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In the rituximab era, one-third of diffuse large B-cell lymphoma patients experience relapse/refractory disease after first-line anthracycline-based immunochemotherapy. Optimal management remains an unmet medical need. The aim of this study was to report the outcomes of a cohort of refractory patients according to their patterns of refractoriness and the type of salvage option. We performed a retrospective analysis, which included 104 diffuse large B-cell lymphoma patients treated at Lyon Sud University Hospital (2002-2017) who presented with refractory disease. Refractoriness was defined as progressive/stable disease during first-line treatment (primary refractory, N = 47), a partial response after the end of first-line treatment that required subsequent treatment (residual disease, N = 19), or relapse within 1 year of diagnosis after an initial complete response (CR) (early relapse, N = 38). The 2-year overall survival (OS) rates for primary refractory, early relapse, and residual disease patients were 27%, 25%, and 52%, respectively, while the event-free survival rates for those groups were 13%, 13%, and 42%, respectively. In a univariate analysis, lactate dehydrogenase level, Ann Arbor stage, poor performance status, high age-adjusted International Prognostic Index score, and age > 65 years were associated with shorter OS. The use of rituximab and platinum-based chemo during the first salvage treatment was associated with prolonged OS. In a multivariate analysis, age (HR:2.06) and rituximab use (HR:0.54) were associated with OS. Among patients <65 years who achieved a CR, autologous stem-cell transplant was associated with higher 2-year OS (90% vs 74%, P = 0.10). Patients who were treated with a targeted therapy in the context of a clinical trial after second-line treatment had a higher 2-year OS (34% vs 19%, P = 0.06). In conclusion, patients with primary refractory disease or early relapse have very poor outcomes but may benefit from rituximab retreatment during the first salvage treatment. [ABSTRACT FROM AUTHOR]

Peripheral T-cell lymphoma ( PTCL) is a heterogeneous group of aggressive non-Hodgkin lymphomas typically associated with poor prognosis. Most patients with PTCL receive chemotherapy as first-line treatment, but many experience rapid relapse. For patients with relapsed/refractory PTCL, responses to treatment and long-term outcomes tend to worsen with increasing lines of therapy. Romidepsin is a potent class I histone deacetylase inhibitor approved by the US Food and Drug Administration for the treatment of PTCL in patients who have received ≥1 prior therapy. A pivotal phase 2 trial of romidepsin in patients with relapsed/refractory PTCL demonstrated an objective response rate of 25% (33/130), including 15% with confirmed/unconfirmed complete response, and a median duration of response of 28 months. In the analysis presented herein, romidepsin was shown to have similar responses and long-term outcomes in patients with 1, 2, and ≥3 prior lines of treatment, including in patients with disease refractory to the last prior therapy. Although adverse events increased with increasing lines of treatment, the rate of dose modifications and discontinuations due to adverse events was not significantly different. These data support the use of romidepsin as salvage treatment for PTCL irrespective of the number of prior therapies. [ABSTRACT FROM AUTHOR]

This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma ( NHL) confirmed by centralized histological review. Patients received 28-d cycles of 85 mg/m2 pixantrone dimaleate (equivalent to 50 mg/m2 in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2-6) with pixantrone and 3 (2-6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response ( CR) (23·1% vs. 5·1% comparator, P = 0·047) and overall response rate ( ORR, 43·6% vs. 12·8%, P = 0·005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45·0% vs. 11·1%, P = 0·033), CR (30·0% vs. 5·6%, P = 0·093) and progression-free survival (median 5·4 vs. 2·8 months, hazard ratio 0·52, 95% confidence interval 0·26-1·04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B-cell NHL in the 3rd or 4th line setting, independently of previous rituximab. [ABSTRACT FROM AUTHOR]

