Pacylex Pharmaceuticals Research Articles

Validation of NMT1 and NMT2 As Novel Drug Targets in Adult Acute Myeloid Leukemia: Rationale for N-Myristoyltransferase Inhibition with Pclx-001 for Clinical Trials

Background: N-terminal myristoylation is the transfer of the saturated fourteen carbon fatty acid myristate to an N-terminal glycine residue. This co- or post-translational protein modification promotes protein-protein and protein-lipid interactions and is essential for proper membrane localization and/or activity of up to 600 human intracellular proteins. N-myristoyltransferases (NMTs) are the enzymes responsible and two isoforms are found in humans. NMT1 (ubiquitous and essential for cell survival) and NMT2 (more variably expressed) differ in activity level and substrate specificities. NMT expression levels vary in some cancers, and with myristoylation being essential for activity of certain oncogenes including Src Family Kinases (SFKs). NMTs have therefore been proposed as an anti-cancer target. Dysregulation and oncogenic activity of SFKs occurs frequently in acute myeloid leukemia (AML), suggesting NMT inhibition could provide therapeutic benefit. PCLX-001 is a low nanomolar small molecule pan-NMT inhibitor with high oral bioavailability in clinical trials as once daily oral therapy for lymphoma and solid tumors.Methods and Results: Data from the TCGA Transcriptome database showed high NMT1 and low NMT2 were associated with reduced overall and event-free survival in adult AML, and high NMT1 - but not NMT2 - expression is associated with proliferative gene sets in AML cell lines. AML cell lines treated with PCLX-001 showed a significant reduction in total protein myristoylation, as well as reduced levels of SFK proteins and SFK phosphorylation. PCLX-001 induced apoptosis in AML cell lines and patient blasts at concentrations which spared a large proportion of peripheral blood lymphocytes and monocytes from healthy individuals. AML cell lines showed significant increase in BIP protein and ER stress in response to PCLX-001, along with caspase 3 cleavage. In an AML cell line derived xenograft (CDX) and two AML patient derived xenograft (PDX) series (n=1 DX for MV-4-11 and n=2 PDX), PCLX-001 monotherapy had dose-dependent anticancer activity and resulted in complete remissions in subcutaneous AML cell deposits. In tail-vein injection PDX models, PCLX-001 treatment resulted in up to 95% reduction of human CD45+ cells in peripheral blood and bone marrow.Conclusions: These findings validate NMT inhibition as a novel therapeutic strategy for AML. PCLX-001 preferentially targeted AML cells that rely on oncogenic activity of myristoylated proteins, inducing apoptosis and reducing leukemic burden. PCLX-001 warrants evaluation in clinical trials for adult AML. DisclosuresGamma: Pacylex Pharmaceuticals: Current holder of individual stocks in a privately-held company. Yap: Pacylex Pharmaceuticals: Current holder of individual stocks in a privately-held company, Patents & Royalties. Beauchamp: Pacylex Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company, Patents & Royalties. Mackey: Pacylex Pharmaceuticals, Inc.: Current holder of individual stocks in a privately-held company. Pemmaraju: Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Aptitude Health: Consultancy; Sager Strong Foundation: Other; Celgene Corporation: Consultancy; LFB Biotechnologies: Consultancy; Plexxicon: Other, Research Funding; MustangBio: Consultancy, Other; Roche Diagnostics: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; DAVA Oncology: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Springer Science + Business Media: Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; CareDx, Inc.: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Borthakur: Astex: Research Funding; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Brandwein: AbbVie: Honoraria; Jazz: Honoraria; Taiho: Honoraria; Astellas: Honoraria; Bristol Myers Squibb: Honoraria; Roche: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Berthiaume: Pacylex Pharmaceuticals, Inc.: Current holder of individual stocks in a privately-held company.

