ALBERT

Description: BACKGROUND: Acute Graft versus Host Disease (aGVHD) represents a serious and sometimes life-threatening condition associated with patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Development of aGVHD is characterized by increased levels of inflammatory mediators and activated T cells in circulation, leading to tissue and organ damage. Corticosteroids are primarily utilized as first line treatment for aGVHD; however, this approach does not provide therapeutic benefit for a significant portion of aGVHD subjects. The combination of itacitinib, a JAK1-selective inhibitor, with corticosteroids was evaluated in a parallel-cohort phase 1 trial (NCT02614612) and resulted in improved overall responses for both steroid naïve and refractory aGVHD subjects. Previous studies have demonstrated that a panel measuring the plasma levels of ST2, REG3A, and TNFR1 can be utilized to distinguish steroid treated subjects with an increased risk of progressive aGVHD; however, it is unknown if these biomarkers are predictive of response to the combination of corticosteroids and itacitinib. In this study, we compared the plasma levels of ST2, REG3A, TNFR1, and Trappin-2/Elafin in order to distinguish response to combination treatment. Additionally, we conducted a broad proteomic analysis to identify potential prognostic biomarkers of response to the combination treatment. METHODS: Plasma samples were collected from 31 subjects enrolled in the Phase 1 clinical trial prior to and at designated times following treatment. Levels of REG3A, ST2, TNFR1, and Trappin-2/Elafin were measured using SimplePlex multiplex platform based on manufacturer instructions. Broad proteomic analysis was additionally conducted by OLINK Proteomics using a proximity extension assay. Statistical differences were identified using unpaired T tests and significance conferred when p

Description: Abstract 509 Background: The JAK family of enzymes has a central role in normal hematopoiesis and immune response. Mutations of JAK2 gene that result in constitutive activation of JAK-STAT signaling and enhanced proliferation and survival signals have been described. This aberrant signaling pathway has been clearly demonstrated in myeloproliferative disorders (MPDs), but also reported in other hematological cancers including acute leukemias. Aim: To explore the activity of INCB018424 in patients (pts) with advanced hematological cancers Method: We are conducting a phase II study of INCB018424 in pts with relapsed/refractory leukemias for which no standard therapies are anticipated to result in a durable remission. Pts with performance status 0 – 2 with adequate organ function and no active, uncontrolled intercurrent illness or infection, receive INCB018424 orally at 25 mg twice daily for 4 weeks (one cycle). Response is assessed after every 2 cycles of treatment. Responding pts or pts with stable disease are allowed to continue until progression. Dose escalation to 50 mg twice daily is permitted in pts demonstrating a benefit. Result: Thirty eight pts [median age, 69 years; (range, 45–88)] with relapsed and refractory leukemias (15 sAML, 13 AML, 3 ALL, 1 MDS, 4 CMML & 2 CML) have been treated. The median number of prior therapies is 2 (range, 1 to 6). Eleven pts (7 with sAML, 2 with AML, and 2 with CMML) had the JAK2 V617F mutation. Cytogenetic analysis showed diploid karyotype in 11, chromosome 5 and 7 abnormalities in 7, t(2;9) in 1, Philadelphia chromosome in 2 and other various abnormalities in 17. Pts who completed 2 cycles of INCB018424 are defined as having stable disease (SD). Pts have received a median of 2 cycles of therapy (range, 1 –18 cycles) with 15 pts having SD or better (5 for 2 cycles, 4 for 3 cycles, 3 for 4 cycles, 2 for 5 cycles and 1 for 18 cycles). Among these, 3 pts (2 with sAML and 1 with CMML with JAK2 mutation) have had a significant reduction in their bone marrow blasts (to 〈 5%) associated