Explore the vast range of titles available.

Background Long-term lymphoma survivors often complain of persistent fatigue that remains unexplained. While largely reported in Hodgkin lymphoma (HL), long-term fatigue is poorly documented in non-Hodgkin lymphomas (NHL). Data collected in two cohort studies were used to illustrate the fatigue level changes with time in the two populations. Methods Two cross-sectional studies were conducted in 2009–2010 (HL) and in 2015 (NHL) in survivors enrolled in European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group and Lymphoma Study Association (LYSA) trials. The same protocol and questionnaires were used in both studies including the Multidimensional Fatigue Inventory (MFI) tool to assess fatigue and a checklist of health disorders. Multivariate linear regression models were used in the two populations separately to assess the influence of time since diagnosis and primary treatment, age, gender, education level, cohabitation status, obesity and health disorders on fatigue level changes. Fatigue level changes were compared to general population data. Results Overall, data of 2023 HL and 1619 NHL survivors with fatigue assessment available (99 and 97% of cases, respectively) were analyzed. Crude levels of fatigue were similar in the two populations. Individuals who reported health disorders (61% of HL and 64% of NHL) displayed higher levels of fatigue than those who did not ( P  <  0.001). HL survivors showed increasing fatigue level with age while in NHL survivors mean fatigue level remained constant until age 70 and increased beyond. HL survivors showed fatigue changes with age higher than those of the general population with health disorders while NHL survivors were in between those of the general population with and without health disorders. Conclusions Among lymphoma survivors progressive increase of fatigue level with time since treatment completion is a distinctive feature of HL. Our data suggest that changes in fatigue level are unlikely to only depend on treatment complications and health disorders. Investigations should be undertaken to identify which factors including biologic mechanisms could explain why a substantial proportion of survivors develop high level of fatigue.

High-risk large B-cell lymphoma (LBCL) has poor outcomes with standard first-line chemoimmunotherapy. In the phase 2, multicenter, single-arm ZUMA-12 study (ClinicalTrials.gov NCT03761056) we evaluated axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, as part of first-line treatment in 40 patients with high-risk LBCL. This trial has completed accrual. The primary outcome was complete response rate (CRR). Secondary outcomes were objective response rate (ORR), duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), assessment of safety, central nervous system (CNS) relapse and blood levels of CAR T cells and cytokines. The primary endpoint in efficacy-evaluable patients ( n  = 37) was met, with 78% CRR (95% confidence interval (CI), 62–90) and 89% ORR (95% CI, 75–97). As of 17 May 2021 (median follow-up, 15.9 months), 73% of patients remained in objective response; median DOR, EFS and PFS were not reached. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in three patients (8%) and nine patients (23%), respectively. There were no treatment-related grade 5 events. Robust CAR T-cell expansion occurred in all patients with a median time to peak of 8 days. We conclude that axi-cel is highly effective as part of first-line therapy for high-risk LBCL, with a manageable safety profile. In a phase 2 trial, first-line treatment with axicabtagene ciloleucel, an autologous CD19-targeting CAR T-cell therapy, exhibited a high complete response rate and a manageable safety profile in adults with high-risk large B-cell lymphoma.

Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival 1 , 2 . T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3’s plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL. Our findings highlight HLH–SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH–SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences. This study finds germline loss-of-function mutations in HAVCR2 , which encodes the immune modulator TIM-3, in individuals with subcutaneous panniculitis-like T cell lymphomas and hemophagocytic lymphohistiocytosis, a life-threatening inflammatory condition.

The outcome of diffuse large B-cell lymphoma has been substantially improved by the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy regimens. We aimed to assess, in patients aged 18–59 years, the potential survival benefit provided by a dose-intensive immunochemotherapy regimen plus rituximab compared with standard treatment plus rituximab. We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18–59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595. One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75–86) in the R-ACVBP group and 67% (59–73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38–0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81–91] vs 73% [66–79]; HR 0·48 [0·30–0·76]; p=0·0015) and overall survival (92% [87–95] vs 84% [77–89]; HR 0·44 [0·28–0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3–4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183]). Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18–59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable. Groupe d'Etudes des Lymphomes de l'Adulte and Amgen.