In this phase II, multicentre, single-arm study, 52 patients with relapsed/refractory diffuse large B-cell lymphoma ( DLBCL) received the anti- CD19 antibody-drug conjugate coltuximab ravtansine (55 mg/m2) and rituximab (375 mg/m2) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate ( ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [ CI]: 22·0-41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2-78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0-72·1%]) or first-line therapy (15·4% [80% CI: 6·9-28·4%]). Median progression-free survival, overall survival and duration of response were 3·9 [80% CI: 3·22-3·98], 9·0 [80% CI: 6·47-13·67] and 8·6 (range: 0-18) months, respectively. The pharmacokinetics of both drugs were unaffected by co-administration. Common adverse events included gastrointestinal disorders (52%) and asthenia (25%). No patients discontinued due to adverse events. In conclusion, coltuximab ravtansine with rituximab was well tolerated and yielded clinical responses in a subset of patients with relapsed/refractory DLBCL. [ABSTRACT FROM AUTHOR]

Ofatumumab is a human monoclonal antibody directed at CD20 approved for treatment of chronic lymphocytic leukemia. The population pharmacokinetics of intravenous ofatumumab were characterized in patients with relapsed/refractory chronic lymphocytic leukemia, relapsed/refractory follicular lymphoma, and rheumatoid arthritis, diseases with widely varying CD20+ B-cell counts in blood. Serum concentration data from a total of 477 patients who received ofatumumab doses ranging from 100 mg to 2000 mg in different dosing regimens were analyzed to determine the pharmacokinetic characteristics of ofatumumab across different patient groups and to identify factors contributing to the pharmacokinetic variability. Ofatumumab pharmacokinetics were well described by a linear two-compartment model component to represent non-specific monoclonal antibody clearance from the central compartment interacting with a model component representing the target-mediated clearance of ofatumumab by binding to CD20 expressed on B cells. The clearance (7.5 mL/h) and steady-state volume of distribution (5.3 L) for the linear, non-specific component were consistent with results obtained for other monoclonal antibodies. The target-mediated clearance component was related to the disease-specific number of circulating B cells, which will allow simulation of the contribution of target-mediated clearance to ofatumumab pharmacokinetics in untested disease states with data on B-cell counts and turnover. [ABSTRACT FROM AUTHOR]

Follicular Lymphoma ( FL) is the second most common non-Hodgkin lymphoma ( NHL) subtype and its course is heterogeneous. At diagnosis, some patients with FL manifest a detectable leukaemic phase ( FL- LP), but this feature has been seldom described and is poorly characterized. Among 499 patients diagnosed with FL in Lyon-Sud hospital, 37 (7·4%) had characteristic FL- LP (by cytological blood smears and flow cytometric analysis). In addition, 91/1135 FL patients from the PRIMA study presented FL- LP at study entry. In order to evaluate the outcome of this Lyon-Sud cohort, FL- LP patients were matched with 111 newly diagnosed FL without LP according to the Follicular Lymphoma International Prognostic Index ( FLIPI) score, age and treatment. Presence of FL- LP was associated with shorter progression-free survival ( PFS) and overall survival ( OS) ( P = 0·004 and P = 0·031, respectively). Presence of FL- LP and high FLIPI score remained independent prognostic factors in a Cox model for time to progression ( TTP). A number of circulating lymphoma cells ( CLC) >4 × 109/l was the most significant predictor for a shorter TTP in this Cox model. The prognostic impact of FL- LP on TTP was validated in the PRIMA cohort ( P = 0·0004). In conclusion, FL- LP is a rare event associated with shorter PFS and patients with CLC >4 × 109/l have a poorer outcome. These patients should be monitored carefully to consider alternative therapeutic options. [ABSTRACT FROM AUTHOR]