with a significant decrease in spleen size and clinical improvement. Three pts are too early for assessment of response. Pts having benefit include sAML (9, or 60% of pts with sAML), AML (2, 15%), CMML (3, 75%) & MDS (1, 100%). Overall, 22 pts have had no response or progressed (12 after 1 cycle, 4 after 2 cycles, 2 after 3 cycles, 2 after 4 cycles, and 2 after 5 cycles). Nine pts died from causes unrelated to the treatment with INCB018424. Four pts continue with treatment (1 after 18 cycles, 1 after 3 cycles, & 2 after 2 cycles). One pt had a successful allogeneic SCT after 3 cycles with SD. Two pts came off protocol for unrelated complications. Overall INCB018424 was tolerated very well. One pt had elevated liver enzymes (G3) along with neutropenia (G3), another pt had G3 liver enzyme elevation and 2 pts developed G2 thrombocytopenia. 1 pt had G5 intracranial hemorrhage. Conclusion: INCB018424 is well-tolerated and has activity particularly in pts with sAML and CMML but also in AML and MDS, with or without JAK2 V617F mutation. Clinical studies combining INCB018424 with chemotherapy in sAML are warranted. Disclosures: Off Label Use: Use of arsenic trioxide in frontline therapy of APL. Verstovsek:INCYTE: Research Funding. Cortes:NOVARTIS: Research Funding. Newton:Incyte Corporation: Employment. Kantarjian:NOVARTIS: Research Funding. Ravandi:Incyte Corporation: Research Funding; Novartis: Honoraria, Speakers Bureau.

Description: Background: Signaling of PI3Kd has been implicated in proliferation, migration, and function of B cells. PI3Kd inhibitors have demonstrated clinical activity in a number of lymphoid tumor types. INCB050465 is a novel, potent, and highly specific inhibitor of PI3Kd (≥19,000-fold more selective for the d vs other isoforms) with no hepatotoxicity in preclinical evaluation at clinically relevant exposures. Here we report the emerging safety, pharmacokinetics, and efficacy results of INCB050465 monotherapy in B-cell malignancies. Methods: This phase 1/2 study (NCT02018861) enrolled patients aged ≥18 years with relapsed/refractory B-cell malignancies. After an initial single-patient cohort of oral INCB050465 5 mg once daily, a 3+3 dose escalation was conducted with doses ranging from 10 to 45 mg once daily; the dose-limiting toxicity observation period was 21 days. The 20 mg and 30 mg once daily doses were selected for monotherapy expansion. Efficacy was assessed every 9 weeks by Lugano Classification or International Working Group on Chronic Lymphocytic Leukemia (CLL) criteria. Results: As of the data cutoff (May 20, 2016), 39 patients had been enrolled and treated with INCB050465 monotherapy. The median age was 63 and 62% were men. Subtypes included diffuse large B-cell lymphoma (n=13); Hodgkin lymphoma (HL; n=8); follicular lymphoma (FL; n=6); CLL (n=5); marginal zone lymphoma (MZL; n=4); and mantle cell lymphoma (n=3). At baseline, the median number of prior systemic regimens was 3, and the median time since diagnosis was 4.9 years. INCB050465 demonstrated low oral clearance and linear pharmacokinetics, with a terminal half-life that supports once-daily dosing. The steady-state Cavg was 15-fold greater than the whole blood IC90 at the 30-mg dose. Pharmacodynamic analysis indicated maximal inhibition of the target throughout the dosing interval at all doses tested. Patients received INCB050465 for a median duration of 82 days (range: 4+ to 382+ days); no DLTs were observed. Treatment was discontinued in 16 patients due to disease progression (n=12), adverse events (AEs; n=3), or loss to follow-up (n=1). Dose interruption occurred in 6 patients (15%) and dose reduction in 1 (3%). The most common nonhematologic AEs were nausea (33%), pyrexia (21%), and cough (18%), all of which were grade 1 or 2. All observed alanine aminotransferase (15%) and aspartate aminotransferase elevations (15%) were grade 1. Nine patients (23%) experienced 16 grade ≥3 nonhematologic