An Open-Label, First-in-Human, Phase I Trial of Daily Pclx-001

Background:Myristoylation regulates numerous membrane-bound signal transduction pathways important in cancer biology. This modification is catalyzed by N-myristoyltransferases 1 and 2 (NMT1 and NMT2). PCLX-001 is an oral small molecule with high affinity for both NMT proteins (IC50 of 5nM and 8nM, respectively) with high bioavailability and drug-like pharmacokinetic properties. In ex vivo sensitivity screening cell lines of hematologic cancer origin were exquisitely sensitive to PCLX-001, although high sensitivities and cell killing were also seen in some solid tumor lines derived from lung, pancreas, breast, colon, and bladder carcinomas. PCLX-001 demonstrated strong preclinical single-agent antitumor activity and tolerability in vivo in subcutaneous tumor xenograft models derived from lymphoma cell lines, lung cancer cell lines, a breast cancer cell line, as well as in a patient derived xenograft model from a patient with refractory DLBCL. The primary objective of this study is to determine the MTD and/or recommended phase II dose, safety, tolerability, and pharmacokinetics of PCLX-001 as a single agent, in patients with refractory lymphomas and advanced solid tumors. The secondary objective of the study is to evaluate the preliminary single agent anti-tumor activity of PCLX-001 in the patient populations studied.Methods:We are now accruing to a multicenter, open-label, phase I dose-escalation study of oral PCLX-001 comprised of two parts (dose escalation and dose expansion). Eligible patients will have: histologically-confirmed advanced solid tumor or B-cell lymphomas who have failed prior therapy and/or are not eligible for therapies; ages ≥ 18 years; adequate organ function; life expectancy of at least 12 weeks; and measurable disease. Part A (dose-escalation) patients will be accrued in cohorts of 3 to 6 patients to each dose level, starting at 20 mg daily on a 28 day cycle. Dose escalation will follow a modified Fibonacci design such that the magnitude of escalation decreases as the dose level nears the human equivalent dose of the highest non-severely toxic dose in dogs and then escalate at 1.4 times the previous dose. Dose escalation and determination of the maximum tolerated dose will be based on the occurrence of dose limiting toxicities in cycle 1. Part B will have two single agent expansion cohorts (n = 20 each) in advanced solid malignancies and relapsed/refractory B-cell lymphoma, to determine the preliminary clinical activity of PCLX-001 to determine the recommended phase II dose.Results:Updated study results will be presented, summarizing the outcomes in the preliminary dose cohorts. DisclosuresSangha: Pfizer: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli-Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Mackey: Pacylex Pharmaceuticals, Inc.: Current holder of individual stocks in a privately-held company. Sehn: Debiopharm: Consultancy; Genmab: Consultancy; Novartis: Consultancy. Kuruvilla: AbbVie: Honoraria; Amgen: Honoraria; Medison Ventures: Honoraria; Seattle Genetics: Honoraria; Incyte: Honoraria; Antengene: Honoraria; TG Therapeutics: Honoraria; Pfizer: Honoraria; Roche: Honoraria, Research Funding; Novartis: Honoraria; Merck: Honoraria; BMS: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board. Weickert: Pacylex Pharmaceuticals, Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Berthiaume: Pacylex Pharmaceuticals, Inc.: Current holder of individual stocks in a privately-held company.

Nonclinical Efficacy and Toxicity and Selection of a Safe Clinical Starting Dose for an NMT Inhibitor in Development for Hematological Malignancies

