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PURPOSE Standard therapy for myelofibrosis comprises Janus kinase inhibitors (JAKis), yet spleen response rates of 30%-40%, high discontinuation rates, and a lack of disease modification highlight an unmet need. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi). METHODS MANIFEST (ClinicalTrails.gov identifier: NCT02158858 ), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. The primary end point is a spleen volume reduction of ≥ 35% (SVR35) at 24 weeks. RESULTS Eighty-four patients received ≥ 1 dose of pelabresib and ruxolitinib. The median age was 68 (range, 37-85) years; 24% of patients were intermediate-1 risk, 61% were intermediate-2 risk, and 16% were high risk as per the Dynamic International Prognostic Scoring System; 66% (55 of 84) of patients had a hemoglobin level of < 10 g/dL at baseline. At 24 weeks, 68% (57 of 84) achieved SVR35, and 56% (46 of 82) achieved a total symptom score reduction of ≥ 50% (TSS50). Additional benefits at week 24 included 36% (29 of 84) of patients with improved hemoglobin levels (mean, 1.3 g/dL; median, 0.8 g/dL), 28% (16 of 57) with ≥ 1 grade improvement in fibrosis, and 29.5% (13 of 44) with > 25% reduction in JAK2V617F-mutant allele fraction, which was associated with SVR35 response ( P = .018, Fisher's exact test). At 48 weeks, 60% (47 of 79) of patients had SVR35 response. Grade 3 or 4 toxicities seen in ≥ 10% patients were thrombocytopenia (12%) and anemia (35%), leading to treatment discontinuation in three patients. 95% (80 of 84) of the study participants continued combination therapy beyond 24 weeks. CONCLUSION The rational combination of the BETi pelabresib and ruxolitinib in JAKi-naïve patients with myelofibrosis was well tolerated and showed durable improvements in spleen and symptom burden, with associated biomarker findings of potential disease-modifying activity.

7015 Background: Ruxolitinib (RUX), a Janus kinase (JAK) 1/2 inhibitor, is the current standard of care for patients (pts) with myelofibrosis (MF) that improves splenomegaly and disease symptoms with limited impact on disease biology. Many pts lose response over time, highlighting an unmet need for novel therapies. Navitoclax (NAV) is an oral, small-molecule inhibitor of BCL-XL and BCL-2 that has a synergistic effect when used in combination with JAK inhibitors to enhance apoptosis. This ongoing, open-label, multicenter, phase 2 trial (NCT03222609) is evaluating the efficacy and safety of NAV with/without RUX in pts with MF. Here, we report results from JAK inhibitor-naïve pts treated with NAV+RUX. Methods: Enrolled pts had primary or secondary MF with splenomegaly (DIPSS ≥INT-1) and did not receive prior JAK-2 therapy or bromodomain and extraterminal motif (BET) inhibitors. Pts initiated NAV at 100 mg QD or 200 mg QD if baseline (BL) platelet count was ≤150 × 109/L or >150 × 109/L, respectively. RUX was given BID with starting dose based on BL platelet count per local label. The primary endpoint was spleen volume reduction of ≥35% (SVR35) from BL at wk 24. Key secondary endpoints were ≥50% reduction in total symptom score (TSS50), bone marrow (BM) fibrosis reduction, and anemia response. Adverse events (AEs) were monitored throughout the study. Results: As of Oct 04, 2021, 32 pts received NAV+RUX. Median duration of f/u was 6.1 (range, 1.9 ─ 18.6) mos. 28 (88%) pts received NAV 200 mg and 4 (13%) received 100 mg OD. Median age was 69 (44 ─ 83) yrs, and median spleen volume was 1889.08 cm3 (645.6 ─ 7339.6). Median NAV and RUX exposures were 24.1 (5.1 ─ 80.9) and 20.1 (0.1 ─ 80.1) wks, respectively. 31 (97%) pts reported ≥1 AE (Grade ≥3 AEs, 25 [78%]; serious AEs, 6 [19%]). Most common Grade ≥3 AEs were anemia (34%), thrombocytopenia (31%), and neutropenia (19%). 3 (9%) and 2 (6%) pts reported an AE leading to NAV and RUX discontinuation, respectively, and 2 (6%; 1 PD, 1 cardiac disorder unrelated to NAV) AEs led to death ≤30 days after last NAV dose. SVR35 was achieved by 52% of evaluable pts at wk 24 (SVR35 in INT-2, 50%; HR, 33%) and by 76% at any time on treatment (Table). Median time to first SVR35 was 12.1 (11 ─ 47) wks. Conclusions: The combination of NAV+RUX was well tolerated and demonstrated early and robust reductions in spleen volume, anemia, and BM fibrosis in pts without prior JAK-2 inhibitor exposure. SVR35, TSS50, and BM fibrosis improved over time. Clinical trial information: NCT03222609. [Table: see text]

