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PURPOSE To determine the efficacy and toxicity of chemoimmunotherapy followed by either whole-brain radiotherapy (WBRT) or intensive chemotherapy and autologous stem-cell transplantation (ASCT) as a first-line treatment of primary CNS lymphoma (PCNSL). PATIENTS AND METHODS Immunocompetent patients (18 to 60 years of age) with untreated PCNSL were randomly assigned to receive WBRT or ASCT as consolidation treatment after induction chemotherapy consisting of two cycles of R-MBVP (rituximab 375 mg/m2 day (D) 1, methotrexate 3 g/m2 D1; D15, VP16 100 mg/m2 D2, BCNU 100 mg/m2 D3, prednisone 60 mg/kg/d D1-D5) followed by two cycles of R-AraC (rituximab 375 mg/m2 D1, cytarabine 3 g/m2 D1 to D2). Intensive chemotherapy consisted of thiotepa (250 mg/m2/d D9; D8; D7), busulfan (8 mg/kg D6 through D4), and cyclophosphamide (60 mg/kg/d D3; D2). WBRT delivered 40 Gy (2 Gy/fraction). The primary end point was 2-year progression-free survival. Cognitive outcome was the main secondary end point. Analysis was intention to treat in a noncomparative phase II trial. RESULTS Between October 2008 and February 2014, 140 patients were recruited from 23 French centers. Both WBRT and ASCT met the predetermined threshold (among the first 38 patients in each group, at least 24 patients were alive and disease free at 2 years). The 2-year progression-free survival rates were 63% (95% CI, 49% to 81%) and 87% (95% CI, 77% to 98%) in the WBRT and ASCT arms, respectively. Toxicity deaths were recorded in one and five patients after WBRT and ASCT, respectively. Cognitive impairment was observed after WBRT, whereas cognitive functions were preserved or improved after ASCT. CONCLUSION WBRT and ASCT are effective consolidation treatments for patients with PCNSL who are 60 years of age and younger. The efficacy end points tended to favor the ASCT arm. The specific risk of each procedure should be considered.

IntroductionChronic myelomonocytic leukemia (CMML), which is the most frequent myelodysplastic/myeloproliferative disorder, 1 is characterized by the accumulation of monocytes and a variable proportion of immature dysplastic granulocytes in the PB and the BM. 2 Clonal cytogenetic abnormalities are detected in ϳ 40%, 3 and a copyneutral uniparental disomy in leukemic cells of ϳ 50% of the patients. 4 Mutations in ASXL1, TET2, and RUNX1 genes are detected in 25% to 50% of patients, RAS and CBL gene mutations in 10% to 25% of patients, and mutations in JAK2, FLT3, LNK, UTX, EZH2, IDH1, and IDH2 in Ͻ 10% of patients. 5 Epigenetic changes could also play a role in the disease pathogenesis. 6 For example, transcription-intermediary factor-1␥ gene (TIF1␥), whose disruption in myeloid cells induces an age-dependent CMML phenotype in the mouse, is down-regulated in leukemic cells of ϳ 35% of CMML patients because of the gene promoter hypermethylation. 7 The prognosis of this disease of the elderly is quite variable, with an approximately 2.5-year median survival. 3 BM and PB blast percentages have major prognostic value and distinguish CMML-1, with Ͻ 10% BM and Ͻ 5% PB blasts, from CMML-2 with Ն 10% BM and/or Ն 5% PB blasts. 1 Other well-documented prognostic factors include white blood cell (WBC) count, splenomegaly (SMG), extramedullary disease (EMD), cytopenias, and cytogenetic abnormalities. [8][9][10][11] ASXL1 and EZH2 mutations negatively affect the disease outcome, whereas the prognostic influence of TET2 mutation is more controversial. [12][13][14][15][16] The short survival of patients with poor prognostic factors is related to the limited availability of effective treatments. 3 The only The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on March 24, 2019. by guest www.bloodjournal.org From potentially curative therapeutic option is allogeneic stem cell transplantation, however excluded in most patients by age and comorbidities. 17 In the only randomized trial conducted specifically in CMML, to our knowledge, hydroxyurea appeared more efficient than oral etoposide 18 but still associated with short survival; whereas in other reports, the response rate of CMML to low-dose cytarabine, 19 oral topotecan, 20 and intensive chemotherapy 21 remained low. The hypomethylating agents, 5-azacitidine (AZA) and 5-aza-2Ј-deoxycytidine (decitabine [DAC]) received Federal Drug Administration approval for treatment of myelodysplastic syndrome, including CMML, AZA being also approved in the European Union for CMML with marrow blasts Ͼ 10%. Pooled AZA and DAC published studies suggest an overall response rate of 39% to 45% and an overall survival (OS) benefit for responders. [22][23][24][25][26] However, CMML patient populations included in those series were generally heterogeneous. ...