This international, multicentre phase II study was conducted to assess ofatumumab, a human anti- CD20 monoclonal antibody, in patients with relapsed/progressive diffuse large B-cell lymphoma ( DLBCL) who were ineligible for autologous stem cell transplantation ( TI) or who had relapse/progression after transplantation ( PT). Eighty-one patients received ofatumumab 300 mg intravenously ( IV) on Day 1, followed by seven weekly IV infusions of 1000 mg. Patients in the TI and PT groups had received a median of 3 (range, 1-7) and 5 (range, 2-7) prior therapies, respectively. One-third of patients did not respond to the last prior therapy, and 53% had failed two or more rituximab-containing therapies. Overall response rate was 13% for the TI group (seven partial responses) and 8% for the PT group (two complete responses). Median progression-free survival was 2·6 months, and median duration of response was 9·5 months. The most common Grade 3-4 adverse events were neutropenia (11%), leucopenia (6%), lymphopenia (6%) and thrombocytopenia (6%). Sixteen deaths have been reported, with disease progression as the most common cause of death. In conclusion, ofatumumab monotherapy was well tolerated and provided clinical benefit to some DLBCL patients in this study. This trial was registered at www.clinicaltrials.gov ( NCT00622388). [ABSTRACT FROM AUTHOR]

Aims To describe 76 cases of splenic marginal zone lymphoma ( SMZL), including correlations with clinical and other characteristics. Methods and results Patients were predominantly female, with a median age of 62 years. The main clinical presentation was splenomegaly, except for eight cases presenting with evolution of autoimmune disorders or spontaneous splenic rupture. White pulp infiltration was nodular, with a monophasic (42%) or biphasic (53%) pattern, and associated diffuse or nodular infiltration of the red pulp, except for four cases which had atrophic white pulp. Plasmacytic differentiation and the MYD88 L265P mutation were observed in 18% and 5% of the cases, respectively. Histological progression was considered in cases with a significant association of large cells with Ki67 > 30% and macronodular architecture ( P = 0.001). Other significant correlations were found between del7q (44%) and del6q (17%) ( P = 0.018), IGHV1-2*04 segment usage (35%) ( P = 0.001) and unmutated IGHV (39%) ( P = 0.019), and between CD5 expression (27%) and higher lymphocytosis ( P = 0.002). Patients requiring intensive chemotherapy after splenectomy because of clinical and/or histological progression had significantly shorter overall survival ( P = 0.012). Conclusions We report the histological spectrum of SMZL, and discuss the differential diagnosis and requirement for molecular and cytogenetic analysis in atypical cases. [ABSTRACT FROM AUTHOR]

The purpose of this phase 1–2 study was to investigate the association between the pharmacokinetic properties of ofatumumab, a human monoclonal CD20 antibody, and outcomes in 33 patients with relapsed/refractory chronic lymphocytic leukaemia receiving 4 weekly infusions of ofatumumab. The ofatumumab concentration profiles were fitted well by a two-compartment model with different elimination rate constant at first infusion compared to the remaining infusions in line with the observed rapid and sustained B-cell depletion. Exposure to ofatumumab was linked to clinical outcomes: high exposure was associated with higher probability of overall clinical response and longer progression-free survival. This association still remained statistically significant even when adjusting for relevant baseline covariates including tumour burden. The trial was registered at (NCT00093314). [ABSTRACT FROM AUTHOR]

Tumour lysis syndrome (TLS) is a life-threatening oncological emergency characterized by metabolic abnormalities including hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia. These metabolic complications predispose the cancer patient to clinical toxicities including renal insufficiency, cardiac arrhythmias, seizures, neurological complications and potentially sudden death. With the increased availability of newer therapeutic targeted agents, such as rasburicase (recombinant urate oxidase), there are no published guidelines on the risk classification of TLS for individual patients at risk of developing this syndrome. We convened an international TLS expert consensus panel to develop guidelines for a medical decision tree to assign low, intermediate and high risk to patients with cancer at risk for TLS. Risk factors included biological evidence of laboratory TLS (LTLS), proliferation, bulk and stage of malignant tumour and renal impairment and/or involvement at the time of TLS diagnosis. An international TLS consensus expert panel of paediatric and adult oncologists, experts in TLS pathophysiology and experts in TLS prophylaxis and management, developed a final model of low, intermediate and high risk TLS classification and associated TLS prophylaxis recommendations. [ABSTRACT FROM AUTHOR]

The article focuses on a research about the long-term results of the registered patients and their rate of histologic transformation (HT) rate to diffuse large B-cell lymphoma (DLBCL). It states that 164 patients with nodular, lymphocyte-predominant Hodgkin lymphoma (NLPHL) served as subjects of the study. Findings show that there was no significant difference in the overall survival rate after HT of patients who underwent autologous stem cell transplantation (ASCT) and the others.

