Showing papers by "Pauline Brice published in 2018"

Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma

Abstract: BACKGROUND: Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin's lymphoma. METHODS: We conducted this multicenter, international, phase 3 superiority trial to evaluate rituximab plus lenalidomide, as compared with rituximab plus chemotherapy, in patients with previously untreated follicular lymphoma. Patients were randomly assigned to receive one of the two regimens, followed by maintenance monotherapy with rituximab. Treatment with rituximab plus lenalidomide consisted of 18 cycles of the two drugs, followed by rituximab maintenance therapy every 8 weeks for 12 cycles (six additional doses). Treatment with rituximab plus chemotherapy consisted of the investigator's choice of one of three rituximab-based regimens, followed by maintenance monotherapy with rituximab every 8 weeks for 12 cycles. The primary end points were complete response (confirmed or unconfirmed) at 120 weeks and progression-free survival. RESULTS: A total of 1030 patients were randomly assigned to receive rituximab plus lenalidomide (513 patients) or rituximab plus chemotherapy (517 patients). The rate of confirmed or unconfirmed complete response at 120 weeks was similar in the two groups: 48% (95% confidence interval [CI], 44 to 53) in the rituximab-lenalidomide group and 53% (95% CI, 49 to 57) in the rituximab-chemotherapy group (P=0.13). The interim 3-year rate of progression-free survival was 77% (95% CI, 72 to 80) and 78% (95% CI, 74 to 82), respectively. A higher percentage of patients in the rituximab-chemotherapy group had grade 3 or 4 neutropenia (32% vs. 50%) and febrile neutropenia of any grade (2% vs. 7%), and a higher percentage of patients in the rituximab-lenalidomide group had grade 3 or 4 cutaneous reactions (7% vs. 1%). CONCLUSIONS: Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy (with both regimens followed by rituximab maintenance therapy). The safety profile differed in the two groups. (Funded by Celgene; RELEVANCE ClinicalTrials.gov numbers, NCT01476787 and NCT01650701 , and EudraCT number, 2011-002792-42 .).

A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts

Abstract: Summary Background Patients with follicular lymphoma have heterogeneous outcomes. Predictor models to distinguish, at diagnosis, between patients at high and low risk of progression are needed. The objective of this study was to use gene-expression profiling data to build and validate a predictive model of outcome for patients treated in the rituximab era. Methods A training set of fresh-frozen tumour biopsies was prospectively obtained from 160 untreated patients with high-tumour-burden follicular lymphoma enrolled in the phase 3 randomised PRIMA trial, in which rituximab maintenance was evaluated after rituximab plus chemotherapy induction (median follow-up 6·6 years [IQR 6·0–7·0]). RNA of sufficient quality was obtained for 149 of 160 cases, and Affymetrix U133 Plus 2.0 microarrays were used for gene-expression profiling. We did a multivariate Cox regression analysis to identify genes with expression levels associated with progression-free survival independently of maintenance treatment in a subgroup of 134 randomised patients. Expression levels from 95 curated genes were then determined by digital expression profiling (NanoString technology) in 53 formalin-fixed paraffin-embedded samples of the training set to compare the technical reproducibility of expression levels for each gene between technologies. Genes with high correlation (>0·75) were included in an L2-penalised Cox model adjusted on rituximab maintenance to build a predictive score for progression-free survival. The model was validated using NanoString technology to digitally quantify gene expression in 488 formalin-fixed, paraffin-embedded samples from three independent international patient cohorts from the PRIMA trial (n=178; distinct from the training cohort), the University of Iowa/Mayo Clinic Lymphoma SPORE project (n=201), and the Barcelona Hospital Clinic (n=109). All tissue samples consisted of pretreatment diagnostic biopsies and were confirmed as follicular lymphoma grade 1–3a. The patients were all treated with regimens containing rituximab and chemotherapy, possibly followed by either rituximab maintenance or ibritumomab–tiuxetan consolidation. We determined an optimum threshold on the score to predict patients at low risk and high risk of progression. The model, including the multigene score and the threshold, was initially evaluated in the three validation cohorts separately. The sensitivity and specificity of the score for the prediction of the risk of lymphoma progression at 2 years were assessed on the combined validation cohorts. Findings In the training cohort, the expression levels of 395 genes were associated with a risk of progression. 23 genes reflecting both B-cell biology and tumour microenvironment with correlation coefficients greater than 0·75 between the two technologies and sample types were retained to build a predictive model that identified a population at an increased risk of progression (p Interpretation We developed and validated a robust 23-gene expression-based predictor of progression-free survival that is applicable to routinely available formalin-fixed, paraffin-embedded tumour biopsies from patients with follicular lymphoma at time of diagnosis. Applying this score could allow individualised therapy for patients according to their risk category. Funding Roche, SIRIC Lyric, LYSARC, National Institutes of Health, the Henry J Predolin Foundation, and the Spanish Plan Nacional de Investigacion.

