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Lenalidomide is manageable and effective in multiple myeloma, particularly in elderly patients. Surprisingly, the combination of lenalidomide with rituximab produced clinically significant anemia at 25 mg/day for 21/28 days, the highest possible dose, in Waldenstrom's Macroglobulinemia (WM). We aimed to determine the maximum tolerated dose (MTD) of single agent lenalidomide and determine its impact on WM. RV-WM-0426 is a multicenter dose escalation open label phase 1/2 study of lenalidomide in relapsed/refractory WM (RRWM). Lenalidomide was given orally 21/28 days per cycle for 1 year, at escalated dose of 15 to 20 mg during phase 1 to determine the MTD; the phase 2 part was conducted at the MTD. Seventeen RRWM patients were included. The MTD was established at 15 mg/day 21/28. By ITT analysis, the overall response rate was 29%. With a median follow-up of 36 months, median TTP was 16 months (95% CI 5.5-26), the 5-year OS was 91%. The most frequent adverse events ≥ grade 3 at 15 mg were 14% anemia and 43% neutropenia. The MTD of lenalidomide is 15 mg/day 21/28 days in RRWM. Lenalidomide is active in the treatment of RRWM and the safety profile appears manageable. Future studies may look into combinations of lenalidomide and continuous dosing.

PP2A is a serine/threonine phosphatase critical to a number of physiological and developmental processes. In this manuscript, we show that a peptide, specifically blocking the caspase- 9/PP2A interaction, DPT-C9h, induces apoptosis in primary tumour B cells isolated from peripheral blood mononuclear cells or bone marrow of chronic lymphocytic leukemia (CLL) patients, but not on B cells obtained from healthy donors (HD). Moreover, in both CLL patients and HD, DPT-C9h does not induce apoptosis on T- and NKcells and monocytes. Our results strongly suggest that DPT-C9h peptide has tumour specificity and that caspase-9/PP2Ac interaction constitutes a novel therapeutic approach for the treatment in CLL patients.

International audience; Background - The Autorisation Temporaire d'Utilisation (ATU) is an early access program available in France for drugs aimed at treating severe diseases not yet covered by a marketing authorization, for patients without any other therapeutic option and who cannot be included in a clinical trial. Patients and methods - This report presents the use of single-agent ofatumumab in 30 patients with advanced chronic lymphocytic leukemia (CLL) in the French ATU program. Results - These very-high-risk patients had received multiple previous treatments (median = 6), and most had disease that was fludarabine-refractory or alemtuzumab-refractory (or both) or was unsuitable for alemtuzumab treatment. In the intent-to-treat analysis, the overall response rate was 47% (4 of 30, complete response; 10 of 30, partial response). Of 13 patients with 17p deletion, 6 displayed response to ofatumumab, including 2 complete responses. Treatment was well tolerated, with 17 grade 3 or 4 adverse events; 4 cases of grade 3 or 4 infusion reactions were reported, with favorable immediate outcome. Among nonhematologic complications, infections were the most frequent. Conclusion - The results confirm the efficacy and acceptable tolerability profile of ofatumumab as a single agent in severely ill patients with CLL. Attention should be paid to possible early infusion reactions to ofatumumab, as well as to the risk of infection.

Primary cerebral nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma (NHL) which is confined to the CNS and the eyes. PCNSL should be distinguished from secondary CNS involvement...

Purpose The Sequential Treatment of CD20-Positive Posttransplant Lymphoproliferative Disorder (PTLD-1) trial ( ClinicalTrials.gov identifier, NCT01458548) established sequential treatment with four cycles of rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy as a standard in the management of post-transplant lymphoproliferative disorder (PTLD) and identified response to rituximab induction as a prognostic factor for overall survival. We hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response after rituximab induction. Patients and Methods In this prospective, international, multicenter phase II trial, 152 treatment-naive adult solid organ transplant recipients, with CD20+ PTLD unresponsive to immunosuppression reduction, were treated with four weekly doses of rituximab induction. After restaging, complete responders continued with four courses of rituximab consolidation every 21 days; all others received four courses of rituximab plus CHOP chemotherapy every 21 days. The primary end point was treatment efficacy measured as the response rate in patients who completed therapy and the response duration in those who completed therapy and responded. Secondary end points were frequency of infections, treatment-related mortality, and overall survival in the intention-to-treat population. Results One hundred eleven of 126 patients had a complete or partial response (88%; 95% CI, 81% to 93%), of whom 88 had a complete response (70%; 95% CI, 61% to 77%). Median response duration was not reached. The 3-year estimate was 82% (95% CI, 74% to 90%). Median overall survival was 6.6 years (95% CI, 5.5 to 7.6 years). The frequency of grade 3 or 4 infections and of treatment-related mortality was 34% (95% CI, 27% to 42%) and 8% (95% CI, 5% to 14%), respectively. Response to rituximab induction remained a prognostic factor for overall survival despite treatment stratification. Conclusion In B-cell PTLD, treatment stratification into rituximab or rituximab plus CHOP consolidation on the basis of response to rituximab induction is feasible, safe, and effective.

International audience; We here report for the first time that low levels of interleukin (IL)-10 do not exclude lymphomatous meningitis (LM) in B-cell lymphoproliferative disorders (CLPD). Unexpectedly, IL-10 levels and IL-10:IL-6 ratio in CLPD differed from the levels observed in diffuse large B-cell lymphoma (DLBCL). We report the usefulness of adding the IL-10:IL-6 ratio in order to potentially reveal more aggressive lymphomas: either a transformation or an association with another “hidden” lymphoma such as primary CNS lymphoma (PCNSL).

Aims The urinary coproporphyrin I/(I + III) ratio may be a surrogate for MRP2 activity. We conducted a prospective study in patients receiving methotrexate (MTX) to examine the relationship between this ratio and the pharmacokinetics of a MRP2 substrate. Methods Three urine samples were collected from 81 patients for UCP I/(I + III) ratio determination: one before (P1), one at the end of MTX infusion (P2), and one on the day of hospital discharge (P3). Three polymorphisms of ABCC2 were analysed and their relationships with basal UCP I/(I + III) ratio values assessed. All associated drugs were recorded and a drug interaction score (DIS) was assigned. Population pharmacokinetic analysis was conducted to assess whether MTX clearance (MTXCL) was associated with the basal UCP I/(I + III) ratio, its variation during MTX infusion, the DIS or other common covariates. Results The basal UCP I/(I + III) ratio was not associated with ABCC2 polymorphisms and did not differ according to the DIS. Significant changes in the ratio were observed over time, with an increase between P1 and P2 and a decrease at P3 (P < 0.001). No association was found between basal UCP I/(I + III) ratio and MTXCL. The final model indicates that MTXCL was dependent on the change in the ratio between P1 and P3, DIS and creatinine clearance. Conclusion The basal UCP I/(I + III) ratio is not predictive of MTXCL. However, it is sensitive to the presence of MTX, so it is plausible that it reflects a function modified in response to the drug.

Primary central nervous system lymphomas (PCNSL) in immunocompetent patients have long suffered from their rarity. Biological studies as well as initiation of comparative prospective therapeutic studies have been delayed in this population. A significant improvement in survival was observed when radiotherapy was preceded by chemotherapy with high dose methotrexate (MTX). Median survival improved from 16 months, with radiotherapy alone, to 35-45 months with combined treatments, at the cost of a risk of neurological toxicity especially common among people over the age of 60. From then, many studies have attempted to improve outcomes while reducing the toxicity on the central nervous system. If the optimal treatment is not yet established, these studies, mostly retrospective, provide a better understanding of the therapeutic issues to be addressed. Controversies regarding the impact of monoclonal anti-CD 20 antibodies as well as the role and the best modalities of radiotherapy remain and intensive chemotherapy. The latest imaging techniques provide useful elements to rule out differential diagnosis, but histological diagnosis remains mandatory. The evaluation of therapeutic response needs to be improved. Recent biological studies initiated the biological characterization of PCNSL and potential therapeutic targets are identified. Target therapies used in systemic non-Hodgkin's lymphomas have to be tested in PCNSL. PCNSL occurring in the context of immunosuppression are increasingly rare, especially in human immunodeficiency virus (HIV) infected population. They are well characterized in terms of clinical and biological aspects. Epstein-Barr virus (EBV) plays a major role in their lymphomagenesis. Treatment depends mainly on the underlying cause and degree of immunodepression. Whenever possible, similar treatments to those used in immunocompetent PCNSL patients will be offered to immunocompromised patients.

Waldenström’s macroglobulinemia is a rare B-cell malignancy defined by medullar infiltration by clonal lymphoplasmocytic cells and monoclonal IgM secretion. Treatment is reserved for symptomatic patients. The main first-line treatment strategies combine immunotherapy (principally the anti-CD20 monoclonal antibody rituximab) with chemotherapeutic agents, including alkylating agents, purine analogs and/or bortezomib. The overall response rate to these conventional treatments is between 70 and 90%, but a cure cannot be expected. For patients with relapsed or refractory disease, drugs that were not used for first-line treatment and other agents such as immunomodulators can be tried, but the response rate is generally lower and the responses are shorter lived. Recently, advances in our understanding of the biology of Waldenström’s macroglobulinemia have led to the development of new drugs targeting hyperactive pathways. This review focuses on current treatment options and on new therapeutic developments.

Item does not contain fulltext In chronic lymphocytic leukemia (CLL) medical progress is driven by clinical studies with relapse-free survival (RFS) as the primary endpoint. The randomized EBMT-Intergroup trial compared high-dose therapy and autologous stem cell transplantation (ASCT) to observation and demonstrated a substantial improvement of RFS without showing improved overall survival for the transplant arm. Here we report quality of life (QoL) information of the first 3 years following randomization from that study. The main objective was to assess the impact of treatment on QoL over time. Two secondary analyses were performed to further investigate the impact of ASCT and relapse on QoL. In the primary analysis, we demonstrate an adverse impact of ASCT on QoL which was largest at 4 months and continued throughout the first year after randomization. Further, we demonstrated a sustained adverse impact of relapse on QoL which worsened over time. Despite better disease control by ASCT the side effects thus turned the net effect towards inferior QoL in the first year and comparable QoL in the following 2 years after randomization. This study emphasizes the importance of information concerning QoL impacts when patients are counseled about treatments aimed at improving RFS in the absence of a survival benefit.

Our aim was to review MRI characteristics of patients with primary CNS lymphoma (PCNSL) enrolled in a randomized phase II trial and to evaluate their potential prognostic value and patterns of relapse, including T2 fluid attenuated inversion recovery (FLAIR) MRI abnormalities.Neuroimaging findings in 85 patients with PCNSL enrolled in a prospective trial were reviewed blinded to outcomes. MRI characteristics and responses according to International PCNSL Collaborative Group (IPCG) criteria were correlated with progression-free survival (PFS) and overall survival (OS).Multivariate analysis showed that objective response at 2 months (P.001) and at end of treatment (P = .015) were predictors of prolonged OS. Infratentorial location (P = .008) and large (11.4 cm3) enhancing tumor volume (P = .006) were associated with poor OS and PFS, respectively. Ratio of change in product of largest diameters at early MRI evaluation but not timing of complete response achievement (early vs delayed) was prognostic for OS. Sixty-nine patients relapsed. Relapse in the brain (n = 52) involved an initial enhancing site, a different site, or both in 46%, 40%, and 14% of patients, respectively. At baseline, non-enhancing T2-FLAIR hypersignal lesions distant from the enhancing tumor site were detected in 18 patients. These lesions markedly decreased (50%) in 16 patients after chemotherapy, supporting their neoplastic nature. Of these patients, 10/18 relapsed, half (n = 5) in the initially non-enhancing T2-FLAIR lesions.Baseline tumor size and infratentorial localization are of prognostic value in PCNSL. Our findings provide evidence that non-enhancing FLAIR abnormalities may add to overall tumor burden, suggesting that response criteria should be refined to incorporate evaluation of T2-weighted/FLAIR sequences.

