ALBERT

Description: Key Points INTERIM treatment affects cytogenetic and molecular response, but not the outcome. No patients treated with INTERIM progressed to accelerated or blast phase.

Description: Introduction. Chronic myeloid leukemia (CML) patients (pts) treated with imatinib first line achieve complete cytogenetic response (CCyR) in 〉 70% of cases and major molecular response (MMR) in 18-58%. These pts have a life expectancy similar to the general population. However even undetectable BCR-ABL may not equate to eradication of the disease because of the sensitivity of Q-RT-PCR. A new diagnostic method, the digital-PCR (dPCR), able to detect 1 BCR-ABL+ cell out of 107 cells, has been recently developed (Goh HG et al., 2011). dPCR corresponds to a 100 fold increase in sensitivity as compared to Q-RT-PCR. Therefore, dPCR by assessing the presence of minimal residual disease with higher sensitivity, could potentially identify pts in whom CML has been eradicated. Aims. The Imatinib Suspension And Validation (ISAV) study is aimed at validating the capability of dPCR to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR results. Methods. This study involves 15 sites, 10 in Italy and 1 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. CML pts (Chronic or Accelerated Phase) under imatinib therapy since more than 2 years and in complete molecular remission (CMR) were eligible for this study. Patients had to be in CMR for at least 18 months (mts), with a minimum of 3 Q-RT-PCR performed at their own sites. After signing the informed consent, blood samples are obtained for dPCR and the pts discontinue imatinib therapy. Standard Q-RT-PCR is performed monthly (mts 1-6) and then bimonthly for 36 mts to assess the maintenance of the molecular remission. The loss of molecular remission is defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resume imatinib treatment at the same dosage used before interruption. Patients’ quality of life during imatinib discontinuation/resumption is evaluated through the EORTC – C30 Quality of Life questionnaire. Results. The enrolment in ISAV began in November 2011 and ended in July 2013. The study enrolled 112 pts: Italy 69.6%, Germany 21.4%, Canada 5.3%, Spain 2.6% and Israel 0.9%. Among the 112 pts, 59.3% were male and 37.0% were aged 65 or older; median duration of imatinib treatment was 103.1 mts with median duration of CMR of 25.8 mts before imatinib discontinuation. To date, the median follow-up (FUP) time is 16.6 mts [95% CI: 14.9-18.2]. Forty-seven pts (43.5%, 95% CI: 34.0-53.4) of the 108 eligible pts relapsed and resumed imatinib; 38/47 (80.9%) of them relapsed in the first 9 mts and the last relapse occurred 19.6 mts after imatinib discontinuation. A loss of CCyR occurred in 11 pts (23.4%): 10/11 CCyR losses were recovered; 1 patient withdrew the consent shortly after obtaining a partial cytogenetic response. No case of CML progression was observed. After the resumption of imatinib the median time to either MMR or CMR was 1.9 [95% CI: 1.2-2.4] mts. Of the 61 not-relapsed pts, 43 (39.8% of the total) regained Q-RT-PCR positivity but never lost MMR. The median time to Q-RT-PCR positivity was 3.6 mts [95% CI: 3.0-4.8] and the range of duration of Q-RT-PCR positivity (below 0.1%) was between 5.7 and 29.2 mts. No significant correlation between relapse and previous duration of imatinib treatment, use of interferon, time to CCyR or duration of CMR was identified. An inverse relationship between pts age and risk of relapse is evident: 90% of pts 〈 45 years relapsed vs 37.5% in the class ≥ 45 - 〈 65 years and 27.5% of pts ≥ 65 years, p(χ2)

Description: Background: Polycythemia vera (PV) is characterized by erythrocytosis, thrombocytosis, and/or leukocytosis and a broad range of disease-related symptoms. In high-risk patients, the most common first-line treatment is hydroxyurea (HU). The open-label RESPONSE trial demonstrated that ruxolitinib (RUX), a JAK1/JAK2 inhibitor, provided superior efficacy compared with best available therapy in patients with PV who were resistant to or intolerant of HU according to modified European LeukemiaNet (ELN) criteria. This study (RELIEF) was conducted in patients receiving a stable dose of HU and who were generally well controlled but reporting disease-associated