AEs, 3 of which were considered treatment-related by the investigator. New or worsening grade ≥3 anemia, thrombocytopenia, and neutropenia occurred in 8%, 10%, and 15% of patients, respectively. There was 1 instance (3%) each of colitis (grade 3) and pneumonitis (grade 2). Thirteen patients (33%) experienced a serious AE (SAE); SAEs occurring in more than 1 patient included diarrhea, exfoliative dermatitis, and hypotension (n=2 each). Among efficacy-evaluable patients (n=35), the objective response rate (ORR) was 57% and varied by disease subtype (Table 1). The ORRs for non-Hodgkin lymphoma (NHL) and HL were 66% (19/29) and 17% (1/6), respectively. Objective responses were observed in both transformed and non-transformed DLBCL, and both germinal center B-cell (GCB) and non-GCB subtypes. Objective responses were observed for all 10 patients with FL or MZL. Ninety percent of objective responses were observed at the first response assessment, and responses occurred at all but the 5-mg dose. Conclusion: The linear pharmacokinetics and absence of DLTs allow INCB050465 to achieve higher levels of target inhibition at the recommended phase 2 dose (30 mg once daily) than have been reported for other PI3Kd inhibitors. INCB050465 monotherapy was well tolerated at all doses tested with no significant transaminase elevations or early-onset diarrhea, and no cases of Pneumocystis jirovecii pneumonia. Objective responses, including complete responses, were observed in both aggressive and indolent NHL. Enrollment is ongoing at the 30 mg once daily dose level. Disclosures Gutierrez: Bayer Health Care Pharmaceuticals, Inc.: Other: Traveling and Lodging- Food and Beverage; Pfizer Inc: Consultancy; Merck Sharp & Dohme Corporation: Consultancy, Other: Travel and Lodging; Pharmacyclics LLC, An AbbVie Company: Other: Food and Beverage; Incyte Corporation: Consultancy; E.R. Squibb & Sons, LLC (Bristol Myers Squibb): Consultancy, Other: Travel and Lodging. Edenfield:Astellas/Medivation: Speakers Bureau; Novartis: Speakers Bureau; Greenville Health System Cancer Institute: Employment. Dawkins:Incyte Corporation: Employment, Other: Stocks. DeMarini:Incyte Corporation: Employment, Other: Stocks. Zhou:Incyte Corporation: Employment, Other: Stocks. Yeleswaram:Incyte Corporation: Employment, Other: Stocks. Newton:Incyte Corporation: Employment, Other: Stocks. Chen:Incyte Corporation: Employment, Other: Stocks. Forero-Torres:Seattle Genetics: Research Funding; Genentech/Roche: Research Funding; Juno: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Research Funding.

Description: We conducted a phase 2 study of ruxolitinib in patients with relapsed/refractory leukemias. Patients with acceptable performance status (0-2), adequate organ function, and no active infection, received ruxolitinib 25 mg orally twice a day for 4 weeks (1 cycle). Response was assessed after every 2 cycles of treatment, and patients who completed 2 cycles were allowed to continue treatment until disease progression. Dose escalation to 50 mg twice daily was permitted in patients demonstrating a benefit. Thirty-eight patients, with a median age of 69 years (range, 45-88), were treated. The median number of prior therapies was 2 (range, 1-6). Twelve patients had JAK2V617F mutation. Patients received a median of 2 cycles of therapy (range, 1-22). Three of 18 patients with postmyeloproliferative neoplasm (MPN) acute myeloid leukemia (AML) showed a significant response; 2 achieved complete remission (CR) and one achieved a CR with insufficient recovery of blood counts (CRi). The responding patients with palpable spleens also had significant reductions in spleen size. Overall, ruxolitinib was very well tolerated with only 4 patients having grade 3 or higher toxicity. Ruxolitinib has modest antileukemic activity as a single agent, particularly in patients with post-MPN AML. The study was registered at www.clinicaltrials.gov as NCT00674479.

