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Background. The PI3Kδ inhibitor idelalisib given in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia (R/R CLL) has been associated with an objective response in 81% of cases with a median PFS of 20.3 months in a phase-3 clinical trial (Sharman et al, JCO 2019). Because the efficacy of new drugs reported in clinical trials may not translate into similar results in the day-to-day practice, we performed an observational retrospective-prospective study on the efficacy and safety of idelalisib and rituximab (IR) in R/R CLL patients treated outside of clinical trials in Italian centers belonging to the GIMEMA group. Methods. R/R CLL patients treated with IR outside of clinical trials between July 2014 and May 2017 were enrolled. Treatment was initiated at symptomatic progression; treatment response and disease progression were assessed according to the NCI criteria. The data were extracted from the medical files and entered into case record forms (CRF) by each treating physician. Computerized and manual consistency checks were performed by the GIMEMA data center on newly entered forms and queries were issued in case of inconsistencies. The primary endpoint was progression-free survival (PFS), secondary endpoints were overall response rate (ORR), the percentage of patients on treatment at 12, 24 and 36 months, overall survival (OS) and response to the subsequent anti-leukemic treatment. Results. 149 R/R CLL patients from 35 Italian centers were included in the study. The baseline characteristics are shown in Table 1. At a median follow-up of 39.4 months, the median PFS was 22.9 months (95% CI 20.5-28.8). In univariate analysis, a shorter PFS was associated with ≥3 lines of therapy (p=0.0175) (Fig. 1a). The ORR (CR + PR) was 72.5%. Age ≤70 yrs (p=0.037) and a PS grade 3 during RI treatment were neutropenia (35% of cases), gastrointestinal disorders (17%), infections (17%) and transaminitis (6%). Conclusions. The results hereby observed show that the efficacy of IR in a cohort in a real-life RR/CLL with a long follow-up is superimposable to those reported in the pivotal clinical trial, suggesting that the patient population who received IR in the day-to-day clinical practice mirrored that enrolled in the trial. Advanced clinical stage and 3 or more previous lines of therapy were associated with shorter PFS and OS. Interestingly, PFS and objective measures of efficacy such as the proportion of patients still on treatment at 12, 24 and 36 months, as well as OS, were not influenced by the TP53 status. Furthermore, the majority of patents responded to the subsequent anti-leukemic treatment and relatively durable responses were observed in patients who discontinued IR due to toxicity. Disclosures Rigolin: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Visentin:Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Coscia:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Farina:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Gaidano:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Sunesys: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Murru:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Varettoni:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Sportoletti:Janssen: Honoraria; AbbVie: Honoraria. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Marasca:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Marchetti:Takeda: Other: Sponsored meetings; Gilead: Consultancy; Novartis: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Other: Sponsored meetings; Pfeizer: Other: Sponsored meetings. Mauro:Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Octopharma: Consultancy; Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Molica:Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pane:Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gozzetti:Janssen: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Galieni:Celgene: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Montillo:AbbVie: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Verastem: Honoraria; Gilead: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria. Foà:Incyte: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees. Cuneo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with specific morphologic and molecular features and excellent prognosis. Although high rate of complete response (CR) has been reported after treatment with purine analogs, expecially cladribine (2CDA), relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long term remission rate and overall survival (OS) in those patients (pts) that received 2CDA as first line treatment. We retrospectively reviewed