symptoms, comparing the change in PV-related symptom burden in patients continuing their HU therapy with those switching to RUX treatment. Methods: RELIEF was a randomized, multicenter, double-blind, double-dummy, phase 3b study of patients with PV aged ≥18 years on a stable dose of HU monotherapy and reporting PV-related symptoms. Patients were required to be receiving HU for ≥12 weeks prior to enrollment and on the same dose level for the last 4 weeks, and have a score ≥8 on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) cytokine total symptom score (TSS-C). The TSS-C comprised symptoms of itching, tiredness, muscle ache, night sweats, and sweats while awake; each symptom was rated on a scale of 0=absent to 10=worst imaginable, with a maximum TSS-C score of 50. Patients also had to meet one of the following: ≤1 phlebotomy in the previous 6 months or no palpable splenomegaly. Those eligible were randomized 1:1 to receive RUX 10 mg BID and HU-placebo, or HU at the same dose/schedule and RUX-placebo. Dose adjustments were permitted for safety and efficacy. After Week 16, patients could receive open-label RUX until Week 48. The primary endpoint was the proportion of patients with a ≥50% reduction in TSS-C at Week 16; secondary endpoints included proportion of patients with a ≥50% reduction in individual TSS-C symptoms and safety. Results: Overall, 54 and 56 patients were randomized to RUX and HU, respectively; 87.0% and 89.3% remained on treatment through Week 16. At baseline, the median age (range) was 64 (36-87) in the RUX group and 66 (19-85) in the HU group; 44% and 61% were men. The majority of patients in the RUX and HU groups did not have baseline platelet counts or WBC above ELN thresholds: platelets 〉400 and ≤600 x 109/L (RUX 31.5%, HU 28.6%), 〉600 x 109/L (3.7%, 8.9%); WBC 〉10 and ≤15 x 109/L (16.7%, 16.1%), 〉15 x 109/L (11.1%, 14.3%). In the RUX and HU groups, the mean TSS-C at screening (22.4, 23.1) was higher than that at baseline (16.7, 18.0); the ratio of screening to baseline TSS-C was 1.7 and 1.6. The proportion of patients achieving a ≥50% reduction from baseline in TSS-C at Week 16 (primary endpoint) was 43.4% in the RUX group and 29.6% in the HU group (P=0.139; OR, 1.82; 95% CI, 0.82-4.04). The proportions of patients in the RUX vs HU groups achieving a ≥50% reduction in scores for itching and tiredness at Week 16 were 40.0% vs 26.4% and 54.2% vs 32.0%, respectively. Median percentage changes in individual TSS-C symptoms are shown in Table 1. Additional analyses found no correlation between individual changes in HU dose from baseline to Weeks 13-16 and percentage change in TSS-C in the HU arm (r2=0.030). Even patients maintaining the same HU dose from prior to study entry through Week 16 reported symptom improvement: 12/35 (34.3%) with no dose change, 4/12 (33.3%) with a dose increase, and 0/9 (0%) with a dose decrease had a ≥50% reduction in TSS-C. The most common nonhematologic adverse events in the RUX arm on randomized treatment were fatigue (20.4% RUX vs 10.7% HU), headache (16.7% vs 5.4%), and dizziness (13.0% vs 8.9%). The most common adverse events on HU were diarrhea (9.3% RUX vs 19.6% HU) and constipation (7.4% vs 12.5%); most events were grade 1 or 2. Grade 3 or 4 anemia or thrombocytopenia (lab values) were not reported in the RUX group; two patients in the RUX group had grade 3 or 4 neutropenia. Conclusion: In generally well controlled PV patients receiving a stable dose of HU, there was a positive trend in symptom improvement for patients switched to RUX therapy versus those continuing on HU therapy, although this was not statistically significant. The 34% response rate among patients who continued to receive a stable HU dose suggests a placebo effect that led to an underpowered study. Further analyses are required to better interpret these findings. Disclosures Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yacoub:Alexion Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees. Koschmieder:Novartis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne:Novartis Pharmaceuticals: Honoraria. Verstovsek:Incyte Corporation: Research Funding. Hunter:Incyte Corporation: Employment, Equity Ownership. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Morozov:Novartis Pharmaceuticals: Employment, Equity Ownership.