An association between autoimmunity and hematological malignancies has been reported including the detection of antinuclear autoantibodies (ANAs) in patients suffering from non-Hodgkin's lymphoma (NHL), with a high prevalence of ANAs directed to components of the mitotic apparatus or the mitosis-associated proteins. Previous studies have demonstrated that one of the targets of such ANAs could be the CENP-F protein, especially in some carcinomas. The prevalence and specificity of anti-CENP-F autoantibodies (aAbs) thus were analyzed in 347 patients with different histological subgroups of NHL before any treatment of NHL, along with 150 controls. The detection of these aAbs was performed using two techniques: a radioimmunological assay (RIA) and an indirect immunofluorescence technique (IIF). Twenty-five (7.2%) NHL patients and 2 (1.3%) control patients displayed anti-CENP-F aAbs using RIA. This difference between the two groups was found to be significant (P < 0.01), with a higher prevalence of aAbs in the follicular (13%) and in the marginal zone B and MALT (10.2%) lymphoma subgroups. By IIF, 10 (2.9%) patients with NHL displayed aAbs with a CENP-F or CENP-F-like pattern, whereas none of the control group did. In conclusion, these data demonstrate that a significant incidence of anti-CENP-F aAbs is observed, before any treatment, in some histological subgroups of NHL patients. In addition to the usefulness of anti-CENP-F aAbs as a marker for some NHL subgroups, prospective studies may be important to evaluate the predictive value of anti-CENP-F aAbs for the development of carcinomas. [ABSTRACT FROM AUTHOR]

Summary. The presence of antinuclear autoantibodies (ANA) was investigated in a large cohort of patients with non-Hodgkin's lymphoma (NHL) in order to assess their frequency, specificity and prognostic relevance. ANA were analysed in 347 patients with different histological subgroups of NHL and in 213 controls using an indirect immunofluorescence technique on HEp2 cells. As the appearance of autoantibodies may be found after treatment of NHL, samples were collected at the time of diagnosis of NHL before any therapy. Sixty-six (19%) NHL patients and 12 (5·6%) patients from the control group displayed ANA. The prevalence between the two groups was found to be significantly higher in NHL patients (P < 0·0001) with a marked increased prevalence in follicular and mantle cell lymphoma subgroups. Autoantibodies directed against mitotic proteins or mitotic-associated proteins were found in 6·9% of NHL patients versus 0·5% in the control group (P < 0·001), with a significantly increased incidence in follicular and mantle cell lymphoma subgroups (P < 0·0001). Some 28% of the patients with positive ANA displayed clinical symptoms that could correspond to classical autoimmune manifestations, this frequency appearing to be higher in the marginal zone/mucosa-associated lymphoid tissue lymphoma subgroup. These data demonstrate a significant incidence of ANA before any treatment in NHL occurrence, which seems to be higher in some histological subgroups with particular ANA, such as ANA directed against mitotic proteins or mitotic-associated proteins. [ABSTRACT FROM AUTHOR]

