ALBERT

Description: Background: We have previously shown that CMR predicts better outcomes in Ph+ ALL. The lack of achievement of CMR and particularly major molecular response (MMR) at 3 months may confer poor outcomes. We sought to investigate the outcomes of pts who did not achieve CMR at 3 months as best response in terms of progression free survival (PFS) and overall survival (OS), and the role of allogeneic stem cell transplant (ASCT) in this population. Methods: We reviewed 204 pts with newly diagnosed Ph+ ALL treated at our institution between January 2001 and June 2019 with the combination of Hyper-CVAD plus tyrosine kinase inhibitors (TKI); dasatinib (n=88, 43%), ponatinib (n=72, 35%) and imatinib (n= 44, 22%). PFS was defined from the start of therapy to relapse or death. OS was defined from diagnosis to death or last follow-up. Backward multivariate Cox regression was used to identify prognostic factors for PFS and OS after variable selection at a p-value cutoff of 0.200. Time to ASCT was handled as a time-dependent variable. Survival curves were estimated by Kaplan-Meier method. Landmark analysis at the median time to ASCT was analyzed to evaluate the impact of ASCT. Results: We identified 94 pts (46%) who did not achieve 3-month CMR. Of pts treated with imatinib, 29 (66%) did not achieve 3-month CMR and 16 pts (36%) achieved 3-month MMR. Of pts treated with dasatinib, 42 (48%) did not achieve 3-month CMR and 29 pts (33%) achieved 3-month MMR. Of pts treated with ponatinib, 23 (32%) did not achieve 3-month CMR and 17 pts (24%) achieved 3-month MMR. Patient characteristics are summarized in table 1. Median age was 54 years (range: 21-80). The TKI administered was dasatinib, imatinib and ponatinib in 42 (45%), 29 (31%) and 23 (24%) pts, respectively. Overall, ASCT was performed in 28 pts (30%); 21 out of 62 pts (34%) with 3-month MMR, and 7 out of 32 pts (22%) who did not achieve MMR, within a median time of 5 months (range, 2.3-12.3). After a median follow-up of 97 months, median PFS was 21 months and median OS was 46 months. There was no difference in survival by TKI choice. The 5-year PFS and OS rates were 52% and 23% (p=0.001) (Figure 1A), and 58% and 26% (p=0.001) (Figure 1B) for pts with and without 3-month MMR, respectively. In multivariate analysis (table 2), 3-month MMR predicted longer PFS (p

Description: Abstract 313 Background: While advanced PV and ET patients at high thrombotic risk are managed primarily with HU, patients who are intolerant or refractory to HU have limited therapeutic options. Identification of a dominant gain-of-function mutation in the JAK2 kinase, V617F, in myeloproliferative neoplasms (MPNs), including PV and ET, provided a key rationale for the development of a molecularly targeted therapy for these diseases. Long term follow-up data from an ongoing trial of INCB018424, a selective JAK 1/ JAK 2 inhibitor, in PV and ET patients refractory or intolerant to HU are presented. Methods: Study 18424-256 is an uncontrolled open-label Phase 2 study being conducted at 6 sites in the United States and Italy. An initial 8-week run-in evaluation established 10-mg and 25-mg twice daily as starting doses for expansion cohorts in PV and ET, respectively; dose adjustments for safety and efficacy are allowed so that each subject is titrated to their most appropriate dose. For PV, response is defined based on Hct control in the absence of phlebotomy, improvement or elimination of palpable splenomegaly when present, and normalization of leukocytosis and thrombocytosis. For ET, response is defined based on improvement or normalization of WBC and platelet counts and, when present, elimination of palpable splenomegaly. PV results (n=34; median 108 months from diagnosis): After a median follow-up of 15 months (range 8–21), 97% of enrolled subjects achieved Hct control to 15×109/L was present in 47% of subjects and improved (≤ 15×109/L) or normalized (≤ upper limit of normal) in 88% and 63%, respectively. Thrombocytosis 〉 600×109/L was present in 38% of subjects and improved (≤ 600×109/L) or normalized (≤ upper limit of normal) in 92% and 69%, respectively. 