Early identification of ultra-risk diffuse large B-cell lymphoma (DLBCL) patients is needed to aid stratification to innovative treatment. Previous studies suggested high baseline total metabolic tumor volume (TMTV) negatively impacts survival of DLBCL patients. We analyzed the prognostic impact of TMTV and prognostic indices in DLBCL patients, aged 60 to 80 years, from the phase 3 REMARC study that randomized responding patients to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) into maintenance lenalidomide or placebo. TMTV was computed on baseline positron emission tomography/computed tomography using the 41% maximum standardized uptake value method; the optimal TMTV cutoff for progression-free (PFS) and overall survival (OS) was determined and confirmed by a training validation method. There were 301 out of 650 evaluable patients, including 192 patients classified as germinal center B-cell–like (GCB)/non-GCB and MYC/BCL2 expressor. Median baseline TMTV was 238 cm3; optimal TMTV cutoff was 220 cm3. Patients with high vs low TMTV showed worse/higher Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, stage III or IV disease, >1 extranodal site, elevated lactate dehydrogenase, International Prognostic Index (IPI) 3-5, and age-adjusted IPI 2-3. High vs low TMTV significantly impacted PFS and OS, independent of maintenance treatment. Although the GCB/non-GCB profile and MYC expression did not correlate with TMTV/survival, BCL2 >70% impacted PFS and could be stratified by TMTV. Multivariate analysis identified baseline TMTV and ECOG PS as independently associated with PFS and OS. Even in responding patients, after R-CHOP, high baseline TMTV was a strong prognosticator of inferior PFS and OS. Moreover, TMTV combined with ECOG PS may identify an ultra-risk DLBCL population. This trial was registered at www.clinicaltrials.gov as #NCT01122472.

Despite very similar gene expression profiles, the clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is heterogeneous. Immunoglobulin VH (IgVH) mutational status and expression of B-cell receptor (BCR) signaling mediators have been associated with disease progression. However, the consequences of BCR engagement on cell survival and evolution of the disease remain unclear. We show here that B-CLL cell survival is dependent on the threshold of BCR stimulation induced by immobilized antibody, in contrast to soluble anti-M F(ab) ¶2 antibody, which leads to apoptosis. Measurement of metabolic activity and apoptotic response discriminated two subgroups. ''Nonresponders'' showed low metabolic activity and unmodified apoptotic response upon BCR stimulation. In contrast,''responders'' exhibited increased metabolic activity and inhibition of spontaneous apoptosis. This survival advantage was associated to a BCR-dependent activation profile leading to induction of cyclin D2/cyclindependent kinase 4 (cdk4) expression and G 1 cell cycle progression. The ability to respond to BCR ligation correlated with an unfavorable clinical course and allowed to define an additional group of patients among IgVH-mutated cases exhibiting a risk of progression. Remarkably, we show that Zap70 expression was neither mandatory nor sufficient to generate downstream survival signals and cyclin D2/cdk4 up-regulation. In conclusion, BCR engagement has a significant effect on B-CLL cell survival, activation, and G 1 progression. Furthermore, our results provide new insights in the physiopathology of progressive IgVH-mutated cases.