Hervé Ghesquières

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

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.

Evaluation of core needle biopsy as a substitute to open biopsy in the diagnosis of soft-tissue masses

Open biopsy is recommended for a soft-tissue sarcoma (s-t-S) diagnosis. Core needle biopsy (CNB) was recently associated with minimal morbidity, cost and time-consumption, but also potential inaccuracy. Its diagnostic utility was investigated retrospectively in 110 patients with soft-tissue masses (s-t-M) undergoing CNB between September 1994 and September 2000. Sensitivity (Se), specificity (Sp), positive (PPV) and negative (NPV) predictive values were determined for malignancy (benign/malign), soft-tissue tumour (yes/no), and sarcoma diagnosis (yes/no), comparing CNB and the best standard test available; concordance was evaluated. 103/110 CNB were suitable for analysis. Final diagnosis was 23 benign tumours (19%), 65 s-t-S (59%), 9 lymphomas (8%), 6 fibromatoses (desmoid) (5%) and 7 carcinomas (6%). CNB Sp and PPV were 100%, Se was 95, 99 and 92%, and NPV 85, 95 and 88% for diagnosing malignancy, soft-tissue tumour and sarcoma. CNB Se and NPV were 100% for malignancy, connective tumour and sarcoma in lymphomas, high-grade sarcomas and desmoid tumours. In low grade sarcomas, Se was 94 and 85%, and NPV 84 and 77% for malignancy and sarcoma. Histological grade on CNB seems uneasy, except for grade-III tumours. CNB is accurate, not misleading for s-t-M diagnosis, avoids open biopsy complications, and allows one-surgery or neo-adjuvant chemotherapy planning when combined with appropriate imaging.

Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients.

We retrospectively analyzed 77 patients with pathologically diagnosed angioimmunoblastic T-cell lymphoma from a single city. There were 43 men and 34 women; the median age was 64.5 years (range, 30-91 yr). Average time between first symptoms of the disease and diagnosis was 3.6 months. At diagnosis, peripheral nodes were present in all but 1 patient, and were generalized in 90% of cases. Constitutional symptoms were reported in 77% of cases and spleen enlargement in 51%. A cutaneous eruption-morbilliform, urticarial, or more polymorphic-was present in 45% of patients; in one-third of them, the eruption occurred after drug administration. Other clinical manifestations included pleuritis (22%); arthralgia or arthritis (17%); ear, nose, and throat involvement (14%); central or peripheral neurologic manifestations (10%); and ascites (5%). Most patients presented with advanced disease at diagnosis (bone marrow involvement in 60% of cases). The main laboratory abnormalities were elevated lactate dehydrogenase levels (71%), inflammatory syndrome (67%), hypergammaglobulinemia (50%), anemia (51%), and lymphopenia (52%). Auto- or disimmune manifestations were reported in one-third of patients: autoimmune hemolytic anemia was present at diagnosis in 19% of patients and thrombocytopenic purpura in 7%. Documented vasculitis was described in 12% of cases. Clonality was analyzed in lymph nodes in 47 patients: T-cell and B-cell clones were found in 45 (96%) and 20 (45%) patients, respectively. Chromosomal abnormalities were identified in 62% of cases: trisomies 3, 5, 18, 19, additional X chromosome, and deletion of chromosome 7 were the most common abnormalities. The current study underlines the diversity of presenting manifestations of angioimmunoblastic T-cell lymphoma. Abbreviations: AITL = angioimmunoblastic T-cell lymphoma, AILD = angioimmunoblastic lymphadenopathy with dysproteinemia, CSF = cerebrospinal fluid, EBERs = Epstein-Barr virus-encoded small RNAs, ENT = ear, nose, and throat, HIV = human immunodeficiency virus, Ig = immunoglobulin, IL = interleukin, IPI = International Prognostic Index, LDH = lactate dehydrogenase, PCR = polymerase chain reaction, TCR = T-cell receptor.

