ALBERT

Description: Metastatic disease of the bone is a rare complication of chronic lymphocytic leukemia (CLL), it may be result from richter's transformation or metastatic from non lymphoid malignancies. CLL is the most common form of adult leukemia, with the median age of 70 years at diagnosis [Siegel et al. 2013]. The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes.The result is the increased number of lymphocytes in the peripheral blood, leukocytosis with absolute lymphocytosis, the increase of the lymphnodes, the increase in size of the spleen. The diagnosis of chronic lymphocytic leukemia B requires the presence of Clonal B cells in the peripheral blood at or above 5,000 / ul for at least 3 months. Typing immunophenotypical pathological lymphocytes are positive for surface antigens CD5, CD19, CD23, weakly positive for CD20 and CD22, generally negative FMC7 and CD79b; also expressing surface immunoglobulins. The Rai and Binet staging systems, which are established by physical examination and blood counts, have been recognized as standards for deciding whether to begin treatment. Patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. For fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab represents the current standard therapy. For unfit patients, treatment with an anti-CD20 antibody (obinutuzumab, rituximab, ofatumumab) plus a milder chemotherapy (Chlorambucil) may be applied. At relapse, if the treatment-free interval exceeds two to three years, the initial treatment may be repeated, if the disease relapses earlier, drugs such as bendamustine (plus rituximab), alemtuzumab, lenalidomide, ofatumumab, ibrutinib, or idelalisib, must be choosen. Patients with a del(17p) or TP53 mutation can be treated with ibrutinib or a combination of idelalisib and rituximab. in relapsing patients with TP53 mutations or del(17p) or patients that are refractory to repeated chemoimmunotherapies, an allogeneic SCT may be considered [Hallek M 2015]. In this article we show a case of a 66-year-old man with CLL and a bone localization. In 2011 diagnosis of CLL, Rai Stage 0, Binet Stage A. Principal characteristics at diagnosis: HB 13.2 g /dl, White Blood Cells 15.800 / mm3, lymphocytes 61%, neutrophils 32%, monocytes 4%, platelets 141.000/mm3; normal hepatic end renal function; flowcytometric immunophenotyping of the peripheral blood revealed B-cell CLL; prognostic factors: CD38 negative, ZAP70 positive, rearrangement of the immunoglobulins mutated; FISH: negative; CT chest / abdomen / pelvis: presence of multiple aorto-pulmonary and axillary adenopathies (max diameter of 2 centimeters); bone marrow biopsy: infiltration of CLL equal to 60% of global cellularity. The patient was only observed until January 2015, when he was hospitalized due to acute anemia, requiring supportive therapy, and right foot pain . So it was decided to re-evaluate the whole disease in order to decide whether to start chemotherapy. The disease was staged again with instrumental and laboratory tests: presence of renal insufficiency, egd and colonoscopy negative, Coombs' test negative, bone marrow biopsy confirmed the diagnosis of chronic lymphocytic with bone marrow infiltration of 90%, abdomen ultrasound showed only moderate splenomegaly. On February, persistence of right foot pain and appearance of swelling, assessed by the orthopedic as a suspected algic and dystrophic syndrome. So he suggested to perform scintigraphy which revealed: pronounced inflammatory osteometabolic reaction of the right tibia/fibula/ankle third distal which could be referred, in the first evaluation, to algic and dystrophic syndrome. However, a local biopsy was performed: localization of chronic lymphocytic leukemia. On March 2015 a total body TC showed 2 nodular calcifications in the right lung lobe, multiple right paratracheal, barety space, aortopulmonary and axillary adenopathies. Prostate size increased. In order to study carefully the liver and prostate lesions, an ultrasound abdomen was performed that documented only enlarged spleen, normal size liver, free of focal disease, increased prostate due to symmetric bilobate hypertrophy . After the second cycle of chemotherapy, prolonged thrombocytopenia, so he continues only with a radiotherapy program. Disclosures No relevant conflicts of interest to declare.

Description: The aim of our perspective observational study was identify a fast molecular biomarker of tumorigenic-proliferative haematological disorders at on set using a non-invasive method. At this end, to better discriminate between myeloproliferative or lymphoproliferative hematological disease, from May to July 2014, we collected peripheral blood mononuclear cells (PBMCs) from patients at the first medical examination and without drug therapy. The patients were divided into groups on the basis of the diagnosis. Group 2 (n=8) included patients suffered from mixed disorders such as myeloproliferative neoplasms (MPD) associated to monoclonal gammopathy of undetermined significance (MGUS). Group 3 (n=8) included patients with only MGUS, group 4 included 9 patients with only primary myelofibrosis (M). Healthy donors (Group 1, n=16) were considered as normal subject or calibrator in molecular analysis. Their PBMCs were used to perform relativegene expression profile of a transcriptome involved in apoptotic control, stem-cell differentiation, immune network, inflammation and leukemogenesis, in order to detect whether these may serve to label the patient groups. A multigene expression assay (47 genes) was carried out with the TaqM,an® Low Density Array Fluidic card. In Group 3 (MGUS), 6 genes were differentially expressed (BMI-1, FLT3, FZD1, FZD5, ICAM1, IMP3). Also, we compared variance, main value for each gene in each group and T-test that showed a significant differential expression pattern (p

Description: Aims: In elderly patients with acute myeloid leukemia (AML), complete remission (CR) rate following intensive chemotherapy is approximately 45%, considerably lower than in younger patients, with a shorter duration of remission and high treatment-related mortality (30-50%). Median survival is about 12 months. Intensive chemotherapy is indicated in a small proportion of "fit" elderly patients. In a phase III, prospective, randomized, open-label, multicenter trial designed to assess the efficacy of post-remission treatment with 5-Azacitidine versus best supportive care (BSC) in patients 〉 60 years of age with AML in CR after conventional induction ("3+7") and consolidation chemotherapy, quality of life (QoL) was assessed from diagnosis. We present interim results of changes of QoL. Methods: Patients with newly diagnosed AML with 〉 30% myeloid marrow blasts, either "de novo" or evolving from myelodysplastic syndrome without contraindications for intensive chemotherapy and with an ECOG performance status 〈 3 are included. Induction chemotherapy consists of two courses of "3+7": Daunorubicin 40 mg/m2 daily days 1-3 and cytarabine 100 mg/m2 daily continuous IV infusion days 1-7. Patients in CR receive consolidation (cytarabine 800 mg/m2 3 hour infusion bid days 1-3) and are randomized 1:1 to receive BSC or 5-Azacitidine maintenance therapy up to 4 years and six months until AML recurrence. QoL assessment was performed using the EORTC QLQ-C30 and the QOL-E v.3 questionaires. Results: QoL results assessed at 3 time points are reported: 1) baseline; 2) at hematological recovery immediately after the first "3+7" course; and 3) after consolidation at randomization. Ninety-nine patients (male/female 50/49) of median age 70 (IQR 65-74) years have been enrolled. At diagnosis, mean hemoglobin was 9.2 (SD ± 2.4) g/dL, leukocytes were 7.9 (2.3-29.6)/µL, platelet count was 54 (IQR 29-85) Gi/L and bone marrow blasts were 70 (IQR 50-85)%. Seventy-five patients had "de novo" AML. Twenty-three patients had comorbidities. Forty-three patients had an ECOG PS 1 and 28 had ECOG PS 2. Baseline median QOL-E scores were poor (≤60) in all dimensions, except for fatigue (76, IQR 52-85). EORTC QLQ-C30 confirmed that fatigue was not prevalent at diagnosis (median 33, IQR 22-56). Median baseline EORTC QLQ-C30 scores were good in all domains except for global health status (GHS, median 50, IQR 33-67). Gender, comorbidities, bone marrow blasts and secondary AML were not related to QoL. Baseline Hb levels correlated with QOL-E functional (r=0.0216, p=0.14), fatigue (r=0.256, p=0.002) and disease-specific (r=0.247, p=0.010) scores and with EORTC QLQ-C30 GHS (r=0.270, p=0.001), physical (r=0.304, p

Description: Background: High-dose melphalan (HDM) is the standard therapy for autologous stem cell transplantation (ASCT) in multiple myeloma (MM), although the optimal conditioning regimen remains yet to be identified. Bendamustine (BENDA) has a proved activity in hematological malignancies including both first line and relapsed MM. Methods: We conducted a phase II trial, adding BENDA to HDM before second ASCT, in a tandem ASCT strategy, in 32 patients with "de-novo" MM. All patients received a bortezomib-based induction therapy. High-dose cyclophosphamide (CY) and G-CSF were used to mobilize stem cells. Four to 6 weeks after the administration of CY, patients received HDM (200 mg/mq), followed by ASCT. Three to 6 months after the first transplantation, patients received a second ASCT with BENDA (200 mg/m2) to HDM (140 mg/m2) as conditioning regimen (BM). Results: The median age was 56 years (range 40 to 66). Overall, there was no transplant related mortality. The incidence of neutropenic fever and mucositis (grade 1-2) was 46.9% and 81.2%, respectively. No mucositis grade 3-4 was observed. Median number of days to neutrophil and platelet engraftment were 11 and 12, respectively. After the second transplantation, the complete response (CR) improved to 62.5%. Overall response rate was 90.6%. After a median follow-up of 18,2 months, 4 patients had progressed and 1 died. Median progression free survival (PFS) was not reached and actuarial 2-year PFS and OS was 78% and 90%, respectively. Conclusion: Bendamustine plus melphalan is feasible as conditioning regimen for second ASCT in MM and should be explored for efficacy in a phase III study. Longer follow-up is needed to evaluate conversion rate and survival. Disclosures No relevant conflicts of interest to declare.

Description: Background: About 10% of low risk patients with myelodysplastic syndromes (MDS) experience severe thrombocytopenia. Bleeding and the scarce efficacy of platelet (PLT) transfusions drive research in novel treatments. Eltrombopag is an oral agonist of the thrombopoetin-receptor (TPO-R). Its potential in increasing platelet (PLT) counts in low risk MDS has not been evaluated. We present interim results on the efficacy and safety of eltrombopag in inducing PLT responses in patients with low and intermediate-1 International Prognostic Scoring System (IPSS) risk MDS with severe thrombocytopenia in a Phase II, multicentre, prospective, placebo-controlled, single-blind study (EQoL-MDS). Methods: Primary endpoints are safety and efficacy of eltrombopag. Secondary endpoints include changes in quality of life (QoL), PLT transfusion requirement, incidence and severity of bleeding, and survival. Inclusion criteria are adult age; PLT200 Gi/L or adverse events. Study design is shown in the figure. PLT response, assessed at each visit, is defined as Response if: 1) baseline PLT〉20 Gi/L: absence of bleeding and increase by at least 30 Gi/L from baseline; 2) baseline PLT20 Gi/L and increase by at least 100%, not due to PLT transfusions; and Complete Response if PLT≥100 Gi/L and absence of bleeding. QoL scores are analysed by MDS-specific instrument, QOL-E v. 3. Results: Seventy patients (46 on eltrombopag - Arm A, 24 on placebo -Arm B) have been randomized at the time of this report. Mean age is 68.3 (SD 13.0) years, M/F 38/32. ECOG performance status was 0 in 47 cases, 1 in 16 cases, 2 in 7 cases. Ten patients had comorbidities. According to the WHO 2008 classification, 22 patients had refractory cytopenia with unilineage dysplasia, 9 had refractory anemia with ringed sideroblasts, 31 had refractory cytopenia with multilineage dysplasia (of which 15 with ringed sideroblasts), 6 had refractory anemia with excess blasts-1 and 2 were unclassified. IPSS score was low in 48 cases. Mean baseline platelet (PLT) count was 17.1 (SD 8.2) Gi/L, mean hemoglobin level 10.8 (SD 2.5) g/dL and mean white blood cell count was 5.0 (SD 3.8) Gi/L. Twenty-five (36%) patients were red blood cell transfusion-dependent. Thirty-three had a WHO bleeding scale of 1, 2 experienced mild blood loss, 4 a gross blood loss and 1 a debilitating blood loss. Fourteen patients in Arm A and 8 in Arm B had required PLT transfusions in the 8 weeks prior to randomization. Twenty-three cases (50%) in Arm A have responded versus 2 (8%) in Arm B (p=0.001). Thirty-three patients have completed at least 24 weeks of study. Median time to response was 14 days (IQR 7-46 days) at