Description: Background: Myelofibrosis (MF) is a clonal neoplastic disease resulting in bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms. The Janus kinase (JAK) pathway is often dysregulated in MF, and agents targeting this pathway have demonstrated efficacy in this disease. Ruxolitinib (RUX), a potent JAK1/JAK2 inhibitor, demonstrated superiority in spleen volume reduction, symptom improvement, and survival compared with the control arm in the phase III COMFORT-I and COMFORT-II studies. Panobinostat (PAN), a potent pan-deacetylase inhibitor (pan-DACi), inhibits JAK signaling through disruption of the interaction of JAK2 with the protein chaperone heat shock protein 90. In phase I/II studies, PAN has shown splenomegaly reduction and improvement of bone marrow fibrosis. The combination of RUX and PAN demonstrated synergistic anti-MF activity in preclinical studies. These preliminary results led to the initiation of a phase Ib study evaluating the combination of RUX and PAN in patients (pts) with MF. The updated results from the expansion phase of this trial are presented here. Methods: Eligible pts had intermediate-1, -2, or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF by International Prognostic Scoring System criteria, with palpable splenomegaly (≥ 5 cm below the costal margin). The primary objective was determination of the maximum tolerated dose (MTD) and/or recommended phase II dose (RPIID). Secondary objectives included safety, efficacy, and pharmacokinetics. Exploratory endpoints included assessment of improvement in bone marrow fibrosis and reduction of JAK2 V617F allele burden. The treatment schedule was RUX (5-15 mg) twice daily (bid) every day and PAN (10-25 mg) once daily 3 times per week (tiw; days 2, 4, and 6) every other week (qow) in a 28-day cycle. Following dose escalation and identification of the potential RPIID, additional pts were enrolled into the expansion phase and treated at this dose. Results: As of March 14, 2014, a total of 61 pts were enrolled (38 escalation phase and 23 expansion phase). The median duration of exposure to PAN and to RUX was 24.6 weeks and 24.0 weeks, respectively, for pts treated in the expansion phase. Three DLTs were observed in the escalation phase (grade 4 thrombocytopenia [n = 2], grade 3 nausea [n = 1]). No MTD was reached. The RPIID was confirmed to be RUX 15 mg bid and PAN 25 mg tiw qow in May 2014. Among the 34 pts treated at the RPIID, grade 3/4 adverse events (AEs) regardless of causality included anemia (32%), thrombocytopenia (24%), diarrhea (12%), asthenia (9%), and fatigue (9%). AEs led to discontinuation in 6% of pts treated at the RPIID. Two pts treated at the RPIID died due to causes unrelated to study treatment (1 due to myocardial infarction and 1 due to progression of myelofibrosis). Among the pts treated at the RPIID, 79% showed a 〉50% decrease in palpable spleen length, with 100% decrease (non-palpable spleen) being observed in 53% of pts. Additionally, 48% of pts treated at the RPIID in the expansion phase achieved ≥35% reduction in spleen volume (Figure). These results are similar to those observed for spleen volume response at 24 weeks among pts who received single-agent RUX on the phase III COMFORT-I (41.9%) and COMFORT-II (32%) studies. Conclusions: The combination of the JAK1/JAK2 inhibitor RUX and the pan-DACi PAN was well tolerated and resulted in high rates of reductions in splenomegaly in pts with intermediate- and high-risk MF. Although a relatively larger proportion of patients experienced spleen volume reductions at week 24 as compared to the COMFORT studies, the smaller sample size, shorter follow up times and potential differences in the patient populations preclude definitive comparisons. Similar to COMFORT-I and II trials, hematological AEs, specifically anemia and thrombocytopenia, were the most common AEs observed in pts treated with the combination therapy. Pts continue to be treated in the expansion phase at the RPIID. Updated safety, efficacy, and exploratory analyses on bone marrow fibrosis, JAK V617F allele burden, and biomarkers, including cytokines, will be presented. Figure Change in Spleen Volume in Expansion Phase Figure. Change in Spleen Volume in Expansion Phase Disclosures Kiladjian: Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Honoraria, Research Funding. Heidel:Novartis: Honoraria, 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. Ribrag:Celgene: Consultancy; Pharmamar: Consultancy; Epizyme: Research Funding; Bayer: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Research Funding. Conneally:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kindler:Novartis: Consultancy. Acharyya:Novartis: Employment. Gopalakrishna:Novartis: Employment. Ide:Novartis: Employment, Equity Ownership. Loechner:Novartis: Employment. Mu:Novartis: Employment. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Gilead: Honoraria; SBio: Consultancy; Shire: Speakers Bureau.

