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Large B-cell lymphomas (LBCLs) constitute a subgroup of aggressive but highly curable lymphoproliferative diseases. Treatment of relapsed/refractory (R/R) patients still represents an unmet clinical need, and novel drugs and combinations are in continuous development. The pan–B cell panel of surface antigens that characterizes LBCL leads to a large umbrella of druggable targets. Monoclonal antibodies (mAbs) express their activity against lymphoma by targeting multiple tumor-specific antigens. This category consists of a number of molecules with different mechanisms of action, including naked mAbs, radioimmunoconjugates, antibody-drug conjugates, checkpoint inhibitors, and bispecific antibodies. In the last decade, apart from the well-known role of the anti-CD20 mAb rituximab, novel mAbs have led to remarkable steps forward in the treatment of R/R LBCL in monotherapy and combined with chemotherapy. Multiple studies are in development trying to bring these novel compounds into the frontline setting to empower the RCHOP effect or as alternative chemotherapy-free options for elderly/unfit patients. This review provides insight into antilymphoma mAbs, focused on the efficacy and safety of the main molecules approved or in development for LBCL andperspectives on the treatment of this disease.

Elderly patients represent a consistent portion of new diagnoses of B cell Non-Hodgkin Lymphoma (B-NHL). The treatment approach in this setting can be challenging for clinicians due to treatment toxicities and patients' comorbidities to deal with. Immunochemotherapy still represents the main option in the front-line setting for diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL), with different options to choose depending on patient characteristics. In the last decade, a number of new drugs and combinations have been investigated, demonstrating efficacy and safety even in the older population and extending the spectrum of treatment choices for this setting.This article reviews the majority data in literature on immunochemotherapy regimens and chemo-free approaches available for DLBCL, FL, and MCL in the elderly, both in front-line and relapse/refractory setting, the incoming drugs and how to identify the best option for each patient.The therapeutic approach for elderly B-NHL is challenging and a tailored approach guided by a geriatric assessment is mandatory, in order to optimize efficacy and minimize treatment-related toxicities. The more extended use of biological drugs may potentially lead to prolonged survival with reduction of toxicities and improved quality of life.

The prognostic role of TP53 disruption has been established in diffuse large B-cell lymphoma (DLBCL). Aim of this analysis was to correlate TP53 mutations by Sanger sequencing, cell of origin (COO) profile by Lymph2Cx panel on the NanoString platform and MYC, BCL2 and BCL6 overexpression or re-arrangements by immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH), with outcome in DLBCL patients enrolled into the FIL-DLCL04 trial (NCT00499018). One hundred and twenty-five DLBCL patients with tumour block available were analyzed. TP53 was mutated in 11/125 (9%) cases; 60/125 patients received high-dose chemoimmunotherapy up-front, as for the randomization arm; COO was reported in 88 patients: 48 germinal centre B-cell like, 25 activated B-cell like and 17 unclassified; 26 patients were double expressors in IHC and 11 double hit in FISH. After a median follow-up of 72 months, five-year failure-free survival (FFS) for TP53 mutated versus wild-type was 24% and 72%, and five-year overall survival (OS) was 34% and 83%, respectively. Adjusted hazard ratio (HR) was 2·28 [95% confidence interval (CI) 0·89-5·86, p = 0·086] and 4·05 (95% CI 1·37-11·97, p = 0·011) for FFS and OS, respectively. In this series of young DLBCL patients, TP53 gene mutation identified a poor prognosis subgroup, regardless of treatment and other biological markers.

Introduction: Secondary central nervous system lymphoma (SCNSL) is a potentially fatal event in the setting of aggressive Non-Hodgkin Lymphomas. Nowadays, despite of the very poor outcome of SCNSL, several studies are going to identify the high-risk patients' subgroup that could early develop this detrimental event and in whom the central nervous system (CNS) prophylaxis could improve survival. Areas covered: Herein, the authors will review the prophylactic and treatment strategy for SCNSL, focusing on the identification of high-risk subgroup. Expert opinion: The validated CNS International Prognostic Index score lacks sensitivity. The role of prophylaxis has been suggested as an important step for selected patients. Intrathecal prophylaxis is always less consolidated, due to its doubtful efficacy, whereas systemic high-dose methotrexate is becoming the favored option to reduce CNS relapse in high-risk aggressive lymphomas. However, there is no a clear guideline to help physicians in clinical practice. The encouraging results on treatment of primary CNS lymphoma prompted new therapeutic strategies for SCNSL, although larger and randomized prospective studies are needed. Future efforts should be addressed to better clarify these open questions.