Description: JAK inhibitors are being developed to treat inflammatory, myeloproliferative and neoplastic disorders. Murine and human studies have demonstrated an essential role for JAK2 in the proliferation of hematopoietic stem/progenitor cells (HSPC) and multiple hematopoietic lineages, including erythrocytes and megakaryocytes, while Jak1 murine studies have shown a role in HSPC proliferation and myelopoiesis, but not in megakaryopoiesis. Patients enrolled in clinical studies of INCB052793, which selectively binds to JAK1, have shown thrombocytopenia occurring within 2 weeks. The aim of this study was to elucidate the basis for thrombocytopenia associated with this JAK1 inhibitor, in comparison to INCB026115, which inhibits JAK2 more so than Jak1 (Jak2/1). Knowing the precise mechanism by which Jak inhibitors induce thrombocytopenia may lead to therapeutic strategies limiting side effects, while preserving intended clinical application. We tested a broad concentration range of each of these Jak1 and Jak2/1 inhibitors from IC50 (40 and 30nM, respectively) to IC90 (400 and 300nM) to 10xIC90 (4 and 3 µM) on mobilized progenitor-derived CD34+ cells incubated 12-14 days under semisolid and under liquid conditions, focusing on effects on megakaryocyte (Meg) and platelet production. At IC90, the Jak1-selective inhibitor limited large Meg colony number to 47±8% of untreated control in semisolid growth conditions. Under similar concentrations in liquid growth conditions, the number of Megs seen was 45±8% of the untreated controls, but with a 139±17% higher level of ≥8N Megs. Agonist response of mature Megs to thrombin was not compromised. Total number of healthy, in vitro-released, platelet-like particles (PLPs) collected from Jak1-exposed cultures at Day 12 was reduced to 57±14% of the control, and similar to the decrease in Meg yield. At a similar level of inhibition, the Jak2/1 inhibitor was more robust at inhibiting megakaryopoiesis. At IC90, the Jak2/1 inhibitor fully inhibited development of large Meg colonies and reduced the number of small colonies to 43±14% of untreated control. Under liquid growth conditions, the number of Megs seen at Day 12 was 20±9% of the untreated controls, but with 132±28% higher % of ≥8N Megs. Agonist response of mature Megs was not compromised. Total number of healthy PLPs collected at Day 12 was insignificantly different despite much lower Meg yield. More detailed Jak2/1 inhibitor cultures analysis revealed enhanced Meg apoptosis by 209±61% at Day 7, and accelerated maturation as indicated by a 2-fold and 3-fold mpl receptor level at Days 7 and 11 and 321±217% higher number of Megs 〉2N at Day 7. As opposite to what might be expected, thrombopoiesis appeared not to be impaired by the Jak2/1 inhibitor. Inhibitor-treated Megs released similar or higher number of platelets per Meg as untreated controls upon their infusion into immunocompromized NSG mice, with similar high levels of young, thiazole orange-positive, low apoptotic, Annexin-V+ platelets. Baseline released platelet CD62p expression and PAC1 binding prior to agonist exposure were similar and increased to the same extent after thrombin (0.1-10U/ml) stimulation. In contrast, Jak1 inhibitor-treated Megs had ~50% lower number of released human platelets upon infusion into NSG mice although the released platelets were healthy and responsive to agonists. In summary, our results shed significant insight into the mechanisms of Jak1 inhibitor-associated thrombocytopenia observed in patients. We show that thrombocytopenia post the Jak2/1 inhibitor INCB026115 is due to impaired megakaryopoiesis with intact thrombopoiesis and functional, released platelets. In contrast, thrombocytopenia post the Jak1 inhibitor INCB052793 is a result of combined impairment of both megakaryopoiesis and thrombopoiesis, although the released platelets appear intact. The exact pathways blocked by the Jak1 inhibitor important for thrombopoiesis remain to be defined. Also, as liver hepatocytes together with bone marrow stromal cells are a source of thrombopoietin (TPO), and Jak1 and Jak2 are known to be involved in regulation of TPO production, studies to check the influence of Jak inhibitors on TPO production from both hepatocytes and marrow stromal cells are needed to fully understand the influence of Jak inhibitors on megakaryopoiesis/thrombopoiesis. Disclosures Jarocha: Incyte Corporation: Consultancy, Research Funding. Gadue:Incyte Corporation: Consultancy, Research Funding. Tong:Incyte Corporation: Consultancy, Research Funding. Newton:Incyte Research Institute: Employment, Equity Ownership. Poncz:Incyte Corporation: Consultancy, Research Funding.

