Pierre Feugier

Prognostic Factors in Patients With Aggressive Non-Hodgkin's Lymphoma Treated by Front-Line Autotransplantation After Complete Remission: A Cohort Study by the Groupe d'Etude des Lymphomes de l'Adulte

PURPOSEnImproved survival has been observed in aggressive non-Hodgkins lymphoma (NHL) patients with adverse prognostic factors when autotransplantation (ASCT) was performed after complete remission. However, there is no agreement on the prognostic factors for patients treated with ASCT. We aimed to estimate the prognostic effect of clinical and biologic variables on relapse and survival rates by pooling the data from two trials.nnnPATIENTS AND METHODSnOf the patients treated in the LNH87 and LNH93 trials, 330 under age 60 years achieved complete remission after high-dose cyclophosphamide, doxorubicin, vincristine, and prednisone, and received consolidative ASCT; 16% of patients had T-cell NHL. The International Prognostic Index (IPI) score was 0 for 11%, 1 for 23%, 2 for 51%, and 3 for 15%. Univariate and Cox multivariate survival analyses were retrospectively performed on this population.nnnRESULTSnOverall survival was 75 +/- 5% at 5 years and disease-free survival (DFS) 67 +/- 5%. For T-cell NHL, these scores were 54% and 44%, respectively. The IPI score had no prognostic value and only the following parameters adversely affected overall survival and DFS (P <.05): marrow involvement; more than one extranodal site; histology (nonanaplastic T-cell v others); and type of anthracycline (mitoxantrone v doxorubicin, for DFS only).nnnCONCLUSIONnThese results suggest that ASCT can prevent relapse in patients with adverse IPI factors. However, patients presenting with a nonanaplastic T-cell phenotype, more than one extranodal site, or marrow involvement still have a higher risk of relapse. These factors should be taken into account when designing post-ASCT maintenance studies.

Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma

Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for patients treated with rituximab. However, no long-term follow up (i.e. > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-α2a or a similar chemotherapy-based regimen plus rituximab, and outcome was up-dated. With a median follow up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary end point) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P<0.0001 and P=0.001, respectively). Considering long-term toxicity, the addition of rituximab in the first-line setting was confirmed as safe with regards to development of secondary malignancies. Long-term follow up of patients with follicular lymphoma treated in the FL2000 study confirms the sustained clinical benefit of rituximab without long-term toxicity. This study was registered at ClinicalTrials.gov (Identifier:00136552).

Peripheral blood involvement in patients with follicular lymphoma: a rare disease manifestation associated with poor prognosis

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.

Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study

BACKGROUNDnMost patients with chronic lymphocytic leukaemia relapse after initial therapy combining chemotherapy with rituximab. We assessed the efficacy and safety of rituximab maintenance treatment versus observation for elderly patients in remission after front-line abbreviated induction by fludarabine, cyclophosphamide, and rituximab (FCR).nnnMETHODSnThis randomised, open-label, multicentre phase 3 trial at 89 centres in France enrolled treatment-naive and fit patients aged 65 years or older with chronic lymphocytic leukaemia without del(17p). Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and adequate renal and hepatic function. Patients in response to complete induction treatment with four monthly courses of full-dose FCR with two interim rituximab doses on day 14 of cycles 1 and 2 (oral fludarabine [40 mg/m2 per day] and oral cyclophosphamide [250 mg/m2 per day] for the first 3 days of each cycle, rituximab at 375 mg/m2 intravenously on day 0 of cycle 1 and subsequently at 500 mg/m2 on day 14 of cycle 1, days 1 and 14 of cycle 2, and day 1 of cycles 3 and 4) were eligible for randomisation. Recovery from FCR toxicity and patient willingness to continue the trial were mandatory. We randomly assigned (1:1) patients to either receive intravenous rituximab (500 mg/m2) every 8 weeks for up to 2 years or undergo observation, with a central computer-generated randomisation list using randomly permuted blocks of variable sizes. Randomisation was stratified by IGHV mutational status, the presence or absence of del(11q), and response level to induction treatment. The primary endpoint was progression-free survival, with the objective to assess the superiority of rituximab maintenance relative to observation. The final analysis was done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug in the rituximab group and in all patients in the observation group. This trial is closed to accrual whilst continuing patient follow-up. The study is registered with ClinicalTrials.gov, number NCT00645606.nnnFINDINGSnBetween Dec 14, 2007, and Feb 18, 2014, 542 patients were enrolled, of whom 525 started FCR induction. Between June 10, 2008, and Aug 14, 2014, 409 (78%) patients were randomly assigned to rituximab maintenance (n=202) or observation (n=207). Four (2%) patients in the rituximab group did not receive the allocated treatment (progressive disease [n=1], adverse events [n=3]). After a median follow-up of 47·7 months (IQR 30·4-65·8), median progression-free survival in the rituximab group (59·3 months, 95% CI 49·6-not estimable) was improved compared with the observation group (49·0 months, 39·9-60·5; hazard ratio 0·55, 95% CI 0·40-0·75; p=0·0002). Neutropenia and grade 3-4 infections were more common with rituximab maintenance (105 [53%] of 198 patients vs 74 [36%] of 207 patients and 38 [19%] vs 21 [10%], respectively) during the study. The most common grade 3-4 infection was lower respiratory tract infection (24 [12%] vs eight [4%]). The incidence of second cancers, except basal cell carcinoma, was similar in both groups (29 [15%] vs 23 [11%]). Deaths were related to adverse events for 23 (11%) patients in the rituximab group and 16 (8%) in the observation group.nnnINTERPRETATIONn2-year maintenance rituximab in selected elderly patients improves progression-free survival and shows an acceptable safety profile. Immunotherapy maintenance strategy is a relevant option in front-line treatment of chronic lymphocytic leukaemia, even in the age of targeted therapy.nnnFUNDINGnFrench National Cancer Institute (INCa), Roche, Chugai.