Introduction Although a large variety of conditioning regimens are used in autologous hematopoietic stem cell transplantation (autoSCT), including the widely used BEAM (carmustine, etoposide, cytarabine, melphalan), there is no consensus regarding a standard approach. In the context of a carmustine shortage, we replaced it with thiotepa. However, clinical data on the TEAM (thiotepa, etoposide, cytarabine, melphalan) conditioning regimen are sparse and only retrospective. Thus, we designed a multicenter prospective study (NCT02504190) to assess the efficacy and toxicity of a TEAM conditioning regimen. Patients and methods The TEAM regimen consisted of a total dose of thiotepa of 8 mg/kg on day -6; etoposide 100 mg/m2/12h and cytarabine 200 mg/m2/12h (day -5 to -2); melphalan 200 mg/m2 on day-1. Inclusion criteria were the following: age between 18 and 65 years, biopsy-proven Hodgkin or non-Hodgkin lymphoma, HIV seronegative, and first autoSCT. Results Seventy-four male and eighteen female patients with a median age of 53 years (range, 19-65) were included. Karnofsky score was Median time to neutrophil recovery was 12 days (range, 9-48) and to platelet recovery >20 G/L was 13 days (range, 7-197). The most significant regimen-related toxicities were mucositis in 100% of patients (median grade=3, range, 1-4) and diarrhea in 98% of patients (median grade=1, range, 0-3). Other non-hematologic grade 3 adverse events occurred in 17 patients (18%). Blood cultures were positive for Staphyloccocus sp. in 27% patents, other Gram- positive bacteria in 5% and Gram negative in 6%. Central line-associated bloodstream infection occurred in 22 patients (24%). Invasive fungal infection occurred in 3 patients. Four patients required transfer to the intensive care unit. The median length of stay in hospital was 27 days (range, 16-62). At day+100, 89 patients were evaluable for response and all were in CR. Deaths directly attributed to disease progression or relapse occurred in 5 patients. After a median follow-up of 31 months (range, 15-48), the non-relapse mortality (NRM) was 3.3%. Two patients died of infection during aplasia and one patient died 67 days after autoSCT of necrotizing fasciitis. At last follow-up, 17 patients (19%) relapsed, 9 died and 83 were alive. The estimated 3-year overall survival (OS) and progression-free survival (PFS) were 90.2% and 77.2%, respectively. In patients with double expressor diffuse large B-cell lymphoma (n=15), the estimated 3-year OS and PFS were 93% and 73%, respectively. None of the 31 patients with intermediate or high-risk CNS international prognostic index experienced CNS relapse. Conclusion The TEAM conditioning regimen is a safe and valid platform in autoSCT for patients with high-risk or relapsed/refractory lymphoma. Although mucositis and diarrhea were frequent, the NRM was similar to that reported for BEAM conditioning. Most notably, no CNS relapse occurred in patients at intermediate or high-risk of CNS relapse. Disclosures Duléry: Keocyt: Honoraria. Choquet:Keocyt: Honoraria. Di Blasi:Novartis: Honoraria. Malard:Therakos/Mallinckrodt: Honoraria; Janssen: Honoraria; Keocyte: Honoraria; Sanofi: Honoraria; JAZZ pharmaceutical: Honoraria; Astellas: Honoraria. Coppo:Ablynx/Sanofi: Consultancy; Shire: Consultancy; Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Introduction: R/R DLBCL patients who have received ≥2 lines of therapy, including those progressed post stem cell transplantation (SCT) or who are not candidates for SCT, have limited treatment options. Selinexor, a selective oral XPO1 inhibitor leads to nuclear accumulation and activation of tumor suppressor proteins and reductions in c-Myc and Bcl-2 oncogenes. Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in relapsed/refractory myeloma in the United States based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. We conducted the SADAL study to evaluate the efficacy and safety of single agent selinexor in patients with R/R DLBCL. In this patient population, selinexor demonstrated deep and durable responses with an overall response rate (ORR) of 28.3% including a 11.0% complete response (CR) rate. The median duration of response (DOR) was 9.2 months. In patients with CR, the DOR was 13.4 months. Here we evaluate the effect of prior therapy on the efficacy and safety of selinexor. Methods: SADAL is a multicenter, open-label study in R/R DLBCL patients with 2-5 prior lines of therapy, who may have progressed post SCT or are not candidates for SCT. Patients were stratified by subtype (germinal center B-cell or non-GCB) and treated with 60 mg selinexor BIW per 28-day cycle. The primary endpoint was ORR. Secondary endpoints included duration of response (DOR) and safety. We performed post-hoc analyses to compare outcomes based on the number (2 vs. >2) and type (SCT vs. no SCT) of prior lines of therapy received. Results: Of 127 patients, 83 (65%) received 2 prior lines of therapy and 43 (34%) received >2 prior lines of therapy. Thirty-six patients (28%) received prior SCT and 91 (72%) had no prior SCT. In general, patient demographic and baseline characteristics were well balanced in both subgroups. ORR was 30.1% vs. 25.6% (P=0.74) in patients with 2 vs >2 prior lines of therapy respectively. The CR rate was 10.8% in patients with 2 prior lines of therapy compared with 11.6% in patients with >2 prior lines of therapy (P=1.00). The median DOR was 9.2 months in patients with 2 prior lines of therapy compared with 8.4 months in those with >2 prior lines of therapy (P=0.64). Median progression free survival was 3.7 months and 1.9 months (P=0.37) and median overall survival was 11.0 months and 9.8 months (P=0.69) in patients with 2 and >2 prior lines of therapy respectively. In patients with prior SCT, the ORR was 44.4% compared with 22.0 % (P=0.02) in patients with no prior SCT. The CR rate was 16.7% in patients with prior SCT compared with 8.8% in patients with no prior SCT (P=0.34). The DOR was 8.4 months in patients with prior SCT and 9.2 months with no prior SCT (P=0.80). Median progression free survival was 5.9 months and 2.3 months (P=0.07) and median overall survival was 9.1 and 9.8 months (P=0.36) in patients with prior SCT and no prior SCT respectively. The most common related adverse events (AEs) [grade ≥3] included thrombocytopenia (2 prior lines: 36%, >2 prior lines: 42%; prior SCT: 58%, no prior SCT: 31%), neutropenia (2 prior lines: 19%, >2 lines: 23%; prior SCT: 25%, no prior SCT: 20%), and anemia (2 prior lines: 15%, >2 prior lines: 14%, prior SCT: 17%, no prior SCT: 14%). Treatment-related serious AEs were reported in 23%, 14%, 25%, and 19% of patients with 2 prior lines, >2 prior lines, prior SCT, and no prior SCT respectively. Conclusions: Single agent oral selinexor with its novel mechanism of action demonstrated deep and durable responses with no new safety signals regardless of prior therapy. Patients with 2 prior lines of therapy had a higher response rate (30.1% vs. 25.6%) compared with those with >2 prior lines of therapy. The greatest benefit, with an ORR of 44.4% was observed in patients with prior SCT. Collectively, these data support the clinical benefit of single agent selinexor and importantly in earlier lines of therapy. Further evaluation of selinexor in combination with other agents to improve outcomes in R/R DLBCL is ongoing. Disclosures Cavallo: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Follows:Roche: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goy:Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hackensack University Medical Center, RCCA: Employment; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Takeda: Other: Grants outside of the submitted work; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company. Casasnovas:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zijlstra:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Choquet:Keocyt: Honoraria. Gurion:Roche: Consultancy. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria. Sancho:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: Advisory board; Novartis: Honoraria; Kern Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celltrion: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Membership on an entity's Board of Directors or advisory committees. Schuster:Celgene: Speakers Bureau; Genentech: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Speakers Bureau; Verastem: Speakers Bureau; Astellas: Speakers Bureau; Actinium: Research Funding; Incyte: Research Funding; Karyopharm Therapeutics: Research Funding; Morphosys: Research Funding; Nordic Nanovector: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau; Rafael: Research Funding; F2G Ltd.: Research Funding; AbbVie: Speakers Bureau; Amgen: Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Vassilakopoulos:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. McCarthy:Karyopharm Therapeutics: Employment, Equity Ownership. Ma:Karyopharm: Employment, Equity Ownership. Corona:Karyopharm Therapeutics: Employment, Equity Ownership. Saint-Martin:Karyopharm Therapeutics: Employment, Equity Ownership. Joshi:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Van Den Neste:Gilead: Other: travel support. Canales:Sandoz: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Takeda: Speakers Bureau; SOBI: Research Funding; iQone: Honoraria; Karyopharm: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Speakers Bureau.