Introduction: High Grade B-cell Lymphomas (HGBL) have been defined as a new separate entity in 2016 revised WHO classification of lymphoid neoplasms. The previously well-known Double- and Triple-Hit Lymphomas (DHL/THL) are included in this umbrella category under the name of HGBL with MYC and BCL2 and/or BCL6 rearrangements (HGBL, R). A comprehensive diagnosis of HGBL is laborious, the diagnostic analyses required are expensive and time-consuming; moreover, a uniform consensus on which patients should be investigated has not been reached yet. Furthermore, there is no agreement on a standard therapeutic approach for this entity. Areas covered: In this article, the biological and clinical peculiarities of HGBL will be reviewed and all tools for a comprehensive diagnosis as well as the current therapeutic landscape will be investigated. Expert opinion: HGBL, R remains a challenging disease in terms of diagnosis and further research should be performed in order to define clear guidelines determining which cases have to be investigated thoroughly with FISH and other probes. Unsatisfying results have been shown in patients with HGBL, R treated with intensified chemoimmunotherapy strategies, therefore, larger prospective clinical trials should be conducted. Investigation into novel drugs that could lead to improvement of the current therapeutic approach should also be addressed.

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.

Ibrutinib is associated with durable responses in patients with Waldenström macroglobulinemia (WM). We hypothesized that response depth is predictive of progression-free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at 6 months in learning and validation cohorts were 64% and 71%, respectively (p=0.29). In the learning cohort, 3-year PFS rates for patients who attained PR or better at 6 months vs. not were 81% and 57%, respectively (p=0.009). In the validation cohort, 3-year PFS rates for patients who attained PR or better at 6 months vs. not were 83% and 54%, respectively (p=0.008). In multivariate analyses, attaining PR or better at 6 months was associated with superior PFS in the learning (HR 0.38; p=0.01) and validation cohorts (HR 0.18; p=0.004). Attaining PR at 6 months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.

Atypical Chronic Myeloid Leukemia, BCR-ABL1 negative (aCML) is a rare hematological entity, included in the group of myelodysplastic (MDS)/myeloproliferative (MPN) overlap syndromes. It is characterized by an aggressive course, a high rate of acute myeloid leukemia (AML) transformation, and a dismal outcome. The clinical presentation includes splenomegaly and leukocytosis with neutrophilia and left-shifted granulocytosis accompanied by granulocytic dysplasia and sometimes multilineage dysplasia. In past years, the disease incidence was likely underestimated, as diagnosis was only based on morphological features. Recently, the improving knowledge in the molecular biology of MDS/MPN neoplasms has made it possible to distinguish aCML from other overlapping syndromes, basing on next generation sequencing. Among the most commonly mutated genes, several involve the Jak-STAT, MAPK, and ROCK signaling pathways, which could be actionable with targeted therapies that are already used in clinical practice, opening the way to tailored treatment in aCML. However, currently, there are few data available for small samples, and allogeneic transplant remains the only curative option for eligible patients.

Waldenström's macroglobulinemia (WM) is a rare, incurable B-cell lymphoma, with a median survival of 5-10 years in symptomatic patients. There is no consensus on the standard of care and several agents are currently used in these patients. Areas covered: In this article, we will review the use of standard therapies and new drugs investigated such as monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, Bruton's tyrosine kinase inhibitors and novel agents in early-stage development. Expert commentary: RCD (Rituximab/Cyclophosphamide/Dexamethasone) is an effective and safe treatment in first line in WM. BR (Bendamustine/Rituximab) or BRD (Bortezomib/Rituximab/Dexamethasone) provide durable responses, and are still indicated in most patients. Ibrutinib is a new option and it was approved as primary therapy and for relapse. Carfilzomib based therapy represents an emerging option for proteasome-inhibitor based therapy for WM. Despite encouraging results, WM remains an incurable disease; therefore, new treatment options are needed. For this reason, continued participation in clinical trials should be encouraged.

Diffuse large B-cell lymphoma (DLBCL) is the most common histotype in non Hodgkin lymphoma, with a peak incidence in the sixth decade. The standard treatment for elderly FIT DLBCL patients is Rituximab-CHOP; in unfit and frail patients, chemotherapy at reduced intensity should be considered. Areas covered: In this article, we will review use of standard therapies and new drugs investigated such as immonomudulating agents (IMiDs), Bruton Tyrosine Kinase (BTK), in fit, unfit, frail and very elderly DLCBL patients. Expert commentary: R-CHOP21 in fit DLBCL patients is still the standard of care, while in elderly unfit patients a reduction of doses of cytotoxic drugs or schemes that avoid antracycline should be considered. The Comprensive Geriatric Assesment based in age, comorbidities and functional abilities of daily living is an important tool in elderly, in order to discriminate between fit, unfit or frail patients. Novel drugs represent valid therapeutic options in relapsed/refractory setting so continued participation in clinical trials should be encouraged.