Present first-line therapy for diffuse large B-cell lymphoma, a subtype of non-Hodgkin lymphoma, is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ibrutinib, a novel oral Bruton's tyrosine kinase inhibitor, has shown single-drug activity in relapsed or refractory B-cell malignancies. We investigated the safety and efficacy of ibrutinib in combination with R-CHOP for patients with previously untreated CD20-positive B-cell non-Hodgkin lymphoma. In this phase 1b, open-label, non-randomised study, patients were recruited across six centres in the USA and France. Eligibility was age 18 years or older and treatment-naive histopathologically confirmed CD20-positive B-cell non-Hodgkin lymphoma. In the dose-escalation phase (part 1), patients with diffuse large B-cell lymphoma, mantle-cell lymphoma, or follicular lymphoma were enrolled. The primary objective was to determine a recommended phase 2 dose of ibrutinib with a standard R-CHOP regimen, by assessing safety in all patients who received treatment. Patients received ibrutinib 280 mg, 420 mg, or 560 mg per day in combination with a standard R-CHOP regimen every 21 days. Safety of the recommended phase 2 dose was then assessed in a dose-expansion population, which consisted of patients with newly diagnosed diffuse large B-cell lymphoma (part 2). Secondary objectives included assessments of the proportion of patients who had an overall response, pharmacokinetics, and pharmacodynamics. This trial is registered with ClinicalTrials.gov, number NCT01569750. From June 22, 2012, to March 25, 2013, 33 patients were enrolled (part 1: 17; part 2: 16) and 32 received ibrutinib plus R-CHOP treatment (one patient in the part 2 cohort withdrew). The maximum tolerated dose was not reached and the recommended phase 2 dose for ibrutinib was 560 mg per day. The most common grade 3 or greater adverse events included neutropenia (73% [24 of 33 patients]), thrombocytopenia (21% [seven patients]), and febrile neutropenia and anaemia (18% each [six patients]). The most frequently reported serious adverse events were febrile neutropenia (18% [six patients]) and hypotension (6% [two patients]). 30 (94%) of 32 patients who received one or more doses of combination treatment achieved an overall response. All 18 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose had an overall response. For those subtyped and treated at the recommended phase 2 dose, five (71%) of seven patients with the germinal centre B-cell-like subtype and two (100%) patients with the non-germinal centre B-cell-like subtype had a complete response. R-CHOP did not affect pharmacokinetics of ibrutinib, and ibrutinib did not alter the pharmacokinetics of vincristine. Pharmacodynamic data showed Bruton's tyrosine kinase was fully occupied (>90% occupancy) at the recommended phase 2 dose. Ibrutinib is well tolerated when added to R-CHOP, and could improve responses in patients with B-cell non-Hodgkin lymphoma, but our findings need confirmation in a phase 3 trial. Janssen.

The combination of ibrutinib and venetoclax leverages complementary mechanisms of action and has shown promising clinical activity in mantle cell lymphoma (MCL). This study evaluated the efficacy and safety of ibrutinib–venetoclax compared with ibrutinib–placebo in patients with relapsed or refractory MCL. SYMPATICO is a multicentre, randomised, double-blind, placebo-controlled, phase 3 study performed at 84 hospitals in Europe, North America, and Asia–Pacific. Eligible patients were adults (aged ≥18 years) with pathologically confirmed relapsed or refractory MCL after one to five previous lines of therapy and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Patients were randomly assigned (1:1) to receive oral ibrutinib 560 mg once daily concurrently with oral venetoclax (5-week ramp-up to 400 mg once daily) or placebo for 2 years, then single-agent ibrutinib 560 mg once daily until disease progression or unacceptable toxicity. Randomisation and treatment assignment occurred via interactive response technology using a stratified permuted block scheme (block sizes of 2 and 4) with stratification by ECOG performance status, previous lines of therapy, and tumour lysis syndrome risk category. Patients and investigators were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03112174, and is closed to enrolment. Between April 26, 2018, and Aug 28, 2019, 267 patients were enrolled and randomly assigned; 134 to the ibrutinib–venetoclax group and 133 to the ibrutinib–placebo group. 211 (79%) of 267 patients were male and 56 (21%) were female. With a median follow-up of 51·2 months (IQR 48·2–55·3), median progression-free survival was 31·9 months (95% CI 22·8–47·0) in the ibrutinib–venetoclax group and 22·1 months (16·5–29·5) in the ibrutinib–placebo group (hazard ratio 0·65 [95% CI 0·47–0·88]; p=0·0052). The most common grade 3–4 adverse events were neutropenia (42 [31%] of 134 patients in the ibrutinib–venetoclax group vs 14 [11%] of 132 patients in the ibrutinib–placebo group), thrombocytopenia (17 [13%] vs ten [8%]), and pneumonia (16 [12%] vs 14 [11%]). Serious adverse events occurred in 81 (60%) of 134 patients in the ibrutinib–venetoclax group and in 79 (60%) of 132 patients in the ibrutinib–placebo group. Treatment-related deaths occurred in three (2%) of 134 patients in the ibrutinib–venetoclax group (n=1 COVID-19 infection, n=1 cardiac arrest, and n=1 respiratory failure) and in two (2%) of 132 patients in the ibrutinib–placebo group (n=1 cardiac failure and n=1 COVID-19-related pneumonia). The combination of ibrutinib–venetoclax significantly improved progression-free survival compared with ibrutinib–placebo in patients with relapsed or refractory MCL. The safety profile was consistent with known safety profiles of the individual drugs. These findings suggest a positive benefit–risk profile for ibrutinib–venetoclax treatment. Pharmacyclics (an AbbVie Company) and Janssen Research and Development.

Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become the standard of care for elderly patients with diffuse large B-cell lymphoma. We aimed to ascertain if a dose-dense R-CHOP regimen administered every 2 weeks (R-CHOP14) was superior to the standard 3-week schedule (R-CHOP21). We did a randomised phase 3 trial at 83 centres in four countries. 602 patients aged 60–80 years with untreated diffuse large B-cell lymphoma and at least one adverse prognostic factor (age-adjusted international prognostic index ≥1) were eligible for the study. We randomly allocated individuals to R-CHOP—ie, rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), vincristine (1·4 mg/m2, up to 2 mg) all on day 1, and prednisone 40 mg/m2 daily for 5 days—administered every 14 days (n=304) or every 21 days (n=298) for eight cycles. We did permuted-block randomisation (block size four, allocation ratio 1:1) stratified by centre and number of adverse prognostic factors. The primary endpoint was event-free survival. Our analysis was of the intention-to-treat population, and we present the final analysis. This study is registered with ClinicalTrials.gov, number NCT00144755. Two patients allocated R-CHOP21 were ineligible for the study and were excluded from analyses. After median follow-up of 56 months (IQR 27–60), 3-year event-free survival was 56% (95% CI 50–62) in the R-CHOP14 group and 60% (55–66) in the R-CHOP21 group (hazard ratio 1·04, 95% CI 0·82–1·31; p=0·7614). Grade 3–4 neutropenia occurred in 224 (74%) of 304 patients allocated R-CHOP14 and 189 (64%) of 296 assigned R-CHOP21, despite increased use of granulocyte colony-stimulating factor in the R-CHOP14 group compared with the R-CHOP21 group. 143 (47%) patients in the R-CHOP14 group received at least one red-blood-cell transfusion versus 93 (31%) in the R-CHOP21 group (p=0·0001). 35 (12%) patients allocated R-CHOP14 received at least one platelet transfusion versus 25 (8%) assigned R-CHOP21 (p=0·2156). 155 (51%) patients who were assigned R-CHOP14 had at least one serious adverse event compared with 140 (47%) who were allocated R-CHOP21. In elderly patients with untreated diffuse large B-cell lymphoma and at least one adverse prognostic factor, a 2-week dose-dense R-CHOP regimen did not improve efficacy compared with the 3-week standard schedule. The frequency of toxic side-effects was similar between regimens, but R-CHOP14 was associated with increased need for red-blood-cell transfusion. Groupe d'Etude des Lymphomes de l'Adulte (GELA), Amgen.