a median daily dose of 75 (IQR 50-162.5 mg). PLT count increased by mean 53.2 (SD 68.1) Gi/L (p=0.001) in Arm A versus no significant changes in Arm B by week 24. QOL-E scores at baseline and 12 weeks in 47 cases in both arms are shown in the table. There was an increase in treatment outcome index,mainly experienced in the first 3 weeks (p=0.034). Fatigue improved from baseline to 12 weeks associated with response (p=0.016). Related Grade III-IV adverse events (AE) occurred in 10 patients (22%) in Arm A and consisted in: nausea (4), hypertransaminasemia (3), hyperbilirubinemia (1), sepsis (1), pruritis (1), heart failure (1), asthenia (1), vomit (1), while in Arm B 1 patient (4 %) experienced grade 3 bone marrow fibrosis. MDS disease progression occurred in 5 (11%) in Arm A versus 2 (8%) in Arm B, p=ns. Conclusions: Preliminary data indicate that lower risk MDS patients with severe thrombocytopenia undergoing treatment with eltrombopag experience significant improvements in PLT counts accompanied by improvements in fatigue. The drug appears to be well-tolerated and not associated with MDS progression. Further follow-up is required to evaluate the impact on survival. Figure 1. Study design Figure 1. Study design Figure 2. QOL-E domains at baseline and 12 weeks between Arm A (eltrombopag) and Arm B (placebo) Figure 2. QOL-E domains at baseline and 12 weeks between Arm A (eltrombopag) and Arm B (placebo) Disclosures Oliva: Novartis: Speakers Bureau; Celgene: Other: Advisory Board, Speakers Bureau; Amgen: Consultancy. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Palumbo:Novartis: Honoraria, Other: Advisory Board. Fenaux:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

Description: Introduction: Management of Ph+ ALL has changed since the introduction of tyrosine kinase inhibitors (TKI). We previously reported the preliminary findings of the GIMEMA LAL 1509 total therapy protocol, based on dasatinib plus steroids administration as induction therapy (Chiaretti et al, ASH 2014). The updated results on overall survival (OS), disease-free survival (DFS) and the impact of a genetic-based prognostic stratification are hereby provided. Methods: Steroids were administered from day -6 to day 31. Dasatinib (140 mg/day) was given between days 1 and 84. Patients reaching a complete molecular response (CMR, i.e. BCR/ABL1 to ABL1 ratio=0) at the end of induction (day 85) continued Dasatinib. Patients in complete hematologic remission (CHR), but not in CMR, underwent chemotherapy (clofarabine-cyclophosphamide) and/or an allogeneic transplant (HSCT), according to eligibility and donor availability. Dasatinib was administered until disease progression. Molecular testing was used to identify the presence of the BCR/ABL1 transcript on bone marrow samples, to define the fusion protein and to quantify BCR/ABL1 levels at baseline and follow-up (FU). Mutational screening was performed in relapsed cases, based on material availability. SNP array analysis was carried out using the Cytoscan HD arrays (Affymetrix, Santa Clara, CA) to identify genomic aberrations. Results: 60/63 enrolled patients were eligible. Median age was 41.9 years (range 18.7-59.1), 34 were males and 26 females; median WBC count was 12.5 x 109/l (range 1.4-178.0); the p190 fusion product was detected in 33 patients, p210 in 18 and p190/p210 in 9. Median FU is 28.4 months (range 4.2-43.7). After the steroid pre-phase, 38 patients (63%) had a blast reduction ≥75%. At day 85, 58 patients were in CHR (97%), while 2, in CHR at day 57, lost it: both harbored the p210 fusion transcript. They both returned into CHR following chemotherapy. A sustained CMR was obtained in 11 patients (18.6%): 72% had a p190 fusion transcript. No deaths in induction occurred. Among the CMR patients, only 1 experienced a hematologic relapse, which carried a T315I mutation. Of the 46 non-CMR cases, 14 relapses occurred, 8 of which in p210+ patients. Overall, there have been 12 deaths in CHR. OS is 58.3% (95%CI: 44.4-76.3) at 36 months and DFS at 30 months is 48.9% (95%CI: 36.8.0-64.9). A better DFS was observed in patients who obtained a CMR compared to cases with minimal residual disease (MRD) at day 85 (75% vs 44%, p=0.06), and in p190+ vs p210+ patients (57.1% vs 39.6%, p=ns). Mutational screening, performed in 7/15 cases at hematologic relapse detected mutations in 5: 3 T315I and 2 V299L, of which 1 with a concomitant F317I and F317L. SNP array analysis, performed in 39 cases with available DNA, showed that the most frequent aberrations were deletions of IKZF1 (85%), PAX5 (38%), CDKN2A/B (33%), MLLT3 (33%), RB1 (28%) and JAK2 (28%). While IKZF1 deletions alone did not impact on CHR or CMRachievement and DFS, a significantly worse DFS (p=0.01) and increased cumulative incidence of relapse (CIR, p=0.024) were observed in cases harboring deletions of IKZF1 plus CDKN2A/B and PAX5 (DFS: 40% vs 65% at 18 months; CIR: 40% vs 14% at 18 months (Fig. 1A and B). The relevance of this finding was further refined by stratifying patients according to the fusion protein: the impact of IKZF1 plus CDKN2A/B and PAX5 deletions is prognostically relevant in p190+, but not in p210+ patients, possibly because of the worse outcome of the latter group (Fig. 2). Finally, this analysis identified a set of genes specifically deleted in CMR cases; investigations are ongoing on additional cases to validate their potential role in predicting response to TKI. Conclusions: In this updated analysis of the GIMEMA 1509 trial, we confirm the effectiveness of a chemo-free induction in inducing CHR in almost all adult Ph+ ALL patients (97%) and CMR in a subgroup of cases (18.6%). OS and DFS at 36 months and 30 months, approaching 60% and 50%, are encouraging. More importantly, CMR achievement at day 85 is associated with extremely promising results, being 75% at 30 months, underlying that CMR should be regarded as a primary endpoint in Ph+ ALL. We confirm that p210+ patients may require an intensified approach, given the lower rate of CMR achievement and the higher relapse rate. Finally, we provide evidence that a broader genetic characterization at diagnosis allows a more refined prognostic stratification of Ph+ ALL patients. Disclosures Martinelli: Pfizer: Consultancy; Ariad: Consultancy; AMGEN: Consultancy; BMS: Consultancy, Speakers Bureau; ROCHE: Consultancy; MSD: Consultancy; Novartis: Consultancy, Speakers Bureau. Foà:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: BACKGROUD: Nilotinib, a potent 2nd generation tyrosin kinase inhibitor, is efficacious in the treatment of chronic myelogenous leukemia (CML). Impaired glucose metabolism represents one of the most frequently observed adverse events and several clinical trials, reported a high diabetes incidence during treatment with this drug. The mechanism of this side effect is poorly understood, but recently has been hypothesized an increased postreceptorial insulin resistence. Moreover, "in vitro"results indicated that c-ABL is involved in the insulin receptor signaling pathway. A large number of genetic variants associated with Type 2 diabetes (T2D) are implicated in beta-cell function but the role of common genetic variants associated with insulin resistance in the etiology of T2D, remains poorly documented. Scott R. and al. (Diabetes 2014) recently identified 10 multiple single nucleotide polymorphisms (SNPs) associated with insulin resistance and created a genetic risk scores (uGRS) as complementary tool to for insulin resistance. AIM of the study was to identify whether this uGRS could be a valid prognostic tool in identifying patients developing diabetes during Nilotinib therapy PATIENTS AND METHODS:45 patients (19 males) were included in the study. Twenty-four were treated with Nilotinib in first-line and 21 as second line (10 for resistance, 8 intolerance and 3 for other reasons). None of the subjects studied had abnormal blood glucose or took any antidiabetic drug before Nilotinib treatment. We genotyped all patients with the GRS created by Scott R. including those in, or near, the IRS1, GRB14, ARL15, PPARG, PEPD, ANKRD55/MAP3K1, PDGFC, LYPLAL1, RSPO3, and FAM13A1 genes that have primary effects on subcutaneous adipocyte function. Also we added 2 new variants, one for TCF7L2 gene, associated with insulin secretion and another in FTO gene, whose effect on insulin levels is mediated by BMI. The uGRS was calculated, as previously reported, by summing the number of risk alleles across the 12 variants (0 for risk allele absent, 1 for heterozygosity and 2 for homozygosity for risk allele). A cut-off point for uGRS, maximizing predictivity and sensitivity of the score was calculated using