Helicobacter pylori (H. pylori) is one of the most common worldwide infections, which can affect both adults and children. The prevalence of this bacterium is variable in different countries, depending on various hygienic and socioeconomic conditions and living customs. The major damaged tissues of the infection are in the upper gastrointestinal tract, causing gastritis, gastric and duodenal ulcer and gastrointestinal malignancy. Nevertheless, other disorders are associated with this pathogen, including several hematological diseases, such as iron deficiency anemia, immune thrombocytopenia and vitamin B12 deficiency. A huge of data in literature support these associations, enough to recognize them in the last Maastricht V/Florence Consensus Report by European Study Group. The pathogenic mechanisms underlying the linkage between H. pylori and these hematological disorders are not clearly identified, but certainly the good hematological response reaches after eradication therapy confirm a central role of the bacterium in this scenario. Instead, the pathogenic mechanisms of H. pylori infection, which lead to the occurrence of mucosa-associated lymphoid tissue (MALT) lymphoma are clearer and more consolidated; so much that nowadays eradication therapy alone represents the only treatment in this disorder, when localized and with a concomitant H. pylori infection. This review focuses on the hematologic diseases related to H. pylori, particularly on iron deficiency anemia, vitamin B12 deficiency, immune thrombocytopenia and gastric MALT lymphoma.

Although sometimes presenting as an indolent lymphoma, mantle cell lymphoma (MCL) is an aggressive disease, hardly curable with standard chemo-immunotherapy. Current approaches have greatly improved patients' outcomes, nevertheless the disease is still characterized by high relapse rates. Before approval by EMA, Italian patients with relapsed/refractory MCL were granted ibrutinib early access through a Named Patient Program (NPP). An observational, retrospective, multicenter study was conducted. Seventy-seven heavily pretreated patients were enrolled. At the end of therapy there were 14 complete responses and 14 partial responses, leading to an overall response rate of 36.4%. At 40 months overall survival was 37.8% and progression free survival was 30%; disease free survival was 78.6% at 4 years: 11/14 patients are in continuous complete response with a median of 36 months of follow up. Hematological toxicities were manageable, and main extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%). Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred. In conclusions, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; regarding effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL also in a clinical setting mimicking the real world.

Diffuse Large B-cell Lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), with an incidence in Europe of 3.8/100.000/year. A multi-drugs chemoimmunotherapy regimen, containing rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone (R-CHOP) administrated every 21 days, is the standard therapy for DLBCL patients. The discovery of several biological features of DLBCL has encouraged the introduction of novel drugs in the treatment. Areas covered: In this article, the use of standard therapies will be reviewed and will be investigated adoption of novel drugs such as Bortezomib, Bruton's tyrosine kinase, IMiDs, Venetoclax, mTOR inhibitors and other biological agents. Expert commentary: A better knowledge of the biology of DLBCL is mandatory to tailor treatment and to ameliorate the poor prognosis of DLBCL. The addition of novel drugs to standard RCHOP should represent a modern approach in the treatment of DLBCL. Ibrutinib and lenalidomide showed important results in DLBCL and the integration of these drugs in first line treatment is under investigation. Despite encouraging results using novel drugs in the setting of relapsed/refractory DLBCL, the rate of failures still remains at 40%; for these reason, continued participation in clinical trials should be encouraged.