59% of subjects achieved phlebotomy independence, resolution of splenomegaly and normalization of leukocytosis and thrombocytosis. 6 patients discontinued therapy (3 due to AEs, 2 withdrew consent, 1 for no response). Grade 3 AEs potentially related to study medication included thrombocytopenia (2 patients), neutropenia (1), renal tumor (1), asthenia (1), viral infection (1), and atrial flutter (1). No Grade 4 drug-related AEs have occurred. ET results (n=39; median 84 months from diagnosis): After a median follow-up of 15 months (range 4–21), 49% of enrolled subjects normalized platelet counts to ≤ upper limit of normal after a median of 0.5 months and for a median duration of 3.5 months. 82% maintained platelet counts 〈 600×109/L, for a median duration of 9.8 months. Of 14 patients with baseline platelet counts 〉 1000×109/L, 13 have experienced 〉 50% reduction. 88% maintained normal WBC (median duration 14.5 months). Palpable spleens resolved in 3 of 4 subjects; 1 reduced 〉50% from baseline. 49% of subjects achieved normalization of WBC and platelet counts in the presence of non-palpable splenomegaly. 9 patients discontinued therapy (4 due to AEs, 2 withdrew consent, 3 for no response). Grade 3 AEs potentially related to study medication included leukopenia (2 patients), GI disorder (1), and peripheral neuropathy (1). No Grade 4 drug-related AEs have occurred. Both patient groups demonstrated reductions in patient-reported symptom scores for pruritus, night sweats, and bone pain. Of 26 PV patients reporting pruritus at baseline (median score of 6 on a 10-point scale), 24 reported scores of 0 after a median duration of 1 month and for a median duration of 7 months. 42% of PV and 56% of ET patients had at least a 20% decrease in JAK2V617F allele burden; 6% of PV and 12% of ET had 〉50% decrease. Clinical responses were unrelated to the presence/absence of JAK2V617F mutation at entry or to the allele burden changes following treatment. Conclusions: Rapid and durable clinical benefits (normalization of hematological parameters, resolution of splenomegaly and alleviation of symptoms) have been demonstrated in advanced PV and ET patients with 〉1 year of follow-up. In this study, INCB018424 continues to be a well tolerated, effective therapy in patients with PV and ET refractory or intolerant to hydroxyurea. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Levy:Incyte Corporation: Employment, Equity Ownership. Bradley:Incyte Corporation: Employment. Garrett:Incyte Corporation: Employment. Vaddi:Incyte corporation: Employment. Huber:Incyte Corporation: Employment, Equity Ownership. Schacter:Pfizer Corporation: Employment. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Cytopenias are a leading cause of ruxolitinib (RUX) discontinuation for patients (pts) with myelofibrosis (MF). Though RUX 5 mg BID is recommended for pts with platelet (PLT) counts of 50 to

Description: Human pentraxins are a family of proteins with a unique pentameric structure. Unlike C-reactive protein (CRP), serum amyloid P (SAP) and pentraxin-3 (PTX3) play an opposite role in tissue remodeling. PTX3 induces whereas SAP inhibits the differentiation of CD14+ monocytes into fiborcytes. While in patients with CLL CRP levels are high and were found to be associated with poor overall survival (OS) (Herishanu et al. Ann Med 2017), little is known about the plasma levels or clinical significance of other pentraxins in CLL. Therefore, we obtained plasma sample from 36 randomly chosen treatment-naïve CLL patients and 12 age-matched healthy individuals and, using an enzyme linked immuno-sorbent assay, found that PTX3, CRP and SAP plasma levels were significantly higher in CLL patients than in healthy individuals (P