Youden's index. Diabetes and impaired fasting Glycaemia were defined using the American Diabetes association (ADA) criteria. Data were reported as median and range, RESULTS:Age at diagnosis was 45(18-82) years, the Sokal was low in 16 (42%), intermediate in 12 (26%) and high in 17 (32%) patients. During treatment and subsequent follow up of 45(7-127) months, 28 patients remained euglycemic, 5 (2 treated in the first line) developed diabetes after 14(1-32) months and 12 (6 treated as first line) developed IFG in 6 (1-12) months. No IFG patients developed an overt diabetes in the subsequent follow-up of 60.3 (33-102) months. We calculated a cut-off point of 12 for uGRS. When the 28 euglycemic patient were compared with 5 patients becoming diabetics after Nilotinib, uGRS showed a sensibility of 100% and a specificity of 46% in predicting diabetes. Consequently, the positive predictive valuewas 25% where the negative predictive values 100%. When the 28 euglycemic patients were compared with the 12 patients developing IFG after Nilotinib, the sensibility and specificity of uGRS was low: 50% and 46% respectively. CONCLUSIONS: A Genetic risk score for insulin resistance showed high specificity and a strong negative predictive values when used to identify CML patients treated with Nilotinib developing an overt diabetes. Further studies in lager populations are needed to confirm this predictivity that can be used in clinical practice to tailor the best anti TKI therapy. Disclosures No relevant conflicts of interest to declare.

Description: Background: Diagnosis of a prefibrotic state (MF0) presents histological diagnostic difficulties. MF0 has a worst prognostic impact than Essential Thrombocythemia (TE) as regard the thrombotic risk and a higher risk towards Idiopathic Myelofibrosis (MI) and acute leukemia evolution. For this reason it is very useful to identify this group of patients. Aims: The aim of this study was to evaluate clinical and hematological impact of the mutational status in patients with an MF0 diagnosis. Methods: A retrospective chart review was performed from January 2010 to July 2015 in a single center in 317 patients affected by Ph negative chronic myeloproliferative neoplasms. Polycythemia vera cases were excluded. Thirty-three patients have been classified as MF0 on the base of the bone marrow histological examination. Onset features include cytogenetics, blood counts, peripheral CD34-positive cells, spleen and liver size, thrombotic events (prior to and post-diagnosis) and thrombotic risk. Fragment analysis was performed to study exon 9 CALR mutation, Real-time PCR was applied for exon 14 JAK2 V617F mutation and Sanger sequencing was used to identify exon 10 MPL mutations for 505 and 515 codons. According to genetic results, patients were identified into four groups according to a positivity for JAK2, MPL, CALR and for triple negativity. Results: The 33 patients with MF0 were: 11 (33%) JAK2 positive, 10 (30%) CALR positive, (10) 30% triple negative and 2 (7%) MPL positive. The latter group was not further considered for analysis due to the low number of cases. Eighty percent of CALR positive patients had a deletion on the exon 9 of the gene (8 del52bp and 2 del46bp), while 20% had the type 2 mutation (ins5bp). The average of JAK2 allelic burden was 20%. The 3 groups of patients were comparable for age, white blood counts and hemoglobin values. There was a female prevalence (23 vs 10 males). Platelet count was higher (median 875.500 103 µl, interquartile range 303.000 103 µl , p = 0.008) in CALR positive patients compared to JAK2 positive (median 569.000 103 µl, interquartile range 433.000 103 µl) and to triple negative patients (median PLT count 629.500 103 µl, interquartile range 378.250 103 µl). Noteworthy, bone marrow cytogenetic exam was normal in all patients. JAK2 positive patients had a larger spleen compared to the other two groups. Pre-diagnosis thrombotic events were exclusive for JAK2 positive patients and absent in the other groups. Triple negative patients do not have a negative prognostic impact for the thrombotic risk. Conclusions: CALR deletion could be considered as an MF0 marker and should be included in diagnostic work-up. JAK2 positivity in MF0 is associated with a high thrombotic risk. Disclosures No relevant conflicts of interest to declare.