Background Cancer incidence is increasing but cancer survival is improving. The life expectancy of PLWHIV also increases with improved HAART, so it is to be expected that PLWHIV are likely to develop a second primitive cancer. It is known that the risk of second cancer is slightly higher after a first cancer and depends on several parameters: the location of the first cancer (the risk is higher after H&N, lung cancer or Hodgkin’s lymphoma) and environmental risk factors such as tobacco or alcohol intake but few studies are available nowadays on this subject. PLWHIV have a high risk of cancer: what for a second cancer incidence? Methods The files of 601 patients presented at the multidisciplinary meeting of the CANCERVIH network were reviewed. CANCERVIH is a national "rare cancers" network, accredited by the French National Cancer Institute. For all these patients, the history of cancer, indicated by the referring physicians, was examined. History of cancer that was neither metastasis nor locoregional relapse was considered a first primitive cancer. Cancers developing in the same location were considered as first primitive cancers only if they were considered in complete response at least 5 years before and no relapse was detected in the meantime. Results Of the 601 patients reviewed, 72 (12%) had a history of at least one cancer. Fourteen (2,3%) patients had at least 2 previous cancers. For one it was his 7th cancer’s case. Table . 2036P First cancer (number of patients) Number of secondary cancer(s) (number of patients) Kaposi (25) 1 (23) 2 (2) NHL (7) 1 (5) 2 (2) Anal canal (6) 1 (2) 2 (3) 3 (1) Prostate (6) 1 (4) 2 (1) 6 (1) Breast (5) 1 (5) Head and Neck (5) 1 (4) 4 (1) Hodgkin lymphoma (4) 1 (4) Kidney (4) 1 (3) 2 (1) Skin melanoma (3) 1 (2) 2 (1) Eye (2) 1 (1) 3 (1) Anal margin (1) 1 (1) Lung (1) 1 (1) Ovary (1) 1 (1) Large intestine (1) 2 (1) Liver (1) 1 (1) Conclusions In this study, the initial locations at risk of second cancer seems to concern primarily AIDS defining cancer and among the non-AIDS defining cancers, anal cancer appeared the first one ahead breast and head and neck cancers, showing the importance of maintaining permanent immuno-virological control in these patients’ population: such results confirm the need to maintain and emphasize prevention and screening programs in this high cancer risk population including for those with a sustained undetectable HIV viral load and/or immune restoration. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background HIV screening is recommended at time of cancer diagnosis. Moreover, HBV screening, is recommended during immunotherapy due to its risk of reactivation. Furthermore, HCV screening, before using immunotherapy is justified by the prevalence of dysimmune disorders during HCV infection. The main objective of this survey was to evaluate screening practices for HIV, HBV and HCV in cancer patients. Methods A cross-sectional study carried- out across 16 French regions between 25/10/2018 and 31/12/2018, evaluating performance of HIV, HBV and HCV systematic screening at time of cancer diagnosis and/or before immunotherapy. An electronic questionnaire was sent to participants in multidisciplinary concertation meetings. Results The responses of 290 participants (including 101 surgeons, 61 organ specialists, 50 oncologists, 30 radiotherapists, 21 hematologists and 13 general practitioners) were analyzed. Of the 16 regions targeted, 8 of them are represented by 160 participants (55%). A systematic screening for HIV, HBV and HCV at time of cancer diagnosis was reported by 59 (20%), 66 (23%) and 63 (22%) respondents, respectively. A screening on a case by case for HIV, HBV and HCV was reported by 113, 103 and 102 respondents, respectively while 117 respondents stated to never prescribe HIV testing (40%), 121, HBV testing (42%) and 125 HCV testing (43%). Before immunotherapy, 122 respondents stated that they were not concerned and 89 routinely screened for HIV (31%), 97 for HBV (33%) and 94 for HCV (32%). A screening on a case by case for HIV, HBV, and HCV was reported by 38, 36 and 34 respondents, respectively while 40 respondents stated to never prescribe HIV testing (14%), 34, HBV testing (12%) and 39, HCV testing (13%). Conclusions This survey highlights the insufficiency of HIV, HBV and HCV systematic screening at time of cancer diagnosis and/or before immunotherapy. There is a need to raise awareness about the importance of systematic screening in health care providers. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Introduction Le depistage du VIH est recommande lors du bilan initial de tout cancers, celui du VHB lors du recours a certaines immunotherapies en raison du risque de reactivation. La prevalence de troubles dysimmunitaires justifie le depistage du VHC avant le recours a une immunotherapie. Cette enquete a pour objectif d’evaluer les pratiques de depistage des virus VIH, VHB et VHC chez les patients atteints de cancer. Materiels et methodes Etude transversale evaluant la realisation d’un depistage au bilan initial de cancer et en cas de recours a une immunotherapie via un questionnaire par voie electronique aux participants de reunions de concertation pluridisciplinaire entre le 25/10/2018 et 31/12/2018. Resultats Les reponses de 290 participants (dont 101 chirurgiens, 61 specialistes d’organes, 50 oncologues, 30 radiotherapeutes, 21 hematologues, 13 medecins generalistes) ont ete analysees. Sur les 16 regions ciblees, 8 sont representees par 160 participants (55 %) en region PACA/pour Paca, Corse et Monaco, 42 en Occitanie (14 %), 35 dans les Hauts de France (12 %), 31 en Ile de France (11 %), 18 en Bretagne (6 %), 2 en Bourgogne-Franche Comte, 1 en Guyane, et 1 en Normandie. Au bilan initial d’un cancer, 59 repondants declarent realiser un depistage systematique pour le VIH (20 %), 66 pour le VHB (23 %) et 63 pour le VHC (22 %). Ils sont 113 a le realiser selon les cas pour le VIH, 103 pour le VHB et 102 pour le VHC et 117 declarent ne jamais prescrire de depistage du VIH (40 %), 121 du VHB (42 %) et 125 du VHC (43 %). Lors de la prescription d’une immunotherapie, 122 repondants declarent ne pas etre concernes et 89 prescrire de facon systematique un depistage du VIH (31 %), 97 du VHB (33 %) et 94 du VHC (32 %). Ils sont 38 a le realiser selon les cas pour le VIH, 36 pour le VHB et 34 pour le VHC et 40 declarent ne jamais prescrire de depistage du VIH (14 %), 34 du VHB (12 %) et 39 du VHC (13 %). Conclusion Cette enquete souligne l’insuffisance du depistage du VIH, du VHB et du VHC lors du bilan initial d’un cancer et/ou le recours a une immunotherapie et la necessite de renforcer l’information en direction des professionnels de sante.

