ALBERT

Description: Introduction Tyrosine Kinase Inhibitors (TKI) have completely changed the scenario of CML and dramatically improved the outcomes. Thus, early identification of patients expecting poor outcome is crucial to offer alternative TKI regimens or in some selected cases stem cell transplantation before disease progression may occur. The Evaluating Nilotinib Efficacy and Safety in Trial as First-Line Treatment (ENEST1st) is a phase 3b is an open-label study of nilotinib 300 mg twice daily (BID) in adults with newly diagnosed BCR-ABL positive CP-CML. Aim of the ENEST1st sub-study N10 was to investigate BM microenvironment markers that regulate leukemic stem cells in the bone marrow (BM) niche of Nilotinib-treated patients. Methods The study enrolled patients in 21 Italian ENEST1st participating centers. Response was based on ELN recommendations (Baccarani M, et al. Blood 2013 122:872-884). In an interim analysis, molecular and cytogenetic response by 24 months was assessed. Mononuclear cells were collected from BM and PB samples at the screening visit (V0) and after 3 months of treatment (V4). RT-qPCR for the expression of 10 genes (ARF, KIT, CXCR4, FLT3, LIF, NANOg, PML, PRAME, SET and TIE), involved in the stemness and hematopoietic stem cells survival signaling regulation was conducted. RT-qPCR data were normalized by the expression of GUS mRNA (normalized copy number, NCN). Plasma samples were collected at different time points from both BM or PB samples. Concentrations of 20 different analytes, including IL-1a, IL-3, M-CSF, SCF, SDF1-a, TRAIL, HGF, PDGF-bb, IL1b, IL-6, IL-7, IL-8, IL-10, IL-12, IL-15, G-CSF, GM-CSF, MIP-1a, TNF-a, and VEGF, were simultaneously evaluated using commercially available multiplex bead-based sandwich immunoassay kits. Results 33 out of 37 patients enrolled were available for an interim molecular analysis at 24 months: an optimal response was achieved in 25 patients, a warning response in 5 patients and a failure response in 3 patients. We observed a significant correlation between the expression of two genes involved in the regulation of stem cell pluripotency (NANOg) or cytokine signaling (SET) and patient outcome. Indeed, NANOg and SET mRNA were significantly down-regulated in PB samples at diagnosis of patients with optimal response compared to patients with warning/failure response (NANOg mRNA: 0.3±0.25 NCN vs 0.6±0.7 NCN, respectively; p=0.05; SET mRNA: 0.2±0.3 NCN vs 2.3±4.2 NCN, respectively; p=0.03). We also investigated the plasma level of several factors involved in the hematopoietic stem cells (HSCs). Some of these markers showed a significant correlation with patient's outcome when evaluated at diagnosis in either PB or BM samples. Indeed, high level of IL12 (in the BM samples), or HGF, mCSF and SCF (in the PB samples) were associated to a worst prognosis markers, since significantly correlating with no MMR@12months (IL12, p=0.03), intermediate/high Socal score (mCSF, p=0.03; SCF, p=0.03), no reduction of MMR below to 1 at 3 month (SCF, p=0.04) or warning/failure response to Nilotinib treatment (HGF, p=0.03; SCF, p=0.04). Indeed, we find a lower levels of PDGFb, SDF1, TNFa, TRAIL (in the BM samples), and HGF, SDF1, TRAIL (in the PB samples) in those patients with intermediate/high Hasford or Sokal score (PDGFb, p=0.0007; SDF1, p=0.02), warning/failure response to Nilotinib treatment (HGF, p=0.03) or lacking of MMR4.0 (SDF1, p=0.01; TNFa, p=0.02; TRAIL, p=0.05). Conclusion/Summary Taken together, our results suggest that the expression analysis of genes involved in cell pluripotency (NANOg) and/or cell signaling (SET) at baseline, may indicate early achievement of deep molecular response in shown CML-CP patients treated with nilotinib. In addition, in patients with optimal response to Nilotinib, high concentration of SDF-1, TRAIL (inversely correlated with BCR-ABL, and associated to an higher susceptibility to apoptosis in the leukemic blasts) were observed as well as BM TNF (cell-extrinsic and potent endogenous suppressor of HSC activity). A lower concentration of several factors associated to hematopoietic progenitor cell growth and survival (including HGF, SCF and IL12) were observed compared to patients failing to achieve response to Nilotinib. These data strongly suggest that stromal microenvironment supports the viability of BCR-ABL cells in BM niches through direct feeding, or environment releasing of survival factors. Disclosures Soverini: Novartis, Briston-Myers Squibb, ARIAD: Consultancy. Martinelli:MSD: Consultancy; BMS: Speakers Bureau; Roche: Consultancy; ARIAD: Consultancy; Novartis: Speakers Bureau; Pfizer: Consultancy. Saglio:Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Novartis Pharmaceutical Corporation: Consultancy, Honoraria. Galimberti:Novartis: Employment. Giles:Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Description: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment of stage I-II NLPHL is undefined. We conducted a multicenter retrospective study including patients ≥16 years of age with stage I-II NLPHL diagnosed from 1995 through 2018 who underwent all forms of management, including radiotherapy (RT), combined modality therapy (CMT; RT+chemotherapy [CT]), CT, observation after excision, rituximab and RT, and single-agent rituximab. End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups. We identified 559 patients with median age of 39 years: 72.3% were men, and 54.9% had stage I disease. Median follow-up was 5.5 years (interquartile range, 3.1-10.1). Five-year PFS and OS in the entire cohort were 87.1% and 98.3%, respectively. Primary management was RT alone (n = 257; 46.0%), CMT (n = 184; 32.9%), CT alone (n = 47; 8.4%), observation (n = 37; 6.6%), rituximab and RT (n = 19; 3.4%), and rituximab alone (n = 15; 2.7%). The 5-year PFS rates were 91.1% after RT, 90.5% after CMT, 77.8% after CT, 73.5% after observation, 80.8% after rituximab and RT, and 38.5% after rituximab alone. In the RT cohort, but not the CMT cohort, variant immunoarchitectural pattern and number of sites 〉2 were associated with worse PFS (P 〈 .05). Overall, 21 patients (3.8%) developed large-cell transformation, with a significantly higher transformation rate in those with variant immunoarchitectural pattern (P = .049) and number of involved sites 〉2 (P = .0006). OS for patients with stage I-II NLPHL was excellent after all treatments.