Diffuse large B-cell lymphoma is a common cancer in elderly patients. Although treatment has been standardised in younger patients, no prospective study has been done in patients over 80 years old. We aimed to investigate the efficacy and safety of a decreased dose of CHOP (doxorubicin, cyclophosphamide, vincristine, and prednisone) chemotherapy with a conventional dose of rituximab in elderly patients with diffuse large B-cell lymphoma. We did a prospective, multicentre, single-arm, phase 2 study of patients aged over 80 years who had diffuse large B-cell lymphoma. Patients were included from 38 centres in France and Belgium. All patients received six cycles of rituximab combined with low-dose CHOP (R-miniCHOP) at 3-week intervals. Patients received 375 mg/m 2 rituximab, 400 mg/m 2 cyclophosphamide, 25 mg/m 2 doxorubicin, and 1 mg vincristine on day 1 of each cycle, and 40 mg/m 2 prednisone on days 1–5. The primary endpoint was overall survival, both unadjusted and adjusted for treatment and baseline prognostic factors. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01087424. 150 patients were enrolled between Jan 9, 2006, and Jan 23, 2009 and 149 were included in the intention-to-treat analyses. Median age was 83 years (range 80–95). After a median follow-up of 20 months (range 0–45), the median overall survival was 29 months (95% CI 21 to upper limit not reached); 2-year overall survival was 59% (49–67%). In multivariate analyses, overall survival was only affected by a serum albumin concentration of 35 g/L or less (hazard ratio 3·2, 95% CI 1·4–7·1; p=0·0053). Median progression-free survival was 21 months (95% CI 13 to upper limit not reached), with a 2-year progression free survival of 47% (38–56). 58 deaths were reported, 33 of which were secondary to lymphoma progression. 12 deaths were attributed to toxicity of the treatment. The most frequent side-effect was haematological toxicity (grade ≥3 neutropenia in 59 patients; febrile neutropenia in 11 patients). R-miniCHOP offers a good compromise between efficacy and safety in patients aged over 80 years old. R-miniCHOP should be considered as the new standard treatment in this subgroup of patients. Groupe d'Etude des Lymphomes de l'Adulte (GELA).

Optimal chemotherapy with minimal toxicity is the main determinant of complete remission in patients with newly diagnosed hematological malignancies. Acute organ dysfunctions may impair the patient's ability to receive optimal chemotherapy. To compare 6-month complete remission rates in patients with and without acute kidney injury (AKI), we collected prospective data on 200 patients with newly diagnosed high-grade malignancies (non-Hodgkin lymphoma, 53.5%; acute myeloid leukemia, 29%; acute lymphoblastic leukemia, 11.5%; and Hodgkin disease, 6%). According to RIFLE criteria, 137 (68.5%) patients had AKI. Five causes of AKI accounted for 91.4% of cases: hypoperfusion, tumor lysis syndrome, tubular necrosis, nephrotoxic agents, and hemophagocytic lymphohistiocytosis. Half of the AKI patients received renal replacement therapy and 14.6% received suboptimal chemotherapy. AKI was associated with a lower 6-month complete remission rate (39.4% vs. 68.3%, P<0.01) and a higher mortality rate (47.4% vs. 30.2%, P<0.01) than patients without AKI. By multivariate analysis, independent determinants of 6-month complete remission were older age, poor performance status, number of organ dysfunctions, and AKI. AKI is common in patients with newly diagnosed high-grade malignancies and is associated with lower complete remission rates and higher mortality.

T cell non-Hodgkin lymphomas (T-NHLs) are aggressive malignancies which have a high risk of life-threatening complications. However, their prognosis in the intensive care unit (ICU) setting has not yet been assessed. We conducted a study including 87 ICU patients either with newly diagnosed T-NHLs or those undergoing first-line therapy admitted between January 1, 2000, and December 31, 2014. The primary subtypes were peripheral T cell lymphoma (PTCL) (n = 41, 47%), anaplastic large-cell lymphoma (ALCL) (n = 13, 15%), and adult T-leukaemia/lymphoma (ATLL) (n = 11, 13%). Six in every ten patients had malignancy-related complications (haemophagocytic syndrome 37%, tumour lysis syndrome 18% and hypercalcaemia 9%), while infections accounted for one quarter of ICU admissions. Nine fungal infections were documented, including six invasive aspergillosis. Urgent chemotherapy was started in the ICU in 59% of the patients, and urgent surgery was required in 13%. ICU and day-90 mortality were 22% and 41%, respectively. Multivariate analysis showed that SOFA score at day 1, age, sepsis and haemophagocytic syndrome were independent predictors of day-90 mortality. Compared to 66 ICU-matched controls with non-Hodgkin B cell lymphomas, patients with T-NHLs had a similar ICU survival. Overall survival rates of patients with T cell NHLs and B cell NHLs were 20% and 46%, respectively (hazard ratio for death associated with T cell NHLs 2.00 [1.12–3.58]). Patients with T cell NHLs had a very poor long-term outcome. Although the high rate of short-term survival suggests that an ICU trial is a reasonable option for patients newly diagnosed for the malignancy, extended stay in the ICU or further readmission should be considered only for highly selected patients who respond to the haematological treatment.