data of all HCL pts treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers. Among 553 pts reported, only 513 were evaluable because treated with 2CDA alone. Considering the clinical carachteristics, M/F ratio was 4.5 with a median age of 54 years (range 24-88) and ECOG 0 in 85% of cases. Splenomegaly and presence of circulating hairy cells recorded by morphology were reported in 241 (47%) and 138 (27%) pts, respectively. Thirty-seven (7%) pts presented with an infection. Other comorbidities were cardiovascular in 29 (6%) pts, a previous cancer or diabetes in 27 (5%) each, chronic hepatic disorders in 18 (3%), obstructive pulmonary disease in 16 (3%), chronic kidney disease in 3 (1%). Three hundred-thirty (64%) pts received 2CDA intravenously (253 as daily continuous infusion for 5-7 consecutive days and 77 as weekly infusion for 5-7 consecutive weeks) and 183 (36%) subcutaneously. Response criteria were defined as per recent consensus guidelines (Grever MR et al. Blood 2017). The overall response rate (ORR) was 83%: CR in 335 pts (65%) and partial response (PR) in 96 (19%); 40 (8%) pts obtained hematological improvement (HI) and in 42 (8%) no response was observed. Nine of 11 (82%) pts with HI and 18/25 (72%) non responders who received salvage therapy obtained a major response (fig. 1). A slightly higher hemoglobin value (12.4 vs 11.4 g/dl, p=0.044), a reduced frequency of circulating hairy cells (28.7% vs 31.8%, p=0.039), absence of palpable splenomegaly (p= 2CDA is greatly effective in treating HCL, with an ORR of 83%. Early and long term adverse events were rare and easily managed: although HCL-related mortality is still possible, OS at 15 years is higher than 80% Disclosures Motta: Roche: Honoraria; Janssen: Honoraria. Offidani:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Tedeschi:Abbvie: Honoraria, Speakers Bureau; Sunesis: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Varettoni:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Visentin:Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Falini:Roche: Research Funding. Pulsoni:Sandoz: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Gilead: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; roche: Consultancy, Speakers Bureau; Merk: Consultancy. Tiacci:Roche: Research Funding; Abbvie: Other: Travel and meeting expenses. Zinzani:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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We performed gene expression profiling (GEP) of 36 patients with Waldenström's Macroglobulinemia (WM), 13 subjects with Monoclonal Gammopathy of Uncertain Significance (IgMMGUS), and 7 healthy subjects (CTRLs) by Affymetrix GeneChip Human Genome U133 Plus 2.0. GEP was performed on 36 WM bone marrow (BM) CD19+ cells vs. 10 IgMMGUS BM CD19+cells vs. 7 CTRLs BM CD19+ cells. We analyzed 32 WM BM CD138+ cells vs. 10 IgMMGUS BM CD138+ cells vs. 7 CTRLs BM CD138+ cells by microarray. Data was preprocessed and normalized using RMA and ComBat and analyzed using Statistical Analysis for Microarrays (SAM) on 3 groups and a false discovery rate threshold of 5%, followed by a pair-wise SAM test. We found 2038 and 29 unique genes in the comparison between WM, IgMMGUS and CRTLs in CD19+ and CD138+ cells, respectively. There were 16 differently expressed (DE) genes in common between the CD19+ and the CD138+ cells. Genes were grouped accordingly to the following patterns of differential expression: 1) WM>MGUS>CTRL, 2) WMMGUS but MGUSCTRL (Tab.1). Functional enrichment analysis and annotation clustering (DAVID) were run on each pattern. We demonstrated gene expression changes between WM, IgMMGUS and CTRLs in genes encoding hematopoietic cell lineage markers. We showed thatIL2RA, CD1D,andCD44were over expressed in WM vs. IgMMGS, and WM vs. CTRLs.CD25expression characterizes Waldenström's clone (García-Sanz et. al. Best Pract Res Clin Haematol 2016). The over expression ofCD1Don WM B cells compared to IgMMGUS and CTRLs, suggests its possible role as a marker in WM as previously shown in B-cell chronic lymphoproliferative disorders (Kotsianidis et. al. Am J Clin Pathol 2011). We found thatCD44,encoding a glycoprotein over expressed in cancer stem cells, was up regulated in WM B cells compared to the same cell counterpart of IgMMGUS and CTRLs (Chen et. al. J Hematol Oncol 2018). Functional clustering identified several genes encoding cell adhesion molecules (CAM) which are expressed on the surface of B lymphocytes and are involved in the binding with other cells, immune response (T cells), and inflammation. Class I histocompatibility genesHLA-A, HLA-C, HLA-B, HLA-E,andHLA-Gwere over expressed in WM vs. IgMMGUS, and WM vs. CTRLs. Previous