Description: Hematopoietic progenitor cells of myeloproliferative neoplasms with myelofibrosis (MPN-MF) exhibit constitutive activation of JAK-STAT5/3 and NFkB signaling. Transformation of MPN-MF to AML (post-MPN sAML) occurs in up to 15% of patients with MPN-MF. Standard induction anti-AML chemotherapy and the JAK1 & 2 inhibitor (JAKi) ruxolitinib are ineffective in post-MPN sAML. BET protein BRD4 is a non-oncogene addiction target in AML, and treatment with acetyl-lysine mimetic BET protein inhibitor (BETi) disrupts binding of BRD4 to acetylated chromatin and transcription factors (TFs). This attenuates transcription of super-enhancer regulated oncogenes, including MYC, Bcl-xL, PIM1 and CDK4/6, inhibiting growth and survival of post-MPN sAML blasts. BETi treatment also inhibits binding of BRD4 to acetylated RELA (NFkB-p65), inhibiting its transcriptional activity and attenuating levels of its target cytokines. However, BETi treatment induces BRD4, potentially reducing BETi activity in repressing oncogenes. Preclinical and clinical studies have demonstrated that innate or adaptive BETi-resistance is common in sAML cells. To model BETi-resistance, we repeatedly exposed (10 times) secondary (s) AML SET2 and HEL92.1.7 (HEL) cells to 1.0 µM of the BETi OTX015 for 48 hours followed by full recovery, thus generating BETi persister-resistant (BETi-P/R) SET2-P/R and HEL-P/R cells. These cells showed 〉 10-fold resistance to OTX015 and cross-resistance to other BETis. Compared to the parental controls, BETi-P/R cells lacked additional genetic alterations or altered levels of TRIM33, SPOP, DUB3 or phosphorylated BRD4 (previously described mechanisms of BETi-resistance). However, ATAC-Seq and ChIP-Seq (H3K27Ac mark) analyses demonstrated that, as compared to their parental controls, BETi-P/R cells showed gain of peaks and active enhancers with enrichment of STAT5, MYC, PU.1 and GATA2 binding sites. Newly gained peaks were in the enhancers of JAK1/2, RUNX1, PU.1, MYC and BCL2L1. RNA-Seq determined mRNA level alterations, included induction of gene-sets involving MYC/MAX, STAT5, NFkB and TCF7L2 targets. QPCR and Western analyses confirmed increase in the mRNA and protein levels of TCF7L2, JMJD6, c-Myc, Survivin and PIM1 in HEL-P/R over HEL92.1.7 cells. Expression of the arginine demethylase JMJD6, recruited by BRD4 to regulate enhancer-mediated transcriptional pause-release, was also increased. This was associated with increased expression of the nuclear β-catenin-TCF7L2 targets, including Cyclin D1, TERT, survivin, c-Myc and PU.1. Patient-derived human AML blasts that exhibited innate resistance ex vivo to BETi, also demonstrated increased expression of TCF7L2, JMJD6 and c-Myc. We next probed the mechanistic role of the β-catenin-JMJD6-TCF7L2-MYC axis in conferring BETi-resistance. CRISPR-Cas9-mediated knockout of TCF7L2 or JMJD6 significantly reversed BETi-resistance in BETi-P/R sAML cells (p 〈 0.001). Conversely, ectopic overexpression of TCF7L2 or JMJD6 significantly conferred BETi-persister-resistance in HEL and SET2 cells (p 〈 0.001). Notably, confocal microscopy demonstrated increased binding of β-catenin with TBL1 and TCF7L2 in the nucleus of BETi-P/R sAML cells. BC2059, which disrupts binding of nuclear β-catenin with TBL1 and TCF7L2, depleted β-catenin levels and exerted similar lethality in BETi-P/R sAML and control sAML cells. shRNA-mediated knockdown of BRD4 and treatment with BRD4-PROTAC (proteolysis-targeting chimera) ARV-771 (Arvinas, Inc.) that degrades BRD4/3/2, also induced similar levels of apoptosis in BETi-P/R and control sAML cells. Co-treatment with ARV-771 and BC2059 synergistically induced lethality in BETi-P/R sAML cells as well as in patient-derived, CD34+ sAML BPCs (combination indices 〈 1.0). This was associated with marked attenuation of c-Myc, TCF4, Survivin, CDK6, PIM1 and Bcl-xL levels. Also, compared to each agent alone, in vivo treatment with ARV-771 (30 mg/kg SQ daily x 5, per week) and BC2059 (30 mg/kg IP BIW per week) for 3 weeks, significantly reduced sAML burden and improved survival of NSG mice engrafted with HEL-P/R cells (p 〈 0.01). Collectively, these findings underscore that increased levels and activity of β-catenin-TCF7L2-JMJD6-MYC axis is mechanistically responsible for BETi-P/R, and co-targeting with BRD4 degrader and β-catenin-TCF7L2 inhibitor is a promising therapeutic strategy against BETi-P/R sAML BPCs. Disclosures Bhalla: Beta Cat Pharmaceuticals: Consultancy. Verstovsek:Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding.