Primary Central Nervous System Lymphoma (PCNSL) is most often non-Hodgkin lymphoma diffuse large B cell lymphoma (NHL-DLBCL) confined exclusively to the central nervous system. Its pathogenesis remains unknown in immunocompromised patients. Recent studies pointed out that systemic NHL, especially B cell NHL, might be associated with Hepatitis B virus (HBV) [1, 2]. We thus reported the prevalence of HBV in immunocompetent patients with PCNSL and search for a possible association. We included 109 patients treated for PCNSL in our department in Paris, France, from 2002 to 2012. The inclusion criteria were: (i) aged C18 years, (ii) pathologically documented diagnosis of ocular or cerebral DLBC-PCNSL, (iii) HIV seronegative and (iv) available HBV serology. The control population included 319 patients treated in the same Department, from 1993 to 2011, for other primary brain tumors (PBT) and with available HBV serology. We compared prevalence of HBsAg, anti-HBc and anti-HBs between these populations using a Fischer’s test (STATA 8.0, Woolf test). We also compared prevalence of HBsAg and anti-HBc in the PCNSL group to the French and greater Paris’ area (GPA) populations using an exact test based on binomial probability function [3]. The characteristics of the PCNSL and the PBT populations are reported in Table 1. Prevalence of HBsAg was greater among the PCNSL patients than within the French population (p = 0.01) and the GPA population (p = 0.02). In addition, prevalence of anti-HBc in the PCNSL patients was higher than within the French population (p = 0.01). Although no statistically significant difference was found between PCNSL and PBT patients (p = 0.49 regarding HBsAg, p = 0.10 regarding anti-HBc and p = 0.23 regarding anti-HBs), a trend for a positive association between HBV and PCNSL was highlighted. Regarding active (p = 0.49) and past infections (p = 0.10) and Electronic supplementary material The online version of this article (doi:10.1007/s11060-015-1879-x) contains supplementary material, which is available to authorized users.

Whether sex chromosome loss (SCL) is an age-related phenomenon or a cytogenetic marker of hematological disease is unclear. To address this issue in chronic lymphocytic leukemia (CLL), we investigated 20 cases with X or Y chromosome loss detected by conventional cytogenetics (CC). The frequency of SCL was low in CLL (2.3%). It was the sole abnormality, as detected by CC, in 10/20 (50%) patients. Fluorescence in situ hybridization (FISH) analyses confirmed SCL in all patients tested, present in 5-88% of cells (median: 68%). Deletions of 13q were observed by FISH in 16/20 (80%) patients. Compared with CLL without SCL, SCL was significantly associated with 13q deletion, especially when bi-allelic (P = 0.04). Co-hybridization analyses showed that SCL could be a concomitant, primary or secondary change, or be present in an independent clone. FISH analyses were performed on blood sub-populations isolated by Ficoll or flow cytometry. Comparing mononuclear cells (including CLL cells) and polynuclear cells separated by Ficoll, a maximum of 2% of polynuclear cells were found with SCL, whereas mononuclear cells exhibited a significantly higher loss frequency (range: 6-87%) (P = 0.03). Comparing B-cells (including CLL cells) and T-cells sorted by flow cytometry, the proportion of B-CD19+ cells with SCL was significantly higher (range: 88-96%) than that observed in T-CD3+ cells (range: 2-6%) (P = 0.008). We conclude that SCL has to be considered as a clonal aberration in CLL that may participate in the oncogenic process.

Waldenstrom's macroglobulinemia is a rare chronic lymphoproliferative disorder. Treatment is usually based on nucleoside analogues, alkylators, bortezomib and monoclonal antibodies, alone or in combination. Fludarabine is a fluorinated purine analogue effective in chronic lymphoproliferative disorders. In Waldenstrom's macroglobulinemia, fludarabine was first studied in patients with relapsed or refractory disease after alkylator therapy, yielding an overall response rate of 30%. In the late 1990 s, fludarabine started to be used as a first-line treatment monotherapy yielding response rates between 36 and 94%. A recent Phase III trial showed that fludarabine monotherapy was more effective than chlorambucil in terms of progression-free survival, duration of response and overall survival. Fludarabine has also been studied in combination with rituximab and/or alkylating agents, leading to better-quality and longer lasting responses. Hematological toxicity is a major concern; however, restricting first-line use of fludarabine in patients who do not qualify for autologous stem cell transplantation, require rapid disease control or have factors of poor prognosis.

We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32-5.17, p = 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29-13.46, p = 0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56-29.57, p = 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity. In an international analysis of solid organ transplant recipients with primary central nervous system posttransplant lymphoproliferative disease, the authors find that the disease is associated with renal transplantation, typically occurs late and retains EBV positivity, and the dominant prognostic factor for survival is response to first-line therapy.

