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Gastrointestinal involvement is a rare event in patients with B-cell chronic lymphocytic leukemia (B-CLL) and is usually associated to lymphomatous transformation. However, in autopsy studies the reported incidence of microscopic infiltration can reach up to 50% of cases. Seven B-CLL patients in advanced stage/progressive disease were evaluated by colonoscopy because of continuous diarrhea. Five out of seven patients (71%) presented histological evidence of colonic infiltration. Persistent diarrhea in patients with progressive/advanced B-CLL can be a clinical sign of intestinal infiltration and justifies endoscopic examinations.

Dear Editor,ArecentmutationlocatedintheJAK2 gene, JAK2 V617F, hasbeen shown to play a transcendental role in the constitutiveactivation of its tyrosine kinase activity in an importantnumber of cases of Philadelphia negative myeloproliferativedisorders (Ph-MPDs). This mutation is a useful tool fordiagnosing this diseases because different studies show thatthis mutation is highly frequent in patients with polycythemiavera (PV) and is present in around 50% of the patients withessential thrombocythemia (ET) and idiopathic myelofibrosis(IMF) [1]. Among the clinical features and phenotypes thatcharacterize Ph-MPD patients, thrombotic and hemorrhagicepisodes have been shown to be frequent in these patients.Range values for thrombosis at diagnosis fluctuate between34% to 39% for PV and 10% to 29% for ET [ 2]. Forhemorrhage, the values are much more variable [ 3].The mechanisms accounting for the increased risk ofthrombosis and hemorrhage in Ph-MPD patients are notwell understood. It has been accepted that the occurrence ofprevious venous thrombotic events and age increase the riskof thrombosis [4, 5]. The contribution of cardiovasculardisease risk factors in the development of thrombosis inPh-MPD patients is still unclear. Risk factors for hemor-rhage are more elusive and few have been described [2, 4].Studies are limited concerning the impact of hereditarythrombophilia in the development of thrombotic episodes inPh-MPD patients [6, 7]. In addition, the effect of the JAK2F617 allele in the development of thrombotic events is stillcontroversial [2, 8, 9].Thus, we aimed to ascertain the role of JAK2 V617F andother genetic risk factors in the development of thrombosisin patients diagnosed with Ph-MPD. For this purpose, weevaluated the prevalence of JAK2 V617F mutation andnine additional genetic alterations [FV Leiden, PTG20210A, and ZPI R67Stop are polymorphisms associatedwith venous thrombosis; HPA-1 located in the αIIbβ3integrin, HPA-2 located in von Willebrand factor receptorGIb/IX/V, GPIa C807T, and PSGL-1 are polymorphismsassociated with arterial thrombosis; FVII -323 Del/Ins andTUBB1 Q43P located in the megakaryocyte-specifictubulin β1 are two polymorphisms that increase the riskof hemorrhage] in 212 patients [74 PV, 128 ET, and tenIMF] (94 males, 118 females, median age 60.5±16.1, range21–85 years) followed during a 4-year period in HospitalMorales Meseguer (Murcia) and Hospital del Mar (Barce-lona). Thrombotic complications included venous (N=13)and major arterial thromboses (N=42) as well as microvas-cular alterations such as erythromelalgia (N=17). Severalpatients had two episodes of vascular events: five patientshad both venous and major arterial thromboses and twopatients with erythromelalgia developed an episode ofarterial thrombosis. Fifteen patients had hemorrhage. Weconsidered asymptomatic patients those with no thromboticor hemorrhagic episodes. The analysis of the role of genetic

Thyroid incidentalomas are thyroid lesions encountered during imaging study for nonthyroid diseases [1]. In the general population, the prevalence of thyroid nodules is 4 – 7% through physical exam...

UNLABELLED We assessed the feasibility of a rapid infusion of rituximab with or without steroid-containing chemotherapy. INCLUSION CRITERIA previous infusion of rituximab without grade 3 or 4 toxicity, lymphoid cells

The JAK2V617F allele burden has been identified as a risk factor for vascular events and myelofibrotic transformation in polycythemia vera (PV) and essential thrombocythemia (ET). However, all previous studies have evaluated a single time point JAK2V617F measurement. Therefore, the frequency and the clinical significance of changes in the JAK2V617F mutant load occurring during the disease evolution remain unknown. In the present study, JAK2V617F monitoring was performed during the follow-up of 347 patients (PV = 163, ET = 184). According to their JAK2V617F evolutionary patterns, patients were stratified as stable 50% (n = 261), stable ≥50% (n = 52), progressive increase (n = 24) and unexplained decrease (n = 10). After a 2,453 person-years follow-up, a total of 59 thrombotic events, 16 major hemorrhages, and 27 cases of myelofibrotic transformations were registered. At multivariate analyses, patients with a persistently high (≥50%) or unsteady JAK2V617F load during follow-up had an increased risk of myelofibrotic transformation (Incidence rate ratio [IRR]: 20.7, 95% CI: 6.5-65.4; P 0.001) and a trend for a higher incidence of thrombosis (IRR: 1.7, 1-3.3; P = 0.05) than patients with a stable allele burden below 50%. In conclusion, JAK2V617F monitoring could be useful in patients with PV and ET for predicting disease's complications, especially myelofibrotic transformation.

Aims The diagnosis of primary myelofibrosis (PMF) strongly relies on the bone marrow biopsy findings, but a report model has not been standardised. Our aim was to establish general recommendations for bone marrow evaluation and standardised reporting in a case suspicious of PMF. Methods The Delphi method was employed to obtain expert consensus. An advisory panel of 10 leading members identifies a total of 37 haematopathology experts to participate. The first Delphi round included a questionnaire with three main groups of items: minimal clinical and laboratory data considered necessary before reporting, minimal descriptive aspects to record and main histological differential diagnosis. The final report content was based on consensus obtained after the second Delphi round. Results The minimal data considered necessary were age, splenomegaly, haemoglobin, leucocyte and platelet counts, differential blood cell count, leucoerythroblastic blood picture, lactate dehydrogenase (LDH) level, BCR-ABL and JAK2 mutational status, reticulin stain and the internal control for the reticulin staining. The minimal descriptive aspects to report were cellularity, osteosclerosis, megakaryocytic morphology and localisation, dense megakaryocytic clusters, quantity of granulocytic precursors, grade of myelofibrosis in a scale of 4, and a proposed final diagnostic approach. The entities to be considered for differential diagnosis were mainly the other classical chronic myeloproliferative neoplasms. Conclusions The Delphi method is a robust tool to determine essential information to be included in a pathology report. A standardised good-quality histopathological report form may help to homogenise PMF diagnosis. A close collaboration between the pathologist and the haematologist is desirable according to our survey.

Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even among patients within the same MPN diagnosis. Using cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In MF (4 clusters identified), clusters significantly differed by Dynamic International Prognostic Scoring System (DIPSS) risk (P < .001), leukopenia (P = .009), thrombocytopenia (P < .001), and spleen size (P = .02). Although an association existed between clusters and DIPSS risk, high symptom burden was noted in some low and intermediate-1-risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (P < .001), but clusters did not significantly differ by PV risk or the risk assessment variable of age. Among ET patients (5 clusters identified), clusters differed by gender (P = .04), anemia (P = .01), and prior hemorrhage (P = .047). Total symptom score increased across clusters (P < .001), but clusters did not significantly differ by International Prognostic Score for ET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype, sometimes independent of disease features or prognosis.

We have characterized the molecular changes underlying the transformation of a JAK2V617F+-myelofibrosis with trisomy 8, into a JAK2V617F-negative leukemia. Leukemic clone did not carry JAK2V617F mutation, but showed ASXL1 mutation (R693X). This mutation was identified in a low percentage at diagnosis by next-generation sequencing. Using this technology in serial specimens during the follow-up, we observed a progressive expansion of the ASXL1-mutated minor clone, whereas the JAK2V617F+-clone carrying trisomy 8 decreased. Hematologic progression occurred simultaneously with an ASXL1-R693X-negative lung-cancer. This is the first report showing a clear association between the expansion of an ASXL1-mutated clone and the leukemic transformation of myelofibrosis.

Background We have previously reported on the high prevalence and severity of challenges with intimacy and sexuality amongst a large international cohort of MPN patients (Emanuel JCO 2012). We sought to further analyze the relationships between issues of intimacy (sexual desire and function), their relationships to MPN disease features, individual MPN symptom prevalence and severity, language, and overall quality of life. Methods Data was collected among an international cohort of patients with MPNs. Subjects completed the BFI, MPN-SAF, and EORTC QLQ-C30 instruments. Surveyed symptoms on the MPN-SAF included the patient’s perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Specifically, the MPN-SAF sexuality item asked about “problems with sexual desire or function”. Total symptom score (TSS) was computed based on 10 symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. Pairwise associations between the MPN-SAF sexuality item and continuous and categorical covariates were investigated using Pearson correlations and analysis of variance/t-tests, respectively. Multivariate regression models were used to investigate impact of groups of covariates on the sexuality item with the final multivariate model selected using forward regression. Results Demographics A total of 1908 MPN patients (essential thrombocythemia=799, polycythemia vera=671, myelofibrosis=432, missing=6) completed the sexuality item. Participants were of typical age (median=60, range 15-94) and gender (female=53%). Overall, 1218 subjects described sexuality related complaints (score >0) with an overall mean symptom score of 3.5 (median=2.0, SD=3.7, range 0-10); 725/1908 (38%) patients had severe sexuality related complaints (score >4). Univariate Analysis Among the QLQ-C30 functioning scales, all domains had similar statistically significant correlations (r=-.26 to -.32, all p Multivariate Analysis In a multivariate model of MPN-SAF sexuality containing all QLQ-C30 functioning scales, physical (p=0.001), emotional (p=0.01), cognitive (p=0.005) and social (p=0.002) functioning were all statistically significant. Numerous symptoms were also significant in a multivariate model of MPN-SAF sexuality containing all other MPN-SAF symptoms (all p Conclusions Sexuality related complaints have been linked to both physiologic and psychologic origins and are highly prevalent within the MPN population. The results of this study congruently identified close associations between sexuality and function within emotional, cognitive and social domains. Additionally, the correlations of sexuality issues with MPN symptoms and disease features further suggest this item is a key correlate of overall functionality and quality of life. Future investigations into the causative factors and biological correlates of this complaint may assist in addressing this ongoing challenge. Disclosures: Etienne: novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Roy:Novartis, BMS: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; S Bio: 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. Birgegard:Vifor Pharma: Honoraria. Mesa:Eli Lilly and Co: Research Funding; Genetech: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Sanofi: Research Funding; NS pharma: Research Funding; Celgene: Research Funding.