Efficacy of chemotherapy or chemo-anti-PD-1 combination after failed anti-PD-1 therapy for relapsed and refractory Hodgkin lymphoma: A series from Lysa centers.

Abstract: Anti-PD-1 therapy provides high response rates in Hodgkin lymphoma (HL) patients who have relapsed or are refractory (R/R) to autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV), but median progression free survival (PFS) is only one year. The efficacy of treatment following anti-PD-1 is not well known. We retrospectively investigated the efficacy of salvage therapies for unsatisfactory response to anti-PD-1 therapy, assessed by PET-CT according to the Lugano criteria, in 30 R/R HL patients. Patients were highly pre-treated before anti-PD-1 (70% received ASCT and 93% BV). Unsatisfactory responses to anti-PD1 therapy were progressive disease (PD) (n=24) and partial response (PR) (n=6). For the 24 PD patients, median anti-PD-1 related PFS was 7.5 months (95%CI, 5.7-11.6); 17 received subsequent CT alone (Group 1) and 7 received CT in addition to anti-PD-1 (Group 2). 16/24 patients (67%) obtained an objective response. In the 15 patients treated with the same CT, twelve obtained PR or complete response (CR). In Group 1, there were 7 CR (41%), 3 PR (18%), and 7 PD (41%). In Group 2, there were 4 CR (57%), 2 PR (29%), and 1 SD (14%). No unexpected toxicity was observed. Six patients who achieved response proceeded to allogeneic SCT. With a median follow-up of 12.1 months (7-14.7), the median PFS following the initiation of CT was 11 months (95%CI, 6.3; not reached) and the median of overall survival was not reached. These observations in highly pre-treated HL patients suggest that anti-PD-1 therapy might re-sensitize tumor cells to CT. This article is protected by copyright. All rights reserved.

Randomized phase III study comparing an early PET driven treatment de-escalation to a not PET-monitored strategy in patients with advanced stages Hodgkin lymphoma: Final analysis of the AHL2011 LYSA study.

Abstract: 7503Background: Escalated BEACOPP (BEA) improves PFS but not OS in pts with advanced HL compared to ABVD and is associated to a higher risk of hematological toxicity, secondary leukemia and inferti...

Bendamustine and rituximab in elderly patients with low-tumour burden follicular lymphoma. Results of the LYSA phase II BRIEF study.

Abstract: The treatment of low-tumour burden follicular lymphoma (LTBFL) remains a challenge. Rituximab-based strategies may be improved by adding chemotherapy. This Lymphoma Study Association multicentre phase II study assessed rituximab and bendamustine in 63 patients with untreated LTBFL who were aged over 60 years old and had a follicular lymphoma International Prognostic Index (FLIPI) score ≥2. Induction comprised 4 weekly cycles of rituximab 375 mg/m2 intravenously combined with 2 cycles of bendamustine 90 mg/m2 days 1-2 with a 28-day interval, followed by twelve cycles of 375 mg/m2 rituximab maintenance therapy every 8 weeks. The primary endpoint was complete response (CR)/unconfirmed CR (CRu), at 12 weeks. Median age was 67·4 years and median FLIPI was 3. Ultimately, 18 patients (29%) had high tumour burden according to Groupe d'Etude des Lymphomes Folliculaires criteria. The 12-week CR/CRu rate was 54·0% and the overall response rate was 93·7%. Surprisingly, 3 patients died during maintenance (2 sepsis, 1 neoplasm). Progression-free survival was 85·4% at 24 months. In LTBFL patients with FLIPI ≥2, two cycles of rituximab and bendamustine result in a CR rate of 54·0%. However, the treatment-related deaths observed do not allow this regimen to be recommended for LTBFL patients aged over 60 years. EudraCT: 2010-020757-14; ClinicalTrials.gov: NCT01313611.

Tandem haematopoietic stem cell transplantation for High Risk relapsed/refractory Hodgkin Lymphoma: a LYSA study

Abstract: Tandem stem cell transplantation (SCT) is an option for high-risk relapsed/refractory Hodgkin Lymphoma (HL) patients. We evaluated the tolerance/efficacy of double autologous or autologous SCT (ASCT) followed by allogenic SCT (alloSCT) in 120 HL patients prospectively registered on a French nationwide database. Median age was 26 (14-56) years. Complete remission rate was 60%, including 33% after a single line, and another 27% after two or more salvage regimens. Partial response rate was 32%, and 8% suffered treatment failure. Overall, 115 (96%) patients underwent a first ASCT, and 73 (61%) had a tandem SCT, including alloSCT in 44 (60%) and ASCT in 29 (40%). The median follow-up was 43 months (4.8-73.7 months). The two-year progression-free survival rate for the whole population and for patients receiving tandem transplant was 56% (95% confidence interval [CI]: 46-65%) and 71% (95% CI: 49-84%), respectively. Among tandem transplants, we observed 20 deaths (17%), 10 of which were transplant-related (6 alloSCT and 4 ASCT). We suggest that tandem SCT is efficient in high-risk relapsed/refractory HL patients, although transplant-related mortality remains high. The benefit of tandem SCT should be balanced with the efficacy of Brentuximab vedotin-based post-transplant consolidative strategies in high-risk relapsed/refractory HL patients.

Are myelodysplastic syndromes and acute myeloid leukaemia occurring during the course of lymphoma always therapy related

Abstract: Berger, J.R., Aksamit, A.J., Clifford, D.B., Davis, L., Koralnik, I.J., Sejvar, J.J., Bartt, R., Major, E.O. & Nath, A. (2013) PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology, 80, 1430–1438. Carson, K.R., Evens, A.M., Richey, E.A., Habermann, T.M., Focosi, D., Seymour, J.F., Laubach, J., Bawn, S.D., Gordon, L.I., Winter, J.N., Furman, R.R., Vose, J.M., Zelenetz, A.D., Mamtani, R., Raisch, D.W., Dorshimer, G.W., Rosen, S.T., Muro, K., Gottardi-Littell, N.R., Talley, R.L., Sartor, O., Green, D., Major, E.O. & Bennett, C.L. (2009a) Progressive multifocal leukoencephalopathy after rituximab therapy in HIVnegative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood, 113, 4834–4840. Carson, K.R., Focosi, D., Major, E.O., Petrini, M., Richey, E.A., West, D.P. & Bennett, C.L. (2009b) Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncology, 10, 816–824. Carson, K.R., Newsome, S.D., Kim, E.J., WagnerJohnston, N.D., von Geldern, G., Moskowitz, C.H., Moskowitz, A.J., Rook, A.H., Jalan, P., Loren, A.W., Landsburg, D., Coyne, T., Tsai, D., Raisch, D.W., Norris, L.B., Bookstaver, P.B., Sartor, O. & Bennett, C.L. (2014) Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project. Cancer, 120, 2464–2471. Gonzalez, H., Bolgert, F., Dampro, P. & Leblond, V. (1999) Progressive multifocal leukoencephalitis (PML) in three patients treated with standard-dose fludarabine (FAMP). Hematology and Cell Therapy, 41, 183–186. Maddocks, K.J., Ruppert, A.S., Lozanski, G., Heerema, N.A., Zhao, W., Abruzzo, L., Lozanski, A., Davis, M., Gordon, A., Smith, L.L., Mantel, R., Jones, J.A., Flynn, J.M., Jaglowski, S.M., Andritsos, L.A., Awan, F., Blum, K.A., Grever, M.R., Johnson, A.J., Byrd, J.C. & Woyach, J.A. (2015) Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. Journal of the American Medical Association Oncology, 1, 80–87. Teramoto, T., Kaneko, H., Funato, M., Sawa, H., Nagashima, K., Hirose, Y. & Kondo, N. (2003) Progressive multifocal leukoencephalopathy in a patient with X-linked agammaglobulinemia. Scandinavian Journal of Infectious Diseases, 35, 909–910.

Management of relapsed or refractory follicular lymphoma patients in daily practice - a French non-interventional study.

Abstract: Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma (NHL) subtype, accounting for approximately 20% of all NHLs [1]. This indolent and incurable disease usually displays a low...

L’arrivée de l’immunothérapie dans le lymphome de Hodgkin.

Abstract: Resume Touchant preferentiellement les jeunes adultes, le lymphome de Hodgkin (LH) classique est une hemopathie maligne dont le traitement par chimiotherapie plus ou moins radiotherapie engendre de bons taux de guerison (> 80 %) avec cependant une toxicite a long terme significative. Certains cas sont refractaires a la chimiotherapie ou rechutent precocement et necessitent des chimiotherapies intensives aux lourds effets secondaires. L’etude de la physiopathologie des LH revele que d’importantes alterations des interactions entre les cellules de Reed-Sternberg et leur micro-environnement impliquent la voie de signalisation Programmed Cell Death 1 (PD-1)/PD-Ligand-1. Recemment, les anticorps anti-PD-1 ont montre des resultats spectaculaires dans les LH refractaires ou en rechute avec une toxicite moderee, mais leur efficacite a long terme n’est pas encore etablie. La place de ces traitements dans la strategie globale de prise en charge des LH reste a determiner.