Summary. Epoetin beta, three-times weekly (t.i.w.), is effective in reversing anaemia in lymphoproliferative disorders. The current study investigated whether an epoetin beta dose of 30 000 IU given subcutaneously once weekly (q.w.) was at least as effective as 10 000 t.i.w. administration in anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin (Epo) production. Overall, 241 anaemic patients with multiple myeloma, low-grade non-Hodgkin's lymphoma or chronic lymphocytic leukaemia, all with serum Epo values ≤ 100 mU/ml, were randomized to receive the q.w. (n = 119) or t.i.w. (n = 122) regimen for 16 weeks. The primary efficacy criterion, i.e. the time-adjusted area under the haemoglobin–time curve from weeks 5–16, was comparable between the q.w. and t.i.w. groups [difference = - 0·20 g/dl (90% confidence interval - 0·52–0·11)]. Moreover, response rates were high and similar in both arms (72%vs 75%, q.w. and t.i.w. groups respectively). Baseline serum Epo was predictive of response: the lower serum Epo, the higher the likelihood of response (P = 0·002). Thus, epoetin beta administered q.w. is an effective and convenient treatment for anaemia in patients with lymphoproliferative disorders. Tailoring this treatment modality to subjects with defective endogenous Epo production represents a rational use of epoetin from both a medical and a community perspective. [ABSTRACT FROM AUTHOR]

Summary. Death during the induction phase of chemotherapy remains a common event in patients with aggressive non-Hodgkin's lymphoma (NHL). In a series of patients with aggressive NHL homogeneously treated with intensive induction chemotherapy [ACVB (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) regimen], we determined the clinical and biological parameters that were predictive of early death. Early death was defined as death, for whatever reason, occurring within 100 d of randomization. Predictive factors were identified by logistic regression and an index predictive for individual risk of early death was designed. Among the 2210 patients treated with ACVB, there were 162 (7·3%) early deaths. There was no significant reduction in the rate of early death between 1987 and 1998. In a multivariate analysis, age > 60 years, Eastern Cooperative Oncology Group performance status > 1, serum lactate dehydrogenase > normal, serum albumin < 30 g/l, leucocyte counts > 10 × 109 /l and haemoglobin levels < 8·5 g/dl were found to be independent predictive factors for early death. An early death index was designed, enabling the evaluation of the individual risk of early death in young (range 2–31% risk of early death) and elderly patients (range 5–53%). Clinical and biological parameters available at diagnosis can help physicians identify patients with aggressive lymphoma at low or high risk of early death. [ABSTRACT FROM AUTHOR]

Patients receiving high-dose cyclophosphamide as a conditioning regimen for peripheral stem cell collection are subjected over a short period of time to significant exposure to reactive oxygen species (ROS). All these patients undergo profound leucopenia. Various other short-term toxicities are observed in a fraction of the patients, including febrile aplasia requiring hospitalization, thrombocytopenia and mucositis. Although stem cell collection is feasible in the majority of patients stimulated with haematopoietic growth factors, in some instances, graft collection cannot be performed because of insufficient concentrations of stem cells in peripheral blood. There is currently no predictive assay to determine which patients treated with high-dose cyclophosphamide have a high risk of febrile aplasia or will successfully undergo cytaphereses for stem cell collection. In order to identify such predictive factors, we analysed the level of expression before treatment of various ROS detoxification mechanisms in the peripheral blood of 37 patients receiving high-dose cyclophosphamide for lymphoproliferative diseases. Various parameters involved in the metabolism of ROS were measured in plasma and/or erythrocytes, including superoxide dismutase, glutathione, glutathione peroxidase, glutathione reductase and malondialdehyde. High levels of erythrocyte superoxide dismutase before cyclophosphamide therapy were correlated with an increased risk of hospitalization for febrile aplasia (65% vs. 29%, P = 0·013). High superoxide dismutase and low erythrocyte glutathione reductase were associated with lower CD34 yields. These data suggest that components of the ROS detoxification system modulate the degree of short-term toxicity of cyclophosphamide and could be used as predictive markers in individual patients. [ABSTRACT FROM AUTHOR]

Within the tumour necrosis factor (TNF) family the induction of apoptosis is restricted to some ligand–receptors pairs, including TNF–TNF receptor type I (TNFRI/p55), FasL-Fas, TNF-related apoptosis-inducing ligand (TRAIL) and its death-receptors (DR)-4 and -5. The pair CD40L–CD40 belongs to the same family but rescues B cells from apoptosis. To investigate how these opposing actions are cross-linked, purified follicular lymphoma (FL) cells were activated upon a human CD40L-transfected murine fibroblastic layer, then RNA messengers for the above molecules were analysed using RT-PCR. The observed down-modulation of TRAIL and up-regulation of TNF and Fas transcripts might account for CD40-CD40L-mediated FL cell survival. [ABSTRACT FROM AUTHOR]