Background: Non-driver mutations and JAK2V617F allele burden have been involved in progression to myelofibrosis (MF) or acute myeloid leukemia (AML) in patients with polycythemia vera (PV) and essential thrombocythemia (ET). It is unknown if both mechanisms play a different role in disease transformation and if they are useful in routine clinical practice. Methods: JAK2V617F allele burden was monitored in 208 patients (PV n=106, ET n=102) for a median of 6.5 years (range: 1-13). Quantification of JAK2V617F allele burden was assessed on the first available sample and every year thereafter. The evolutionary pattern of JAK2V617F allele burden was categorized as persistently low (50%), progressive increase (> 25% from baseline) or unexplained decrease (not therapy related). Next generation sequencing (NGS) analysis of 51 myeloid-related genes was performed in 100 patients with a median molecular follow-up of 10 years including all cases with transformation to AML or MF. Detected mutations by NGS in the last sample were studied in first paired sample obtained in the chronic phase (median time from diagnosis: 1.6 years). Time to myelofibrosis and time to AML were calculated according to the presence of non-driver mutations or the JAK2V617F evolutionary pattern. Multivariate analysis was performed by Cox regression. Results: With a median follow-up of 13 years (range: 1-30) 32 patients died whereas 24 and 12 patients progressed to MF and AML, respectively. Median age at diagnosis was 63 years (range: 20-94), 115 were women (55%) and 173 (83%) received cytoreduction. A persistently low JAK2V617F allele burden was observed in 62% of patients whereas the remainder presented a persistently high (25%), a progressive increase (11%) or a non-therapy-related decrease of JAK2V617F allele burden (2%). Non-driver mutations were detected in last sample in 48% of patients. Median number of mutations was 1 (range: 1-5). Mutational frequencies were: TET2 12%, DNMT3A 12%, TP53 9%, ASXL1 7%, RUNX1 4%, SF3B1 4%, SRSF2 4%, IDH1/2 4%, SH2B3 3 % and Mutations were detected in first sample in 28% of patients (58% of those with mutations in last sample). Frequencies of mutations in first sample were: TET2 10%, DNMT3A 5%, TP53 5%, ASXL1 4%, SRSF2 4%, IDH1/2 3%, and < 2% for SF3B1, SH2B3, KMT2A and ZRSR2. The evolutionary pattern of JAK2V617F allele burden was not associated with the presence of mutations in first or last sample. Twelve patients progressed to AML (post-PV n=7, post-ET n=5), nine of them presented mutations in first sample. AML transformation at 15 years was 27% and 6.8% for patients with and without additional mutations in first sample, respectively (p=0.001). Mutated genes associated with a higher probability of AML transformation were DNMT3A (p 65 years (p=0.012) and exposure to busulfan (p=0.003). Evolutionary JAK2V617F pattern was not associated with the probability of AML (p=0.667). In multivariate analysis, an increased risk of AML transformation was observed for patients with additional mutations in the chronic phase (HR: 6.3; 95%CI 1.6-24.7, p=0.008) after adjusting for initial diagnosis, age and exposure to busulfan. Twenty-four MF transformations were documented (post-PV n= 18, post-ET n=6). Presence of additional mutations was not associated with the probability of MF (p=0.189). Patients with persistently high or a progressive increase of the JAK2V617Fallele burden showed a higher probability of MF transformation (24% versus 1.5% at 10 years, p Conclusion: Non-driver mutations are involved in the progression of PV and ET to AML but not to MF. NGS could be useful for identifying patients with PV or ET at risk of AML transformation. Acknowledgment:This work was supported by grants from the Instituto de Salud Carlos III, Spanish Health Ministry, FISPI13/00557, FISPI1300393, RD012/0036/0004, 2014 SGR567. Alicia Senín received a grant from Sociedad Española de Hematología y Hemoterapia. Disclosures No relevant conflicts of interest to declare.

BACKGROUND: Symptom burden in essential thrombocythemia (ET) and polycythemia vera (PV) is severe even among individuals with low risk disease (Blood 2012. 12;123(24):3803-10). New therapies exist which alleviate the severe symptom burden and reduce splenomegaly in ET and PV patients (N Engl J Med 2015; 372:426-435). This analysis is the first to date to evaluate thresholds at which symptom-based treatment can be considered for ET and PV patients who are intolerant or resistant to hydroxyurea (HU). METHODS: Patient demographics, symptom burden, and disease traits were collected from ET and PV patients at a single time point during therapy. The MPN-10 total symptom score (TSS, JCO 2012;30(33)4098-103) was utilized to assess symptom burden. Symptom criteria models were determined as previously described among a population of MF patients (Scherber et. al. EHA 2016: a2250). Cutoffs were then evaluated in a cohort of ET and PV patients to assess for utility as a symptom model among this population. RESULTS: Demographics and symptom burden: 838 PV and 867 ET patients with previous hydroxyurea therapy were included in this analysis. Patients were of mean age (54.9 years ET, 64.0 years PV) and gender (69.2% female ET, 55.7% female). Mean disease duration was 6.0 years for ET and 7.3 years for PV.Among ET and PV patients, 15.0% and 24.2% had prior thrombosis respectively. In evaluating prognostic risk, ET patients tended to be low (45.5%) or intermediate risk (42.9%) with only a minority of patient meeting criteria forhigh risk disease (11.6%). Laboratory findings: ET patients had a mean platelet value of 598.7x 109/L(SD=283.4). Among PV patients, mean hematocrit was 45.8% (SD=8.1) and 42.6% of patients had a hematocrit of greater than 45%. White blood cell count was normal between the two groups (ET mean 8.3 x 109/L, PV mean 9.0 x 109/L). Symptoms: Mean worst symptom severity was 6.4 out of 10 (SD=2.7). Among ET patients, worst symptom was most frequently fatigue (32.7%, mean 5.0/10, SD=3.1, overall prevalence 88%) followed by night sweats (13.6%, mean 2.0/10, SD=3.0, overall prevalence 53%) and concentration difficulties (8.6%, mean 3.1/10, SD=3.0, overall prevalence 68%). For PV, worst individual symptom items were most frequently fatigue (29.2%, mean 5.2/10, SD=3.0, overall prevalence 91%), pruritus (14.1%, mean 3.2/10, SD=3.2, overall prevalence 69%), and night sweats (12.8%, mean 2.5/10, SD=3.0, overall prevalence 57%). Cutoff Scoring: 47.0% of ET patients fit criteria for TSSgreater than to equal to 20; 59.0%% had a single itemgreater than 5; and 45.7% had both a TSS greater than or equal to 20 and a single item greater than 5. Among PV participants, 54.5% had aTSS greater than to equal to 20; 66.1% had a single itemgreater than 5; and 51.5% had both a TSS greater than or equal to 20 and a single item greater than 5. Each scoring method was significantly associated with individual item scores (Table 1). Prognostic scoring was not significantly associated with any of the symptom cutoffs evaluated. Correlations: Among ET patients, a prior history of thrombosis was significantly associated with having a worst symptom item greater than 5 (p=0.043). ET patients with lower hemoglobin were significantly more likely to meet criteria for a MPN-10 score greater than or equal to 20 or to meet combined criteria for a MPN-10 greater than or equal to 20 and single worst item greater than 5 (for both p=0.01 or less). For PV, lower hematocrit levels were significantly associated with having an individual worst symptom score of greater than 5 (44.9% versus 46.7%, p=0.0376). CONCLUSION: Assessment of ET and PV symptoms, now measurable through standardized and practical instruments such as the MPN-10, is an integral part of determining therapeutic impact of newer therapies in both clinical practice and trial settings. In our modeling, patients with severe symptom burden profiles are well represented by utilizing cutoff criteria including aworst individual symptom item of greater than 5 out of 10, an MPN-10 score of greater than or equal to 20, or combined criteria of both cutoffs. These cutoffs can be considered when determiningwhich HU intolerant or resistant patients would most benefit fromsymptom orientedtreatment. Disclosures Kiladjian: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding. Schouten:Novartis: Consultancy; Sanofi: Consultancy. Etienne:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Pfizer: Speakers Bureau; novartis: Consultancy, Speakers Bureau. Harrison:Incyte Corporation: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Radia:Pfizer: Honoraria; Novartis: Honoraria. Cervantes:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mesa:Promedior: Research Funding; Celgene: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy.

BACKGROUND: The presence of constitutional symptoms has been associated with increased mortality risk in myelofibrosis (MF) (Blood 2010;115(9):1703-8). New therapies exist which alleviate the severe symptom burden profile observed in MF patients but are only approved for use in those with intermediate-2 or high risk disease (N Engl J Med 2012;366:787-798). However, it has been proposed that there are patients who may benefit from symptom based treatment regardless of prognostic score (Am Soc Hematol Educ Program 2014;2014:277-286). We have recently characterized symptom score cutoffs at which patients would statistically benefit from treatment based on symptom scores alone (Scherber et. al. EHA 2016: a2250). These treatment thresholds included aMyeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10) total score of greater than or equal to 20, a worst individual item score of greater than 5, or a combined criteria of those with both an MPN-10 total score of greater than or equal to 20 and a worst individual item score greater than 5. This abstract represents an additional analysis of our MF cohort to better characterize the profile of patients who meet criteria for symptom-based therapy. METHODS: Patient demographics, symptom burden via the MPN-10 score (JCO 2012;30(33)4098-103), and disease traits were collected from MF patients and their physicians at a single time point during therapy. Previously we identified MPN-10 cutoffs via AkaikeÕs Information Criterion (AIC) analysis (Ecology 2014;95: 631-6), which represented the optimal model among all models specified for the data at hand to determine which patients would most benefit from symptom-directed therapy. RESULTS: Demographics. 695 MF patients without previousruxolitinib therapy were included in this analysis. Overall, of 455 patients (65.4%) fit a cutoff of having a single worst symptom item of greater than 5/10. 401 patients (57.7%) had a MPN-10 score of equal to or greater than 20. A total of 381 (54.8%) patients fit both of these criteria. A distribution of worse MPN-10 individual scores is shown in Table 1. Mean TSS score was 26.4 (SD=17.7). Symptom Criteria Associations. Demographics and disease traits: Neither mean age or age greater than 60 was significantly associated with meeting any of the symptom score cutoff criteria. Females were significantly more likely to meet any of the symptom score cutoffs (for all criteria, p=0.0003 or less). Patients with splenomegaly, particularly spleen size of greater than 15cm below the LCM, were significantly more likely than those with a normal sized spleen to meet any of the three criteria (spleen enlargement of any size p=0.014 or less; spleen greater than 15cm p=0.0114 or less). Patients who met any of the three symptom criteria tended to have a longer MPN duration, although this trend did not meet significance. A prior history of thrombosis was not associated with achieving any cutoff criterions. Symptom burden: Individuals who met the any symptom criteria were significantly more likely to have higher DIPSS prognostic risk score (for all p=0.0002 or less). Laboratory values: For those meeting criteria for a worst symptom greater than 5, mean WBC was 11.7 vs 9.1 x 109/L (p=0.025) and platelet count was 238.7 versus 329.1 (p=0.023). For those meeting criteria for a TSS greater than or equal to 20, mean WBC was 11.8 vs 9.5 x 109/L (p=0.04). For individuals meeting both criteria, mean WBC was 11.9 vs 9.5 x 109/L (p=0.034). The presence of peripheral blasts were significantly more common in patients with an individual worst symptom score greater than 5 (p=0.0364). Hemoglobin level was not significantly associated with symptom criteria for any cutoffs. CONCLUSION: Our analysis indicates that patients who would be treated based on symptom criteria are similar to patients who would be treated based on high risk features such as high DIPSS prognostic score, concerning blood count abnormalities (i.e., leukocytosis, thrombocytopenia, presence of peripheral blasts), and splenomegaly (particularly massive splenomegaly). Thrombosis history and age were not associated with criterion cutoff assignment, and it is notable that elderly age nor history of thrombosis alone would likely alter treatment choice other than anticoagulation. This data supports that JAK2 inhibitor treatment be strongly considered in patients meeting symptom based criteria. Disclosures Dueck: Bayer: Honoraria. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schouten:Sanofi: Consultancy; Novartis: Consultancy. Etienne:ARIAD: Speakers Bureau; Pfizer: Speakers Bureau; novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau. Harrison:Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Radia:Novartis: Honoraria; Pfizer: Honoraria. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mesa:Promedior: Research Funding; Celgene: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy.

INTRODUCTION Chemotherapy-induced hepatitis B virus (HBV) reactivation is a well-recognized complication and is a potentially life-threatening condition in cancer patients with chronic HBV (hepatitis B surface antigen [HBsAg]-positive). Rituximab has been associated with an increase in HBV reactivation in chronic HBV patients (45%) and even in patients with resolved infection (HBsAg negative and hepatitis B core antibody [anti-HBc]-positive (22%); however, the reported frequency varies among different studies. Current guidelines for management of chronic HBV recommend routine antiviral HBV prophylaxis with lymphoma before starting chemotherapy. In contrast, there is little evidence-based consensus regarding patients with resolved HBV infection. Aim: To analyze the incidence of HBV reactivation and the role of antiviral HBV prophylaxis in lymphoma patients with chronic HBV or resolved HBV treated with chemotherapy, immunotherapy or immunochemotherapy managed according to our institutional HBV guidelines. Secondary endpoints were to analyze the incidence of HBV in this population and HBV guidelines adherence. PATIENTS AND METHODS Lymphoma patients with chronic HBV or resolved HBV in a single center. HBV viral status definitions: Active Chronic HBV infection: HBsAg positive, anti-HBc positive and HBV DNA >2000 IU/mL; Inactive Carriers: HBsAg positive, Anti-HBc positive, HBV DNA undetectable or HBV reactivation was defined as increased serum HBV DNA (≥1 log10), regardless of liver biochemistry or HBsAg status. Institutional HBV guidelines: serum samples were collected at baseline for HBsAg and anti-HBc testing in all lymphoma patients. Patients were evaluated by a hepatologist if any of them fulfilled HBV viral status definition. Baseline at screening and monitoring every 3 months during therapy and up to 24 months after completing therapy (assessment of liver biochemistry, serum HBV DNA, HBsAg and anti-HBs levels). Specific prophylaxis strategies according to HBV status: Group A (Active chronic HBV): treatment for HBV; Group B (Inactive carriers): antiviral HBV prophylaxis; Group C (Resolved HBV): antiviral HBV prophylaxis if rituximab containing-therapy or follow-up only if rituximab-free therapy. HBV antiviral prophylaxis was started before therapy and finished 12 months after completing therapy. RESULTS From January 2012 to January 2015, 227 lymphoma patients received chemotherapy or immunochemotherapy. 142 (63%) patients received rituximab-containing therapy. 43 (19%) patients were anti-HBc positive. Group A: 2 (1%) patients; Group B: 2 (1%) patients; Group C: 39 (17%) patients. 14 (6%) patients have coinfection with hepatitis C virus and 12 (5%) patients co-infection with human immunodeficiency virus (HIV). Adherence to HBV guidelines was 90%. Patients in Group A (n=2) and B (n=2) received antiviral treatment/prophylaxis before starting therapy. In the Group C, 16 (41%) patients underwent only follow-up and 23 (59%) patients received HBV antiviral prophylaxis (lamivudine in 4, entecavir in 8 and tenofovir in 11). Median duration of HBV prophylaxis was 18 months (95% CI: 16-19 months). After a median follow-up of 21 months, 2 patients developed HBV reactivation during lymphoma treatment: 1 from group B (reactivation rate of 50%) and 1 from group C (reactivation rate of 3%). Both patients had received rituximab-containing treatment and both developed HBV reactivation (without hepatitis flare) within the first 6 months after finishing antiviral HBV prophylaxis (delayed HBV reactivation). Outcome was favorable in both patients. Characteristics of HBV reactivation patients are shown in table I. Cumulative incidence of HBV reactivation at 12 and 24 months were 0% and 8%, respectively. CONCLUSION Our strategy of close monitoring patients with chronic HBV or resolved HBV that receive chemotherapy and adding antiviral HBV prophylaxis only in selected patients clearly decrease HBV reactivation. Nevertheless, this strategy may not fully protect patients from late HBV reactivations. Larger validation studies are needed to confirm our data and to establish the best cost-effective strategy in this lymphoma population, especially in the new era of inmunomodulatory drugs of their real involvement in HBV reactivation is unknown. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

Abstract 1726 Background: We previously reported that symptom burden among persons with ET and PV can be severe and adversely affect QOL. The presence of severe symptoms is linked to poor prognosis. There is considerable inter-subject heterogeneity regarding which symptoms are present in which subjects. No studies have empirically evaluated whether disease characteristics can be grouped in related symptom clusters. Using our previously validated 18 item Myeloproliferative Neoplasm Assessment Form (MPN-SAF) (Blood 2011;118:401–408) given in conjunction with the 9 item Brief Fatigue Inventory (BFI) (Cancer 1999;85:1186–1196), we sought to evaluate symptom burden by means of cluster analysis. Methods: Data was collected from an international cohort of subjects with MPNs including demographics, disease features and the completed BFI and MPN-SAF instruments. Surveyed symptoms included fatigue, early satiety, abdominal pain and discomfort, inactivity, headaches, concentration, dizziness, extremity tingling, insomnia, sexual difficulties, mood changes, cough, night sweats, pruritus, bone pain and fever on a 0 (absent) to 10 (worst-imaginable) scale. Development of symptom clusters was based on consideration of r-squared in hierarchical clustering using Ward linkage. Final cluster assignment was based on the nonhierarchical k-means method. Comparisons between symptom clusters were based on ANOVA and chi-squared tests. Results: Subject Demographic and Disease Characteristics: Data from 1,141 subjects with PV (N=519) and ET (N=622) was prospectively collected (Chinese 236, French 305, German 45, Italian 114, Dutch 191, English 56, Spanish 109, Swedish 85. Age (mean 59, range, 26–87) and gender (54% F) were typical. Five clusters were selected (Figure 1). Frequencies of prior bleeding, spleen size, anemia, presence of any lab abnormality, language, gender, and MPN type varied significantly between clusters (P Cluster 1: The “Reduced Symptom” Profile (n=421 (37%; 60% ET, 40% PV) The largest cluster, subjects had increased complaints of sexual difficulties and fatigue. There was a slightly higher proportion of subjects with ET (60%) versus PV. There were fewer lab abnormalities (28% prevalence) and less prior bleeding (3%) compared to other clusters. Spleen size was smallest of the cluster (1 cm below costal margin). Cluster 2: The “Fatigue-dominant” Group (n=286 (25%; 56% ET, 44% PV)). Subjects in this cluster were predominantly female and had relatively few laboratory abnormalities (19%) than other cohorts. They are characterized by high severity of fatigue compared to end-organ symptoms. Symptom profiles emphasize fatigue, QOL and insomnia with some end-organ complaints. The cohor 63% of the cohort. Cluster 3: The “End-Organ Complaints” Group (n=210 (18%; 49% ET, 51% PV)). Male predominant (56%), subjects had mainly macro-vascular symptom complaints including sexual difficulties, insomnia, and overall QOL, with few microvascular related symptoms (low itching/night sweats). Cluster 4: “Cognitive Complaints” Cluster (n=110 (10%; 53% ET, 47% PV)). The smallest cluster and female predominant (64%), main complaints include fatigue, insomnia, loss of concentration, numbness, and sad mood. Cluster 5: The “Highly Symptomatic” Cluster (n=114 (10%; 44% ET, 56% PV)). Subjects had many cognitive complaints and symptoms correlated with severe micro-vascular abnormalities (pruritus) and or splenomegaly. This cluster had the largest spleen sizes (mean 3 cm), the highest prevalence of prior thrombosis (29%), and highest frequency of lab abnormalities (43%). Cognitive and end-organ complaints were rated as most severe. Conclusion: This analysis offers new means of evaluating persons with PV and ET utilizing symptom clusters. Laboratory and physical abnormalities differed significantly between symptom clusters indicating that our groupings likely result from biological alterations present in specific disease phenotypes. Future studies should investigate correlations between clusters and prognosis and genotype. Disclosures: Kiladjian: Celgene: Research Funding; Novartis: Honoraria, Research Funding; Shire: Honoraria. Roy:Novartis, BMS: Speakers Bureau. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Passamonti:Novartis: 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; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Essential thrombocythemia is a chronic myeloproliferative neoplasm characterized by sustained thrombocytosis, bone marrow megakaryocytic hyperplasia and an increased risk of thrombosis and hemorrhage. The goal of treatment is to prevent the development of vascular complications without increasing the risk of transformation. Patients aged60 years or a history of thrombosis have a high risk of thrombosis while those with a platelet count1,500 x 10(9)/l have a higher risk of hemorrhage. Patients with low-risk essential thrombocythemia can be managed appropriately with low-dose of acetylsalicylic acid or even observation only, while patients with a high-risk disease are candidates to receive cytoreductive treatment, hydroxyurea being the first choice therapy. Anagrelide is the most suitable option for patients with resistance or intolerance to hydroxyurea. All patients must be submitted to a rigorous control of cardiovascular risk factors.

Objective To ascertain the role of patient age as an influencing factor in the pharmacokinetics of anagrelide and to clarify whether different dosing is required in young (18 - 50 years) vs. elderly (≥ 65 years) patients with essential thrombocythemia (ET). Method This Phase II, multicenter, open-label study compared the pharmacokinetics, pharmacodynamics and tolerability of anagrelide and its active metabolite, 3-hydroxy-anagrelide, in young and elderly patients with ET. Three days prior to pharmacokinetic assessment, patients divided their normal daily anagrelide into a structured twice-daily dosing (BID) schedule. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic analysis over a 12-h dosing interval. Anagrelide and 3-hydroxy-anagrelide plasma concentrations were normalized to a common dose (1 mg BID) to control for dosing differences between patients. Patients were monitored routinely for adverse events (AEs) and vital signs. Results A total of 24 patients (12 young; 12 elderly) completed the study. The dose-normalized anagrelide maximum observed plasma concentration (Cmax) and area under the plasma concentration vs. time curve over one dosing interval (AUCτ), were higher in elderly patients compared with young patients (Cmax: 3.63 vs. 2.66 ng/ml; p = 0.09, AUCτ: 10.3 vs. 6.4 ng×h/ml; p = 0.01). In contrast, the dose-normalized 3-hydroxy-anagrelide Cmax and AUCτ were lower in the elderly patients when compared with young patients (Cmax: 4.19 vs. 7.26 ng/ml; p = 0.02, AUCτ: 17.4 vs. 27.6 ng×h/ml; p = 0.03). No significant difference was observed in the geometric mean terminal half-life (t1/2) of anagrelide in elderly and young patients (1.4 vs. 1.3 h, respectively; p = 0.38), whereas the geometric mean t1/2 of 3-hydroxy-anagrelide was significantly longer in the elderly patients compared with the young patients (3.5 vs. 2.7 h, respectively; p = 0.01). There were no significant differences in platelet count or vital signs between the age groups. Anagrelide was well tolerated; there were no serious AEs or AEs that led to withdrawal from the study. Conclusions To conclude, the differences observed in anagrelide and 3-hydroxy-anagrelide pharmacokinetics do not justify using a different dosing regimen in young vs. elderly patients with ET.

EXELS is an ongoing phase IV non-interventional study; 3643 high-risk patients with essential thrombocythemia (ET) were recruited across 13 European countries. We report patient characteristics and cytoreductive treatment patterns of ET across Europe. Hydroxycarbamide (HC; 64.3%) and anagrelide (22.0%) were the two main cytoreductive treatments prescribed. The proportions of patients taking either HC or anagrelide varied across countries, as did the number of patients receiving anti-aggregatory therapy in addition to cytoreductive treatment. This real-world evidence demonstrates that, generally, treatment patterns of ET across Europe adhere to expert recommendations, with some notable variations between countries.

Abstract 1731 Background: Symptom burden in primary, post-ET and post-PV myelofibrosis (MF) is frequently severe and correlates with a poor prognosis. However, symptom manifestations are heterogeneous with variable presence of specific symptoms, splenomegaly and cytopenias. We sought to identify the spectrum and features of MF symptomatic phenotypes by cluster analysis of prospectively gathered information on MF symptoms and disease features. Methods: Data was collected among an international cohort of subjects with MF. Data included demographics, disease features and completion of the Brief Fatigue Inventory (BFI) and Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) (Blood 2011; 118:401–408). Surveyed symptoms addressed key disease features on a 0 (absent) to 10 (worst-imaginable) scale. Cluster development was based on consideration of r-squared in hierarchical clustering using Ward's linkage. Final cluster assignment was based on the nonhierarchical k-means method. Comparisons between symptom clusters were based on ANOVA and chi-squared tests. Results: Subject Demographic and Disease Characteristics: Data from 329 prospectively enrolled persons with MF was collected (Chinese 102, French 54, German 19, Italian 22, Dutch 45, English 51, Spanish 29, Swedish 7) including 223 PMF, 67 post-ET MF and 39 post-PV MF patients. Participants were of typical age (mean 59) and gender (47% F). Among all participants, four natural symptom clusters were identified (Figure 1). Among clusters, disease features including leukopenia, thrombocytopenia, and enlarged spleen varied significantly between clusters (P Cluster 1: The “Fatigue Dominant with Few Lab Abnormalities” Profile (n=150 (46%; 69% PMF, 20% post-ET MF, 11% post-PV MF)). Cluster 1, the largest, is characterized by fatigue-dominant complaints in the setting of the lowest overall MPN-SAF TSS and highest proportion of males (59%). Individuals among this group have the lowest prevalence of laboratory abnormalities (65% total; anemia, 67%; thrombocytopenia, 20%) or clinical deficiencies including enlarged spleen (average 6.0 cm below costal margin), prior thrombosis (9%), prior hemorrhage (5%) or prior RBC-transfusions (20.4%). Interestingly, individuals in this group are most likely to have had prior splenectomy (5.8%). Cluster 2: The “Cognitive Complaints with Enlarged Spleen” Cluster (n=105 (32%; 65% PMF, 20% post-ET MF, 15% post-PV MF)). Cluster 2 is the 2nd largest cluster. Subjects have relatively few abnormal lab values (67% vs 65%–77%) but have high severity of fatigue, sexual difficulties, insomnia, inactivity and reduced QOL. These individuals have the largest spleen size (8.7cm below costal margin). Cluster 3: The “Nighttime and Cognitive Complaints” Group (n=53 (16%; 64% PMF, 25% post-ET MF, 11% post-PV MF)). Cluster 3 is the smallest cluster. Subjects have many cognitive and nighttime-related complaints including sexual difficulties, night sweats, insomnia, and concentration problems. Subjects with post-ET MF are predominant. This cluster also has the 2ndsmallest spleen size (7 cm) or history of prior thrombosis (9.6%), hemorrhage (7.8%) or requirement for transfusions (21.2%). Cluster 4: The “Severe Fatigue with Few End-organ Complaints” Cluster (n=21 (6%; 81% PMF, 14% post-ET MF, 5% post-PV MF)). Cluster 4 is the most symptomatic cohort with the highest proportion of subjects with PM. There is a lower frequency of end-organ complaints including abdominal pain, cough, and headaches. Symptoms including sexual difficulties, sad mood and insomnia are predominant. No subjects had prior splenectomy. Subjects also have the highest prevalence of prior thrombosis (29%), hemorrhage (14%), and transfusions (43%). Additionally, this cohort has the largest prevalence of lab abnormalities (77%) with thrombocytopenia (71%), leukopenia (41%) and anemia (41%). Conclusion: This analysis will allow us to examine a new framework for evaluating persons with MF using symptom profiles and is the 1st cluster evaluation of MF. Lab and physical findings contrast significantly between symptom clusters indicating these phenotypic symptoms likely result from etiological factors present in specific disease phenotypes. Future studies should evaluate whether there is a correlation between cluster profiles, prognosis and genotype. Disclosures: Kiladjian: Celgene: Research Funding; Novartis: Honoraria, Research Funding; Shire: Honoraria. Roy:Novartis, BMS: Speakers Bureau. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Passamonti:Novartis: 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; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Background Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm and to compare its clinical outcome with that of refractory anemia with ring sideroblasts and essential thrombocythemia. Design and Methods We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis. For each of these patients, each patient diagnosed with refractory anemia with ring sideroblasts was matched for age and sex. At the same time, a cohort of 454 patients with essential thrombocythemia was used to compare outcomes of the two diseases. Results In patients with refractory anemia with ring sideroblasts and marked thrombocytosis, depending on the Janus Kinase 2 V617F mutational status (positive or negative) or platelet threshold (over or below 600×109/L), no difference in survival was noted. However, these patients had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia ( P

Abstract 3839 BACKGROUND: We have previously reported on the validation of the 18 item Myeloproliferative Neoplasm Assessment Form (MPN-SAF) (Blood 2011;118:401–408) given in conjunction with the 9 item Brief Fatigue Inventory (BFI) (Cancer 1999;85:1186–1196) to assess symptomatic burden in an international sample of MPN patients (pts), including validation in English, Italian, Swedish, German, French, Spanish, and Dutch. We desired to assess the utility of an average total symptom score (TSS) from the most pertinent and representative MPN symptoms for purposes of assessing the burden of symptoms in MPN pts, and subsequent tracking in response to therapy. METHODS: Data was collected among an international cohort of MPN pts and their physicians, including patient demographics and disease features and completion the BFI, MPN-SAF and the EORTC-QLQ-C30. Among pts who completed at least 5 of 10 specific items on the BFI and MPN-SAF, an average score was calculated as the TSS. TSS items included “worst” fatigue from the BFI and 9 items from the MPN-SAF including concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss and fever. The TSS thus had a possible range of 0–10 with 10 representing the highest level of symptom severity. Data was then analyzed for internal consistency, and divergent, convergent validity, and construct validity. RESULTS: Patient Demographic and Disease Characteristics:1433 MPN pts were prospectively enrolled (Argentina 22, France 482, Germany 59, Italy 186, Netherlands 236, Puerto Rico 10, United Kingdom 57, United States 102, Spain 157, Sweden 114, Uruguay 8) including 594 ET, 538 PV and 293 MF pts (8 missing; MF: 61% Primary MF, 23% post-ET MF, 15% post-PV MF). 1408 pts completed at least 5 of the 10 items necessary to calculate a TSS. Pts were of characteristic age (mean 62, range 20–94) and gender (54% female) common to disease. TSS Burden of MPN Symptoms: Consistent with prior studies, the majority of pts (>50%) were symptomatic in each TSS item except for items associated with high disease severity, namely bone pain (48.6%), weight loss (30.6%) and fever (18.4%). Fatigue carried the highest symptom intensity (4.4, SD=2.8), followed by problems with concentration (2.5, SD=2.8) and early satiety (2.5, SD=2.7). Overall mean TSS was 2.1 (SD=1.6). Divergent Validity: TSS significantly differed among MPN disease subtypes (p4, n=480) versus non-clinically deficient QOL (2 of 6 common MPN-related symptoms as clinically significant (2.8, n=400) versus 0.50 except social functioning [r=0.48]). Additionally, excellent correlations were observed between the TSS and EORTC-QLQ-C30 fatigue and pain symptom scales (r>0.5, p1). Factor loadings ranged from 0.43 for fever and weight loss to 0.71 for inactivity. The single factor suggests that the arithmetic mean of the 10 items is an appropriate global TSS score. CONCLUSION: The TSS demonstrated excellent psychometric properties. Overall, results of validity and internal consistency indicate that the TSS is a concise, valid, and accurate assessment of symptom burden among MPN pts. This new scoring will facilitate ease of implementation of the MPN-SAF into larger clinical trials and reduce ambiguity associated with interpreting response outcomes. Future analyses to investigate the impact of therapies on TSS are ongoing. Disclosures: No relevant conflicts of interest to declare.

NT-proBNP provides diagnostic and prognostic information in heart syndromes but its role in cancer has not yet been established. The prognostic value of NT-proBNP was prospectively studied in 104 non-Hodgkin lymphoma (NHL) patients treated with chemotherapy. Echocardiography and NT-proBNP were determined prior to treatment. In multivariate analysis, NT-proBNP ≥ 900 pg/ml was the variable with higher risk of death (adjusted hazard ratio 11.1; 95% CI 3.8-32.9; P0.001). The C statistic for NT-proBNP ≥ 900 pg/ml was significantly better than IPI score for prediction of survival. These findings suggest that NT-proBNP ≥ 900 pg/ml could be considered a useful marker for risk assessment in NHL patients treated with chemotherapy.

The effectiveness of antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia (ET) is not proven. In this study, the incidence rates of arterial and venous thrombosis were retrospectively analyzed in 300 low-risk patients with ET treated with antiplatelet drugs as monotherapy (n = 198) or followed with careful observation (n = 102). Follow-up was 802 and 848 person-years for antiplatelet therapy and observation, respectively. Rates of thrombotic events were 21.2 and 17.7 per 1000 person-years for antiplatelet therapy and observation, respectively (P = .6). JAK2 V617F–positive patients not receiving antiplatelet medication showed an increased risk of venous thrombosis (incidence rate ratio [IRR]: 4.0; 95% CI: 1.2-12.9; P = .02). Patients with cardiovascular risk factors had increased rates of arterial thrombosis while on observation (IRR: 2.5; 95% CI: 1.02-6.1; P = .047). An increased risk of major bleeding was observed in patients with platelet count greater than 1000 × 109/L under antiplatelet therapy (IRR: 5.4; 95% CI: 1.7-17.2; P = .004). In conclusion, antiplatelet therapy reduces the incidence of venous thrombosis in patients with JAK2-positive ET and the rate of arterial thrombosis in patients with associated cardiovascular risk factors. In the remaining low-risk patients, this therapy is not effective as primary prophylaxis of thrombosis, and observation may be an adequate option.

Cytogenetic studies were performed in 112 untreated cases of myelodysplastic syndrome (MDS) between 1985 and 1990. Among 112 patients who were examined at the time of diagnosis, 54 had an abnormal karyotype (48%). The highest frequency of chromosome abnormalities was observed in refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-t) and the lowest in refractory anemia with ring sideroblasts (RARS) and chronic myelomonocytic leukemia (CMMoL). Numerical changes were observed in 19 cases and structural in 17; chromosome 8 was most frequently gained (11 cases), whereas chromosome 7 was most frequently lost (6 cases), 5q− in 14 (4 as a sole anomaly); involvement of 7q22 was seen in 3 cases, 11p in 2 patients, 11q in 3 (one patient as a sole anomaly), 12p in 4 (2 patients as a sole anomaly), i(17q) in 4 (3 patients as a sole anomaly), and complex chromosomal defects in 10 patients. If one takes into account the prognosis value, a complex karyotype and the presence of ring chromosomes were correlated with the worst prognosis, followed by −77q−; an intermediate prognosis corresponds to i(17q), 12p as a sole anomaly, +8 (as a sole anomaly or plus other anomalies), and involvement of 12p. Patients with a 5q− as a sole anomaly or with a normal karyotype, had the best prognosis.

A retrospective analysis of a registration database was used to assess the efficacy and tolerability of anagrelide for treating essential thrombocythemia (ET). The study was conducted by analysing information on response to treatment, time to response and tolerability.A total of 411 patients with ET from 54 centres in Spain were included in a retrospective chart review. Patients who had started treatment with anagrelide as a first- or second-line therapy before December 31, 2004 were included.Of 411 patients, anagrelide was given as a first-line therapy in 110 patients, following hydroxyurea in 280 patients, and following other drugs in 21 patients. Overall response (OR) with anagrelide was 81.2% (77,0-84,9; p=0,05). Complete response (platelets400x10(9)/L) was observed in 53.6% (48,6-58,5; p=0,05) and partial response (600x10(9)/L) in 27.6% (23,4-32,2; p=0,05) of patients. There was no significant correlation of previous treatment with OR rate (p=0.103) despite a higher OR for previously untreated patients (86.4%) than for previously treated patients (79.3%). The most frequent treatment-related adverse reactions were headache (13.1%), palpitations (10.2%) and tachycardia (7.5%).The observed response rates and tolerability profile are similar to those reported previously. Anagrelide is well tolerated and effective in reducing platelets to target levels in patients with ET.

The purpose of this work was to study retrospectively the molecular response and outcome of 19 gastric mucosa associated lymphoid tissue (MALT) lymphoma patients achieving histological remission after chemotherapy or surgery. Immunoglobulin heavy chain variable (IgV(H)) gene rearrangements were studied by PCR in biopsies obtained at diagnosis and follow-up. Presence of t(11;18)(q21;q21) was studied by FISH or RT-PCR. Sequencing analysis of three t(11;18)(q21;q21) positive and two negative lymphomas with persistent monoclonal IgV(H) rearrangements was also performed. Long-term IgV(H) monoclonality was demonstrated in 11/19 patients (58%); in five of them monoclonal rearrangements were present in all samples throughout the follow-up. Persistent IgV(H) monoclonality was detected a median of 49 months after the achievement of histological response and did not condition histological relapse in most cases. All three t(11;18)(q21;q21) positive patients had maintained IgV(H) monoclonality and sequencing analyses revealed the same mutated IgV(H) alleles in the diagnostic and the follow-up samples. Over half of the patients with gastric MALT lymphoma with histological response after chemotherapy and/or surgery have long-term persistent monoclonality. The presence of t(11;18)(q21;q21) seems to condition long-term persistence of the initial lymphoma clone.trade mark.

To explore the gene expression signature in essential thrombocythemia (ET) patients in relation to JAK2V617F mutational status, expression profiling in circulating granulocytes was performed. Twenty ET were studied by microarray analysis and the results were confirmed by real-time quantitative RT-PCR in 40 ET patients, not receiving cytoreductive treatment. A heterogeneous molecular signature characterized by two main gene expression patterns was found: one with an upregulation of inflammatory genes related to neutrophil activation and thrombosis, and the other with significantly lower expression of these genes. Supervised clustering analysis showed 30 genes differentially expressed between JAK2V617F-negative and JAK2V617F-positive ET patients. Among the JAK2V617F-negative, a set of 14 genes (CISH, C13orf18, CCL3, PIM1, MAFF, SOCS3, ID2, GADD45B, KLF5, TNF, LAMB3, HRH4, TAGAP and TRIB1) showed an abnormal expression pattern. In this group of patients, CISH, SOCS2, SOCS3 and PIM1 genes, all involved in JAK-STAT signalling pathway, presented a lower expression. A two-gene predictor model was built comprising FOSB and CISH genes, which were the best discriminators of JAK2V617F status. In conclusion, JAK2V617F-negative ET patients present a characteristic gene expression profile, different from JAK2V617F-positive patients. Other pathways, besides JAK-STAT, might be implicated in the pathophysiology of JAK2V617F-negative ET patients.

