ALBERT

Description: 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

Description: BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that has demonstrated superiority over standard therapies in the treatment of MF. In the phase 3 COMFORT studies, patients (pts) receiving RUX had improvements in splenomegaly and symptoms as well as longer survival compared with pts in the control arms. Study 258 extended these findings to pts with a platelet (PLT) count of 50 to ˂ 100 × 109/L (pts excluded from the COMFORT studies) and showed that starting at 5 mg bid with dose escalation to ≥ 10 mg bid offered similar benefits (Talpaz 2013). EXPAND aims to evaluate the safety of RUX and establish a maximum safe starting dose (MSSD) in pts with low PLTs. METHODS: EXPAND is a phase 1b, dose-finding study (NCT01317875) in pts with MF and baseline PLTs 50 to 99 × 109/L. The study has 2 phases: dose escalation and safety expansion. In the dose-escalation phase, RUX doses were 5 mg bid, 5 mg AM/10 mg PM, 10 mg bid, 10 mg AM/15 mg PM, and 15 mg bid. A Bayesian logistic regression model with overdose control was used to guide dose escalation; intra-pt dose modification was allowed up to the MSSD in each stratum. Pts were assigned to 2 strata based on their baseline PLTs: S1, 75 to 99 × 109/L; S2, 50 to 74 × 109/L; doses in S2 were open if that dose and the next were deemed safe in S1. At data cutoff (20 Jan 2015), enrollment was ongoing in the safety expansion phase at the MSSDs; this interim analysis was preplanned for when the last patient enrolled in the dose escalation phase completed the core study (day 168). RESULTS: 46 pts (S1, n = 27; S2, n = 19) received RUX; 12 pts were treated at each of the MSSDs for S1 (15 mg bid) and S2 (10 mg bid). Baseline pt characteristics were generally balanced across strata in all pts: 65% were aged ≥ 65 y, 48% were male, 74% had PMF (20% PPV-MF, 7% PET-MF), and 54% had high-risk MF. Median (range) baseline spleen length was 16 (5-30) and 12 (4-33) cm in S1 and S2, and median (range) hemoglobin was 104.7 (83-138) g/L in S1 and 100.0 (58-133) g/L in S2. Overall, 10 (37%) and 11 (58%) pts were still receiving treatment in S1 and S2. The primary reason for discontinuation was AEs (S1, 22%; S2, 21%). At the MSSDs, 1 pt (8.3%) in each group ended treatment due to AEs; 67% and 75% of pts at MSSDs in S1 and S2 were still on treatment at data cutoff. There were no DLTs in S1 and 1 DLT in S2 at 10 mg bid (grade 4 thrombocytopenia). AEs were consistent with the known safety profile of RUX. At the MSSDs, thrombocytopenia was the most common reason for dose modifications (S1, n = 8; S2, n = 8) but led to discontinuation for only 1 pt (S2). Deaths during the study included 1 cardiac arrest (S1), 1 sudden death (S1), 1 multi-organ failure (S2), and 1 transformation to AML (S2; ˃ 30 days after discontinuation), none of which were assessed as related to study drug. The most common AEs overall (S1, S2) were thrombocytopenia (all grade: 82%, 79%; grade 3/4: 63%, 79%) and anemia (all grade: 56%, 37%; grade 3/4: 33%, 26%). Other common AEs (〉 30% in either stratum) included diarrhea (33%) in S1, and cough (42%), nasopharyngitis (32%), and diarrhea (32%) in S2. At the MSSDs, the most frequent AE was also thrombocytopenia (Table). A ≥ 50% reduction in spleen length (spleen response) was achieved at week 24 in 41% of pts (7/17) in S1 and 30% of pts (3/10) in S2; 50% (13/26) in S1 and 68% (13/19) in S2 achieved a response at any time (Figure). At the MSSDs, 37.5% (3/8) and 40% (2/5) of pts in S1 and S2 achieved a spleen response at week 24; 50% (6/12) and 67% (8/12) of pts achieved a response at any time. CONCLUSIONS: RUX was tolerated at starting doses of up to 10 or 15 mg bid in pts with MF and low PLTs (PLTs 50 to 74 × 109/L and 75 to 99 × 109/L). AEs were consistent with the known safety profile of RUX with no new or unexpected adverse findings. Spleen length reductions were observed across all dose levels, including the MSSDs, and are similar to those observed in pts without low PLTs. The study is currently open for enrollment and aims to evaluate the benefit vs risk of RUX further in this subgroup of pts, with emphasis on optimal dosing and long-term safety. Disclosures Vannucchi: Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Gisslinger:Janssen Cilag: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Consultancy. Harrison:Sanofi: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria; Shire: Speakers Bureau. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Kiladjian:Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy; Incyte Corporation: Consultancy. Nicolini:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mo:Novartis Pharmaceuticals Corporation: Employment. Atienza:Novartis Pharmaceuticals Corporation: Employment. Gopalakrishna:Novartis Pharma AG: Employment. te Boekhorst:CTI Biopharma: Consultancy; Novartis: Consultancy.

Description: Introduction: There are few effective treatment options available for patients (pts) with myelofibrosis (MF). Pts with thrombocytopenia, a risk factor for shorter overall survival, have poorer prognosis (Gangat, J Clin Oncol 2010). Pacritinib is a kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFSR1 and has demonstrated minimal myelosuppression in clinical trials (Hart, Leukemia 2011; Komrokji, Blood 2015; Mesa, ASCO 2015). In the phase III open-label PERSIST-1 trial, a significantly greater proportion of pts treated with pacritinib achieved spleen volume reductions (SVR) ≥35% vs BAT (ITT: 19.1% vs 4.7%, p=0.0003; pts evaluable at baseline and Week 24: 25.0% vs 5.9%, p=0.0001; Mesa, ASCO 2015). This analysis examines pt responses across subgroups. Methods: Pts naive to treatment with JAK inhibitors were randomized 2:1 to receive oral pacritinib 400 mg once daily or BAT. Stratification factors included DIPSS risk status and baseline platelet count. Pts were eligible who had DIPSS Intermediate (Int)-1, Int-2, or High risk disease; absolute neutrophil count 〉500/µL; palpable splenomegaly ≥5 cm; and baseline Total Symptom Score (TSS) ≥13 using the Modified MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS and TSS 2.0). There was no restriction on baseline platelets or hemoglobin (Hgb) levels. The primary endpoint was the proportion of pts achieving SVR ≥35% at Week 24 by centrally-reviewed MRI or CT and the secondary endpoint was the proportion of pts achieving ≥50% reduction in TSS from baseline at Week 24 using 6 symptoms from the MPN-SAF TSS. Pt responses were analyzed by baseline risk factors for MF including platelet counts (

Description: 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