Description: DAC is a potent hypomethylating agent with clinical activity in patients with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). VPA is a histone deacetylase inhibitor used as an antiepileptic agent. In vitro, the combination of DAC with VPA results in synergistic antileukemia activity at doses of VPA above 1mM. Based on this data, we have developed a phase I/II study of this combination for pts with leukemia. The phase I of the study followed a classic 3+3 design. The dose of DAC was fixed: 15 mg/m2 iv daily for 10 days. This was based on a previous phase I study (Blood2004;103:1635) that indicated that this schedule had an optimal toxicity-response profile in this population. Three dose levels of VPA were selected: 20, 35 and 50 mg/kg. VPA was given orally for 10 days concomitantly with DAC. 22 pts have completed the phase I portion of the study (median age 56 years, range 4–78, 20 pts AML, 2 MDS). At dose level 1 (20 mg/kg of VPA) no grade III-IV toxicity was observed. At dose level 2 (VPA 35 mg/kg), 2 out 6 pts developed grade III neurotoxicity. Both pts were receiving high doses of other neurotropic agents. After IRB approval, 3 mores pts were treated at this dose level with no significant toxicity. Subsequently, 3 pts were treated at the highest planned dose level (50 mg/kg) with no toxicity observed. This cohort was then expanded to a total of 10 pts. One pt developed grade III neurotoxicity. No other severe drug-related toxicities were observed, but 5 patients at all dose levels developed grade II sedation/somnolence. Pancytopenia was induced in all pts. At dose level 1, one pt with refractory AML achieved complete remission (CR) after the second course of therapy. This is now maintained for 5 courses. At dose level 2, a patient with HIV disease and relapsed AML achieved CR after the third course of therapy, and 2 pts with relapsed AML achieved complete marrow responses (marrow blasts less then 5%, no recovery of peripheral counts). Of 3 pts evaluable for response at dose level 3, 1 pt with MDS has achieved CR after 1 course, and 1 with relapsed AML a complete marrow response. Median free VPA levels pretreatment were 0, and 25 mg/L on both days 5 and 10 and returned to 0 prior to next course. Histone acetylation measured by Western blot was observed in 3 pts (25%), all at doses above 20 mg/kg of VPA. Reactivation of p21 expression was induced in 4 out 11 pts analyzed. Global hypomethylation measured using a bisulfite PCR LINE assay was induced in 1 out 3 pts so far studied. Based on the toxicity observed, the phase II portion of the study was initiated. This is restricted to pts with AML/MDS. Seven pts have been accrued to this phase, and 8 out the 10 pts at dose level 3 of the phase I are also evaluable. The response data of this pts will be updated at the meeting. In summary, the combination of low dose DAC and VPA up to doses of 50 mg/kg can be safely administered to pts with leukemia although it may be complicated by neurotoxicity. Clinical and biological activity was observed at all dose levels.