Vascular events and evolution to either myelofibrosis (MF) and acute leukemia (AL) are the main causes of morbidity and mortality in individuals with essential thrombocythemia (ET). However, the frequency of these complications in young ET patients is not well known. The objective of the present study was to assess the frequency of vascular events and the incidence of MF and AL in young patients with ET and to identify the factors associated with the development of such complications. In 126 subjects diagnosed with ET at a median age of 31 years (range: 5–40), overall survival and probability of survival free of either thrombosis, bleeding, MF, AL, and polycythemia vera (PV) were analyzed by the Kaplan-Meier method, followed by the log-rank test. With a median follow-up of eleven years (range: 4–25) three patients have died, being the probability of survival 98% at ten years. A total of 31 thrombotic events were registered in 25 patients; thrombosis-free survival (TFS) was 84% at ten years. Tobacco use was the only factor associated with an increased thrombotic risk, since TFS at 10 years was 72% in smokers versus 90% in non-smokers (p=0.03). Severe hemorrhagic complications were observed in 11 patients, and the estimated probability of bleeding-free survival was 92% at ten years. Evolution to MF was seen in 6 patients, four of whom had never received treatment for ET. MF-free survival was 97% at 10 years, with the risk being higher in patients showing an increased reticulin network in the bone marrow biopsy performed at diagnosis of ET (p=0.005). Transformation to AL was registered in one patient. JAK2 was mutated in 33 out of the 87 assessable patients (38%) and the mutation was associated with higher Hb values at diagnosis (p = 0.001). ET evolved into PV in five patients, being the probability of evolution into PV of 15% in JAK2 V617F positive patients versus 0% in JAK2 V617F negative patients (p=0.01). In conclusion, severe vascular complications are not infrequent in young subjects with ET, whereas transformation to MF or AL is a rare event.

Background: The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) all have a time dependent risk of progression to either an advanced myelofibrotic state (post ET/PV MF) and/or to acute myeloid leukemia. The impact of disease duration upon the MPN symptom burden is not well understood, nor are the precise mechanisms of disease progression. We sought to better understand the impact of disease duration on MPN symptom burden. Methods: Symptom burden data was collected utilizing the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) amongst MPN patients, collected at the time of an office visit in an international cohort of MPN patients as previously described (Scherber et. al.). Symptom burden assessment was a previously validated 27-item symptom burden questionnaire scored on a 0-10 scale (0= as good as it can be, 10 = as bad as it could be). The patient or provider was asked to report the time since MPN diagnosis. MPN duration was determined to be early if the diagnosis was established between 0 to 5 years ago, intermediate if the diagnosis was established between 6 to 10 years ago, and late if the diagnosis was established 11 years ago or more. Anemia was defined as a red blood cell count less than 10 g/dL, leukopenia was defined as a white blood cell count was below 4 x 109, and thrombocytopenia if the platelet count was below 150 x109. Statistical significance was calculated using ANOVA f-test and chi squared. Results: Patient demographics and disease burden: A total of 1443 patients responded to the survey, including 592 (41%) ET, 549 (38%) PV, and 302 (21%) MF patients, including 181 (60%) primary MF, 67 (22%) post-ET MF, and 54 (18%) post-PV MF. Among MF patients, mean duration of MPN diagnosis was 9 years, and mean duration MF diagnosis was 4.7 years. Among respondents, 757 fit criteria for early disease duration, 353 fit criteria for intermediate disease duration, and 333 fit criteria for late disease duration. Respondent mean age was 62 years and approximately half of respondents were female (55%). Patients with longer diagnosis duration tended to be older (p=0.009) and were most likely to have anemia (0.02), leukopenia (p=0.01), or thrombocytopenia (p=0.03). These individuals were also most likely to have a history of hemorrhage (p=0.007) or require red blood cell transfusions (p Combined cohort symptom burden: On average among the combined cohort of ET, PV and MF patients, symptoms tended to worsen with time with this effect being significant for symptom items of fatigue (BFI, p Symptom burden in MPN subtypes. When evaluating specific MPN types, patients with essential thrombocythemia experienced significantly greater sexual difficulties over time (p=0.03). The severity (p=0.01) and incidence (p=0.03) of pruritus and incidence of night sweats (p Discussion Overall, significant worsening in symptom burden can be recognized over time for individuals diagnosed with MPNs. Diagnosis may not necessarily correlate with disease duration as the timing of diagnosis may be delayed from onset of disease. Given the intent of this abstract to evaluate changes with disease duration, we did not investigate correlations between symptom burden and cytopenias. We do know that risk factors for survival in the MPNs include older age and thrombosis, however, disease duration should be investigated as an alternative marker of burden in future survival studies. Disclosures Harrison: CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Kiladjian:Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Zweegman:Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Barbui:Novartis: Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria, Speakers Bureau. te Boekhorst:CTI Biopharma: Consultancy; Novartis: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

Background: Thrombotic and hemorrhagic complications are commonly encountered in uncontrolled essential thrombocythemia (ET). Both anagrelide and hydroxyurea (HU) have proven efficacious in cytoreduction as well as reducing these events and remain first line therapy for most high-risk ET patients. Independent of their role in risk-reduction, little is known about how these therapies impact patient symptomatology or quality of life. In this study, we compared the clinical and symptomatic profiles of ET patients receiving HU or anagrelide against patients with no previous experience with these agents. Methods: Data was assessed from a prospectively collected international database of ET patients in which demographics, disease features, and ET symptoms utilizing the myeloproliferative neoplasm symptom assessment form (MPN-SAF; Scherber et al, 2011). The MPN-SAF includes the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Total symptom score (TSS) was computed based on symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. ET risk scores were calculated using the IPSET scoring algorithm (Passamonti 2012). Thrombocytopenia was defined as a platelet count Results Hydroxyurea vs. HU Naive A total of 402 ET patients with active HU use were compared to 392 ET patients with no history of HU use. Patients using HU were older (63.5 years vs. 52.3 years, p Anagrelide vs. Anagrelide Naive A total of 49 ET patients with active anagrelide use were compared to 794 ET patients with no history of anagrelide use. Patients using anagrelide had a longer mean disease duration (8.1 years vs. 5.8 years) and were more anemic (9.1% vs. 1.2%, p HU vs. Anagrelide A total of 402 patients currently using HU were compared to 39 patients currently using anagrelide. Overall, HU users were slightly older (63.5 years vs. 55.1 years, p Discussion In this retrospective analysis, it does not appear cytoreduction with either HU and/or anagrelide has a significant impact on ET symptom burden despite reducing vascular events. Importantly, the higher risk scores in HU patients did not translate directly into greater patient symptomatology supporting previous studies demonstrating a poor association between these two items. Prospective trials measuring ET symptom change, in the setting of randomized trials will better quantify impact of cytoreduction on symptom burden as well as quantify impact of newer agents such as interferon or jak inhibition. Figure 1. Symptom Comparisons Between HU, Anagrelide and Other Therapy Figure 1. Symptom Comparisons Between HU, Anagrelide and Other Therapy Disclosures Kiladjian: Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Cervantes:Sanofi-Aventis: Consultancy; Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding. te Boekhorst:Novartis: Consultancy; CTI Biopharma: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

Background Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) associated with a high degree of symptomatology, progressive cytopenias and potential to transform into acute myelogenous leukemia (AML). Thrombocytopenia amongst MF patients is a proven negative prognostic indicator and predictor of transformation to AML. Ruxolitinib is an effective JAK inhibitor for MF symptoms and splenomegaly, but is not indicated in patients with severe thrombocytopenia. Phase III trials of pacritinib have shown alleviation of the MF symptom burden amongst patients with thrombocytopenia (ASCO 2015 Mesa et. al.). In this study, we assessed the symptom burden of MF patients with significant thrombocytopenia who were naïve to pacritinib. Methods Data was assessed from a prospectively collected international database of MF patients in which demographics, disease features, and MF symptoms utilizing the myeloproliferative neoplasm symptom assessment form (MPN-SAF; Scherber et al, 2011). The MPN-SAF includes the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Total symptom score (TSS) was computed based on symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. MF risk scores were calculated using the DIPSS criteria (Gangat, 2011). Thrombocytopenia was defined as a platelet count Results Demographic and Disease Features: A total of 418 patients with (n=89) and without (n=329) thrombocytopenia completed the MPN-SAF. Patients with thrombocytopenia were slightly younger (57.4 vs. 61.0, p=0.01) with longer disease durations (11.9 years vs. 8.8 years, p=0.0489) and had a higher prevalence of primary myelofibrosis (PMF; 82% vs. 66%, p=0.01). The presence of thrombocytopenia was associated with other laboratory abnormalities including anemia (60.7% vs. 25.3%, p Symptoms Scores for individual MPN-SAF items were assessed for each subgroup. Patients with thrombocytopenia had markedly higher total symptom scores than patients without thrombocytopenia (32.8 vs. 24.1, p Discussion MF patients with thrombocytopenia have distinctive clinical characteristics and face a significantly more severe symptom burden. Importantly, despite thrombocytopenia being a recognized risk factor for disease advancement, no correlations are noted between patient symptomatology and risk category. In addition, patients with severe thrombocytopenia do not differ symptomatically from patients with moderate thrombocytopenia despite having more severe anemia, leukopenia and transfusion requirements. This implies that the degree of symptomatology expressed by thrombocytopenic MF patients occurs independent from the exact platelet value. Conclusion The results of this study suggest that patients with thrombocytopenia will benefit from aggressive symptomatic control, potentially from targeted agents. Figure 1. MF Symptoms in Patients With and Without Thrombocytopenia Figure 1. MF Symptoms in Patients With and Without Thrombocytopenia Disclosures Kiladjian: Novartis: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Incyte Corporation: Consultancy. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Shire: Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Gilead: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Vannucchi:Shire: Speakers Bureau; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

JAK2 V617F mutation analysis in different myeloid lineages (granulocytes, platelets, CFU-MK, BFU-E and CFU-GM) in essential thrombocythemia patients

The numerical and morphological findings of erythroid burst colonies from the peripheral blood and bone marrow of two patients with congenital dyserythropoietic anemia type II (CDA-II) are described. In both patients there was an increase of medullary and peripheral BFU-E that was explained by a compensating mechanism against the destruction of erythrocytes. In most of the colonies normal and abnormal erythroblasts co-existed. The ultrastructural analysis of erythroblasts showed, as in vivo, bi- and multinuclearity, autophagic vacuoles, and aberrant membranes that sometimes gave rise to the double-membrane appearance. These abnormalities were found in both patients simultaneously in the blood and bone marrow. These findings point to defective erythroid stem cells. The clinical expression of the disease may depend partly on the ratio of normal to abnormal erythroid colonies.

Introduction: The dominance of the JAK2V617F-positive clone at the CD34+ compartment is an important modifier of the disease phenotype in myeloproliferative neoplasms (MPN). Recently, mutations in the calreticulin gene (CALR) have been described in around 40-70% of JAK2V617F and MPL wild-type essential thrombocythemia (ET) and myelofibrosis (MF) patients. However, there is limited information regarding the role of CALR mutant clone in hematopoietic progenitor cells. Objective: To study the mutant allele burden at progenitor level in JAK2V617F-positive and CALR-mutated MPN. Methods: Sixty-five patients with MPN including 36 with polycythemia vera (PV) all JAK2V617F-positive, 13 with ET (7 JAK2V617F-positive and 6 CALR-mutated) and 16 with MF (9 JAK2V617F-positive post-PV MF, 4 CALR-mutated primary MF and 3 CALR-mutated post-ET MF) were included in the study. Granulocytes were isolated from peripheral blood by density gradient, whereas CD34+ cells were purified by immunomagnetic positive selection. Stem cells (CD34+CD38-) and progenitors (CD34+CD38+) populations were further separated by fluorescence-activated cell sorting. JAK2V617F and CALR allele burden was measured by quantitative PCR and PCR followed by fragment analysis, respectively, in stem cells, progenitor cells and granulocytes. The study was approved by the local Ethics Committee and informed consent was obtained according to the Declaration of Helsinki. Results: CALR-mutated ET patients harbored a higher mutant load in CD34+CD38- than JAK2V617F-positive ET patients (30.6 vs 6.3%, p=0.01), whereas no significant differences were observed in CD34+CD38+ and in granulocytes allele burdens. Moreover, CALR-mutated ET patients showed a higher mutational load in CD34+CD38- than JAK2V617F-positive PV (30.6% vs 15.7%, p=0.04) but the mutant load in granulocytes was lower (29.6% vs 63.3%, p The mutant allele burden in granulocytes and CD34+ cells was higher in patients with JAK2V617F-positive MF than in those with CALR-mutated MF (CD34+CD38-: 71% vs 47.2% p=0.05, CD34+CD38+: 68.4% vs 40.6% p=0.018, granulocytes: 76.9% vs 53.7% p=0.05). Finally, we could demonstrate that the mutant load was lower in CALR-mutated ET patients than in CALR-mutated MF at progenitor level and in granulocytes (CD34+CD38-: 30.6% vs 47.1% p=0.08, CD34+CD38+: 17.8% vs 40.6% p=0.03, granulocytes: 29.6% vs 53.7% p=0.004). Conclusion: CALR-mutated ET patients have a higher mutant load in CD34+CD38- than JAK2V617F-positive ET and PV patients, whereas the JAK2V617F-positive hematopoietic progenitor cells have more differentiation potential than those CALR-mutated. Moreover, in the MF phase of MPN, the expansion of the mutated clone at the progenitor level is greater in JAK2V617F-positive than in CALR-mutated patients. Disclosures No relevant conflicts of interest to declare.

BACKGROUND Somatic mutations in the myeloid differentiation primary response gene 88 (MYD88) have been described in B-cell lymphomas, including DLBCL. Our group has confirmed the remarkable site-specific occurrence of MYD88 mutations at some immune-privileged locations and, in addition, has described that DLBCL patients are at high risk of progression and death after first-line treatment, with independence of other well-known clinical prognostic factors (Leukemia 2014). AIMS To further analyze the clinical responsiveness and outcome after second-line treatment in DLBCL patients carrying MYD88 L265P. METHODS A series of 175 patients with DLBCL diagnosed at our institution between 2000 and 2013 were included. Inclusion criteria were: full clinical data available, treatment with remission intention, enough material for DNA extraction and absence of HIV infection. The presence of MYD88 L265P mutation was assessed by allele-specific oligonucleotides (ASO)-PCR in DNA samples extracted from FFPE tissue. RESULTS In 129 patients (74%) treatment consisted on rituximab plus CHOP or CHOP-like schedules, while the remaining cases received other treatments depending on their clinical requirements. With a median follow-up time of 57 months, progression free survival (PFS) at 5 years after first-line treatment was 57%. Twelve of these patients (9.3%) had MYD88 L265P mutation, and these patients had a significantly worse PFS that patients who did not (18% vs 59%, p=0.018). Overall survival (OS) at 5 years after first line treatment was 65% (17% vs 72%, with vs without MYD88 mutation, respectively; p=0.001). We further analyzed the outcome after second-line treatment in 32 cases: 6 patients had refractory disease (0 with MYD88 mutation) and 26 patients were in first relapse. Three out of 5 patients carrying MYD88 mutation and 25 out of 27 patients without MYD88 mutation were treated with chemotherapy. Only one out of 5 cases (20%) with MYD88 mutation responded to second-line therapy whereas response was observed in 16 out of 27 cases (59%) without MYD88 mutation(p=0.106). PFS at 4 years from starting second-line therapy was 0 % in cases with MYD88 DLBCL and 34% in those without MYD88 mutation (p=0.092). Moreover, OS at 4 years from starting second-line therapy was 0 % in cases with MYD88 DLBCL and 37% in those without MYD88 mutation (p=0.019)(Figure 1). CONCLUSION Our study shows that MYD88 L265P in DLBCL patients is not only associated to worse respond after first -line therapy, but also to a very poor response to second-line therapy, and consequently to a dismal outcome. New treatments are urgently needed for these patients. Acknowledgments: This study was supported in part by 2014SGR567 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