Baseline differential blood count and prognosis in CD20-positive post-transplant lymphoproliferative disorder in the prospective PTLD-1 trial

Waldenström macroglobulinemia is a rare chronic lymphoproliferative disorder. Treatments are currently reserved for symptomatic patients and usually consist of nucleoside analogues (NAs), alkylating agents, bortezomib, and monoclonal antibodies, alone or in combination. Fludarabine and 2-chlorodeoxyadenosine (2-CdA) have been studied in first-line treatment of Waldenström macroglobulinemia (WM) since the end of the 1990s. In monotherapy, response rates vary between 36% and 94%. In a phase III trial, fludarabine in monotherapy was more efficient than chlorambucil for progression-free survival (PFS) (37.8 vs. 27.1 months), duration of response (DOR) (38.5 vs. 21.3 months) and overall survival (OS) (median not reached vs. 69.8 months), but the overall response rate (ORR) was similar (45.6% and 35.9%). NAs have been studied in combination with rituximab and/or alkylating agents for increasing the quality and duration of the response. Hematologic toxicities are a major concern, limiting the indication for NAs in first-line treatment to patients who are not candidates for autologous stem cell transplantation, those in need of rapid control of the disease, or those with poor prognostic factors.

Purpose Treatment options for patients with Waldenström macroglobulinemia (WM) and closely related disorders include alkylating agents, purine analogs, and monoclonal antibodies. No large randomized studies have yet been reported comparing any of these approaches. Patients and Methods The randomized WM1 study (Trial Comparing Chlorambucil to Fludarabine in Patients With Advanced Waldenström Macroglobulinemia) was undertaken in 101 centers in five countries enrolling 414 eligible patients (339 with WM, 37 with non–mucosa-associated lymphoid tissue marginal zone lymphoma, and 38 with lymphoplasmacytic lymphoma) who were randomly assigned to receive chlorambucil or fludarabine. The primary end point was the overall response rate (ORR). Results On the basis of intent-to-treat analysis, the ORR was 47.8% (95% CI, 40.9% to 54.8%) in the fludarabine arm versus 38.6% (95% CI, 32.0% to 45.7%) in the chlorambucil arm (P = .07). With a median follow-up of 36 months (interquartile range, 18 to 58 months), median progression-free survival (PFS), and duration of response (DR) were significantly improved in the fludarabine arm compared with the chlorambucil arm: PFS, 36.3 versus 27.1 months (P = .012) and DR, 38.3 versus 19.9 months (P < .001). In patients with WM, median overall survival (OS) was not reached in the fludarabine arm versus 69.8 months in the chlorambucil arm (95% CI, 61.6 to 79.8 months; P = .014). Grade 3 to 4 neutropenia was significantly higher among patients treated with fludarabine (36%) compared with patients treated with chlorambucil (17.8%; P < .001). Second malignancies were significantly more frequent in the chlorambucil arm with 6-year cumulative incidence rate of 20.6% versus 3.7% in the fludarabine arm (P = .001). Conclusion In the complete intent-to-treat study population, fludarabine significantly improved PFS compared with chlorambucil, and in patients with WM, it improved OS.

The use of anti-CD20 monoclonal antibody is a standard of care in Waldenstrom’s macroglobulinemia (WM) patients in first line and in relapse. The combination of anti-CD20 monoclonal antibody with chemotherapy or with bortezomib remains a recommended therapy in most patients with WM. Most of the published series are small phase II trials using rituximab in combination with alkylating agents (cyclophosphamide), with purine analogues (fludarabine) with or without alkylating agents, and with proteasome inhibitors (bortezomib). The studies with new anti-CD20 monoclonal antibodies (ofatumumab, ubituzumab) or with anti-CD52 and anti-CD22 monoclonal antibodies are scarce. The choice of immunochemotherapy depends on the patient’s comorbidities, the toxicity, and the need of hematopoietic stem cell collection. Chemo-free combinations with new target agents such as BCR inhibitors are promising.

Purpose Primary plasma cell leukemia (pPCL) is a rare and aggressive malignancy with a poor prognosis. With conventional chemotherapy, patients typically die within 1 year. In all but one of the retrospective studies reported to date, bortezomib and lenalidomide seem to improve survival. We conducted a prospective phase II trial in patients with pPCL to assess the efficacy of an alternate regimen that combines standard chemotherapy, a proteasome inhibitor, and high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) followed by either allogeneic transplantation or bortezomib/lenalidomide maintenance. Patients and Methods Patients 70 years old and younger with newly diagnosed pPCL received four alternating cycles of bortezomib, dexamethasone plus doxorubicin or cyclophosphamide. Peripheral blood stem cells were collected from responding patients with < 1% of circulating plasma cells before HDM/ASCT. As consolidation, young patients received a reduced-intensity conditioning allograft, whereas the remaining patients underwent a second HDM/ASCT followed by 1 year of bortezomib, lenalidomide, dexamethasone. The primary end point was progression-free survival (PFS). Results Forty patients (median age, 57 years; range, 27 to 71 years) were enrolled. The median follow-up was 28.7 months. In the intention-to-treat analysis, the median PFS and overall survival were 15.1 (95% CI, 8.4; -) and 36.3 (95% CI, 25.6; -) months, respectively. The overall response rate to induction was 69%. One patient underwent a syngeneic allograft and 25 HDM/ASCT (16 of whom subsequently received a reduced-intensity conditioning allograft and seven a second ASCT followed by maintenance). Conclusion In this prospective trial in patients with pPCL, we show that bortezomib, dexamethasone plus doxorubicin or cyclophosphamide induction followed by transplantation induces high response rates and appears to significantly improve PFS.

Post-transplant lymphoproliferative disorders (PTLDs) are a group of conditions that involve uncontrolled proliferation of lymphoid cells as a consequence of extrinsic immunosuppression after organ or haematopoietic stem cell transplant. PTLDs show some similarities to classic lymphomas in the non-immunosuppressed general population. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in many early-onset cases, through multiple mechanisms. The incidence of PTLD varies with the type of transplant; a clear distinction should therefore be made between the conditions after solid organ transplant and after haematopoietic stem cell transplant. Recipient EBV seronegativity and the intensity of immunosuppression are among key risk factors. Symptoms and signs depend on the localization of the lymphoid masses. Diagnosis requires histopathology, although imaging techniques can provide additional supportive evidence. Pre-emptive intervention based on monitoring EBV levels in blood has emerged as the preferred strategy for PTLD prevention. Treatment of established disease includes reduction of immunosuppression and/or administration of rituximab (a B cell-specific antibody against CD20), chemotherapy and EBV-specific cytotoxic T cells. Despite these strategies, the mortality and morbidity remains considerable. Patient outcome is influenced by the severity of presentation, treatment-related complications and risk of allograft loss. New innovative treatment options hold promise for changing the outlook in the future.