Lymphoma Recurrence 5 Years or Later Following Diffuse Large B-Cell Lymphoma: Clinical Characteristics and Outcome

PURPOSE Patients with diffuse large B-cell lymphoma (DLBCL) usually relapse early following diagnosis but some relapses happen at 5 years or later. Few data exist regarding clinical characteristics and outcome of these patients. PATIENTS AND METHODS We performed a retrospective analysis of all patients from two centers in Lyon, France, between 1985 and 2003 who had a biopsy-proven relapse 5 years or later following diagnosis of DLBCL. All available biopsies were reviewed and immunohistochemistry was completed. Results Among 1,492 patients with DLBCL, 54 were eligible. At diagnosis, 63% of patients had stage I-II, 82% had low/low-intermediate International Prognostic Index (IPI) score, 65% had extranodal involvement, 24% had an indolent component associated with DLBCL, 57% had germinal center phenotype, and 43% had non-germinal center phenotype. Median time from diagnosis to relapse was 7.4 years (range, 5 to 20.5 years). At time of relapse, 83% had DLBCL histology, and 17% had indolent histology. Having an indolent component at diagnosis was associated with indolent histology at relapse (P = .028). Five-year event free-survival (EFS) was 17% for patients with DLBCL relapse and 61% for patients with indolent relapse (P = .027). Five-year overall survival was 27% for patients with DLBCL and 75% for patients with indolent relapse (P = .029). For DLBCL relapse, 3-year EFS was 56% versus 18% with autologous stem-cell transplantation or not, respectively (P = .0661). CONCLUSION Patients with DLBCL who had a late relapse usually had localized stage, favorable IPI score, and extranodal involvement at diagnosis. The outcome of patients with DLBCL at time of relapse remains poor, and aggressive treatment such as autologous stem-cell transplantation should be pursued whenever possible. Biopsy at relapse is essential because some patients relapse with indolent histology.

Survival impact of rituximab combined with ACVBP and upfront consolidation autotransplantation in high-risk diffuse large B-cell lymphoma for GELA

Background As rituximab combined with CHOP improves complete remission and overall survival in diffuse large B-cell lymphoma, intensified chemotherapy followed by autologous stem-cell transplantation has also been advocated for high-risk patients. The aim of this study was to establish whether or not combining rituximab with high-dose chemotherapy and auto-transplantation also benefits patient survival. Design and Methods The LNH2003-3 study was a phase II trial including diffuse large B-cell lymphoma patients with 2 or 3 International Prognostic Index factors. They received four cycles of intensive biweekly chemotherapy with rituximab, doxorubicine, cyclophosphamide, vindesine, bleomycine, prednisolone (R-ACVBP) followed by auto-transplantation in responding patients. Two hundred and nine patients under 60 years of age were included in the study and 155 responding patients underwent auto-transplantation. In addition, a case-control study was performed by matching (1:1) 181 patients treated with R-ACVBP with ACVBP patients not given rituximab but submitted to auto-transplantation from the previous LNH1998-3 trial. Results With a median follow up of 45 months, 4-year progression-free survival and overall survival were estimated at 76% (CI: 69–81) and 78% (CI: 72–83), respectively. There was no difference between patients with 2 or 3 International Prognostic Index factors. Four year progression-free survival was significantly higher in R-ACVBP than ACVBP patients (74% vs. 58%; P=0.0005). There was also a significant increase in 4-year overall survival (76% vs. 68%; P=0.0494). Conclusions In high-risk diffuse large B-cell lymphoma patients, treatment with R-ACVBP followed by auto-transplantation results in a 78% 4-year overall survival which should be compared to other approaches. (Clinicaltrials.gov identifier: NCT00144807)

Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma

Allogeneic hematopoietic cell transplantation (allo-HCT) is indicated for patients with relapsed or refractory Hodgkin lymphoma (HL). Although long-term disease control can be achieved, relapse is still frequent. The programmed cell death protein 1 (PD-1) pathway-blocking antibody nivolumab has shown substantial therapeutic activity and an acceptable safety profile in patients with relapsed or refractory HL who did not receive allo-HCT. However, PD-1 blocking strategy can increase the risk of graft-versus-host disease (GVHD) in murine models. We retrospectively assessed the efficacy and toxicity of nivolumab as a single agent in 20 HL patients relapsing after allo-HCT. GVHD occurred in 6 patients (30%) after nivolumab initiation. All 6 patients had prior history of acute GVHD. The patients with nivolumab-induced GVHD were managed by standard treatment for acute GVHD. Two patients died as a result of GVHD, 1 of progressive disease and 1 of complications related to a second allo-HCT. Overall response rate was 95%. At a median follow-up of 370 days, the 1-year progression-free survival rate was 58.2% (95% CI, 33.1%-76.7%) and the overall survival rate was 78.7% (95% CI, 52.4%-91.5%). Among 13 patients still in response, 6 received a single dose of nivolumab and 7 remain on nivolumab. Compared with standard options for this indication, our results show that nivolumab is effective with an acceptable safety profile.

90 Y Ibritumomab Tiuxetan (Zevalin) Combined With BEAM (Z -BEAM) Conditioning Regimen Plus Autologous Stem Cell Transplantation in Relapsed or Refractory Low-grade CD20-positive B-cell Lymphoma. A GELA Phase II Prospective Study

BACKGROUND This study was designed to evaluate the safety and efficacy of a conventional dose of yttrium-90 ((90)Y) ibritumomab tiuxetan combined with the etoposide rabinoside acytarabine melphalan (BEAM) regimen before autologous stem cell transplantation (ASCT) in chemosensitive relapsed or refractory low-grade B-cell lymphomas. PATIENTS AND METHODS From March 2005 to August 2006, 77 prospective patients were included, 69 (90%) with follicular lymphomas. RESULTS The last salvage chemotherapy regimen included rituximab for 74 patients and ASCT for 75 patients. Before ASCT, rates of complete response/unconfirmed response (CR/CRu) and partial response were 77% and 23%, respectively. After zevaline-BEAM (Z-BEAM), time to >1 × 10(9)/L neutrophils was 12 days (range, 9-35 days), and time to >20 × 10(9)/L platelets was 12 days (range, 3-42 days). No other significant extrahematologic toxicity was observed. Three months after ASCT, 68 patients (88%) were in CR/CRu. After a median follow-up of 28 months, 2-year event-free survival (EFS) and overall survival were 63% and 97%, respectively, but EFS for first-relapsed patients was 72%. When using patients as their own controls, 2-year EFS was superior after ASCT and compared favorably with the duration of response of last chemotherapy (62% vs. 37%, P = .007) (Point 1.10). CONCLUSION Z-BEAM appears safe and needs to be further evaluated in a randomized trial.

Oral moxifloxacin or intravenous ceftriaxone for the treatment of low-risk neutropenic fever in cancer patients suitable for early hospital discharge

Goals of workPatients with low-risk neutropenic fever as defined by the Multinational Association of Supportive Care in Cancer (MASCC) score might benefit from ambulatory treatment. Optimal management remains to be clearly defined, and new oral antibiotics need to be evaluated in this setting.Materials and methodsCancer patients with febrile neutropenia and a favorable MASCC score were randomized between oral moxifloxacin and intravenous ceftriaxone. All were fit for early hospital discharge. The global success rate was related to the efficacy of monotherapy, as well as to the success of ambulatory monitoring.Main resultsThe trial was closed prematurely because of low accrual. Ninety-six patients were included (47 in the ceftriaxone arm and 49 in the moxifloxacin arm). A total of 65% were women, 30.2% had lymphoma, 34.4% had metastatic, and 35.4% had non-metastatic solid tumors. The success rates of home antibiotics were 73.9% and 79.2% for ceftriaxone and moxifloxacin, respectively. Seven patients were not discharged, and 14 required re-hospitalization. There were 17% of microbiologically documented infections that were, in most cases, susceptible to oral monotherapy.ConclusionsThese results suggest that MASCC is a valid and useful tool to select patients for ambulatory treatments and that oral moxifloxacin monotherapy is safe and effective for the outpatient treatment of cancer patients with low-risk neutropenic fever.

Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial

BACKGROUND No standard chemotherapy regimen exists for primary CNS lymphoma, reflecting an absence of randomised studies. We prospectively tested two promising methotrexate-based regimens, one more intensive and a milder regimen, for primary CNS lymphoma in the elderly population, who account for most patients. METHODS In this open-label, randomised phase 2 trial, done in 13 French institutions, we enrolled immunocompetent patients who had neuroimaging and histologically confirmed newly diagnosed primary CNS lymphoma, were aged 60 years and older, and had a Karnofsky performance scale score of 40 or more. Participants were stratified by Karnofsky performance scale score (<60 vs ≥60) and treating institution and randomly assigned (1:1) to receive methotrexate (3·5 g/m(2)) with temozolomide (150 mg/m(2)) or methotrexate (3·5 g/m(2)), procarbazine (100 mg/m(2)), vincristine (1·4 mg/m(2)), and cytarabine (3 mg/m(2)). Neither regimen included radiotherapy; both included prophylactic G-CSF and corticosteroids. The primary endpoint was 1-year progression-free survival. Analysis was intent to treat, in a non-comparative phase 2 trial design. This study is registered with ClinicalTrials.gov, number NCT00503594. FINDINGS Between July 16, 2007, and March 25, 2010, 98 patients were enrolled, of whom 95 were randomly assigned and analysed; 48 to methotrexate with temozolomide and 47 to methotrexate, procarbazine, vincristine, and cytarabine. 1-year progression-free survival was 36% (95% CI 22-50) in the methotrexate, procarbazine, vincristine, and cytarabine group and 36% (22-50) in the methotrexate with temozolomide group; median progression-free survival was 9·5 months (95% CI 5·3-13·8) versus 6·1 months (3·8-11·9), respectively. Objective responses were noted in 82% (95% CI 68-92) of patients in the methotrexate, procarbazine, vincristine, and cytarabine group versus 71% (55-84) of patients in the methotrexate with temozolomide group. Median overall survival was 31 months (95% CI 12·2-35·8) in the methotrexate, procarbazine, vincristine, and cytarabine group and 14 months (8·1-28·4) in the methotrexate with temozolomide group. No differences were noted in toxic effects between the two groups. The most common grades 3 and 4 toxicities in both groups were liver dysfunction (21 [4%] in the the methotrexate and temozolomide group and 18 [38%] in the methotrexate, procarbazine, vincristine, and cytarabine group), lymphopenia (14 [29%] and 14 [30%]), and infection (six [13%] and seven [15%]). To date, 33 (69%) patients in the methotrexate and temozolomide group have died, versus 31 (55%) in the methotrexate, procarbazine, vincristine and cytarabine group. Quality-of-life evaluation (QLQ-C30 and BN20) showed improvements in most domains (p=0·01-0·0001) compared with baseline in both groups. Prospective neuropsychological testing showed no evidence of late neurotoxicity. INTERPRETATION In this study of two different methotrexate-based combination regimens in elderly patients, the efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting pursuing treatment in these poor prognosis patients is worthwhile. New alternatives are needed to improve response duration in this population. FUNDING Schering-Plough/Merck and French Government.

A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus

Recent genome wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio [OR] = 0.81, 95% confidence interval [95% CI] = 0.76–0.86, Pcombined = 3.5 × 10−10), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16.1, 5q31, 6p31.2, 8q24.21 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk