Christian Gisselbrecht

Non-Hodgkin lymphoma (NHL) is the eighth most common malignancy worldwide. Diffuse large B cell lymphoma (DLBCL) is the most frequent subtype, accounting...

Temsirolimus, a selective inhibitor of the mammalian target of rapamycin, has demonstrated clinical benefit versus investigator’s choice (INV) of therapy in patients with relapsed/refractory mantle cell lymphoma (MCL). This post hoc study retrospectively assigned simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) scores (ie, secondary MIPI) based on parameters at the time of randomization in patients with MCL (N = 162) who received temsirolimus 175 mg once weekly for 3 weeks followed by once-weekly 75 mg or 25 mg or the INV of active therapy. Outcomes were analyzed according to the low-, intermediate- or high-risk category. Patient distribution by MIPI risk category was 31%, 39%, and 30% in the low-, intermediate-, and high-risk groups, respectively. Among patients in all categories, objective response rate (complete response + partial response) was higher in patients in the temsirolimus 175/75-mg group versus the INV group, respectively: 42% versus 0% (low-risk); 33% versus 5% (intermediate-risk); 10% versus 0% (high-risk). Median progression-free survival was significantly longer with temsirolimus 175/75 mg versus INV, respectively, in patients with intermediate (4.3 vs 1.9 months; P = 0.035) or high (4.5 vs 1.6 months; P = 0.0025) risk, and a trend toward improvement was observed in patients with low risk (5.3 vs 2.6 months; P = 0.091). Improvement in median overall survival was observed with temsirolimus 175/75 mg versus INV in low-risk patients (18.0 vs 10.5 months, respectively; P = 0.069). This analysis suggests that, compared with INV, temsirolimus demonstrated benefit in all MIPI risk categories in patients with MCL. In all treatment groups, patients with high secondary MIPI scores at baseline faced a dismal prognosis. ClinicalTrials.gov NCT00117598 .

This study evaluated the safety and efficacy of inotuzumab ozogamicin (INO), a targeted humanized anti-CD22 antibody conjugated to calicheamicin, plus rituximab (R-INO) every 3 weeks, up to six cycles, followed by high dose therapy and autologous stem cell transplant (HDT-aSCT) in patients with high-risk relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The primary endpoint was overall response (OR) rate after three cycles of R-INO. Sixty-three patients were enrolled. Common grade 3/4 adverse events during R-INO treatment were thrombocytopenia, lymphopenia and neutropenia. OR rate after three cycles of R-INO was 28.6% (95% confidence interval: 17.9-41.4). Eighteen patients underwent HDT-aSCT; 2-year progression-free survival (PFS) for these patients was 61.1%. Serious infections and hepatic toxicity following aSCT occurred in 33% and 22%, respectively. One- and 2-year PFS rates for all enrolled patients were 28.9% and 25.3%, respectively (median, 3.0 months). R-INO had lower than expected activity as a salvage regimen for transplant eligible patients with DLBCL.

Purpose: The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. Patients and Methods: In total, 477 patients with CD20⁺ DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. Results: After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P = .7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P < .05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01). Conclusion: In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT.

In the past decade, an unprecedented number of new drugs have been developed for lymphomas. Most of them target the important pathways of proliferation of lymphoma cells. Outstanding progress has been made in the treatment of B-cell lymphoma but not in the treatment of peripheral T-cell lymphoma (PTCL). PTCL is a heterogeneous group of lymphomas, except anaplastic lymphoma, that are associated with poor prognosis and 5-year overall survival rate less than 30%. New agents under evaluation in relapse or refractory PTCL include antifolate drugs (pralatrexate), histone deacetylase inhibitors (romidepsin, belinostat, vorinostat), purine analogs (bendamustine, gemcitabine), monoclonal antibodies (alemtuzumab, anti CD4) and immunoconjugates (denileukin-diftitox, SGN-35). Not all of them are available in the market, and most of them still have certain limitation. New combinations with chemotherapy will have to be designed. However, a new era of clinical and translational research is open. The main purpose of this review is to understand the biology of PTCL for the development of new therapies. Dans la dernière décennie, un nombre sans précédent de nouveaux médicaments ont été développés pour le traitement des lymphomes. La plupart sont des molécules qui ciblent des voies importantes de prolifération des lymphomes. Si des progrès majeurs ont eu lieu dans le traitement des lymphomes B, celui des lymphomes T périphériques (PTCL) n’a pas encore suivi le même chemin. Les Lymphomes T constituent aussi un groupe hétérogène de lymphomes qui, à l’exception des lymphomes anaplasiques, ont une probabilité de survie à cinq ans de moins de 30 %. Les nombreux agents en cours d’évaluation dans les rechutes comprennent des antifolates (pralatrexate) les inhibiteurs des histones déacétylases (romidepsin), les analogues des purines (bendamustine, gemcitabine), les anticorps monoclonaux (alemtuzumab, anti-CD4), les immunoconjugés (denileukin-diftitox, SGN-35). Tous ne sont pas commercialisés et la plupart ont encore une activité modeste qui va nécessiter de nouvelles combinaisons avec la chimiothérapie. Cependant, ils ouvrent la voie vers une période riche pour la recherche clinique et translationnelle. Une meilleure connaissance de ces pathologies complexes va guider les stratégies de développement de ces nouveaux traitements et est l’objet de cette revue.

We aimed to assess quality of life (QoL) following front-line autologous stem cell transplant (ASCT) and the QoL relationship with rituximab maintenance, in patients with diffuse large B-cell lymphoma. Patients were then randomized to either one weekly rituximab injection for 4 weeks, or observation alone. Patients (n = 269) were given the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaires. Scales for all symptoms exhibited similar temporal patterns, with a marked increase, followed by a plateau after 1 year. The proportion of patients with a clinically significant improvement varied from 6% (constipation) to 56% (fatigue). Age, gender, and previous treatment-induced toxicities were not predictive of variations in QoL. Rituximab significantly reduced pain and symptom severity. Our results for QoL showed that patients experienced rapid recovery after ASCT in all the domains tested. Differences in QoL improvement with time were not connected with rituximab maintenance.