Description: Background: According to recent findings, the management of myeloproliferative neoplasms (MPNs) is highly dependent on presence or absence of thrombotic events. The JAK2 mutation has been identified as a marker of MPNs. It is also an occult marker in several patients with splanchnic venous thrombosis (SVT), but its contribution as an additional thrombotic risk factor in MPNs is still under discussion. Moreover, a pro-thrombotic risk factor, either inherited or acquired (Factor V Leiden mutation, deficiencies in protein C, protein S and Prothrombin mutation 20210) can be identified in these patients. Recently, another milestone in the molecular diagnosis of MPNs, somatic mutations in the CALR gene, has been reported. A total of 36 types of frame-shifting insertions and deletions were detected in the exon 9 of CALR gene, which encodes a Ca2+ binding protein in endoplasmic reticulum called calreticulin. Type-1, 52-bp deletion (p.L367fs*46), and type-2, 5-bp TTGTC insertion (p.K385fs*47) variants constitute more than 80% of these mutations These mutations were reported to have a incidence of over 60% to 80% in JAK2 and MPLmutation-negative Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) patients. Compared to those with JAK2 mutation, CALR-mutated ET patients are younger and have a lower leukocyte count and higher platelet count. CARL mutations have been also reported as a favorable prognostic factor on thrombosis-free survival (TFS) for ET patients. Aims: In this study, we evaluated the incidence of SVT, JAK2 and CALR mutations, and prothrombotic risk factors in patients with MPNs observed in our center from January 2000 to January 2014. Methods: We performed a retrospective review of clinical charts of 466 Ph1 negative MPN patients followed in our center, classified according to the WHO 2008 classification. Patient and disease characteristics, including JAK2V617F, MPL and CALR mutations and thrombotic risk factors were recorded. Results: The median age of patients with diagnosis of MPN was 43 years. Fourteen patients (13 females, 1 male; 3%) of median age 46 years presented a SVT. Three had a Budd Chiari syndrome and 11 a portal venous thrombosis. According to a histological review, these patients were classified as follows: ET, 2 cases, PMF, 3 cases, Polycythemia Vera (PV) 1 case, Myelofibrosis in a prefibrotic phase (MF0) 8 cases. Classification of 11 cases with Myelofibrosis according to the IPSS identified 7 as INT1, 1 as INT2 and 3 as low risk. Among all 14 patients diagnosed with SVT, 12 were JAK2V617F positive with a median allelic burden of 30%, 1 patient was MPL positive, and 1 patient was triple-negative. CALR mutation was not observed in any of the patients. Two cases were diagnosed with MPN 30 months after SVT, 3 patients experienced SVT after a median follow-up of 108 months from MPN diagnosis while in 9 patients the diagnosis of MPN was concomitant to SVT. In the latter patients, median Hb levels were 12.4 g/dL , WBC 8260 /µL, HCT 36.3%, PLT 337.000/ µL and a modest hepatomegaly and splenomegaly were documented. Prothrombotic risk factors were found in 9 of 13 patients. Two patients experienced a thrombotic episode prior to the diagnosis of SVT and two subsequently during the follow-up. Interestingly, 9 (70%) of MPN patients with SVT exhibited at least one prothromobtic risk factor, such as factor V Leiden, Protein C deficiency, hyperhomocystinemia and 50% had two or more associated defects. Thirteen of the 14 patients are currently being