common with ibrutinib versus zanubrutinib (cohort 1). Zanubrutinib was associated with lower risk of AE-related treatment discontinuation. Overall, these findings confirm the long-term response quality and tolerability associated with zanubrutinib.
Objective: To describe how coronavirus disease 2019 (COVID-19) affects patients with hematological malignancies treated with autologous hematopoietic stem cell transplantation (ASCT).
Methods: This ...retrospective observational cohort study includes all patients with hematological malignancies treated with ASCT in Sweden from 1 January 2020 to 31 December 2020. Patients who subsequently tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) until 31 March 2021 were analyzed for morbidity, mortality, need for supportive care, and risk factors related to COVID-19.
Results: This study identified 442 patients who underwent ASCT in Sweden in 2020, among whom 20 (4.5%) subsequently tested positive for COVID-19. The overall mortality was 15%, and the COVID-19-related mortality was 10% among the patients who contracted COVID-19. Six (35%) patients were hospitalized, of which four (24%) needed supplementary oxygen and two (12%) needed intensive care. The absolute risk of COVID-19-related mortality was 0.45%.
Conclusions: ASCT patients have a higher risk of severe outcome of COVID-19 compared to the normal population. However, the risks of death, inpatient care, oxygen therapy, and intensive care seem lower in this study compared to previous studies, possibly due to fewer mildly ill patients in other studies. The risk of contracting SARS-CoV-2 appears to be comparable to that in the general population. This study suggests that the COVID-19 pandemic is not a strong argument for refraining from ASCT in the case of hematological malignancy.
CAR-NK cells can induce remission in lymphoma patients. We speculate that the full potential of adoptive NK cell immunotherapy against lymphoma is restricted by their poor lymph node (LN) homing ...capacity. Here, we have utilized a clinically approved transfection method with the aim of redirecting NK cells to LNs. Electroporation of ex vivo expanded NK cells with mRNAs coding for CCR7, CXCR5, and CD62L resulted in increased in vitro migration towards chemokines and mouse LN-derived supernatant. Following infusion into SCID/Beige mice, modified NK cells showed enhanced LN homing. Importantly, lymphoma patient-derived NK cells were equally well expanded and engineered as healthy donor NK cells, highlighting their translational potential. Additionally, the introduction of high-affinity CD16, together with the homing molecules, also augmented their ADCC capacity against autologous lymphoma cells. Hence, genetic engineering can be utilized to enhance NK cell LN homing. The homing concept may synergize with CAR- or monoclonal/bi-/tri-specific antibody-based approaches.
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