Systematic review of the recent evidence for the efficacy and safety of chlorambucil in the treatment of B-cell malignancies

Abstract Emergence of new agents has deeply modified treatment options and the role of chlorambucil (CLB) in B-cell malignancies. We conducted a systematic review of prospective, randomized, controlled trials (RCTs) investigating the benefits and harms of CLB used alone or in combination with other treatment in patients suffering from chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin lymphoma (NHL) or Waldenström macroglobulinemia (WM). For CLL, review of the nine RCTs showed that the main advantage of CLB is its low toxicity in comparison with purine nucleoside analogs like fludarabine in either CLL or NHL. In CLL, the major disadvantage is the very low rate of complete response, except when combining an anti-CD20 antibody. For B-cell lymphoma and WM, six RCTs were summarized. Results according to the usual criteria are presented and the role of CLB, used mostly in combination with an anti-CD20 antibody, is discussed for each indication, in particular for unfit patients.

Recommandations 2014 de la Société française d’hématologie pour le diagnostic, le traitement et le suivi de la leucémie à tricholeucocytes

Nous presentons les recommandations d’un groupe de onze experts appartenant a plusieurs centres hospitaliers francais. Ce groupe s’est reuni en novembre 2013 pour examiner les criteres de prise en charge des patients presentant une leucemie a tricholeucocytes (HCL). Les reflexions et propositions du groupe se sont basees sur une analyse critique des recommandations deja diffusees dans la litterature et sur un etat des pratiques de services d’hematologie clinique habitues a prendre en charge ces patients. La HCL est une hemopathie maligne rare, avec environ 195 nouveaux cas incidents en France. Le diagnostic repose sur l’examen attentif du frottis sanguin et l’immunophenotypage des cellules tumorales, avec un panel de quatre marqueurs dedies a la recherche de tricholeucocytes : CD11c, CD25, CD103 et CD123. En 2011, la mutation V600E du gene BRAF au niveau de l’exon 15 a ete identifiee dans la HCL : presente dans la maladie, elle est absente dans sa forme variante (HCL-v) et dans le lymphome splenique de la pulpe rouge de la rate (SRPL), deux entites proches de la HCL. La prise en charge des patients avec une HCL s’est modifiee ces dernieres annees. Une moins bonne reponse aux analogues des purines (PNA) est observee chez les patients avec une leucocytose elevee, une splenomegalie volumineuse, un profil non mute des genes IGVH, une utilisation de VH4-34 ou avec des mutations de TP53. Le traitement de premiere intention utilise les PNA : cladribine ou pentostatine. La place des inhibiteurs de BRAF, associes ou non aux inhibiteurs de MEK, est discutee.

Quality of life in 269 poor-risk diffuse large B-cell lymphoma patients treated with rituximab versus observation after front-line auto transplantation: The GELA LNH98-3 randomized trial.

8082 Background: Little is known about the longitudinal course of health-related quality of life (QoL) in DLBCL patients during their post-treatment follow-up. We report on the QoL of patients treated in the randomised LNH98-3 trial of the Groupe dEtudes des Lymphomes de lAdulte (GELA). We aimed to assess QoL and fatigue following front-line autotransplantation (ASCT) and to analyse relations with rituximab maintenance. Methods: This study is registered with www.ClinicalTrials.gov number NCT00169169 (C Haioun, Annals of Oncology, 2009). High-dose CHOP induction therapy was received by 476 patients, and 330 responder-patients received ASCT. Following response to ASCT, 269 patients were randomized to rituximab treatment (4 cycles) or observation. They received the EORTC QLQ-C30 questionnaires at day 45 after ASCT and during follow-up (100 days, 1yr, 2yr, and 3 yr). Changes of mean QoL scores over time were analysed with mixed models. Analyses were done on an intention-to- treat basis. Results: From the 55...