treated as follows hydroxyurea (9), interferon (1), and ruxolitinib (3). All patients received oral anticoagulant treatment except for three who are on antiplatelet therapy. MPN patients without SVT had a lower prevalence of prothrombotic risk factors and developed venous thrombosis in different anatomical sites: in these cases WBC count, platelet values and the presence of JAK2V617F mutation correlated with the development of the thrombotic event. Conclusions: Although SVT has a low incidence in MPN patients, a potential benefit of testing for mutations in CALR gene and for additional prothrombotic risk factors is suggested in the whole MPN population for the prevention and treatment of this complication. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 2293 Background. Dasatinib is a tyrosine kinase inhibitor that has 325-fold greater in vitro activity against native BCR-ABL (breakpoint cluster region-Abelson leukemia virus) compared with imatinib and can overcome primary (intrinsic) and secondary (acquired) imatinib resistance. A phase III dose optimization study showed that in patients with chronic phase (CP) chronic myeloid leukaemia (CML), dasatinib at 100 mg once daily improved the safety profile while maintaining efficacy compared with the previously recommended dose of 70 mg twice-daily. Few data exist on the efficacy and safety of dasatinib in elderly CML patients. Aims. The aim of the study was to evaluate the impact of dose reduction on dasatinib efficacy. Methods. We revised 129 unselected pts with CP CML aged 〉60 yrs treated in 21 Italian haematological Institution, who received dasatinib after being resistant/intolerant to imatinib. Among this group 70 pts were given dasatinib at adjusted-dosage below the standard recommended dose of 100 mg daily for 〉 6 months. In relation to the dose modulation, patients were divide in 2 groups: group-a (21/70, 30%) received a starting dose of 20 mg daily dose excalated to the maximum tolerated dose of 70 mg daily; group-b (49/70=70%) received a starting dose of 100 mg daily, successively adhusted according to tolerance. Sokal score was evaluable for 59/70 patients (low for 16, intermediate for 28, high for 15). All patients were analyzed for haematological, cytogenetic and molecular response. Results. All patients were fully evaluable for response at a median FU time of 25 mos (range 0,7- 56,3 mos). Eight pts (11.4%) discontinued treatment due to intolerance. Response rates were 25,7% (18pts), 24.3% (17 pts), 15.7% (11 pts), 10% (7 pts), 12.8% (9 pts) for complete haematologic response (RHC), complete cytogenetic response (RCyC), major molecular response (RMolM), complete molecular response (RMolC), partial cytogenetic response (RCyP), respectively. Median Cumulative event free survival (EFS) and overall survival (OS) were 21.3 and 27.3 mos respectively. We did not observe any significative difference in term of response between group A and B receiving different doses. Interestingly, 3/9 patients in group A who had a transient loss of molecular response achieved major molecular response after dose escalation to 50 mg. Conclusions: Dasatinib given at a lower dose than currently recommended is still effective in elderly CML patients. However, more close molecular monitoring is advised when lower doses are prescribed. Studies in larger series are warranted to better define optimal dose and schedule of dasatinib in this frail patient population. Disclosures: Rosti: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.