Peripheral blood progenitor cells (PBPC) were mobilized and harvested in 200 patients treated for non-Hodgkin's lymphoma (n = 148), Hodgkin's disease (n = 22) and multiple myeloma (n = 30). The variables predicting the collection of a minimal (>2.5 × 106/kg) or a high (>10 × 106/kg) CD34+ cell count were analysed. Patients were mobilized with haemopoietic growth factors following either standard chemotherapy (n = 49) or high-dose cyclophosphamide, given alone (n = 55) or combined with high-dose VP16 (n = 86). 10 patients received haemopoietic growth factors only. The first mobilization resulted in a PBPC harvest with enough CD34+ cells in 179/200 patients (90%). High-dose cyclophosphamide, with or without VP16, did not mobilize a higher progenitor cell yield than standard chemotherapy. When performing multiple regression analysis in the 190 patients who received chemotherapy-containing mobilization, only the number of previous chemotherapy regimens and the exposure to fludarabine predicted for a failure to collect a minimal PBPC count (P = 0.06 and 0.0008 respectively). The target to collect a high CD34+ cell count was negatively associated with the number of previous chemotherapy regimens (P = 0.002). When only non-Hodgkin's lymphoma patients were considered for multivariate analysis, low-grade histology with fludarabine appeared to be associated with poor PBPC cell yield (P = 0.08 and 0.005 respectively). This data confirms that PBPC harvest should be planned early in the disease course in transplant candidates, and can be obtained after a standard course of chemotherapy. [ABSTRACT FROM AUTHOR]

The article presents information on a study which characterized the expression profile of microRNAs (miRNAs) in splenic marginal zone B cell lymphoma (SMZL) and compared it with clinico-pathological characteristics. Under the study, 15 spleen specimens were obtained from 15 selected untreated SMZL patients.

A letter to the editor is presented in response to a study "Insight into the molecular pathogenesis of hairy cell leukaemia, hairy cell leukaemia variant and splenic marginal zone lymphoma, provided by the analysis of their IGH rearrangements and somatic hypermutation patterns," by S. L. Hockley and colleagues in the 2010 issue.

Discusses the use of epoetin beta and darbepoetin alfa to treat anemia in patients with cancer. Regimen of anemic patients with lymphoproliferative malignancies; Importance of rapid hemoglobin response in patients receiving chemotherapy; Consideration of the potential need for dose adjustment with epoetin.

Lenalidomide maintenance therapy prolonged progression-free survival (PFS) versus placebo in elderly patients with diffuse large B-cell lymphoma (DLBCL) responding to induction chemotherapy in the phase 3 REMARC study. This subpopulation analysis assessed the impact of lenalidomide maintenance and treatment-emergent adverse events (TEAEs) on health-related quality of life (HRQOL). Global health status (GHS), and physical functioning and fatigue subscales were evaluated in patients who completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-C30 v3.0. The impact of TEAEs classified post hoc as subjective (patients can feel) or observable (only measurable by physicians) on dose reductions and discontinuations was assessed. Among 457 patients (lenalidomide, n = 229; placebo, n = 228), mean (standard deviation) GHS was similar between treatment arms [68·2 (20·7) Versus 72·0 (17·8)] at randomisation and remained similar during maintenance. Patients receiving lenalidomide experienced no meaningful changes in GHS, physical functioning, or fatigue. Observable TEAEs were more common (81·1% Versus 66·3%) and more likely to lead to dose reductions, than subjective TEAEs in both arms. PFS was superior in the lenalidomide arm regardless of dose reduction. Lenalidomide maintenance prolonged PFS and did not negatively impact HRQOL in patients with DLBCL despite TEAEs being more common, when compared with placebo., (© 2019 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)