studies demonstrated the higher levels of HLA-Gs in WM and IgMMGUS compared to CTRL. Moreover, HLA-G could represent a marker of clonality since high levels of HLA-Gs were observed in both IgG and IgA MGUS and MM patients (Moreau et. al. EJH 2008). CNTNAP2andADAM23were down regulated in WM vs. CTRLs.CNTNAP2,encoding CASPR2 protein, is expressed in CNS and PNS and is involved in neurodevolpmental disorders and the autoimmune disease Sjogren's syndrome (SS) (Xiao Clin Rheumatol 2017). In addition, Caspr2 and ADAM23 take part in the peripheral neuropathy by controlling the activity of potassium channels in neurological autoimmune diseases (Saint-Martin et al. Eur J Neurosci 2018). We can speculate the role of both genes in WM patients with Sjogren's syndrome. VWF(von Willebrand factor),TFPI, andSERPINE1belonging to the complement and coagulation cascade were under expressed in WM vs. IgMMGUS. Notably, some authors have demonstrated that a low level of VWF was associated with high serum IgM levels and withCXCR4mutations in WM patients, and that response to treatment improves VWF in WM patients (Castillo et. al. BJH 2019). Genes encoding zinc finger proteins (ZNF) (n=120) were deregulated in the comparison between WM vs. IgMMGUS, and vs. CTRLS CD19+ cells in all patterns. We suggest the possible role of ZNF in the transcription regulation and cancer progression in the comparison between the 3 groups of subjects. Of note,ZNF804AandZNF215were upregulated in WM vs. IgMGUS and WM vs. CTRLs with high FC (Guerrera et. al. Haemat 2018). TJP1was under expressed in WM CD19+ and WM CD138+ cells. We noted very high FC in CD138+ cells: WM vs. IgMMGUS (FC=-2,65), and WM vs. CTRLs (FC=-6,18). HighTJP1expression in myeloma plasma cells was associated to a better and longer response to protease Inhibitors (PI) suggesting this gene as a biomarker to identify patients which can benefit from PI-based therapy (Zhang et. al. Cancer Cell 2016). Our findings demonstrate that B cells show different gene expression levels in membrane adhesion and cell lineage pathways in WM compared to IgMMGUS and CTRLs, suggesting the possible role of these genes in the progression of IgMMGUS to WM. Disclosures Tedeschi: AstraZeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen spa:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;BeiGene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Department of Hematology Niguarda Hospital Milano:Current Employment;Sunesis:Consultancy.Montillo:F. Hoffmann-La Roche:Honoraria, Research Funding;Astra Zeneca:Honoraria;AbbVie:Honoraria, Speakers Bureau;Janssen:Honoraria, Speakers Bureau;Verastem:Honoraria;Gilead:Honoraria, Speakers Bureau.

Introduction. Observational, real-life studies are relevant to understand whether data derived from prospective controlled trials (CTs) are reproducible in the day-to-day clinical practice. Within a named patient program (NPP), free and early access to ibrutinib was made available for the treatment of relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL) until this agent was approved in Italy. To define the efficacy and toxicity profile of patients treated with ibrutinib in this real-life setting, the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) group carried out a retrospective analysis on the outcome of R/R patients with CLL who received ibrutinib in the NPP. Methods. Between April 2014 and January 2015, 216 R/R patients with CLL managed at 20 centers in Italy were included in the NPP. Patients were required to have R/R disease with disease progression within 24 months after prior chemo-immunotherapy. All patients received ibrutinib at the standard dose of 420 mg daily, continuously until disease progression or unacceptable toxicity. The period of observation included the duration of the NPP and was extended up to January 2016 for patients still on treatment with the commercial drug. Clinical data were reported retrospectively by the treating physicians using the Research Electronic Data Capture (REDCap) system. Results. The median age of patients was 58.3 years (range 27.5-81); 89% of patients were in Binet stage B-C. The median number of prior treatments was 3 (range 1-14). Thirty-seven % of patients was refractory to prior treatment. Deletion 17p and/or TP53 mutations were found in 54% of patients and deletion 11q in 11.6%. Seventy-eight % of patients had an unmutated IGHV gene profile. Prior atrial fibrillation (AF) was reported in 13 cases (6%), while 7 patients with AF (3.3%) were on anti-arrythmic treatment. Hypertension was recorded in 76 cases (35.2%). The median follow-up of patients was 24 months (range, 1-24 months. A response to ibrutinib was observed in 172 patients (79.6%) with a clinical CR/CRi in 34 (15.7%) and a PR/PR-L in 138 (63.9%). Similar response rates were observed in patients with an unmutated IGHV gene status (82.1%) and in those with deletion 17p/TP53 mutations (79.6%). The progression-free survival (PFS) and overall survival (OS) at 24 months were 64.6% (95%CI: 58.0-71.9) and 72.7% (95%CI: 66.5-79.4), respectively. No differences in PFS and OS were observed according to the IGHV mutational status (IGHV unmutated vs mutated: PFS, 65.2% vs 61.0%; p=0.7; OS, 65.2% vs 72.0%, p=0.6) and the presence of TP53 aberrations (TP53 aberrations, present vs absent: PFS, 64.8% vs 64.1%; p=0.6; OS, 69.8% vs 72.7%; p=0.8). Forty-eight patients (22.2%) discontinued ibrutinib within 12 months and 22 (10.2%) within 12-24 months from the start of ibrutinib. Progressive disease and Richter syndrome were the most common reasons for discontinuation that accounted for 16.2% (35 patients) and 1.8% (4 patients) of cases, respectively, and occurred after a median of 17 months from the start of ibrutinib. Treatment discontinuations due to adverse events (AEs) were recorded in 25 patients (11.6%) after a median time of 6 months from the start of treatment and included infections/febrile events in 7 cases, bleeding events in 3 (intracranial hemorrhage 1), sudden death in 3, acute myocardial infarction in 1, ischemic stroke in 2, second malignancy in 3, diarrhea in 1. AF occurred during treatment in 14 (6.5%) patients and was the reason of ibrutinib discontinuation in 2. AEs leading to discontinuation was not specified in 3 cases. Other reasons for ibrutinib discontinuation in 6 (2.8%) patients were ASCT in 4, unplanned surgery in 1, unknown in 1. Survival probability at 12 months from treatment discontinuation due to AEs or DP/RS was 38.2 and 37.2 months respectively (p= 0.6). Conclusions. The results of this real-life study show that in unselected patients with R/R CLL the clinical activity of ibrutinib was comparable to that reported in CTs. However, a third of patients discontinued ibrutinib within 24 months from the start of treatment. An earlier introduction of ibrutinib in the treatment approach of R/R patients, a careful surveillance and management of toxicities will optimise the clinical benefits of ibrutinib in CLL patients treated in the clinical practice. Disclosures Mauro: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zinzani:TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; MSD: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Cortelezzi:novartis: Consultancy; roche: Consultancy; abbvie: Consultancy; janssen: Consultancy. Carlo-Stella:AstraZeneca: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau; Sanofi: Consultancy; ADC Therapeutics: Research Funding, Speakers Bureau; Boehringher Ingelheim Italia: Consultancy; Genenta Science: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Amgen: Speakers Bureau; MSD Italia: Speakers Bureau. Molica:Roche: Other: Advisory board; Gilead: Other: Advisory board; Jansen: Other: Advisory board; AbbVie: Other: Advisory board. Coscia:Janssen, Karyopharm: Research Funding; Abbvie, Gilead, Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zaja:Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Sandoz: Honoraria; Abbvie: Honoraria. Gaidano:Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Gobbi:Ariad: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Amgen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees. Cuneo:janssen: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau. Foà:JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; NOVARTIS: Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; CELTRION: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD.

In this study, we investigated the transcriptome differences of selected bone marrow (BM) CD19+ and BM CD138+ cells of Waldenström's Macroglobulinemia (WM) patients vs. IgM Monoclonal Gammopathy of Undetermined Significance (IgMMGUS) subjects vs. healthy donors (CTLRs). We performed the gene expression profiling (GEP) considering all the different transcript isoforms of genes, coding and non-coding transcripts. Microarrays were performed on BM CD19+ cells (n=36) and BM CD138+ (n=32) in WM, BM CD19+ cells (n=10) and BM CD138+ (n=10) cells in IgMMGUS, BM CD19+ cells (n=7) and BM CD138+ (n=7) cells in healthy donors (CTRLs), respectively. Data were preprocessed and normalized using RMA and ComBat. We performed a functional annotation clustering and enrichment analysis on each pattern using DAVID 6.7 (https://david.ncifcrf.gov/). Selection of differentially expressed genes (DEg) was performed separately for CD19+ and CD138+ cells using Statistical Analysis for Microarrays (SAM) on 3 groups (WM, IgMMGUS and CTRLs). A false discovery rate threshold of 5% was used followed, for significance comparisons, by a pair-wise SAM test. We identified 3095 unique probe-sets corresponding to 2559 unique genes and 494 not annotated probe-sets from the comparison of WM vs. IgMMGUS vs. CRTLs in CD19+ cells. The comparison of WM, IgMMGUS and CRTLs in CD138+ cells demonstrated 38 unique probe-sets corresponding to 32 unique genes and 2 not annotated probe-sets. There were no genes in common between the CD19+ and the CD138+ DEg lists. To better characterize the genes selected as differentially expressed we considered, for all genes that resulted significantly DE in at least one of the below listed comparisons, the following patterns of differential expression: 1) WM>IgMGUS, IgMGUS>CTRLs, and WM>CTRLs; 2) WM We identified 265 unique genes in the CD19+ cells pattern 1 whereas the CD19+ cells pattern 2 contained 403 unique genes. Enrichment analyses showed that transmembrane, adhesion and flavo proteins were progressively significantly under expressed in the WM>IgMGUS>CTRL CD19+ pattern. IL2RA (CD25), ATP1B1 and ADRB2 (cGMP-PKG signaling pathway), GPER (activating PI3K signaling pathway) and IGHM were up regulated in WM. We found in the hematopoietic lineage that CD1D (positive in WM Natural Killer T cells), CD44 (marker in WM stromal cells), IL6 and IGHM were progressively under expressed in WM vs. IgMMGUS vs. CTRLs. CEACAM1 and ANG, both inducing new blood vessels formation, were progressively down regulated in WM vs. IgMMGUS vs. CTRLs. Notably, ANG was over expressed in WM vs. IgMMGUS vs. CTRLs with the fold change (FC) of 1.54, 2.13 and 3.27, respectively. The WM ADARB1 (alternative splicing) and LEF1 (transcription regulation) were progressively over expressed in WM vs. IgMMGUS vs. CTRLs with the following FC: -2.19, -2.16, -4.72 and -1.50, -2.58, -3.86, respectively. In addition, IL4R (plasma membrane protein) which has been demonstrated to be down regulated in WM B cells, was progressively up regulated in WM vs. IgMMGUS vs. CTRLs with the FC of -1.83, -2.18, and -3.99, respectively. GEP data determined few genes in the CD138+ cells patterns: no genes were differently expressed in the WM>IgMGUS>CTRL CD138+ pattern 1 whereas 26 genes emerged from the WM TJP1 (apoptosis) was progressively over expressed in WM vs. IgMMGUS vs. CTRLs with the FC -2.65, -2.33 and -6.18, respectively. In previous studies it has been demonstrated that the TJP1 lower expression induced resistance to proteasome inhibitors in myeloma. TUBB2B, SEPT10, TTLL,SYNM, PARD3, ARHGAP32, involved in the cytoskeleton, as well as PERP (TP53 apoptosis effector), ESPR1 (RNA splicing), and CADPS2 (protein transport) were progressively down regulated in CTRLs vs. IgMMGUS vs. WM. In conclusion, we demonstrated that transmembrane receptors, cell cycle, and cytoskeleton proteins in BM CD19+ cells as well as transmembrane/cell junctions molecules in BM CD138+ cells were differently and progressively deregulated in WM vs. IgMMGUS vs. CTRLs, respectively. Disclosures Tedeschi: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy. Montillo:AbbVie: Consultancy, Honoraria, Speakers Bureau; Versatem: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Speakers Bureau; Acerta: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau.

From a retrospective analysis of our series of myelodysplastic patients, we found 16 patients who were initially diagnosed as having a refractory anemia with excess of blasts (RAEB) according to FAB criteria, but later on (median time 4 months, range 2-8) developed a peripheral monocytosis1 x 10(9)/L, leading to a disease re-classification into a dysplastic type of chronic myelomonocytic leukemia (MD-CMML). Analysis of clinical and prognostic aspects in this subgroup of patients as compared with those of primarily diagnosed MD-CMML patients, showed some significant differences in Hb level, platelet count, percentage of immature circulating precursor (IPC), bone marrow blastosis and trilineage dysplasia. Median survival for present group of patients was 33 months compared with 20 months for MD-CMML. Different prognostic scores were applied for evaluation of risk distribution and relative impact on survival prediction. We suggest on a possible atypical presentation of CMML and indicate a careful attention to be addressed to myelodysplastic patients who develop peripheral monocytosis, who might have a CMML variant, with more favourable prognosis and prolonged survival. Furthermore, we believe this is a further evidence for the arbitrary nature of current classification systems, which definitely exclude CMML from myelodysplastic syndromes.