Description: BACKGROUND: Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated durable reductions in splenomegaly and MF-related symptoms and improved survival compared with placebo and best available therapy in the 2 large phase 3 COMFORT studies. Those studies required baseline platelet (PLT) counts ≥ 100 × 109/L, limiting safety and efficacy data in patients (pts) with lower PLTs; however, thrombocytopenia is frequent in MF. Ongoing phase 2 clinical trials in pts with low PLTs have shown ruxolitinib to be generally well tolerated and to provide efficacy benefits for these pts. To gather additional safety and efficacy data in pts with low PLTs, recruitment for JUMP (JAK Inhibitor Ruxolitinib in Myelofibrosis Patients), a phase 3b expanded-access trial for countries with no access to ruxolitinib outside a clinical trial, was extended to pts with baseline PLT counts ≥ 50 × 109/L. Here, we present safety and efficacy data from a planned interim analysis of ruxolitinib in pts with baseline PLT count ≥ 50 to 〈 100 × 109/L. METHODS: Eligible pts had high-, intermediate-2, or intermediate-1-risk MF, with a palpable spleen (≥ 5 cm from the costal margin) and baseline PLT counts ≥ 50 × 109/L. The starting doses of ruxolitinib was 5 mg bid for pts with baseline PLTs ≥ 50 to 〈 100 × 109/L. The primary endpoint was assessment of safety and tolerability of ruxolitinib based on the frequency, duration, and severity of adverse events (AEs). An interim analysis of the safety and efficacy of ruxolitinib in pts with PLTs ≥ 50 to 〈 100 × 109/L at baseline (low-PLT group) was planned for when the first 50 low-PLT pts had completed 6 mo of therapy; this analysis includes results from the first 6 mo of treatment. The final analysis will be performed after all pts have completed 24 mo of treatment or ended treatment due to commercial availability. RESULTS: At data cutoff (01 January 2014), 50 pts with low PLTs had been treated for 6 mo and are included in this analysis. Pt characteristics were median age, 68.5 years; median palpable spleen length, 15.5 cm below the costal margin; and female, 50.0%. Median (range) baseline hemoglobin (Hb) was 98 g/L (57-149 g/L) and PLT count was 87 × 109/L (68 to 98 × 109/L). Most pts (76.0%) remained on or completed treatment as per protocol at the time of data cutoff. The primary reasons for discontinuation included adverse events (AEs; n = 9) and disease progression (n = 2). The median daily dose was 11.8 mg/day (range, 5.9-40.0 mg/day). Of evaluable pts at week 24, 38.2% (13/34 pts) achieved a ≥ 50% reduction from baseline in palpable spleen length; 38.2% had reductions of ≥ 25% to 〈 50%. Overall, 44.7% of pts achieved a ≥ 50% reduction from baseline in spleen length at any time. Clinically meaningful improvements in symptoms, as assessed using the FACT-Lymphoma Total Score (the range for the minimally important difference is 6.5 to 11.2 points), were seen as early as week 4 (mean change from baseline, 8.2) and were durable through week 12 (9.6). The most common hematologic grade ≥ 3 AEs were anemia (28.0%) and thrombocytopenia (30%; 4% grade 4); 3 pts discontinued due to thrombocytopenia and 1 due to anemia. Four pts had grade 1/2 hemorrhages (1 conjunctival, 1 gastric, and 2 epistaxis) and 2 pts had grade 3/4 (1 intestinal and 1 esophageal varices). PLT counts decreased slightly from baseline (mean change at nadir, −5.9 × 109/L); 3 pts required PLT transfusions. The mean change from baseline to nadir in Hb was −13.4 g/L. Rates of nonhematologic grade ≥ 3 AEs were low overall (1 pt each), with the exception of pyrexia (6.0%), septic shock (4.0%), and arthralgia (4.0%); 44.0% of pts had ≥ 1 dose modification and 28.0% had ≥ 1 dose interruption. CONCLUSIONS: In this cohort of pts with low PLTs, ruxolitinib demonstrated an AE profile consistent with that previously reported in pts with normal PLTs. As compared to a previous analysis of pts with median baseline PLT counts of 248 × 109/L from this same study (Al-Ali et al. EHA 2014), pts in this low-PLT cohort experienced similar improvements in symptoms (mean change from baseline at week 12, 9.6 vs 11.8) but lower achievement of a ≥ 50% reduction from baseline in spleen length within the first 24 weeks of treatment (44.7% vs 69%), likely due to the lower median daily dose (11.8 mg/day vs 36.8 and 24.0 mg/day for pts with starting doses of 20 and 15 mg bid, respectively). Taken together, these data suggest that low-dose ruxolitinib is generally safe and efficacious in pts with PLTs ≥ 50 to 〈 100 × 109/L. Disclosures Griesshammer: Roche: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Shire: Honoraria; Amgen: Honoraria. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. le Coutre:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Ariad: Honoraria. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Foltz:Promedior: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy. Bouard:Novartis: Employment. Perez Ronco:Novartis: Employment. Ghosh:Novartis: Employment.