Description: INTRODUCTION: Most clinical trials exclude patients with poor performance, organ dysfunction, and presence of other active malignancies or comorbidities. Although some of these criteria are based on clinical reasoning, patients with such clinical features have dismal expected outcomes and limited therapeutic options and could therefore have a more favorable risk/benefit ratio if treated with a low intensity investigational intervention. The current study was designed to test whether it is feasible to treat patients not eligible for conventional studies in a clinical trial. METHODS: We conducted an initial Bayesian designed single-arm study and a subsequent randomized study for patients with AML or higher-risk MDS (intermediate-2 or high risk by IPSS) with either ECOG performance status (PS) ≥3, creatinine or bilirubin ≥2mg/dL, presence of other malignancy or other comorbidities. Primary endpoint was survival at day 60. The study included stopping rules for survival, response and toxicity. All patients received azacitidine 75mg/m2 sc daily for 5 days. Patients in the single-arm study and in the combination arm of the randomized study also received vorinostat 200mg tid for 5 days. Cycles could be repeated every 3-8 weeks. Responses were evaluated following the revised 2006 IWG criteria for patients with MDS and the IWG 2003 recommendations for patients with AML. Comorbidities were evaluated using the Adult Comorbidity Evaluation-27 (ACE-27) index. Adverse events (AEs) were assessed and graded according to the CTCAE v4 criteria. Overall survival (OS) was censored at the time of transplant. Event-free survival (EFS) was defined as the time interval between treatment start and date of resistance, progression or death. RESULTS: A total of 30 patients (16 with MDS, 14 with AML) were enrolled in the initial single-arm study. Patient characteristics and inclusion criteria are detailed in Table 1. Median age was 73 years (44-83). Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. Median number of cycles administered was 3.5 (1-12). The overall response rate (ORR) was 40% with 8 (27%) patients achieving CR, 4 with AML and 4 with MDS. Median OS was 7.8 months (0.3-29, CI 7.54-8.03) (Figure 1A) and median EFS was 5.1 months (0.3-15.9, CI 4.87-5.37) (Figure 1B). Stopping rules for survival and response were not met. Main adverse events (AEs) where grade 1-2 gastrointestinal toxicities. Mortality at 4 and 8 weeks was 10 and 20% respectively. A total of 79 patients were enrolled in the subsequent randomized study: 27 to azacitidine (A) and 52 to azacitidine and vorinostat (A+V). Patient characteristics and inclusion criteria are also shown in Table 1. Median age was 70 years (30-90). Forty-seven (59%) patients had MDS and 32 (41%) had AML. Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rates were 67% (A) and 85% (A+V), respectively (p=0.07). No differences in ORR (48% vs 46%, p=0.87), OS (6.1 vs 7.6 months, p=0.49) (Figure 1C) or EFS (3 vs 5.5 months, p=0.05) (Figure 1D) were observed between groups. Main AEs included grade 1-2 gastrointestinal toxicities with a higher proportion of AEs with A+V (81 vs 56%). Mortality at 4 and 8 weeks was 10% (A: 4, A+V: 4) and 19% (A: 9, A+V: 6) respectively. By univariate analysis neither PS ≥3, creatinine or bilirubin ≥2mg/dL nor presence of other malignancy were predictive for 60-day survival, OS or EFS. There were no significant differences in survival between patients with ACE-27 scores of 0-1 compared to 2-3 both in the single-arm (6.3 vs 7 months, HR=0.88, 95% CI 0.41-1.91, p=0.75) and the randomized phase of the study (A: 13.5m vs 6.1m, HR 0.93, 95% CI 0.27-3.17, p=0.9 and A+V: 12.1m vs 7.4m, HR 1.38, 95% CI 0.61-3.14, p=0.4). CONCLUSION: Most enrolled patients met the study's primary endpoint of survival at 60 days without major toxicity. Patients obtained clinical benefit with acceptable responses and survival despite their high comorbidity burden. Our results support the feasibility of treating patients with MDS or AML not eligible to other clinical trials due to poor performance status, comorbidities or organ dysfunction, with low intensity therapies within a clinical trial. These findings suggest relaxation of such criteria may likely increase the pool of clinical trial patient candidates and allow access to potential beneficial therapies for patients with otherwise dismal prognosis. Table 1 Table 1. Figure 1 Figure 1. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. DiNardo:Abbvie: Research Funding; Novartis: Research Funding; Agios: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Wierda:Genentech: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Abbvie: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Jain:Novimmune: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; BMS: Research Funding; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria.