Description: Hepatitis C virus (HCV) is a global health infection that affects about 170 million persons worldwide an it is the principal cause of chronic live-diseases. Progression to chronic disease occurs in the majority of HCV-infected persons, and infection with the virus has become the main indication for liver transplantation. Initial diagnosis of HCV infection is classically done by serologic methods either by determining anti HCV antibody and by determining the presence of HCV RNA . HCV encodes a virus-specific helicase, protease, and polymerase, and because of the critical function of these proteins in the viral life cycle, they represent attractive targets for antiviral therapy. Multiple myeloma (MM) is a plasmacell neoplasm. The diagnosis is performed on bone marrow aspirate or bone marrow biopsy that show the presence of plasmacells, associated to anemia, hypercalcemia, osteolytic bone lesions, real failure ( C.R.A.B features). It is important distinguish between monoclonal gammopathy of undetermined significance, asymptomatic (smoldering) multiple myeloma, symptomatic multiple myeloma, solitary plasmacytoma, and other plasma cell diseases based on the IMWG criteria . Diagnosis should be based on the following tests: detection and evaluation of the monoclonal (M-) component by serum and 24-h urine protein electrophoresis; quantification of IgG, IgA and IgM immunoglobulins; characterization of the heavy and light chains by immunofixation; serum-free light-chain measurement, evaluation of bone marrow plasma cell infiltration; evaluation of lytic bone lesions, through full skeleton X-ray survey or magnetic resonance imaging (MRI); biological assessments (b2-microglobulin, C-reactive protein, lactate dehydrogenase and serum albumin); cytogenetic and fish analysis, haemoglobin (and full blood cell counts), serum creatinine and calcium level. Bortezomib is the drug used as first line therapy. It is a proteasome inhibitor. During treatment with bortezomib, rare cases of hepatic failure have been reported . lenalidomide is used an second line therapy , it belongs to the immunomodulatory drugs (IMiDs). No dedicated study has been conducted in patients with hepatic impairment, as the elimination of unchanged lenalidomide is predominantly by the renal route. In this article we report a case of a 74-year-old women with MM and HCV-related disease treated with bortezomib and lenalidomide. In 2008 diagnosis of MGUS. From 1976 Hepatitis HCV-related disease after transfusion. During this period periodic abdominal ultrasound showed steatosis of liver and an increase of transaminases. No need of liver biopsy. In July 2011 it showed evolution in Multiple Myeloma. Stage IIA according to Durie and Salmon Stage, I Stage according to ISS Stage System. Principal characteristics at diagnosis: PLT 73.000/mmc, Hb 9.6 g/dl, WBC 4.100/mmc, Plasmacells 33%, SGOT 120 U/L , SGPT 93 U/L, Creatinine 1 mg/dl, IgG 3060 mg/dl, Calcium 8.4 mg/dl, Gammaglobulin 34.7%, Monoclonal Component 3.1 g/dL, Serum Immunofixation IgG-Lambda, Urine Immunofixation Negative, Scheletal Survey Negative, MRI Negative, FISH Negative, Cytogenetics Negative, HCV-RNA 5.120.000 UI/ml. No antiviral therapy with acyclovir. So the patient was treated with bortezomib (1,3mg/m^2) and dexamethasone (20mg) day 1,8,15,22. After 9 cycles of therapy, completed in August 2012, the patient obtained a VGPR (Very Good Partial Response), with an improvement of liver parameters and of the blood counts. SGOT 36 U/L, SGPT 35 U/L, HCV-RNA 2.120.000 UI/mL, PLT 90.0000/mmc. In August 2013 progression of the disease ( HCV-RNA 4.000.000 UI/mL) so the patient started therapy with lenalidomide (25 mg) and steroids dexamethasone 20 mg), still ongoing. Currently normal liver parameters and blood counts. The last HCV RNA value is 1.390.000 UL/ml. The efficacy of bortezomib and lenalidomide in multiple myeloma is known to everyone. In this report, we want to show that, although the patient has been affected by HCV-related liver disease for many years, treatment with bortezomib and lenalidomide allows to obtained a good response to myeloma. Moreover, despite the effectiveness of acyclovir is recognized in the literature in terms of reducing the hepatitis C virus , the HCV RNA value is decreased during treatment with bortezomib and lenalidomide without the use of it. Furthermore, the combination with steroids did not worsen the hepatic pathology. Disclosures No relevant conflicts of interest to declare.