Introduction. The majority of SMZLs display an indolent course, however the disease is still incurable and a significant proportion of patients (~25-30%) experience poor outcomes surviving 5 years, and for whom tumor material collected before initiation of medical therapy was available. Mutation analysis was performed by CAPP-seq targeted deep next generation sequencing of tumor genomic DNA. A stringent bioinformatic pipeline was applied to suppress the background noise allowing to call variants with a sensitivity of 5x10-2 in FFPE derived DNA. Copy number variations (CNVs) were identified by using the sequencing reads-based GATK4-CNV algorithm. IGHV rearrangements were obtained by using LymphoTrack® IGH FR1 Assay Panel kit. Molecular clusters were identified by an iterative algorithm that maximizes genetic distinctiveness of subgroups by reassigning patients between clusters that are created a priori based on the co-occurrence of genetic lesions. Relative survival, defined as the ratio between actuarial survival observed in the SMZL cohort and expected survival of the general population matched to patients by geographical origin, sex, age and calendar year of diagnosis, was calculated using the Ederer II method. Results. The analysis included 303 patients with a SMZL diagnosis confirmed on spleen histology. The sample size allowed to identify 30% differences in survival for molecular subgroups comprising at least 5% of cases with a statistical power between 80-100%. Median follow-up was 9.2 years. At 10 years, 85% of patients were alive, consistent with the known indolent behavior of this lymphoma. Genes recurrently affected by non-synonymous somatic mutations in >10% of SMZL included KLF2 (24%), NOTCH2 (19%), KMT2D (15%), TNFAIP3 (13%), EP300 and TP53 (10%). Deletion 7q was documented in 25% of cases and IGHV1-2*04 usage in 32%. By cluster analysis, three major molecular subgroups were identified, each of them characterized by a NOTCH pathway mutated gene (Fig. 1A). The first cluster was defined by NOTCH2 and/or KLF2 mutations and was enriched in TNFAIP3 mutations and IGHV1-2*04 gene usage (Fig. 1A). The second cluster was defined by SPEN mutations, and was enriched in KMT2D and other epigenetic gene mutations (Fig. 1A). The third cluster was enriched in NOTCH1 mutations (Fig. 1A). By relative survival analysis, the NOTCH2/KLF2 cluster showed a lower survival compared to the matched general population, indicating a significant impact of the disease on patients' expected survival (Fig. 1B). Conclusions. The large sample size and inclusion of SMZL confirmed by spleen histopathology review allowed for precise estimation of the prevalence of KLF2 and NOTCH2 mutations in this lymphoma. Three molecular clusters were identified in SMZL, each of them containing a NOTCH pathway gene, supporting the relevance of NOTCH signaling in the pathogenesis of SMZL. Patients belonging to the NOTCH2/KLF2 cluster had a lower relative survival compared to the matched general population. Disclosures Traverse-Glehen: Astra Zeneca: Other: Travel; Takeda: Research Funding. Gomes da Silva:Roche: Other: Institution's payment for consultancy, Travelling support; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Celgene: Other: Travelling support; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Institution's payment for consultancy, Travelling support; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Research Funding. Ladetto:Celgene: Honoraria; Jannsen: Honoraria; Acerta: Honoraria; Abbvie: Honoraria; Sandoz: Honoraria; Roche: Honoraria. Rambaldi:Pfizer: Consultancy; Novartis: Consultancy; Omeros: Consultancy; Italfarmaco: Consultancy; Amgen Inc.: Consultancy; Roche: Consultancy; Celgene: Consultancy. Vitolo:Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Gilead: Speakers Bureau; Janssen: 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, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Zinzani:MSD: Honoraria, Speakers Bureau; Gilead: 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; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Janssen: Honoraria, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, 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; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: 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; Astra Zeneca: Speakers Bureau. Gaidano:Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Morphosys: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Salles:Servier: Honoraria; Abbvie: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Honoraria; BMS: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Acerta: Honoraria; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Pfizer: Honoraria; Morphosys: Honoraria; Gilead: Honoraria, Other: Advisory Board; Epizyme: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria. Zucca:Celltrion: Consultancy; AstraZeneca: Consultancy.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma, typically affected mature adults and elderly, with a median age at diagnosis of 65 years. The natural history of FL appears to have been favorably impacted by the introduction of Rituximab. Randomized clinical trials have demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival and new strategies of chemo-immunotherapy, such as Bendamustine combined with Rituximab, showed optimal results on response and lower hematological toxicity, becoming one of the standard treatments, particularly in elderly. Moreover maintenance therapy with Rituximab demonstrated improvement of progression-free survival. Despite these exciting results, FL is still an incurable disease. It remains a critical unmet clinical need finding new prognostic factors to better identify poor outcome patients, to reduce the risk of transformation and to explore new treatment strategies, especially for patients not candidate to intensive chemotherapy regimens, such as elderly patients. Some progresses were already done with novel agents, but larger and more validated studies are needed. Elderly patients are the larger portion of patients with FL and represent a subgroup with higher treatment difficulties, because of comorbidities and smaller spectrum for treatment choice. Further studies, focused on elderly follicular lymphoma patients, with their peculiar characteristics, are needed in order to define the best tailored treatment at diagnosis and at the time of relapse in this setting.