Purpose To develop a prognostic system for transplantation-age patients with primary myelofibrosis (PMF) that integrates clinical, cytogenetic, and mutation data. Patients and Methods The study included 805 patients with PMF age ≤ 70 years recruited from multiple Italian centers and the Mayo Clinic (Rochester, MN), forming two independent learning and validation cohorts. A Cox multivariable model was used to select from among a list of 22 variables those that were predictive of overall survival (OS). Integrated clinical and genetic prognostic models with (MIPSS70-plus) or without (MIPSS70) cytogenetic information were developed. Results Multivariable analysis identified the following as significant risk factors for OS: hemoglobin < 100 g/L, leukocytes > 25 × 109/L, platelets < 100 × 109/L, circulating blasts ≥ 2%, bone marrow fibrosis grade ≥ 2, constitutional symptoms, absence of CALR type-1 mutation, presence of high–molecular risk mutation (ie, ASXL1, EZH2, SRSF2, IDH1/ 2), and presence of two or more high–molecular risk mutations. By assigning hazard ratio (HR)–weighted points to these variables, three risk categories were delineated for the MIPSS70 model; 5-year OS was 95% in low-risk, 70% in intermediate-risk, and 29% in high-risk categories, corresponding to median OS of 27.7 years (95% CI, 22 to 34 years), 7.1 years (95% CI, 6.2 to 8.1 years), and 2.3 years (95% CI, 1.9 to 2.7 years), respectively. In the MIPSS70-plus model, which included cytogenetic information, four risk categories were delineated, with 5-year OS of 91% in low-risk, 66% in intermediate-risk (HR, 3.2; 95% CI, 1.9 to 5.2), 42% in high-risk (HR, 6.4; 95% CI, 4.1 to 10.0), and 7% very high–risk categories (HR, 17.0; 95% CI, 9.8 to 29.2). Both models remained effective after inclusion of older patients in the analysis. Conclusion MIPSS70 and MIPSS70-plus provide complementary systems of risk stratification for transplantation-age patients with PMF and integrate prognostically relevant clinical, cytogenetic, and mutation data.

7513 Background: A goal of AML maintenance therapy is to decrease the risk of relapse by suppressing growth of residual leukemic cells post-induction. CC-486 is an oral hypomethylating agent that allows for extended dosing schedules ( >7 days [d]/28d cycle) to sustain therapeutic activity. In the QUAZAR AML-001 trial (NCT01757535), CC-486 maintenance treatment (Tx) significantly prolonged overall (OS) and relapse-free survival vs. placebo (PBO) in pts with AML in first remission following induction chemotherapy (IC), who were not candidates for hematopoietic stem cell transplant (HSCT). Pts initially received CC-486 or PBO for 14d/cycle, but pts who relapsed with 5–15% blasts could receive escalated 21d/cycle dosing. We review outcomes of pts who received 21d dosing in QUAZAR AML-001. Methods: Pts were aged ≥ 55 years, with intermediate- or poor-risk cytogenetics and ECOG PS ≤ 3, and had achieved first CR/CRi after IC ± consolidation. Within 4 mo of CR/CRi, pts were randomized 1:1 to CC-486 300 mg or PBO QD on d 1–14 of 28d Tx cycles. CR/CRi status was assessed every 3 cycles. Pts relapsing with 5%–15% blasts in blood or bone marrow could receive study drug for 21d/cycle at the investigator’s discretion. Tx could continue until > 15% blasts, unacceptable toxicity, or HSCT. Results: 91 patients (CC-486, 51/238 [21%]; PBO, 40/234 [17%]) were assigned to ≥ 1 21d/cycle dosing schedule. Median time to dose escalation was 9.2 mo (range 1.0-52.7) for CC-486 and 6.0 mo (0.5-19.3) for PBO. Median number of 21d dosing cycles was 2.0 (range 1-45) in the CC-486 arm and 2.0 (1-16) in the PBO arm; 43% and 18% of pts, respectively, received > 3 cycles of 21d dosing. Among 78 evaluable pts, 10/43 (23%) CC-486 pts and 4/35 (11%) PBO pts regained CR/CRi (central review) during dose escalation. Median OS from randomization was 22.8 mo vs. 14.6 mo with CC-486 vs. PBO, respectively (HR 0.66 [95%CI 0.42, 1.0]; P = 0.073), and 1-year survival rates were 80.4% vs. 59.5% (+20.9% [95%CI 2.1%, 39.7%]). The most common AEs with first onset during 21d dosing were febrile neutropenia (CC-486 24%, PBO 3%), thrombocytopenia (22%, 23%), anemia (22%, 20%), and neutropenia (20%, 10%). Conclusions: Escalated 21d CC-486 dosing was well tolerated and resulted in prolongation of OS and restoration of remission in approximately one-fourth of pts. Hematologic AEs first reported during escalated dosing in both Tx arms may be due in part to disease relapse. A 21d dosing schedule should be considered for pts receiving CC-486 who experience relapse with 5–15% blasts. Clinical trial information: NCT01757535 .

Purpose Despite the lack of major improvements in the treatment of primary myelofibrosis (PMF), there are recent indications that the survival of patients might have increased over the years. This study was aimed at ascertaining whether survival prolongation has actually occurred in PMF. Patients and Methods A total of 802 patients diagnosed with PMF in four European countries were compared for the presentation of features and survival according to the diagnostic periods 1980 to 1995 (n = 434) and 1996 to 2007 (n = 368); relative survival was estimated for the two groups. Results Patients diagnosed between 1996 and 2007 more often had constitutional symptoms (31% v 23%) but a lower incidence of marked anemia (31% v 39%), leukocytosis greater than 25 × 109/L (9% v 13%), and blood blasts (27% v 33%); risk distribution was comparable between the two groups. Median survival was 4.6 years (95% CI, 4.0 to 5.1) for patients from 1980 to 1995 and 6.5 years (95% CI, 5.5 to 7.4) for patients from 1996 to 2007 (P < .001). The latter group of patients showed improved relative survival, especially for women, patients younger than age 65 years, and patients with low or intermediate-1–risk disease. Rates of PMF-attributable mortality at 5 and 10 years were significantly lower in the second period; this reduction in disease-specific mortality occurred across all patient subgroups, except in intermediate-2–risk or high-risk patients. Conclusion Survival of PMF is steadily improving, except in patients in poor-risk categories. This observation must be taken into account at the time of evaluating the survival impact of newer therapies for PMF, which are currently being tested in these patient subpopulations.

Purpose Thalidomide and lenalidomide can alleviate anemia in myelofibrosis. However, their value is undermined by their respective potential to cause peripheral neuropathy and myelosuppression. We therefore evaluated the safety and therapeutic activity of another immunomodulatory drug, pomalidomide. Methods In a phase II randomized, multicenter, double-blind, adaptive design study, four treatment arms were evaluated: pomalidomide (2 mg/d) plus placebo, pomalidomide (2 mg/d) plus prednisone, pomalidomide (0.5 mg/d) plus prednisone, and prednisone plus placebo. Pomalidomide was administered for up to 12 28-day treatment cycles. Prednisone (30 mg/d) was given in a tapering dose schedule during the first three cycles. Response was assessed by International Working Group criteria. Results Eighty-four patients with myelofibrosis-associated anemia were randomly assigned to the aforementioned treatment arms: 22, 19, 22, and 21, respectively. Response in anemia was documented in 20 patients, including 15 who became transfusion independent. Response rates in the four treatment arms were 23% (95% CI, 5% to 41%), 16% (95% CI, 0% to 33%), 36% (95% CI, 16% to 56%), and 19% (95% CI, 2% to 36%). The corresponding figures for patients receiving ≥ 3 cycles of treatment (n = 62) were 38%, 23%, 40%, and 25%. Response to pomalidomide with or without prednisone was durable (range, 3.2 to 16.9+ months) and significantly better in the absence of leukocytosis (37% v 8%; P = .01); JAK2V617F or cytogenetic status did not affect response. Grade ≥ 3 toxicities were infrequent and included (in each treatment arm) neutropenia (9%; 16%; 5%; 5%), thrombocytopenia (14%; 16%; 9%; 5%), and thrombosis (9%; 5%; 0%; 0%). Conclusion Pomalidomide therapy at 0.5 or 2 mg/d with or without an abbreviated course of prednisone is well tolerated in patients with myelofibrosis and active in the treatment of anemia.

