Jan Walewski

CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group

BACKGROUND The role of rituximab in combination with different CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy regimens in young patients with good-prognosis diffuse large-B-cell lymphoma remains to be defined. We aimed to compare CHOP-like chemotherapy and rituximab with CHOP-like chemotherapy alone in these patients. METHODS 824 patients who were from 18 countries; aged 18-60 years; and who had no risk factors or one risk factor according to age-adjusted International Prognostic Index (IPI), stage II-IV disease, or stage I disease with bulk were enrolled. These patients were randomly assigned to six cycles of CHOP-like chemotherapy and rituximab (n=413) or to six cycles of CHOP-like chemotherapy alone (n=411). Bulky and extranodal sites received additional radiotherapy. The primary endpoint was event-free survival; secondary endpoints were response, progression under therapy, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat and per protocol. This trial is registered at http://www.clinicaltrials.gov, NCT 00064116. FINDINGS After a median follow-up of 34 months (range 0.03-61), patients assigned chemotherapy and rituximab had increased 3-year event-free survival compared with those assigned chemotherapy alone (79% [95% CI 75-83] vs 59% [54-64]; difference between groups 20% [13-27], log-rank p<0.0001), and had increased 3-year overall survival (93% [90-95] vs 84% [80-88]; difference between groups 9% [3-13], log-rank p=0.0001). Event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI: after chemotherapy and rituximab, a favourable subgroup (ie, IPI=0, no bulk) could be defined from a less-favourable subgroup (ie, IPI=1 or bulk, or both). Groups did not differ in the frequency of adverse events. INTERPRETATION Rituximab added to six cycles of CHOP is an effective treatment for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows for a more refined therapeutic approach for these patients.

2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours.

Chemotherapy-induced neutropenia is a major risk factor for infection-related morbidity and mortality and also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact the success of treatment, particularly when treatment intent is either curative or to prolong survival. In Europe, prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim (including approved biosimilars), lenograstim or pegfilgrastim is available to reduce the risk of chemotherapy-induced neutropenia. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. The need for generally applicable, European-focused guidelines led to the formation of a European Guidelines Working Party by the European Organisation for Research and Treatment of Cancer (EORTC) and the publication in 2006 of guidelines for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. A new systematic literature review has been undertaken to ensure that recommendations are current and provide guidance on clinical practice in Europe. We recommend that patient-related adverse risk factors, such as elderly age (≥65 years) and neutrophil count be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy. It is important that after a previous episode of FN, patients receive prophylactic administration of G-CSF in subsequent cycles. We provide an expanded list of common chemotherapy regimens considered to have a high (≥20%) or intermediate (10-20%) risk of FN. Prophylactic G-CSF continues to be recommended in patients receiving a chemotherapy regimen with high risk of FN. When using a chemotherapy regimen associated with FN in 10-20% of patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Clinical evidence shows that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications where indicated. Filgrastim biosimilars are also approved for use in Europe. While other forms of G-CSF, including biosimilars, are administered by a course of daily injections, pegfilgrastim allows once-per-cycle administration. Choice of formulation remains a matter for individual clinical judgement. Evidence from multiple low level studies derived from audit data and clinical practice suggests that some patients receive suboptimal daily G-CSFs; the use of pegfilgrastim may avoid this problem.

CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group

BACKGROUND The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects. METHODS In the randomised open-label MInT study, patients from 18 countries (aged 18-60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II-IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907. FINDINGS The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0·03-119), 6-year event-free survival was 55·8% (95% CI 50·4-60·9; 166 events) for patients assigned to chemotherapy alone and 74·3% (69·3-78·6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18·5%, 11·5-25·4, log-rank p<0·0001). Multivariable analyses showed that event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only. After chemotherapy and rituximab, a favourable subgroup (IPI=0, no bulk) could be defined from a less favourable subgroup (IPI=1 or bulk, or both; event-free survival 84·3% [95% CI 74·2-90·7] vs 71·0% [65·1-76·1], log-rank p=0·005). 18 (4·4%, 95% CI 2·6-6·9) second malignancies occurred in the chemotherapy-alone group and 16 (3·9%, 2·2-6·2) in the chemotherapy and rituximab group (Fishers exact p=0·730). INTERPRETATION Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone. FUNDING Hoffmann-La Roche.

Treatment of Older Patients with Mantle-Cell Lymphoma

BACKGROUND The long-term prognosis for older patients with mantle-cell lymphoma is poor. Chemoimmunotherapy results in low rates of complete remission, and most patients have a relapse. We investigated whether a fludarabine-containing induction regimen improved the complete-remission rate and whether maintenance therapy with rituximab prolonged remission. METHODS We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression. RESULTS Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P=0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P=0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group, but the frequency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% confidence interval, 0.36 to 0.87; P=0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall survival (4-year survival rate, 87%, vs. 63% with interferon alfa; P=0.005). CONCLUSIONS R-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphoma. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT00209209.).

Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND High-dose therapy followed by autologous stem-cell transplantation is standard of care for patients with relapsed or primary refractory Hodgkins lymphoma. Roughly 50% of patients might be cured after autologous stem-cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. We aimed to assess whether brentuximab vedotin improves progression-free survival when given as early consolidation after autologous stem-cell transplantation. METHODS We did this randomised, double-blind, placebo-controlled, phase 3 trial at 78 sites in North America and Europe. Patients with unfavourable-risk relapsed or primary refractory classic Hodgkins lymphoma who had undergone autologous stem-cell transplantation were randomly assigned, by fixed-block randomisation with a computer-generated random number sequence, to receive 16 cycles of 1·8 mg/kg brentuximab vedotin or placebo intravenously every 3 weeks, starting 30-45 days after transplantation. Randomisation was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and primary refractory Hodgkins lymphoma versus relapsed disease less than 12 months after completion of frontline therapy versus relapse 12 months or more after treatment completion. Patients and study investigators were masked to treatment assignment. The primary endpoint was progression-free survival by independent review, defined as the time from randomisation to the first documentation of tumour progression or death. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01100502. FINDINGS Between April 6, 2010, and Sept 21, 2012, we randomly assigned 329 patients to the brentuximab vedotin group (n=165) or the placebo group (n=164). Progression-free survival by independent review was significantly improved in patients in the brentuximab vedotin group compared with those in the placebo group (hazard ratio [HR] 0·57, 95% CI 0·40-0·81; p=0·0013). Median progression-free survival by independent review was 42·9 months (95% CI 30·4-42·9) for patients in the brentuximab vedotin group compared with 24·1 months (11·5-not estimable) for those in the placebo group. We recorded consistent benefit (HR <1) of brentuximab vedotin consolidation across subgroups. The most frequent adverse events in the brentuximab vedotin group were peripheral sensory neuropathy (94 [56%] of 167 patients vs 25 [16%] of 160 patients in the placebo group) and neutropenia (58 [35%] vs 19 [12%] patients). At time of analysis, 28 (17%) of 167 patients had died in the brentuximab vedotin group compared with 25 (16%) of 160 patients in the placebo group. INTERPRETATION Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkins lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation. FUNDING Seattle Genetics and Takeda Pharmaceuticals International.

First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma : results of a phase 1/2 trial

Ofatumumab is a unique monoclonal antibody that targets a distinct small loop epitope on the CD20 molecule. Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocytic leukemia cells with low CD20-antigen density and high expression of complement inhibitory molecules. In a phase 1/2 trial evaluating safety and efficacy of ofatumumab in relapsed or refractory follicular non-Hodgkin lymphoma (FL) grade 1 or 2, 4 dose groups of 10 patients received 4 weekly infusions of 300, 500, 700, or 1000 mg. Patients had a median of 2 prior FL therapies and 13% had elevated lactate dehydrogenase. No safety concerns or maximum tolerated dose was identified. A total of 274 adverse events were reported; 190 were judged related to ofatumumab, most occurring on the first infusion day with Common Terminology Criteria grade 1 or 2. Eight related events were grade 3. Treatment caused immediate and profound B-cell depletion, and 65% of patients reverted to negative BCL2 status. Clinical response rates ranged from 20% to 63%. Median time to progression for all patients/responders was 8.8/32.6 months, and median duration of response was 29.9 months at a median/maximum follow-up of 9.2/38.6 months. Ofatumumab is currently being evaluated in patients with rituximab-refractory FL. This trial was registered at www.clinicaltrials.gov as #NCT00092274.

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

H. Tilly1, M. Gomes da Silva2, U. Vitolo3, A. Jack4, M. Meignan5, A. Lopez-Guillermo6, J. Walewski7, M. Andre8, P. W. Johnson9, M. Pfreundschuh10 & M. Ladetto11, on behalf of the ESMO Guidelines Committee* Centre Henri-Becquerel, Universite de Rouen, Rouen, France; Portuguese Institute of Oncology, Lisbon, Portugal; A.O. Citta della Salute e della Scienza di Torino, Turin, Italy; St James’s University Hospital, Leeds, UK; Henri Mondor University Hospital, Creteil, France; Hospital Clinic, Barcelona, Spain; Maria Sklodowska-Curie Memorial Institute and Oncology Centre, Warsaw, Poland; CHU Dinant-Godinne, UCL Namur, Yvoir, Belgium; Cancer Research UK, University of Southampton, Southampton, UK; Innere Medizin I, Universitat des Saarlandes, Hamburg, Germany; Divisione di Ematologia, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy

Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study

The prognostic impact of minimal residual disease (MRD) was analyzed in 259 patients with mantle cell lymphoma (MCL) treated within 2 randomized trials of the European MCL Network (MCL Younger and MCL Elderly trial). After rituximab-based induction treatment, 106 of 190 evaluable patients (56%) achieved a molecular remission (MR) based on blood and/or bone marrow (BM) analysis. MR resulted in a significantly improved response duration (RD; 87% vs 61% patients in remission at 2 years, P = .004) and emerged to be an independent prognostic factor for RD (hazard ratio = 0.4, 95% confidence interval, 0.1-0.9, P = .028). MR was highly predictive for prolonged RD independent of clinical response (complete response [CR], complete response unconfirmed [CRu], partial response [PR]; RD at 2 years: 94% in BM MRD-negative CR/CRu and 100% in BM MRD-negative PR, compared with 71% in BM MRD-positive CR/CRu and 51% in BM MRD-positive PR, P = .002). Sustained MR during the postinduction period was predictive for outcome in MCL Younger after autologous stem cell transplantation (ASCT; RD at 2 years 100% vs 65%, P = .001) and during maintenance in MCL Elderly (RD at 2 years: 76% vs 36%, P = .015). ASCT increased the proportion of patients in MR from 55% before high-dose therapy to 72% thereafter. Sequential MRD monitoring is a powerful predictor for treatment outcome in MCL. These trials are registered at www.clinicaltrials.gov as #NCT00209222 and #NCT00209209.

Rituximab versus a watch-and-wait approach in patients with advanced- stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial

BACKGROUND Patients with advanced-stage, low-tumour-burden follicular lymphoma have conventionally undergone watchful waiting until disease progression. We assessed whether rituximab use could delay the need for chemotherapy or radiotherapy compared with watchful waiting and the effect of this strategy on quality of life (QoL). METHODS Asymptomatic patients (aged ≥18 years) with low-tumour-burden follicular lymphoma (grades 1, 2, and 3a) were randomly assigned centrally (1:1:1), by the minimisation approach stratified by institution, grade, stage, and age, to watchful waiting, rituximab 375 mg/m(2) weekly for 4 weeks (rituximab induction), or rituximab induction followed by a maintenance schedule of 12 further infusions given at 2-monthly intervals for 2 years (maintenance rituximab). On Sept 30, 2007, recruitment into the rituximab induction group was closed and the study was amended to a two-arm study. The primary endpoints were time to start of new treatment and QoL at month 7 (ie, 6 months after completion of rituximab induction). All randomly assigned patients were included in the analysis of time to start of new treatment on an intention-to-treat basis. The main study is now completed and is in long-term follow-up. The study is registered with ClinicalTrials.gov, NCT00112931. FINDINGS Between Oct 15, 2004, and March 25, 2009, 379 patients from 118 centres in the UK, Australia, New Zealand, Turkey, and Poland were randomly assigned to watchful waiting or maintenance rituximab. 84 patients were recruited to the rituximab induction group before it was closed early. There was a significant difference in the time to start of new treatment, with 46% (95% CI 39-53) of patients in the watchful waiting group not needing treatment at 3 years compared with 88% (83-92) in the maintenance rituximab group (hazard ratio [HR] 0·21, 95% CI 0·14-0·31; p<0·0001). 78% (95% CI 69-87) of patients in the rituximab induction group did not need treatment at 3 years, which was significantly more than in the watchful waiting group (HR 0·35, 95% CI 0·22-0·56; p<0·0001), but no different compared with the maintenance rituximab group (0·75, 0·41-1·34; p=0·33). Compared with the watchful waiting group, patients in the maintenance rituximab group had significant improvements in the Mental Adjustment to Cancer scale score (p=0·0004), and Illness Coping Style score (p=0·0012) between baseline and month 7. Patients in the rituximab induction group did not show improvements in their QoL compared with the watchful waiting group. There were 18 serious adverse events reported in the rituximab groups (four in the rituximab induction group and 14 in the maintenance rituximab group), 12 of which were grade 3 or 4 (five infections, three allergic reactions, and four cases of neutropenia), all of which fully resolved. INTERPRETATION Rituximab monotherapy should be considered as a treatment option for patients with asymptomatic, advanced-stage, low-tumour-burden follicular lymphoma. FUNDING Cancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche.

ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL)

To complete the existing treatment guidelines for all tumor types, ESMO organizes consensus conferences to better clarify open issues in each disease. In this setting, a consensus conference on the management of lymphoma was held on 18 June 2011 in Lugano, immediately after the end of the 11th International Conference on Malignant Lymphoma. The consensus conference convened ∼45 experts from all around Europe and selected six lymphoma entities to be addressed; for each of them three to five open questions were to be discussed by the experts. For each question, a recommendation should be given by the panel, supported by the strength of the recommendation based on the level of evidence. This consensus report focuses on the three most common lymphoproliferative malignancies: diffuse large B-cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia. A second report will concentrate on mantle cell lymphoma, marginal zone lymphoma and T-cell lymphomas.