The WHO classification subdivides the FAB RAEB category into RAEB-1 (bone marrow (BM) blasts10%, peripheral blasts5%) and RAEB-2 (bone marrow blasts10% and peripheral blasts5%). We reclassified according to WHO criteria 228 RAEB patients and analysed them in terms of haematological, karyotypic and prognostic features. We used the database of 680 MDS patients referred to our Institution from 1990 to 2000. Clinical features at presentation, such as sex, age, leukocyte count, polymorphonuclear cell count (PMN), platelet count, haemoglobin level, presence of one or more lineage dysplasia were tested in univariate and multivariate analysis in the two groups of RAEB-1 and RAEB-2 reclassified patients. In multivariate analysis we identified prognostic significant factors in the two patient groups, which consisted of age70 years and platelet count100 x 10(9)l(-1) for RAEB-1 category, while for RAEB-2 group parameters negatively influencing survival and risk of progression were haemoglobin10g/dl, platelet count100 x 10(9)l(-1), bone marrow blastosis15% and complex karyotype. We also found differences in cytogenetic data (more balanced translocations and complex karyotypes in RAEB-2 group, p=0.02), and in survival (23.3 months in RAEB-1 vs. 16.1 months in RAEB-2 group, p=0.001). WHO classification provides valuable prognostic information for RAEB patient population, and can identify those subjects with more unfavourable prognosis who should be offered alternative therapeutic strategies.

Imatinib mesylate is a selective inhibitor of the bcr/abl, c-kit and PDGF receptor tyrosine kinases. Its ocular toxicity is little known with mild periorbital oedema being the most commonly reported side effect. We here describe our experience on ocular complications in imatinib treated Ph+ CML patients, which consisted of a wide spectrum of adverse effects ranging from periobital oedema to serious adverse events such as glaucoma.

Philadelphia positive (Ph+) chronic myeloid leukaemia (CML) presenting synchronously or following non-Hodgkin lymphoma (NHL) has only rarely been reported. Herein, we refer on a case of Ph+ CML occurring after a breast cancer and a NHL with multiple relapses. After obtaining complete cytogenetic remission with imatinib, the patient presented a new NHL relapse, that was treated with rituximab concomitantly to imatinib. Therapy was well tolerated and the patient is presently alive in complete remission of either NHL and CML. We also reviewed the literature relating the uncommon association of these two unrelated diseases.

One of the major changes suggested by the World Health Organization (WHO) classification with respect to the French-American-British (FAB) proposal for myelodysplastic syndromes (MDS) was to lower the bone marrow (BM) blast count from 30 to 20%, thus eliminating the refractory anaemia with excess of blasts in transformation (RAEB-t) category. However, a general consensus has not been reached, and several authors still retain RAEB-t as an MDS sub-entity. We re-evaluated our series of 74 patients classified as RAEB-t according to the FAB criteria by stratifying them into two subsets: patients with at least 5% peripheral blast (PB) cells but with BM blasts 5% PBs, should be included in the RAEB-II category according to the WHO criteria, with a group of 98 patients who were diagnosed as RAEB-II according to the WHO criteria. The findings showed that the aggregation of these two subsets appeared inappropriate, because patients of the two groups showed different clinical features and rates of acute transformation. In conclusion, the RAEB-t entity according to the FAB criteria, although including heterogeneous clinical patient subsets, should more likely be considered as an advanced stage of MDS, rather than a true acute myeloid leukaemia.

Imatinib has become the gold standard therapy for Ph(+) CML, as it induces complete cytogenetic remission (CCR) in 75-90% of patients in chronic phase (CP), and up to 40% of these patients obtain at least a 3 log reduction of BCR/ABL transcript [Kantarjian HM, Cortes JE, O'Brien S, Luthra R, Giles F, Verstovsek S, et al. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood. 2004;104:1979-1988]. However, it is not yet stated whether continued therapy is required to maintain this response or whether imatinib may be discontinued after confirmation of a prolonged complete molecular remission (CMR). We here report on a Ph(+) CML case in long lasting CCR following interferon-alpha treatment (IFN) which reached CMR with imatinib but soon relapsed at molecular level after this latter drug discontinuation; we considered the present observation also in the light of previously reported data.