Description: Activating mutations in Janus kinase 2 (JAK2) have recently been identified in the majority of Philadelphia chromosome negative (Ph-) myeloproliferative disorders (MPDs). Importantly, constitutive JAK2 activation is oncogenic and, in murine models, recapitulates much of the pathobiology observed in MPD patients, suggesting that JAK2 inhibition may be of therapeutic benefit. Here we describe the identification and preclinical characterization of INCB018424, a potent, selective, and orally bioavailable inhibitor of the JAK2 now in clinical trials. INCB018424 was identified through an extensive medicinal chemistry effort designed to optimize potency, selectivity, pharmaceutical and pharmacokinetic properties. INCB018424 inhibits JAK2 at 500–fold selectivity against a broad sampling of the kinome. The potency and selectivity of INCB018424 translated to exceptional cellular activity where it inhibited the proliferation of FDCP cells and BaF/3 cells expressing JAK2V617F with an IC50 of 100–130 nM, but not the proliferation of cell lines expressing activating mutations in either BCR-Abl or cKit (IC50 〉 25 and 4 mM, respectively). The effect of INCB18424 on cell proliferation correlated well with reduced levels of phosphorylated JAK2 and STAT5 in the BaF/3 cell model, suggesting that the effect is mediated by pharmacological inhibition of JAK-STAT pathway. Interestingly, the activation of endogenous wild-type JAKs - by the addition of IL-3 - shifted the potency of INCB018424 in the BaF/3 model greater than five fold suggesting that cells expressing the mutated form of JAK2 may be more sensitive to INCB018424. Indeed, using cells harvested from patients with Jak2V617F-positive polycythemia vera (PV) in colony forming assays, we observed that INCB018424 inhibited the cytokine-independent formation of erythroid progenitor colonies (n=3) with an IC50 of 67nM while normal colony formation from healthy donors (n=3) was inhibited 50% at 〉 400 nM. Further, INCB018424 inhibited proliferation of PV patient samples (n=3) following ex vivo expansion of erythroid progenitors in serum free media, with an IC50 of 60 nM, similar to that observed in semi-solid media. In a mouse model of MPD, where implantation of BaF/3 cells expressing JAK2V617F results in rapid organomegaly and reduced survival, oral administration of INCB018424 was well tolerated and markedly reduced the splenomegaly. Using this animal model, we also demonstrated that selective JAK inhibition eliminates neoplastic cells from the spleen, liver, and bone marrow normalizing the histology of affected organs and significantly prolongs survival. As such, potent and selective JAK inhibitors such as INCB018424 hold great promise for the treatment of MPDs and other disease states associated with elevated JAK activity - a concept currently being tested clinically.