BACKGROUND: The Evaluation of Xagrid Efficacy and Long-term Safety (EXELS) study (NCT00567502) is the largest prospective observational cohort of high-risk patients (pts) with essential thrombocythemia (ET) reported to date. OBJECTIVES: The primary objective was safety and pregnancy outcomes of anagrelide (ANA) compared with other cytoreductive therapies (CRT). Secondary objectives included efficacy, measured by the incidence of thrombohemorrhagic events and platelet reduction. METHODS: High-risk pts (≥1 of age >60 yrs, previous thrombotic event, platelet count >1000 x 109/L) with ET were enrolled across 13 countries in Europe between 2005 and 2009. Pts were required to be receiving CRT. Data, including events predefined in the protocol (PDEs), were collected every 6 mo for 5 yrs for all patients. Event rates are presented as number of pts per 100 patient-years exposure and by treatment at time of event. Event rates are provided rather than p values due to the observational nature of the study. Preliminary final data are presented and final data, including platelet response and pregnancy results, will be available at ASH. Recently, results have remained stable and conclusions are not expected to change. RESULTS: 3649 pts were categorized according to treatment at registration as follows: ANA (n=804), ANA + other CRT (n=141), other CRT (n=2666) and no CRT (n=38). Over 80% of pts received either hydroxycarbamide (HC) or ANA, and 69.8% of pts received anti-aggregatory therapy. At registration, median age was lower in the ANA (55.5 yrs, range 18‒89) and ANA + other CRT (59.0 yrs, range 22–88) groups vs the other CRT group (70.0 yrs, range 17‒95). The arterial thrombotic event rate was similar in ANA (1.63) and other CRT (1.62) groups, whereas venous thrombotic event rates differed (0.35 vs 0.57). The major hemorrhagic event rate was highest in the ANA group, especially in pts also treated with anti-aggregatory therapy (1.24). 105 pts transformed to myelofibrosis (MF) and 62 to acute leukemia (AL). Transformation to MF rates were similar in the ANA (1.31), ANA + other CRT (1.27) groups, and lower in the other CRT (0.32) group. Rate of transformation to AL was 0.17, 0.46, and 0.33, respectively. In pts who had only ever received either ANA or HC, rate of transformation to MF was higher in the ANA vs HC group (0.78 vs 0.17) whereas transformation to AL was higher in the HC vs ANA group (0.22 vs 0). All pts who ever received ANA and transformed to AL had also received prior HC. PDEs of greatest interest are displayed in Table 1. Non-hematological malignancy was the most frequent PDE in the other CRT group. 57.4% of deaths were attributed to a PDE; transformation (event rate, 1.9), most frequently to AL (1.3), and non-hematological malignancies (1.6) were the most frequent causes of PDE-related death. No unexpected side effects were noted. The proportion of pts with a white blood cell (WBC) count >15 x 109/L at any time was higher in pts who died (12.5%) vs alive pts (6.1%) and in pts who had transformed (15.7%) vs those who did not transform (5.7%). CONCLUSION: Pts receiving ANA were younger than those receiving other CRT. Thrombotic event rates were low; arterial events were similar between ANA and other CRT groups, and venous events were lower in the ANA vs other CRT group. Hemorrhage was most frequent in the ANA + anti-aggregatory therapy group, whereas non-hematological malignancy was most frequent in the other CRT group. Transformation to MF and AL were most frequent in the ANA and HC groups, respectively. The incidence of death and transformation was higher in pts with a WBC count >15 x 109/L. Abstract 1846. Table 1 Treatment at time of event ANA N=1127 ANA + other CRTN=451 Other CRT N=2909 No CRT N=645 PDE Pts(events)n Event rate Pts(events)n Event rate Pts(events)n Event rate Pts(events)n Event rate Total thrombohemorrhagic events 92 (113) 2.75 24 (29) 2.86 270 (326) 2.60 30 (33) 4.91 Arterial thrombotic events 55 (65) 1.63 19 (21) 2.25 171 (200) 1.62 17 (19) 2.74 Venous thrombotic events 12 (13) 0.35 1 (1) 0.11 61 (67) 0.57 7 (7) 1.13 Major hemorrhagic events 30 (35) 0.87 6 (7) 0.69 53 (59) 0.49 7 (7) 1.12 Transformation to: Myelofibrosis 45 (45) 1.31 11 (11) 1.27 35 (35) 0.32 14 (14) 2.31 Acute leukemia 6 (6) 0.17 4 (4) 0.46 36 (36) 0.33 16 (17) 2.57 Non-hematological malignancy 17 (18) 0.49 4 (5) 0.46 143 (161) 1.35 12 (13) 1.95 Non-PDE death 22 (22) 0.64 7 (7) 0.8 128 (128) 1.18 30 (30) 4.80 ANA, anagrelide; CRT, cytoreductive therapy; PDE, predefined event; Pts, patients Disclosures Birgegard: Shire Pharmaceuticals: Consultancy, Honoraria, Research Funding. Besses:Shire Pharmaceuticals: honoraria for educational lectures Other. Griesshammer:Amgen: Honoraria; Sanofi: Honoraria; Shire: Honoraria; Novartis: Honoraria; Roche: Honoraria. Gugliotta:Shire Pharmaceuticals: Honoraria, Research Funding. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; S Bio: Honoraria; YMBioscience: Honoraria; CTI: Honoraria; Gilead: Honoraria; Sanofi: Honoraria, Speakers Bureau; Shire Pharmaceuticals: Honoraria, Speakers Bureau. Hamdani:Shire Pharmaceuticals: Employment. Achenbach:Shire Pharmaceuticals: Employee Other. Kiladjian:Shire Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by erythrocytosis, splenomegaly and a frequently burdensome symptom profile. Despite current guidelines of aspirin, phlebotomy, and selective cytoreduction, many patients have inadequately controlled PV-related symptoms and/or disease features. We performed a comparison of PV symptom burden/disease feature phenotypes to understand unmet needs in current medical management. Methods Data was collected prospectively amongst an international cohort of PV patients including symptom burden, demographics, and disease features. Subgroups were identified who had previously failed hydroxyurea (PV-HU), required ongoing phlebotomy (PV-P), had palpable splenomegaly (PV-S), or had all 3 features (PV-HUPS). Control groups were derived from the remaining PV patients lacking the specified subgroup trait; patients in whom the trait status was unknown were excluded from each respective control group. All participants completed the MPN specific symptom burden questionnaire (MPN-SAF TSS (MPN-10 – Table 1)) and had no prior history of splenectomy. Surveyed symptoms on the MPN-10 included the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. PV risk scores were calculated using the 2013 criteria (Leukemia 2013). Comparison of symptoms between groups employed t-tests. Results Patient Demographics and Disease Features Between Phenotypic Groups A total of 1334 PV patients completed the MPN-10, and were assigned to categories of PV-HU (499 [37%]), PV-P (646 [48%]), PV-S (369, [28%]), and PV-HUPS (148 [12%]). The demographics between these groups were similar (comparable age (median range 60-63), PV risk scores (mean risk range: Low 16.4-23.7%; Intermediate 31.4%-36.6%; High 42.8%-47%). Mean hemoglobin was similar among PV subgroups (range 14.4-14.9); PV-HUPS had a higher mean WBC count (20.3 g/dL vs. 8.8-11.8 g/dL) and platelet count (703.5 x 10(9)/L vs. 327.5-462.8 x 10(9)/L), and disease duration (11.5 years vs. 6.4-8.8 years). Prior thrombosis was most common in PV-S patients (28.5% vs. 21.8-25.2%) and prior hemorrhage was most common in PV-HUPS patients (23.8% vs. 13.7-15.8%). Symptom Burden The MPN-10 scores of each problematic PV phenotype (HU, P, S, HUPS) were compared to the remainder of the PV cohort lacking the trait (PV-control; Table 1). Both individual symptom scores and TSS were highest for PV-HUPS patients (mean TSS 32.5 vs. 27.7-29.2). All problematic PV subgroups demonstrated significant differences for individual symptoms and TSS compared to PV-control. Comparing "problematic" subgroup responses, PV-HU patients described more inactivity whereas PV-S patients described more early satiety and pruritus. No statistical differences were noted in PV-HU, PV-P and PV-HUPS patient responses to MPN-10 items of "fever" and "weight loss". Discussion PV patients who have either failed HU, are undergoing phlebotomy and/or have splenomegaly exhibit moderate to severe symptomatology and demonstrate unmet medical need for management. As evidenced in this study, considerable overlap in symptomatology exists in PV-HU, PV-P, PV-S and PV-HUPS. Current randomized trials of JAK inhibitors have demonstrated benefits in a PV-HUPS phenotype. This data suggests that PV patients with any evidence of inadequate control (PV-HU, P, or S) have similarly unmet needs and may be candidates for clinical trials, intensification of medical therapy or perhaps JAK inhibitor therapy. Disclosures Kiladjian: Shire Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding. Besses:Shire Pharmaceuticals: honoraria for educational lectures Other. Birgegard:Shire Pharmaceuticals: Consultancy, Honoraria, Research Funding. Etienne:Novartis, BMS, Pfizer, Ariad: Honoraria. Roy:Merck: Peg-Interferon provided for academic clinical trial in CML Other. te Boekhorst:Novartis: Consultancy. Griesshammer:Novartis: Honoraria; Shire: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Roche: Honoraria. Mesa:Incyte Corporation, CTI, NPS Pharma, Inc., Gilead Science Inc., Celgene: Research Funding.

Among 63 patients with chronic lymphoproliferative disorders (CLPD) studied cytogenetically in our laboratory, four showed a del(7)(q32); in two it was the sole cytogenetic anomaly and in two it was part of a complex karyotype. We suggest that despite the rarity of this anomaly, it could be related to CLPD.

To determine the clinicohematological factors predictive for the appearance of major vascular complications (MVC) in patients with essential thrombocythemia (ET), 148 consecutive such patients were retrospectively assessed for the development of MVC during a median follow-up of 58.5 months. Seventy-seven patients had vascular risk factors, and 37 a history of MVC at ET diagnosis. Forty-nine MVC were registered in 33 patients during the follow-up period. The actuarial probability of MVC was 27% at 6 years in the whole series, 35.6% for patients above 60 years, and 21.4% for patients younger than 60 years, whereas only one of the 36 patients younger than 45 years had MVC. At multivariate analysis, age >60 years, history of major ischemia and hypercholesterolemia were the variables associated with an increased MVC risk. These results suggest that all ET patients above 60 years should be treated, whereas in younger patients treatment decisions should be primarily based on the existence of risk factors for MVC.

Reply to Westerman et al. : ‘Re: Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Alvarez-Larran A et al. Leukemia 2007; 21: 1218–1223’

Reply to ‘Re: Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Alvarez-Larran A et al. ’ by Westerman et al.

We report here a case of drug-related thrombo-cytopenia associated with infliximab and later with adalimumab in a patient with Crohn’s disease. A 42-year-old woman was diagnosed with colonic Crohn’s disease with perianal fistula lesions (Perianal Disease Activity Index (PDAI) = 11). She was treated with metronidazole and azathioprine. After 2 months the patient remained symptomatic and three infusions with infliximab (monoclonal antibody against tumour necrosis factor α (TNFα)) at a dose of 5 mg/kg were administered at 0, 2 and 6 weeks. The symptoms decreased and improvement was noted (PDAI = 2). Maintenance therapy with infliximab every 8 weeks was started. After three additional infusions, a routine blood count showed thrombocytopenia of 44×109/l (fig 1) with normal haemoglobin, white blood cell count and coagulation tests. Pseudo-thrombocytopenia …

A higher JAK2 V617F-mutated clone is observed in platelets than in granulocytes from essential thrombocythemia patients, but not in patients with polycythemia vera and primary myelofibrosis

JAK2 V617F mutation, PRV-1 overexpression and endogenous erythroid colony formation show different coexpression patterns among Ph-negative chronic myeloproliferative disorders

The results of cytogenetic studies are reported in 76 patients with B-chronic lymphoproliferative disorders (B-CLPD): 60 patients with chronic lymphocytic leukemia (CLL), six with follicular lymphoma in leukemic phase (FLLP), five with splenic B-cell lymphoma with villous lymphocytes (SLVL), two with chronic prolymphocytic leukemia (CPL), two with hairy cell leukemia (HCL), and one with plasma cell leukemia (PCL). PHA (phytohemagglutinin), PWM (pokeweed mitogen), LPS (lipopolysaccharide from Escherichia Coli), TPA (phorbol 12-myristate acetate), IL6 (interleukin 6), and DxS (dextran sulfate) were used as mitogens. Mitoses were obtained in 75 cases. Clonal aberrations could be demonstrated in 34 cases (44%). In CLL, classical type, chromosomes 6, 11, and 13 were more frequently involved, whereas trisomy 12 was frequently found in CLL mixed-cell type, in FLLP, and CPL. In SLVL the deletion del(7)(q32) is noteworthy and miscellaneous chromosome abnormalities in the remaining patients were observed. Regarding the efficiency of mitogens, PHA turned to be the most effective in obtaining metaphases and in detecting clonal chromosomal aberrations.