Peripheral T-cell lymphomas are characterized by a poor clinical outcome. We retrospectively analyzed 208 adults treated in our institution between 2000 and 2011. Median age at diagnosis was 55 years. Fifty-one percent had B symptoms and 51% serum elevated lactate dehydrogenase (LDH) levels. Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 63% and 2-4 in 37%. According to Ann Arbor classification, 16% were at stage I-II and 84% at stage III-IV. Histological subtypes were: 39% peripheral T-cell non-Hodgkin lymphoma (NHL) unspecified (PTCL-U), 19.5% anaplastic large cell lymphoma (ALCL), with 9.5% ALK+ and 10% ALK-, and 25% angioimmunoblastic lymphoma (AILT). Primary extranodal lymphoma represented 17%, and 8% were diagnosed with hemophagocytosis. Induction chemotherapy was CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in 87% of patients. The median number of chemotherapy cycles was 2 (1-7). A complete response was obtained in 57% of the patients. Among them, 32% had an autologous stem cell transplant (ASCT) and 10% allogeneic SCT, while 38% were primary refractory. Five-year overall survival (OS) was 28.5% (22.3-36.3), and 5-year event-free survival (EFS) was 18.4% (13.4-25.3). A multivariate analysis showed that ALCL-ALK+ (p = 0.004), AILT (p < 0.01), extranodal involvement (p = 0.001), PS > 1 (p = 0.04), LDH < normal (p = 0.003) and hemophagocytosis (p = 0.001) were independent adverse factors for OS. We conclude that conventional chemotherapy with intensive treatment is not sufficient to improve the response rate. Optimal management is required.
Background In contrast to the high cure rates in young patients (pts) treated with anthracycline-based chemotherapy, classical Hodgkin lymphoma (cHL) prognosis is poor in elderly pts, and very few data exist for pts considered too frail to receive standard-dose chemotherapy. In those patients, limited therapeutic options are available. Among the new immune-oncology drugs, Nivolumab, an anti-PD1 antibody, has demonstrated high response rate and very good tolerance, and is now approved in relapse and refractory (R/R) cHL. However, data on its use in the frontline setting are scarce. Material and methods We designed a prospective, open-label, multi-centric phase II study, to assess the efficacy and safety of nivolumab alone, or in combination with vinblastine in naive pts aged 61 years and older, with cHL and coexisting medical conditions. Pts were eligible if they had a Cumulative Illness Rating Scale-Geriatric (CIRS-G) score of 6 or more. Treatment consisted in an induction phase of 6 nivolumab injections, delivered at a flat dose of 240 mg every 14 days. Early assessment was done at 12 weeks by PET-CT and CT-scan. Pts who achieved complete metabolic response (CMR) at early assessment completed treatment with nivolumab monotherapy for 18 additional cycles (consolidation phase). Pts who obtained partial metabolic response (PMR) or non metabolic response (NMR, stable disease) received a combination of 18 cycles of nivolumab plus vinblastine, administered intravenously. The primary objective of the study was to assess the CMR rate based on central review at the end of treatment (EOT). Results From August 30th, 2018 to April 28 th, 2020, 64 pts were included in 31 centers, which composed the full analysis set (FAS), used for safety evaluation. Among these 64 pts, 56 pts were fully evaluable and constituted the efficacy set (ES) used for the efficacy analysis (8 pts progressed early or were not assessed by PET-CT). The median age at inclusion in the ES was 75 years [range: 62-91]. Patients had a median CIRS-G score of 10 [range: 6-18] at baseline, and a median G8 score of 12.5 [range: 6-17]. Seventy-three percent of pts had a stage III-IV disease and 42.9% of pts had B symptoms. At EOT, 16 pts (28.6%) achieved CMR according to central PET-CT review. Ten pts (17.9%) achieved PMR, 10 pts were in NMR (17.9%) and progressive metabolic disease was observed in 17 pts (30.4%). Three pts were not evaluated. The overall response rate at end of induction was 51.9%, (9 CMR and 18 PMR). 23 pts received a consolidation with nivolumab and vinblastine. With a median follow-up of 20.1 months, median PFS was 9.8 months [95% CI: 4.2;12]. 15/64 pts of the FAS died during treatment (23.4%): 6 pts from lymphoma, 2 pts from toxicity of study treatment and 2 pts from concurrent illness. One patient died from toxicity of additional treatment after progression, and 4 pts from other causes. The 2-year overall survival was 76.7% [95% CI: 59.6;87.3]. 