Description: Abstract 3078 Chronic myeloproliferative neoplasms (CMNs) include Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). So far limited studies of familial clusters of CMNs have been reported.Familial chronic myeloproliferative neoplasms are defined when in the same pedigree at least two relatives have CMNs. Familial CMNs should be distinguished from inherited disorders with Mendelian transmission, high penetrance and polyclonal haematopoiesis named ‘hereditary erythrocytosis' and ‘hereditary thrombocytosis'. Recently a 5- to 7-fold higher risk of MPN among first-degree relatives of patients with MPNs was reported. These findings support the limited studies suggesting a familial clustering in MPNs. The analysis of mutations of JAK2 and MPL may improve our ability to identify these conditions. In a consecutive series of patients observed in our Institution from January 2000 to June 2010, we found that among 460 patients with sporadic CMNs and 94 Ph1 positive chronic myeloid leukemia (CML), the prevalence of familial cases was 4%.With 22 pedigrees, 44 patients (8%) were identified with two relatives affected. Familial CMNs were 11 PV,14 ET,7 PMF, 5 CML respectively, while sporadic cases were 96 PV,204 ET,115 PMF and with other 45 CMNS not furtherly classified. As far as the distribution of the different CMNs within the familial cluster, We observed that only in 4 of 22 families (18%) all the affected relatives were diagnosed with the same disease (homogeneous pattern: PV one family and ET three families), whereas 14 families exhibited a mixed distribution among PV, ET and PMF. 8 families exhibited CMNs associated with other hematological disease such as chrocic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodisplastic syndrome (MDS). Among this, 6 families presented a first or second degree of relationship of first and second generation. In 10 cases the relatives were brothers, affected by familial CMNs with a prevalence of PV and TE clinical phenotype at diagnosis.According to JAK2 (V617F) mutational status, analyzed in 30 out of 44 patients, 19 patients showed a positivity pattern, while 18 families showed a heterogeneous pattern; they included both JAK2 (V617F) -positive and JAK2 (V617F)-negative patients. Among the 19 patients with JAK2 (V617F) positivity, the distribution of positivity according to the diagnosis was 100% of PV, 45% of ET and 55%of PMF; homozygosity was present only in PV cases. In our series, only two members of the same family were affected by familial CMNs. Finally it should be noted that in our series of familial cases clinical presentation, therapeutic approach and type and severity of complications were comparable to that of sporadic cases. In conclusion, the present study indicates the relevant possibility of familial CMNs, thus suggesting the opportunity of a detailed family history as part of the initial work-up of patients with CMDs; in addition it also suggests the usefulness of an accurate biological study. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4090 Transformation to acute myeloid leukemia (AML) is a known complication of MPN but the role of JAK2V617F mutation is still undefined. In 2006, Campbell described a possible model for the development of a JAK2WT-AML in a patient with JAK2V617F-MPN and more recently, Theocharides et al. reported that in up to 53% of the patients who developed secondary AML from a JAK2-mutated MPN the mutation was no longer detectable; however the results obtained with DNA extracted from cells scraped or laser-capture-microdissected from bone marrow (BM) or peripheral blood (PB) smears, were confirmed in fresh samples only in few cases. In this study, we collected, by cell sorting, blast cells and mature myeloid cells (granulocytes, GRA) from whole BM aspirates of 40 newly diagnosed patients with AML secondary to MPN (18 derived from PMF; 13 from PV and 9 from ET) and analyzed the JAK2 status before and after leukemic transformation in selected cell compartments. To evaluate the modification in the JAK2 status before and during leukemic transformation we performed ASO-PCR and (QRT)-PCR assay on total BM of the MPN phase and sorted cell populations from AML phase. At the time of MPN diagnosis, JAK2V617F was detectable in 28 of 40 patients (70%) (10 of 18 PMF; 12 of 13 PV and 6 of 9 ET). No cytogenetic abnormalities