Introduction: MYC and BCL2 overexpression assessed by IHC and rearrangement detected by FISH are important prognostic factor in Diffuse Large B-Cell Lymphoma (DLBCL). Double Hit Lymphoma (DHL) patients have a poor prognosis with conventional therapy and Double expressor Lymphoma (DE) have worse outcome compared with conventional DLBCL although data are controversial. Aimed at a better knowledge of this issue, we performed a retrospective analysis to determine prevalence and outcome of Single Hit Lymphoma (SHL), DHL and DE in patients with de-novo DLBCL treated with Rituximab and CHOP. Methods: de novo DLBCL treated with R-CHOP between January 2003 and December 2013 were included in the study. BCL2 and BCL6 expression were evaluated by IHC at diagnosis while MYC expression was retrospectively investigated with Tissue Micro Arrays (TMA) technique; cases were considered positive for MYC, BCL2 or BCL6 expression by IHC if >40%, >40% or >25% of cells stained positive, respectively. FISH analysis for MYC and BCL2 rearrangements were performed with dual color break apart probes on TMA. PFS and OS were estimated with Kaplan-Meier method and compared between groups with the Cox model. We further evaluated in this series the IHC score proposed by Botto et al. (Blood 2014 124:2964) in DLBCL. The score was based on the assessment in IHC of the expression of MYC, BCL2 and BCL6. The three variable contributed with different risk in the multivariate analysis and an IHC sum additive score of 0-5 was calculated proportionally to the coefficient estimated (coefficient [Log hazard ratio] 0.92 for MYC+, 0.73 for BCL2+ and 0.48 for BCL6-), assigning an individual risk of 2 points for MYC or BCL2 positivity and 1 point for BCL6 negativity. Patients were stratified in three different risk groups; Low risk (0-1 point), Intermediate risk (2 points) and High risk (≥3 points). Results: Of a total of299 DLBCL screened, 267 were evaluable for survival analysis; median age was 65 years (range 20-90). 154 patients had complete immunohystochemical data and 101 were fully investigated by IHC and FISH. No significant differences in clinical presentation or in the outcome were seen between patients with or without available histologic tissue for IHC and FISH. Among 154 patients with complete IHC data we found 12 (8%) DLBCL without expression (DLBCL), 96 (62%) Single expressor (SE), 46 DE (30%). With a median follow up of 60 months, 5-year PFS rates were: DLBCL 90%, SE 60% and DE 43% respectively (fig 1) (HR 8.25 (95% CI: 1.12 -60.99) p 0.039); 5ys OS rates were 91%, 68% and 57% respectively (HR 5.72 (95% CI: 0.77 - 42.82) p 0.08). Applying the prognostic model (adjusted for IPI and age) defined in our previous pilot study we recorded 12/154 patients with low risk score, 61/154 with intermediate and 81/154 patients in high risk group. 5y-PFS rates were 91% vs 67% vs 45% (p=0.014) respectively (HR 1.74 (95% CI: 1.12 -2.69) p 0.014). Among 101 patients investigated by FISH we recorded 10 SHL (10%) and 8 DHL (8%). Clinical characteristics were superimposable among DLBCL, SHL and DHL with a prevalence of non GCB phenotype in DE group (56%). Among 101 patients fully investigated for FISH and IHC, 38 patients had MYC overexpression by IHC; 11 of them had also a MYC translocation. We found 3 cases with MYC rearrangement without protein overexpression. With a median follow up of 60 months PFS in DLBCL, SHL and DHL was 65%, 58% and 25% respectively (fig. 2); 5 ys OS was 70%, 77% and 25% respectively. The worse prognosis of DHL was statistically significant with an HR of 3.3 (95% CI: 1.37- 7.94, p 0.008) in terms of PFS and 3.9 (95% CI:1.59- 9.52 p 0.003) in terms of OS. Conclusion: Our data confirmed that our IHC prognostic score based on MYC, BCL2 and BCL6 expression, is a simple, reproducible and valid prognostic assessment that identify three groups with a different outcome in a large cohort of DLBCL. Moreover these data confirm intermediate prognosis for patients with DE lymphoma and poor prognosis of DHL treated with conventional chemoimmunotherapy. Figure 1 PFS in patients with complete IHC data Figure 1. PFS in patients with complete IHC data Figure 2 PFS in patients with complete FISH data Figure 2. PFS in patients with complete FISH data Disclosures Chiappella: Roche: Speakers Bureau; Celgene: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Teva: Speakers Bureau; Pfizer: Speakers Bureau; Amgen: Speakers Bureau. Cavallo:Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria. Vitolo:Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

We report the first case of 2 patients with a previous diagnosis of post-polycythemic (PV) myelofibrosis who developed chronic myeloid leukemia (CML) seven years later, both treated with an association of a tyrosine-kinase inhibitor (imatinib) and a JAK1/JAK2 inhibitor (ruxolitinib). In 1992, a 46