49/64 pts (76.6%) experienced at least one AE, among which 32 pts experienced grade 3-4 AEs. The 3 more frequent grade 3-4 AEs were neutropenia (8 pts), sepsis (7 pts) and respiratory tract infection (5 pts). Adverse events were related to nivolumab in 36 pts and led to treatment discontinuation in 19 pts (29.7%). Adverse events of special interest i.e., immune-related AEs, were recorded in 22 pts, including 3 pneumonitis, 1 myocarditis, 1 encephalitis and 1 colitis. Among the 64 pts of the FAS, 34% of pts completed the treatment. The median number of cycles administered was 7 [range: 1-24] for nivolumab and 17 [range: 1-18] for vinblastine. Conclusion The NIVINIHO study is the first study to assess the efficacy and safety of an immune checkpoint inhibitor for first line therapy in elderly, frail patients with cHL. The results suggest that in this setting, a nivolumab-based therapy is active in a subset of pts. Further studies and biological analysis are planned to determine which patients may benefit from this approach. Figure 1 Figure 1. Disclosures Lazarovici: Mundipharma: Other: Travel grant. Bouabdallah: Takeda: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Sandoz: Consultancy, Honoraria; Abbvie: Honoraria; Kite/Gilead: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Morschhauser: Roche: Consultancy, Speakers Bureau; Chugai: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Laribi: Takeda: Other: Personal Fees, Research Funding; Novartis: Other: Personal Fees, Research Funding; AbbVie: Other: Personal Fees, Research Funding; BeiGene: Other: Personal Fees; Le Mans Hospital: Research Funding; IQONE: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Jansen: Research Funding. Feugier: Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Astrazeneca: Consultancy, Honoraria. Sibon: iQone: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Roche: Consultancy; Janssen: Consultancy. Ribrag: Gilead: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; GSK: Research Funding; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Nivolumab. Presently labelled for relapse and refractory classical Hodgkin lymphoma and other malignancies
Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating infection of the central nervous system caused by the JC papovavirus usually seen among immunocompromised patients. PML arises upon JC virus reactivation during periods of immunosuppression. PML may be seen among patients with lymphoproliferative disorders and immunosuppression induced by chemotherapy.1 Recently, an association between PML and rituximab in the setting of autologous 2, 3 or allogeneic 4 transplantation has been suggested. We report the first case of a woman with a non Hodgkin lymphoma (NHL) who developed PML after a combination of rituximab with chemotherapy as first line treatment.A 67-year-old woman suffered from a mantle cell lymphoma diagnosed on splenomegaly and hyperlymphocytosis. Staging showed a stage IV with bone marrow involvement. The patient was treated with a combination of rituximab (375 mg . Cerebral magnetic resonance imaging performed three months after the diagnosis showed an increase of the leukoencephalopathy lesions. The patient deceased six months after the beginning of symptoms.Rare cases of PML have been reported among patients with lymphoma. A recent survey retrospectively analyzed 46 cases of PML occurring during lymphoproliferative diseases. 1 The implication of rituximab in these cases, without transplantation setting, has not been highlighted. Moreover, the patients reported were often in relapse, and were heavily pre treated. 1Four cases of PML were recently described in patients who were treated with chemotherapy, transplantation (autologous for three and allogeneic for one) and peritransplantation rituximab.2-4 Despite these cases, a direct association between rituximab and PML remains moreover speculative. The addition of peritransplantation rituximab which results in delayed T-cell reconstitution after transplantation may be involved in the occurrence for late infectious diseases.In our case, the link between rituximab treatment and PML development appears disputable, mostly because the patient showed at the same time a severe suppression of T cell immunity (110 CD4 + T cells/∝L). Interestingly, another case of PML was recently reported in a patient treated with rituximab without transplantation. 5The patient was 62 year-old with chronic lymphocytic leukemia for 14 years and Richter transformation for 2. He was heavily pre treated (chlorambucil, fludarabine) although PML developed 14 months after 6 courses of rituximab with chemotherapy.Our patient is, to our knowledge, the first case of PML after a combination of CHOP with rituximab, in first induction procedure. Although the contributory role of rituximab remains speculative, our additional case highlights the need for an accurate surveillance, even in patients not heavily pre treated, as in first induction procedure with CHOP and rituximab.