Plerixafor (Mozobil) in combination with granulocyte colony-stimulating factor (G-CSF) has shown to increase mobilization of peripheral blood stem cells (PBSC) as compared to G-CSF alone in patients undergoing autologous stem cell transplantation (ASCT). However, up to 25% of patients treated with G-CSF alone still fail mobilization. Adding plerixafor to poor mobilizers allows to rescue these patients from mobilization failure and to reduce the number of apheresis sessions. The goal of this retrospective study was to capture the impact of plerixafor on treatment outcome and on apheresis department efficiency. The latter was measured in terms of time-slots lost, that is, the number of apheresis sessions scheduled but not carried out due to poor mobilization, and the number of elective apheresis sessions performed for patients undergoing extracorporeal photopheresis (ECP). Hospital records of patients treated before and after introduction of plerixafor were collected and analyzed. With plerixafor, the mobilization failure rate dropped from 12% to 4% and the mean number of time-slots lost per patient dropped from 1.39 to 0.89. Additional drug costs due to plerixafor were partially balanced by a reduction in apheresis sessions, resulting in an additional cost of 759€ per ASCT candidate. More importantly, with the use of plerixafor, the availability of time-slots turned from erratic to predictable such that freed capacity could be dedicated to other apheresis procedures. As a result, the number of ECP sessions increased from 0 in 2005 to 685 sessions in 2014.

Therapeutic improvements are required for primary CNS lymphoma (PCNSL) and secondary CNS lymphoma. PCNSLs are predominantly diffuse large B-cell lymphoma (DLBCL) classified in the non-germinal center (non-GC) subgroup.1 The role of B-cell receptor (BCR) signaling to continuously activate the NF-κB pathway is well-established in non-GC DLBCL.2 Mutations of MYD88 , CD79B , and TBL1XR1 , genes involved in the NF-κB pathway, are frequently encountered in PCNSL.3 Ibrutinib, an inhibitor of BCR signaling, led to an objective response rate of 50% in patients with relapsed or refractory systemic non-GC DLBCL.4 As a small molecule (MW = 440), with promising CNS distribution,5 ibrutinib represents a potential treatment for PCNSL. We report a retrospective case series of patients with relapsed and refractory CNS lymphoma treated with ibrutinib.

International audience; Background - Treatment of relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) is poorly defined, because randomized trials and large studies are lacking. The aim of this study was to analyze the characteristics, management, and outcome of R/R PCNSL patients after first-line therapy in a nationwide cohort.Methods - We analyzed R/R PCNSL patients following first-line treatment who had been prospectively registered in the database of the French network for oculocerebral lymphoma (LOC) between 2011 and 2014.Results - Among 563 PCNSL patients treated with first-line therapy, we identified 256 with relapsed (n = 93, 16.5%) or refractory (n = 163, 29.0%) disease. Patients who were asymptomatic at relapse/progression (25.5%), mostly diagnosed on routine follow-up neuroimaging, tended to have a better outcome. Patients who received salvage therapy followed by consolidation (mostly intensive chemotherapy plus autologous hematopoietic stem cell transplantation [ICT + AHSCT]) experienced prolonged survival compared with those who did not receive salvage or consolidation therapy. Independent prognostic factors at first relapse/progression were: KPS ≥ 70 vs KPS < 70), sensitivity to first-line therapy (relapsed vs refractory disease), duration of first remission (progression-free survival [PFS] ≥1 y vs Conclusions - About a third of PCNSL patients are primary refractory to first line treatment. We identified several independent prognostic factors that can guide the management of R/R PCNSL patients.

International audience; Malignancies represent a major cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. The introduction of combined antiretroviral therapy has modified the spectrum of malignancies in HIV infection with a decreased incidence of acquired immunodeficiency syndrome (AIDS) malignancies such as Kaposi's sarcoma and non-Hodgkin's lymphoma due to partial immune recovery and an increase in non-AIDS-defining malignancies due to prolonged survival. Management of HIV-infected patients with cancer requires a multidisciplinary approach, involving both oncologists and HIV physicians to optimally manage both diseases and drug interactions between anticancer and anti-HIV drugs. The French CANCERVIH group presents here a review and an experience of managing non-AIDS malignancies in HIV-infected individuals.

Variable pharmacokinetics of high-dose-methotrexate (MTX) is responsible for severe toxicities. Unpredictable overexposure still occurs during some courses despite having controlled the main factors known to play a role in its elimination. The aim of our study was to evaluate whether the urine metabolomic profile measured at the time of MTX administration is predictive of the drug’s clearance and/or of treatment-related toxicity. We analyzed the urine content of endogenous metabolites before MTX administration in a cohort of adult patients treated for lymphoid malignancies. Individual MTX clearance (MTXCL) was estimated from population pharmacokinetic analyses of therapeutic drug monitoring data. We determined the urine metabolite content by gas chromatography-mass spectrometry (GC–MS) and applied Partial Least Square (PLS) analysis to assess the relationship between the urine metabolome and MTXCL. External validation was applied to evaluate the performances of the PLS model. We used orthogonal partial least squares discriminant analysis (OPLS-DA) to distinguish patients with normal or delayed elimination, and patients with or without toxicity. Sixty-two patients were studied. We obtained a very good prediction of individual MTX clearance using a set of 28 metabolites present in patient urine at baseline. The mean prediction error and precision were −0.36% and 21.4%, respectively, for patients not included in the model. The model included a set of endogenous organic anions, of which the tubular secretion depends on organic anion transporter (OAT) function. Our analyses did not allow us to discriminate between patients with or without delayed elimination or those who did or did not experience toxicity. Urinary metabolomics can be informative about an individual’s ability to clear MTX. More broadly, it paves the way for the development of a biomarker of tubular secretion, easily measurable from endogenous substances.