Description: Introduction - Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for patients with myelofibrosis (MF). MF is stratified into various risk groups based on Dynamic International Prognostic scoring system (DIPSS plus), which determines the eventual prognosis of the disease at any time. Previous studies and expert opinion indicate that for patients with Intermediate-2 risk (INT-2) and High risk (HR) disease, HCT is a reasonable option. How applicable is this to all patients with MF and what are the barriers to doing a transplant are not known. We therefore reviewed medical records of all patients who were referred for HCT. The main purpose of this study was to determine the proportion of patients who underwent transplantation as well as to ascertain the major reasons why patients referred for transplantation did not receive it despite its reported benefit. Methods- This was a retrospective, single institution, observational study. We analyzed patients referred for HCT with a diagnosis of MF. One hundred and ninety-eight consecutive patients with a preliminary diagnosis of MF were seen at the stem cell transplantation and cellular therapy (SCTCT) clinic of MD Anderson cancer center (MDACC) from 1/1/2004 to 12/31/2012. Out of the 198 patients, 26 had a diagnosis other than MF and hence were excluded. We stratified the remaining patients according to their DIPSS plus score at the initial consult and also traced their progression. For the non-transplanted patient with HR and INT-2 DIPSS plus scores, the major reason for deferring transplant was retrieved from the chart. Results & Discussion- Out of 172 patients seen in the stem cell transplant clinic with MF, 70(41%) underwent transplantation and 102(59%) did not receive HCT. Of the 102 patients who did not undergo SCT, 72(70%) had INT-2 or HR disease at the initial consultation (transplant eligible). Of the remaining 30 patients with low risk or intermediate-1 risk disease, 7(23%) patients eventually progressed to INT-2 or HR disease and became transplant eligible. The median time from MF diagnosis to consultation for non-transplanted patients was 331days (11 months) (Range-0-8675). For patients with INT-2 and HR disease (79/102), the major reasons for not receiving a transplant (Figure) are patient choice (36/79; 46%), financial issues (23/79; 29%), comorbidities (9/79; 11%), lack of donor (7/79; 9%) and poor performance status (4/79; 5%). Patient choice of not pursuing transplant is understandable because there was limited data on efficacy of HCT for MF in early years. The most common insurance provider not covering transplantation was Medicare (20/23; 87%). The co-morbidities that precluded HCT were cardiopulmonary disease (4/9; 44%), liver dysfunction due to advanced disease (3/9; 33%) and other comorbidities (2/9; 22%). Of note 5/7 (72%) patients who were not transplanted due to lack of appropriate donor were non-Caucasian patients. Conclusion- Only 41% of patients referred for transplant with MF receive HCT. The major barriers to wider application and usage of HCT for MF were patient choice and lack of coverage by Medicare. Patient education, coverage by Medicare, use of alternative donors, and earlier transplant referrals can further increase the accessibility of transplantation and improve outcomes of patients with MF. Figure 1. Figure 1. Disclosures Alousi: Therakos, Inc: Research Funding.

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: MG-0103 is a novel non-hydroxamic acid inhibitor of human histone deacetylases (HDACs), with selectivity for the cancer-associated isoforms of class I HDACs. Deacetylation of histones by HDACs is postulated to inactivate tumour suppressor genes leading to neoplastic transformation, and therefore inhibition of this enzyme may result in antineoplastic activity. To study the safety and activity of MG-0103, we have developed a phase I open-label dose escalation study of MG-0103 administered orally, three-times weekly in patients with leukemia or MDS, with the primary endpoints being the determination of the maximum tolerated dose (MTD) and the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MG-0103. Eligibility criteria included appropriate performance status and renal and hepatic functions. Patients with relapsed/refractory leukemia or MDS and older patients with untreated AML/MDS were eligible. Eight patients have been enrolled at two dose levels (20 &40 mg/m2) so far. Their characteristics are: median age 70 years (range 33–79); all patients so far treated have AML; median number of prior therapies is 1 (range 0–3). All patients had complex cytogenetics including one elderly patient with t(8;21) that had not achieved CR with high dose ara-C-based therapy. MG-0103 has been well tolerated with no dose-limiting toxicities. No drug-related adverse events (AEs) 〉= Grade (Gr) 3 have been observed. The only Gr 2 drug-related AE has been heartburn (1 patient). All other drug-related AEs were grade 1. No cardiac abnormalities have been observed so far. Two of 3 patients at the first dose level have been treated for 3 or more cycles. PK evaluations are shown in the table below. Analysis of peripheral blood cell HDAC activity indicates that HDAC inhibition occurs in a dose-dependent manner. Enrolment is currently proceeding at a dose of 80 mg/m2. In summary, MG-0103 is a well-tolerated HDAC inhibitor in patients with AML at doses and exposures that result in target inhibition in peripheral blood. Dose 20 mg/m2 40 mg/m2 Pharmacokinectic characteristics AUC (0-∞) ng.hr/ml 260 +/− 10.8 528 +/−275 T 1/2 h 8.09 +/− 2.98 6.24 +/− 0.373