Introduction: allogeneic transplantation (allo-HSCT) is a curative treatment for patients with advanced lymphoma. Haploidentical (haplo-SCT) transplantation extended the accessibility to allo-HSCT, overcoming the issue of donor availability. However, alternative donor allo-HSCT is still considered at higher risk of non-relapse mortality due to the HLA disparity and thus an anticipated higher incidence of GVHD. In this context, the use of a non myeloablative conditioning (NMAC) regimen combined with post transplantation cyclophosphamide (PT-Cy) based GVHD prophylaxis may reduce procedure related toxicity. The aim was to evaluate the toxicity and efficacy of haplo-SCT using NMAC with PT-Cy in advanced lymphoma patients. Methods: We here report the retrospective experience of a bicentric transplantation program. We analyzed a cohort of lymphoma patients undergoing Haplo-SCT and homogeneously receiving NMAC and PT-Cy. Inclusion criteria were: 1) first allo-HSCT for advanced lymphoma between 2009 and 2018; 2) haploidentical donor; 3) NMAC (fludarabine cyclophosphamide and 2 gray TBI GVHD prophylaxis consisted of PT-Cy day+3 and +4 , cyclosporine A and MMF starting from day +5. Multivariate analyses included age, disease type (NHL vs HL), HCT-CI (< vs ≥ 3), graft source (PBSC vs BM), disease status at haplo-SCT (CR vs other). Results: One hundred forty seven patients (73 NHL; 74 HL) with a median age of 46 years (range: 19-71) were included. PBSC (peripheral blood stem cell) was used as graft source in 96 patients (65%). Patients received a median number of 3 conventional chemotherapy lines before haplo-SCT (1-8). Sixty-five (44%) had relapse after Auto-HCT. At the time of haplo-SCT, 96 patients (66%) were in complete remission. The cumulative incidences of day+100 grade 2-4 and 3-4 acute GVHD were 30% and 3%, respectively. The cumulative incidences of 2-year chronic and moderate or severe chronic GVHD were 13% and 8%, respectively. With a median follow up of 39 months (6-114), 2-year NRM was 14%, with a trend for higher risk in patients with HCT-CI ≥ 3 (HR 0.39, 95CI [0.15-1.04] p = 0.061) while age was not associated with an increased risk of NRM (HR 1.01, 95CI [0.98-1.05], p = 0.450). Two-year cumulative incidence of relapse (CIR) was 21% and 18% in HL and NHL patients, respectively. Disease status at the time of haplo-SCT was strongly associated with relapse (HR 2.99, 95CI [1.41-6.35], p = 0.004) In HL patients, 2-year PFS, OS and GRFS were 65%, 77% and 57%, respectively, while corresponding values in NHL patients were 65%, 69% and 55%, respectively. Two-year PFS and GRFS were significantly higher in patients who underwent haplo-SCT in CR (PFS: CR vs. no CR: 72% vs. 55%, p=0.045; GRFS: CR vs. no CR: 63% vs. 42%, p=0.010). There was a trend for better 2-year OS in CR (OS: CR vs. no CR: 78% vs. 63%, p=0.063. Conclusion: We confirm the feasibility of haplo-SCT using NMAC and PT-Cy with low incidence of GVHD (notably severe forms) and NRM. In addition, we observed a relatively low incidence of relapse (19%) in this cohort of heavily pretreated patients, underlining a potent graft-versus-lymphoma effect after haplo-SCT, leading to promising survivals, including high rate of GRFS (>50%), suggesting a preserved long term quality of life in survivors. We conclude that NMAC haplo-SCT with PT-Cy should be considered as a valuable curative option for advanced lymphoma patients, with a favorable toxicity profile and promising long term survival. Figure Disclosures Stoppa: celgene: Other: travel fees, lecture fees; takeda: Other: travel fees. Carlo-Stella:MSD: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Boehringer Ingelheim: Consultancy; Genenta Science sr: Consultancy; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Other: Travel, accommodations; Janssen Oncology: Honoraria; AstraZeneca: Honoraria. Chabannon:EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees; Celgene: Other: speaker's fees; Novartis: Other: speaker's fees; Gilead: Other: speaker's fees, hospitalities; Sanofi SA: Other: research support, speaker's fees, hospitalities. Santoro:Takeda: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; BMS: Consultancy. Blaise:Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria; Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria.
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