Purpose We studied bone marrow (BM) histologic abnormalities in myelodysplastic syndromes (MDS) classified according to WHO criteria to determine their clinical correlates and prognostic value. Patients and Methods Three hundred one consecutive patients were retrospectively evaluated for BM fibrosis and CD34 immunoreactivity. Marrow fibrosis was assessed following the European consensus guidelines. Results Moderate to severe BM fibrosis was detected in 17% of cases and was associated with multilineage dysplasia (P = .001), high transfusion requirement (P < .001), and poor-risk cytogenetics (P = .007). CD34+ cell clusters were found in 23% of patients and were associated with WHO categories with excess of blasts (P < .001) and poor-risk cytogenetics (P = .001). In multivariable analysis, BM fibrosis and presence of CD34+ cell clusters had independent negative impact on overall survival (P < .001 and P = .019, respectively) and leukemia-free survival (P < .001 and P = .004, respectively). A hierarchical clustering analysis identified three subsets of patients with distinct clinical features. One cluster consisted mainly of patients with BM fibrosis, multilineage dysplasia, and high transfusion requirement; these individuals had lower overall survival and leukemia-free survival (P = .001 and P < .001, respectively). Within patients stratified according to International Prognostic Scoring System and WHO classification–based Prognostic Scoring System categories, BM fibrosis involved a shift to a one-step more advanced risk group. Conclusion BM fibrosis identifies a distinct subgroup of MDS with multilineage dysplasia, high transfusion requirement, and poor prognosis and represents an independent prognostic factor that may be useful in clinical decision making. Furthermore, the presence of CD34+ cell clusters is an independent risk factor for progression to acute leukemia.

Purpose The aim of this study was to evaluate the prognostic value of the WHO proposal, to assess the role of the main prognostic factors in myelodysplastic syndromes (MDSs) classified into WHO subgroups, and to estimate mortality (standardized mortality ratio [SMR]) and life expectancy in these groups as a basis for clinical decision making. Patients and Methods Four hundred sixty-seven patients who were diagnosed as having de novo MDS at the Division of Hematology, University of Pavia (Pavia, Italy), between 1992 and 2002, were evaluated retrospectively for clinical and hematologic features at diagnosis, overall survival (OS), and progression to leukemia (leukemia-free survival). Results Significant differences in survival were noted between patients with refractory anemia (RA), refractory cytopenia with multilineage dysplasia, RA with excess blasts, type 1 (RAEB-1), and RAEB-2. The effect of demographic factors on OS was observed in MDS patients without excess blasts (age, P = .001; sex, P = .006), as in the general population. The mortality of RA patients 70 years or older did not differ significantly from that of the general population (SMR, 1.62; P = .06). Cytogenetics was the only International Prognostic Scoring System variable showing a prognostic value in MDS classified into WHO subgroups. Transfusion-dependent patients had a significantly shorter survival than patients who did not require transfusions (P < .001). Developing a secondary iron overload significantly affected the survival of transfusion-dependent patients (P = .003). Conclusion These data show that the WHO classification of MDSs has a relevant prognostic value. This classification, along with cytogenetics, might be useful in decisions regarding transplantation. MDS with isolated erythroid lineage dysplasia identifies a subset of truly low-risk patients, for whom a conservative approach is advisable.

7001 Background: MMB, an oral JAK inhibitor, has been shown in early trials to reduce spleen volume, improve disease associated symptoms (Sx) and improve RBC transfusion requirements in patients (pts) with MF. This study of previously RUX treated pts with MF tested the superiority of MMB vs BAT in splenic volume reduction, Sx amelioration, and transfusion requirement at 24 weeks. Methods: Eligibility included primary or post-ET/PV MF; DIPSS high risk, Int-2, or symptomatic Int-1; prior RUX ≥4 weeks who either required transfusions or dose reduction to ° endpoint was splenic response rate (SRR; ≥35% reduction in volume from baseline). 2°endpoints, evaluated sequentially, were rates of TSS response (TSS RR; ≥50% reduction from baseline), RBC transfusion, RBC transfusion independence (TI) and RBC transfusion dependence (TD). Results: 73 of 104 (70%) and 40 of 52 (77%) pts receiving MMB or BAT, respectively, completed the 24 week randomized treatment phase. BAT for 88% of pts included RUX, and 27% of pts were on RUX in combination with other drugs. Efficacy results are in Table. The most common Gr ≥3 adverse events in MMB pts were anemia (13%) and thrombocytopenia (7%), and in BAT pts, anemia (13%), thrombocytopenia (6%) and abdominal pain (6%); treatment emergent peripheral neuropathy occurred in 11 (11%) of MMB (1 Gr3) and in no BAT pts. Conclusions: In previously RUX-treated patients with MF, 24 weeks of MMB was not superior to BAT for SRR, but significantly better in improving disease related symptoms and transfusion independence. Clinical trial information: NCT02101268. [Table: see text]