Description: Introduction Diffuse large B-cell lymphoma (DLBCL) subtypes can be identified based on immunohistochemistry, somatic mutation and gene expression profiles. These cell-of-origin (COO) subtypes have distinct biological and pathogenic characteristics. In addition, studies have shown the association of COO with drug response such as with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as well as targeted therapy. Therefore, proper assessment of COO subgroup is an important step in treatment selection and outcome. In this study, we sought to develop predictive COO models using RNA-Seq based gene expression profiling and plasma proteomic data, focusing on the two defined major DLBCL subtypes - germinal center B cell-like (GCB) and activated B cell-like (ABC). Methods COO subgroups of patient samples were assigned by the Hans algorithm. Data from archival formalin-fixed paraffin-embedded (FFPE) tissues were obtained using the Illumina HiSeq platform (RNA-Seq). A subset of samples were used as a training set to select differentially expressed genes (DEGs) in ABC vs. GCB lymphomas to build support vector machine (SVM) classification models. The model with best leave-one-out cross validation (LOOCV) on the training set was applied to the remaining samples to assess its initial predictive power. Gene set enrichment analysis (GSEA, Broad Institute) and key pathway analysis (KPA, Clarivate Analytics) were also utilized to further explore the underlying biology of each COO subtype. Protein expression data using the Olink Proteomics platform was obtained from baseline patient plasma samples. Protein biomarkers to differentiate ABC and GCB subgroups were identified from a set of training samples and evaluated in independent cohorts. Due to notable batch effect, batch information was included and specified as a random factor in the model. Results Genes identified by Scott et al. (Blood 2014) for COO assignment were first tested in our RNA-Seq training data of 6 GCB and 8 ABC samples. Thirteen of 15 gene markers showed significant differences between the ABC and GCB subgroups. From these markers, we further selected 6 to build machine learning models based on fold change, false discovery rate and entropy. This 6-gene signature include 3 markers relatively up-regulated in ABC subtype and 3 up-regulated in GCB subtype. A SVM model with these genes achieved 100% LOOCV on the training data and correctly predicted COO of 20/22 samples in the validating cohort with 1 GCB and 1 ABC samples misclassified. These two samples were also misclassified if a larger panel of signature genes from Scott et al. (Blood 2014) was used. KPA on the DEGs from ABC vs. GCB predicted the activation of NFKB1and STAT4/5 transcription factors as key elements upstream of the DEGs, indicating promoted signaling of NFкB and STAT pathways in ABC subgroup. On the other hand, REST was predicted as an inhibited upstream regulator of some DEGs. RCOR1, a corepressor of REST, has significantly lower expression level in the ABC subgroup in our data. These may imply the inhibition of REST/RCOR1 pathway in ABC patients. Plasma protein data from two studies were used to form a training set with 21 GCB and 6 ABC. A set of differentially expressed analytes from ABC vs. GCB were identified which included several targets of the NFкB pathway. In an independent cohort containing 5 GCB and 4 ABC plasma samples, many of these same plasma proteins showed differential expression profiles between ABC and GCB, making them potential blood-based biomarkers for COO determination. Conclusions In this study, we built a SVM model with a subset of genes from Scott et al. (Blood 2014) to accurately predict COO of refractory DLBCL from archival FFPE tissue. Further analyses of the RNA-Seq data disclosed alterations in key transcriptional hubs between the different COO subgroups. Olink plasma data from independent cohorts demonstrated potential protein markers for a plasma-based differentiation of the ABC and GCB subtypes. These biomarkers and machine learning models are being further validated using additional datasets. Disclosures Liu: Incyte Research Institute: Employment, Equity Ownership. Lu:Incyte Research Institute: Employment, Equity Ownership. Dong:Incyte Research Institute: Employment, Equity Ownership. Liu:Incyte Research Institute: Employment, Equity Ownership. Salinas:Incyte Research Institute: Employment, Equity Ownership. Owens:Incyte Research Institute: Employment, Equity Ownership. Pratta:Incyte Research Institute: Employment, Equity Ownership. Smith:Incyte Research Institute: Employment, Equity Ownership. Tada:Incyte Research Institute: Employment, Equity Ownership. Newton:Incyte Research Institute: Employment, Equity Ownership. Burn:Incyte Research Institute: Employment, Equity Ownership.