Description: Background In case of clinical suspicion of lymphoma, the histological examination of lymphadenopathy is essential for defining a correct diagnosis and for developing a proper treatment plan. An open surgical biopsy (OSB) is still the "gold standard", owing to the large amount of tissue obtained. The sensitivity of lymph node core-needle biopsy under imaging guidance requires validation. Aims This randomized study compared the ultrasound-guided core-needle cutting biopsy (CNCB) approach with OSB approach. Patient and methods Institutional review board approval and informed consent were obtained. In a single center between 1 January 2009 and 31 December 2015, patients with lymph node enlargement suspected for lymphoma were randomly assigned (1:1) to biopsy with either OSB (standard group) or ultrasound-guided 16 gauge modified Menghini needle (core-needle group). In the core-needle group, the lymph node to undergone biopsy was determined by power Doppler US, in particular, the main criterion to select the node to be biopsied was the hypervascularization. The primary endpoint was to test the superiority of sensitivity for diagnosis of malignancy for ultrasound-guided CNCB compared with OSB. Secondary endpoints were negative predictive values, likelihood ratio of negative test, biopsy related complications, costs and times to biopsy. Results A total of 372 patients were randomized either to standard group (N= 187) or core-needle group (N= 185). Sensitivity for detection of malignancy was significantly better for US-guided CNCB [98.8%; 95% confidence interval (CI), 95.9-99.9] than standard biopsy [88.7%; 95% CI, 82.9-93] (P

Description: Background Neutropenic enterocolitis (NEC) is an abdominal infection reported in patients with acute myeloid leukemia (AML) following chemotherapy, especially cytarabine. Specific data regarding the impact of different cytarabine schedules and antibacterial regimens for NEC are sparse. Aims The aim of this study was to provide an update on therapeutic interventions of NEC. Predictors of mortality and determinants of favorable outcome at 30 days after NEC onset were considered, and finally we focused on the optimal antibiotic strategy for the preemptive therapy of NEC Methods NEC episodes were retrospectively pinpointed among 440 patients with newly diagnosed AML hospitalized in our institution, from 1 January 2002 to 31 December 2012, for receiving chemotherapy protocols with cytarabine. Two subgroups, survivors versus non-survivors, were compared to identify the predictors of outcome within 30-days of NEC onset. Finally, an optimal antibiotic strategy for front-line NEC treatment was suggested. Patients with severe neutropenia and clinical signs suggestive of NEC, i.e. fever (axillary temperature ³38¡C), diarrhea (〉1 stool daily) and/or abdominal pain, were under strict ultrasonographic monitoring. Patients positive at US examination for pathologic bowel wall thickening (〉4 mm in transversal scans for at least 30 mm length) were diagnosed with NEC, according to standardized criteria. The following variables were selected for the statistical analysis: antileukemic protocols [containing standard-dose (100 mg/m2 daily for at least 7 days), intermediate-dose (200 mg/m2 daily for at least 7 days), and high-dose (2000 to 6000 mg/m2 daily for at least 4 days) cytarabine], ultrasonographic features, microbiological findings, antibacterial therapy (front-line antibiotic treatments of febrile neutropenia that spared tigecycline, and the number and type of antibiotics definitively used after NEC diagnosis), adjunct therapeutic modalities (systemic antifungal therapy, G-CSF, bowel rest and total parenteral nutrition), and severe neutropenia resolution. Results NEC was documented in 100 (23.8%) of analyzed patients: 42.5% had received high-dose cytarabine while 19% and 15% intermediate-dose and standard-dose cytarabine, respectively (P