TPS7080Background: Myelofibrosis (MF) is a clonal hematologic neoplasm characterized by bone marrow fibrosis, splenomegaly, anemia, and debilitating constitutional symptoms. Currently, most patient...

7022^ Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by dysregulation of the Janus kinase (JAK) pathway resulting in bone marrow fibrosis, splenomegaly, and debilitat...

7026 Background: PV is a myeloproliferative neoplasm characterized by increased erythrocytosis, disease-related symptom burden (eg, pruritus), and risk of vascular events (thrombosis and/or hemorrh...

6514^ Background: Ruxolitinib is a potent and selective JAK1/2 inhibitor approved for the treatment of myelofibrosis (MF) based on results of the phase 3 COMFORT studies. Ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life of patients (pts) with MF. Since one measure of efficacy is molecular response, this analysis correlates changes in mutant allele burden (%V617F) with spleen size reduction in COMFORT-II. Methods: COMFORT-II is a randomized, open-label, phase 3 study comparing ruxolitinib 15 or 20 mg twice daily (BID) with BAT. The primary endpoint was a ≥ 35% reduction in spleen volume from baseline (BL) at week 48. Change in %V617F was measured by allele specific qPCR. Pts were stratified by reduction in %V617F (< 10%, 10-20%, > 20%) and results were correlated with achievement of the primary endpoint. Results: More pts in the ruxolitinib arm had ≥ 10% V617F reductions compared with BAT (41% vs 5%; P = .01; Table). The majority of reductions > 20% were gradual and progressive over the course of the study; 2 pts had rapid reductions from 48% to 1% and 45% to 9% over 48 weeks. In the ruxolitinib arm, significantly more pts with a > 20% V617F reduction achieved the primary endpoint compared with pts with a < 10% reduction (79% vs 30%; P = .004); in each group, gender did not affect spleen response. For pts with < 10% reductions (15 mg BID, n = 16; 20 mg BID, n = 24), the average total daily dose (TDD) was ruxolitinib 29.6 mg; pts with > 20% reductions (15 mg BID, n = 3; 20 mg BID, n = 11) had a TDD of 35.3 mg. Conclusions: Pts who received ruxolitinib had larger reductions in JAK2V617F allele burden compared with BAT. %V617F reductions were gradual over the course of the 48-week study; longer follow-up is needed to determine the extent of allele burden reduction. [Table: see text]

6626^ Background: Ruxolitinib has demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms and QoL in 2 phase 3 studies (COMFORT-I and -II) in pts with primary MF (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). The prevalence of individual symptoms among these pts has not been defined. We evaluated the baseline HRQoL and symptoms among pts enrolled in COMFORT-II. Methods: COMFORT-II is a randomized, open-label, multicenter, phase 3 study comparing ruxolitinib with best available therapy. HRQoL and symptoms were assessed at baseline using the European Organisation for the Research and Treatment of Cancer QoL Questionnaire–Core 30 (EORTC QLQ‑C30) and Functional Assessment of Cancer Therapy–Lymphoma (FACT‑Lym); this analysis summarizes these scores for all pts, regardless of assigned treatment. Results: In COMFORT-II (N = 219), 52% of pts were aged > 65 years and 57% were male. By IPSS criteria (Cervantes et al. 2009), 40% had intermediate-2 and 60% had high-risk MF. Mean (95% CI) EORTC global health status/QoL (53.7 [50.6-56.7]; median, 50.0) and FACT-General total scores (73.0 [70.8-75.2]) were comparable to those for pts of similar age with other cancers (Oliva et al. 2011: median global health status score of 50 for acute myeloid leukemia [AML]). The most frequent symptoms (reported as “quite a bit” or “very much”) were fatigue (54%), dyspnea (30%), insomnia (30%), pain (29%), night sweats (23%), and itching (21%), and there were differences in baseline symptoms across MF subtypes (Table). Conclusions: This analysis shows that pts with MF experience severe disease-related symptoms and have diminished HRQoL similar to pts with AML, but because pts with MF have a longer life expectancy (an average of 2.3 to 4 years for high and intermediate-2 risk pts, respectively), they may suffer with a reduced QoL for many years. [Table: see text]