or MPL and JAK2-exone 12 mutations were detected at this stage. Median time to AML progression (TTP) was 5.09 years (yrs) (range 0.38 – 27.81). A significant difference (p= 0.02) in TTP was found grouping patients according to JAK2 status during the MPN phase [JAK2WT-MPN n=12, TTP median 15.10 yrs (0.38-16.32); JAK2 mutated-MPN n=28, TTP median 4.07 yrs (0.67-27.81)]. Eight patients showed additional abnormalities involving chromosomes 1, 5, 7, 8, 9, 12, 14, 17 and 20 while no other AML-associated mutations (FLT3, NPM, CEBPA, RUNX1) were detectable at this stage. In our cohort of patients we found that JAK2V617F mutation was still present at the blast transformation in both compartments: CD34+ cells (blasts) and CD15+ cells (GRA) in 24 of 28 JAK2 mutated MPN (86%). Four of 28 patients (14%) developed JAK2V617F negative AML starting from a mutated PV with a mean TTP of 5.14 yrs. Interestingly, the WT status was confirmed in blast cells but also in GRA. Surprisingly we found 2 cases of JAK2V617F mutated AML transforming from a WT-PMF. Also in this case the JAK2V617F positivity in the AML phase occurred in both GRA and blast compartments. No differences (p= 0.3) in the allele burden were found comparing MNCs from chronic phase with MNCs of leukemic transformations or comparing GRA with blasts in AML phase. In conclusion, these results contrast with the previous study in which the JAK2 mutation was lost in 53% of blasts during leukemia transformation. In our work, the loss of JAK2V617F mutation during AML progression is a rare event (14%). Additional studies in larger patient series and multivariate analysis are needed before a prognostic role of JAK2V617F mutation regarding time to leukemia transformation can be definitely assessed. Disclosures: Vannucchi: Novartis: Consultancy.

Description: Abstract 5057 There is evidence in literature of the clinical and pathogenetic role of JAK2 V617F mutation in MPN, while its contribute as an additional thrombotic risk factor in MPN patients is still under discussion. The jak2 mutation has been identified as occult marker in several patients with splanchnic venous thrombosis (SVT); morover, 45% of patients with Budd-Chiari syndrome (BCS) and 34% of patients with portal vein thrombosis (PVT) have associated MPN. On the other hand, the majority of BCS patients without MPN present additional congenital or acquired thrombosis risk factors. The aim of the present study is to evaluate the incidence of SVT in MPN patients. We also evaluated the presence of other prothrombotic risk factors in MPN patients, in addition to the JAK-2 mutation. Out of the 460 Ph1 negative MPN patients observed in our center from January 2000 to January 2010 and retrospectively evaluated, 9 patients (7 females and 2 males; 2%) presented SVT. Six cases had Essential Thrombocythemia (ET), 2 Primary Myelofibrosis (PMF), and 1 Polycitemia Vera (PV). Five of the 6 cases with ET were females. Among the entire population of ET, SVT incidence was 3%. All the 9 patients diagnosed of SVT were JAK2 V617F positive and they were treated with antiaggregant and anticoagulation therapy; 6 received hydrossiurea. Seven patients had SVT before MPN diagnosis, 2 of them had splenectomy at diagnosis for surgical decision. In these patients developing SVT before MPN diagnosis no other major thrombotic event occurred during follow-up. The remaining 2 MPNs patients presented asymptomatic SVT diagnosed by imaging techniques routinely performed during MPN follow up. Interestingly, 75% of MPNs patients with SVT demonstrated at least one prothromobtic risk factor, such as factor V Leiden, Protein C deficiency, hyperhomocystinemia and 50% had 2 or more associated defects. MPNs patients without SVT (396) had a lower prevalence of prothrombotic risk factors and developed venous thrombosis in different anatomical sites: in these cases white blood cell count, platelets values and the presence of JAK2 V617F mutation correlate with the development of the thrombotic event. Conclusion. Even though SVT has a low incidence in MPNs patients, according to the results of the present retrospective study we suggest the potential benefit of searching for additional prothrombotic risk factors in the whole MPN population in order to prevent and/or properly treat this complication. Disclosures: No relevant conflicts of interest to declare.