International audience; Clinical information about thiotepa-based autologous stem cell transplantation (auto-SCT) outside the primary central nervous system lymphoma (PCNSL) field is sparse. In this registry-based retrospective study, we evaluated potential risks and benefits of thiotepa-based preparative regimens compared with BEAM (carmustine, etoposide, cytarabine, melphalan) in auto-SCT for diffuse large B-cell lymphoma (DLBCL, excluding PCNSL), follicular lymphoma (FL) or Hodgkin lymphoma (HL). A total of 14 544 patients (589 thiotepa and 13 955 BEAM) met the eligibility criteria, and 535 thiotepa- and 1031 BEAM-treated patients were matched in a 1:2 ratio for final comparison. No significant differences between thiotepa and BEAM groups for any survival end point were identified in the whole sample or disease entity subsets. For a more detailed analysis, 47 TEAM (thiotepa, etoposide, cytarabine, melphalan)-treated patients were compared with 75 matched BEAM patients with additional collection of toxicity data. Again, there were no significant differences between the two groups for any survival end point. In addition, the frequency of common infectious and non-infectious complications including secondary malignancies was comparable between TEAM and BEAM. These results indicate that thiotepa-based high-dose therapy might be a valuable alternative to BEAM in DLBCL, HL and FL. Further evaluation by prospective clinical trials is warranted

Introduction We aimed to confirm the diagnostic value and to evaluate the pre- and post-therapeutic prognostic value of cerebrospinal fluid (CSF) concentrations of interleukin (IL)-10 and IL-6 in patients with diffuse large B-cell primary central nervous system lymphoma (PCNSL). Patients and methods IL-10 and IL-6 concentrations were measured in 79 patients with PCNSL at diagnosis and in 40 control individuals. Fifty-four PCNSL patients underwent repeat assessments starting at diagnosis. Results The IL-10 concentration distinguished PCNSL from other neurologic diseases with a sensitivity of 88.6% and a specificity of 88.9% with a cutoff of 4 pg/ml. In a multivariate analysis of PCNSL patients, CSF involvement was associated with a higher IL-10 concentration (mean log (IL-10) of 4.4 versus 2.5 pg/ml, respectively, p = 0.0004). The pre-therapeutic IL-10 concentration had no prognostic impact on outcome. The IL-10 concentration decreased after treatment for most patients tested. Among patients with complete remission or partial remission, as evaluated by magnetic resonance imaging (MRI), a persistent detectable IL-10 level in the CSF at the end of treatment was associated with a negative impact on progression-free survival (PFS) (1-year PFS: 15%, 95% confidence interval [CI]: 2.5–38% versus 59%, 95% CI: 32–78%, respectively, p = 0.0004). Conclusion Our study confirmed that IL-10 is a useful biomarker for the diagnosis of PCNSL. We highlight new findings showing that the IL-10 level in the CSF could be used as a surrogate marker for CSF involvement and that the post-treatment IL-10 concentration could complement standard MRI for therapeutic response assessment in PCNSL.

International audience; Poly-chemotherapy plus rituximab followed by autologous stem cell transplantation (auto-SCT) is standard care for untreated young patients with mantle cell lymphoma (MCL). Despite this intensive treatment, transplant patients remain highly susceptible to relapse over time. The French SFGM-TC performed a national survey on reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) for fit relapsed/refractory patients who failed after auto-SCT (n=106). Median times of relapse after auto-SCT, and from auto-SCT to RIC-allo-SCT were 28 months and 3.6 years, respectively. Sixty per cent of patients received at least three lines of treatment before RIC-allo-SCT. Conditioning regimens for RIC-allo-SCT were heterogeneous. Twenty patients experienced grade III/IV aGvHD, extensive cGvHD was reported in 28 cases. Median follow-up after RIC-allo-SCT was 45 months. Median PFS after RIC-allo-SCT was 30.1 months and median overall survival was 62 months. Treatment-related mortality (TRM) at 1 year and 3 years were estimated at 28% and 32%, respectively. A total of 52 patients died; major causes of death were related to toxicity (n=34) and MCL (n=11). Patients in good response before RIC-allo-SCT experienced a better PFS and OS. Our work highlights the need for new RIC-allo-SCT MCL-tailored approaches to reduce TRM, and early and late relapse.

Purpose: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance. Experimental Design: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n = 29) and whole-exome sequencing (n = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis. Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P = 0.006 and P = 0.01) and CDKN2A homozygous deletion (P = 0.02 and P = 0.01) were significantly associated with shorter progression-free survival and overall survival. Conclusions: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-κB signaling pathway, which may be promising targets for future therapeutic strategies. Clin Cancer Res; 18(19); 5203–11. ©2012 AACR.

Background Relapsing primary central nervous system lymphoma carries a poor prognosis when treated with conventional chemotherapy with a one-year overall survival of 25-40%. Encouraging results have been shown with intensive chemotherapy followed by autologous hematopoietic stem cell rescue. We report the results of a large multicenter retrospective analysis of intensive chemotherapy followed by hematopoietic stem cell rescue in immunocompetent adult patients with primary central nervous system lymphoma or intraocular lymphoma after the failure of high-dose methotrexate-based treatment. Design and Methods Patients were included if they received intensive chemotherapy with a combination of thiotepa, busulfan and cyclophosphamide. Seventy-nine patients (median age 52.4 years, range 23-67 years) were identified. All of the patients except 5 received a salvage treatment after the failure of high-dose methotrexate. After salvage treatment and just before intensive chemotherapy followed by hematopoietic stem cell rescue, 32 patients were in complete response, 26 patients were in partial response, 2 patients had stable disease and 19 patients had progressive disease. Results With a median follow up of 56 months, the 5-year overall survival probability was 51% in the whole population and 62% among patients who were chemosensitive to the salvage treatment. The 5-year event-free survival probability was 37.8% in the whole population and 43.7% in the chemosensitive subpopulation. Neurocognitive assessments in a subset of patients suggest no evidence of intensive chemotherapy-induced neurocognitive decline. Conclusions Thiotepa, busulfan and cyclophosphamide-based intensive chemotherapy is an effective treatment for refractory and recurrent primary central nervous system lymphoma in chemosensitive patients up to 65 years of age. The role of intensive chemotherapy followed by hematopoietic stem cell rescue in chemorefractory patients needs to be more accurately defined.

Les leucemies lymphoides chroniques sont les plus frequentes des hemopathies familiales. Les apparentes au premier degre d’un patient atteint de LLC ont un risque d’hemopathie lymphoide multiplie par 8,5. Ces familles sont le plus souvent composees uniquement de LLC et/ou de lymphocytoses monoclonales de signification indeterminee (familles « pures »), et, dans 40 % des cas, de LLC et d’autres hemopathies lymphoides (familles « mixtes ») ; cette repartition est inversee pour les autres hemopathies lymphoides familiales. Au diagnostic, les LLC familiales ont le plus souvent des criteres de bon pronostic : stade A de Binet, CD38+, IgVH mutes, ZAP70 negatif, del(13q)… Aucun gene n’a a ce jour ete identifie, que ce soit par recherche par gene candidat, par hybridation genomique comparative ou par etude d’associations sur l’ensemble du genome.