6625^ Background: Ruxolitinib is a potent and selective oral JAK1/2 inhibitor that has been approved for the treatment of myelofibrosis (MF). Ruxolitinib has demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms and quality of life (QoL) in 2 phase 3 studies (COMFORT-I and –II) in patients (pts) with primary MF (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). This analysis evaluated associations between cytokine levels and spleen size reductions in the COMFORT-II study. Methods: COMFORT-II is a randomized (2:1), open-label, phase 3 study comparing the safety and efficacy of ruxolitinib with BAT. Spleen volume was measured by MRI every 12 weeks and spleen length by palpation at each study visit. Plasma samples were analyzed using Rules Based Medicines Human MAP v1.6; 89 cytokines were measured at BL and wks 4, 24, and 48. Simple linear regression was used to evaluate the correlation between BL or change from BL in cytokine levels with % change of spleen size. Results: In the ruxolitinib arm, association was found between changes in TNF-α and leptin levels and % spleen volume reduction at wk 24 (TNF-α: N = 93; correlation coefficient [R] = 0.43; false discovery rate adjusted P value [P] < .01; leptin: N = 96; R = -0.28; P = .09) and wk 48 (TNF-α: N = 86; R = 0.43; P < .01; leptin: N = 87; R = -0.34; P = .02) that was not observed with BAT and was independent of JAK2V617F status. For ruxolitinib-treated JAK2V617F+ pts, higher leptin levels at BL were associated with greater % spleen length reductions at wk 48 (N = 45; R = -0.44; P = .11). A clear trend was observed for increased leptin levels that preceded weight gain on ruxolitinib treatment. For ruxolitinib-treated JAK2V617F+ pts, decreased IL-8 at wk 4 was associated with % spleen volume reductions at wk 24 (N = 68; R = 0.28; P = .24) and wk 48 (N = 60; R = 0.38; P = .15). Conclusions: This analysis has shown statistically significant associations between changes in cytokine levels and spleen size reductions. Further analysis is in progress to determine associations between cytokine levels and QoL or symptoms and to confirm these observations in an independent data set.

TPS6639 Background: SAR302503 is an orally administered selective JAK-2 inhibitor being evaluated for the treatment of MF. In a phase 1 study, SAR302503 reduced spleen size and disease-related symptoms and provided clinical benefit, including a reduction in the JAK2V617F allele burden, with an acceptable safety profile in patients with primary MF, post-PV MF, or post-ET MF (J Clin Oncol 2011;29:789). An ongoing open-label extension of this trial confirmed the durability of those results and found that doses between 400–500 mg/day of SAR302503 represented the optimal balance between safety and efficacy (Pardanani, ASH 2011;Abs 3838). These results led us to initiate a Phase 3 trial in December 2011 to evaluate SAR302503 at doses of 400 mg/day and 500 mg/day, compared with placebo, for the treatment of patients with MF (NCT01437787; EFC12153). Methods: Eligibility criteria include age of at least 18 years, platelets >50,000/µl, ECOG PS 0–2, and a diagnosis of high- or intermediate-risk 2 primary MF, post-PV MF, or post-ET MF according to IPSS criteria (Blood 2009;113:2895). Patients are being randomized (1:1:1) to receive 400 mg or 500 mg of SAR302503 or placebo orally once a day for at least 6 consecutive 28-day cycles. Assigned treatment will continue as long as patients are deriving benefit or until progression or unacceptable toxicity. Cross-over is allowed after 6 cycles or in case of progression before completion of 6 cycles according to predefined criteria. The primary endpoint is spleen response (≥35% reduction in spleen volume by MRI/CT at the end of cycle 6). Key secondary objectives are symptom response rate and durability of spleen response. Additional secondary endpoints include assessment of allele burden and bone marrow fibrosis reduction. It is planned to randomize 75 patients per treatment group at approximately 130 sites worldwide.