Description: Background: Current evidence links some of the disease manifestations in myelofibrosis (MF) to abnormal cytokines, likely produced by clonally involved megakaryocytes and monocytes. Furthermore, the recent discovery of JAK2/MPL mutations in MF suggests the contribution of abnormal JAK-STAT signaling to both clonal myeloproliferation and cytokine-driven debility. In order to gain additional pathogenetic insight regarding cytokine-phenotype correlations in MF, we looked into the plasma cytokine profile of MF before and after treatment with INCB018424, a selective JAK1/2 inhibitor. Methods: The current study includes subjects with MF enrolled in an ongoing phase 1–2 study of oral INCB018424 (doses ranging from 25 mg/day to 50 mg BID). Plasma samples were obtained prior to treatment and at intervals of 2 weeks, 1 month and 2 months following INCB018424 dosing. Samples were submitted to Rules Based Medicine Human MAP multiplexed immunoassay system to obtain plasma levels on a range of protein analytes. Results: Plasma cytokine levels in MF patients (n=53) vs. normal healthy volunteers (n=15): Compared to normal controls, plasma levels of pro-inflammatory cytokines and markers of inflammation were significantly increased in MF patients (Table; mean +/− SD values). Furthermore, the observed inflammatory cytokine levels in MF were often higher than those seen in patients with rheumatoid arthritis or cancer-associated cachexia (data to be presented at the meeting). Correlation of plasma cytokine levels in MF with JAK2 V617F mutational status, MF subtype and/or constitutional symptoms/cachexia: Comparison of JAK2V617F positive (n=40) and negative (n=13) MF cases suggested significantly (p

Description: Abstract 631 Background: Mutations of JAK2 gene have been identified in a significant proportion of patients with MPDs with the selective JAK2 inhibitors demonstrating significant activity. Patients with AML following prior MPD (sAML) respond poorly to standard cytotoxic chemotherapy and have a poor outcome. Abnormalities of the Jak-Stat signaling pathway have also been identified in a number of other hematological malignancies; chromosomal translocations resulting in TEL-JAK2 constructs lead to the constitutive activation of STAT5, IL-3-independent cellular proliferation, and leukemogenesis. Similarly, infection with oncogenic viruses such as human T-cell lymphotrophic virus, type I, and Abelson murine leukemia viruses results in enhanced kinase activity of Jaks, possibly accounting for their leukemogenic potential. Furthermore, disrupted Jak-Stat signaling has been reported in a number of leukemias. Aim: To identify potential activity of INCB018424 in patients with advanced hematological cancers. Methods: We are conducting a phase II study of INCB018424 in patients with relapsed/refractory leukemias for which no standard therapies are anticipated to result in a durable remission. Patients with performance status 0,1,and 2 with adequate organ function and no active, uncontrolled intercurrent illness or infection receive INCB018424 orally at 25 mg BID daily for 4 weeks (cycle #1). Response is assessed after 2 cycles of treatment. Responding patients or patients with stable disease are allowed to continue until progression. Predetermined dose modifications to 15 mg or 10 mg BID are allowed for drug related toxicities. Results: Eighteen patients [median age, 68 years; (range, 53-88] with relapsed and refractory leukemias (9 de novo AML, 3 sAML, 2 ALL, 1 MDS, 2 CMML, 1 CML) have been treated. The median number of prior therapies is 2 (range,1 to 6). Five patients (1 with AML, 2 with sAML, and 3 with CMML) had the JAK2 V617F mutation. Cytogenetic abnormalities include diploid in 7, chromosome 5 and 7 in 5, t(2;9) in 1, and the Philadelphia chromosome in 2. Pts have received a median of 1 cycle of therapy (range, 1-5 cycles) with 8 pts having stable disease (3 for 2 cycles, 2 for 3 cycles, 1 for 4 cycles, and 2 for 5 cycles). Three patients (including 2 with sAML and 1 with CMML, all with JAK2 mutation) have had significant declines in their bone marrow blasts (to