N-myristoylation is the addition of the 14-carbon fatty acid myristate to proteins. This plays a fundamental role in cell signaling: Over 500 proteins are myristoylated, including all 9 Src Family Kinases (SFK) Src, Lyn, Lck, Hck, and Fgr, as well as c-Abl, Gα subunits, caspase truncated (ct-) Bid and ct-PAK2, regulating cell growth and apoptosis. Human myristoylation is performed by two ubiquitously expressed N-myristoyltransferases NMT1 and NMT2. PCLX-001 is a new, orally bioavailable, small-molecule, dual NMT inhibitor under investigation as a novel and selective treatment for B-cell malignancies.In vitro, PCLX-001 inhibits the growth of hematological cancer cells at concentrations 10-fold lower than dasatinib and ibrutinib and prevents SFK recruitment to B cell receptor signaling complex, reducing survival signals and triggering apoptosis. PCLX-001 causes complete tumor regression in NOD/SCID mouse xenograft models of Acute Myeloid Leukemia (AML), Burkitt's Lymphoma (BL), and Diffuse Large B-cell Lymphoma (DLBCL), including drug-resistant human tumor in a PDX model. In mice, PCLX-001 produced complete remission of most xenografts at ≥35 mg/kg/day but also produced some deaths associated with bacterial infection and GI hemorrhage. In an AML xenograft mouse model, the drug exposure from oral dosing required to achieve 91% tumor inhibition was 3,423 ng*hr/mL (AUC (0-tlast)). When expressed on the basis of body surface area, the efficacious dose in mice was ≥105 mg/m2. To support clinical development, we evaluated PCLX-001 for safety in 4-week oral toxicity studies with 2-week recovery periods in rats at 50, 125, and 300 mg/kg/day and dogs at 2, 4, 8, and 12 mg/kg/day, performed to Good Laboratory Practice (GLP) standards. The highest non-severely toxic dose levels (HNSTDs) were 125 mg/kg/day for male rats, 300 mg/kg/day for female rats, and 4 mg/kg/day for dogs of both sexes. At higher dose levels, dose-limiting toxicity occurred within the first few days, was similar in both species, and was attributed to GI mucosal damage and decreased hematopoiesis, with secondary complications such as dehydration and inflammation. In dogs, systemic exposure to PCLX-001 increased more-than-proportionally with dose level after the first dose and did not change with repeated daily dosing. After the last dose at the HNSTD, Cmax averaged 651 ng/mL and 24-hour AUC averaged 3,760 h*ng/mL. In rats, systemic exposure to PCLX-001 after the first dose increased approximately proportionally with dose level and was much greater in males than females at all dose levels. With repeated daily dosing, exposure decreased dramatically in male rats but less so in female rats. As a result, exposure to PCLX-001 was similar in rats of both sexes after the last dose. After the last dose at the HNSTD in males and females, Cmax was 1650 and 8510 ng/mL, respectively, and 24-hour AUC averaged 6470 and 7590 h*ng/mL, respectively. When expressed on the basis of body surface area, the HNSTDs in male rats, female rats, and dogs were 750, 1800, and 80 mg/m2, respectively. As recommended in the ICH S9 Guidance, we chose a starting dose level of 20 mg/m2 for the first clinical trial because this was approximately 1/6th of the HNSTD in dogs. Given the dissimilarity of results between species, we compared the sequence of the NMTs in each since their inhibition was the target for PCLX-001. There was no significant difference between species in their sequence homology to humanNMT1(dog was 98%, rat 97% and mouse 99%), but dogNMT2had only 78% identity to humanNMT2while rat and mouseNMT2had 95% identity with humanNMT2. The significance of this dissimilarity is still under investigation. Disclosures Weickert: Pacylex Pharmaceuticals, Inc.:Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.Dillberger:Pacylex Pharmaceuticals, Inc.:Consultancy.Mackey:Pacylex Pharmaceuticals, Inc.:Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.Berthiaume:Pacylex Pharmaceuticals, Inc.:Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.

A Phase II Study of Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)

A Phase II Study of Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)

Phase 1b Study of BET Inhibitor PLX2853 in Patients with Relapsed or Refractory Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome

Phase 1b Study of BET Inhibitor PLX2853 in Patients with Relapsed or Refractory Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome

Ten-Day Decitabine with Venetoclax Versus Intensive Chemotherapy in Relapsed or Refractory Acute Myeloid Leukemia: A Propensity Score Matched Analysis

Ten-Day Decitabine with Venetoclax Versus Intensive Chemotherapy in Relapsed or Refractory Acute Myeloid Leukemia: A Propensity Score Matched Analysis

Roleof Allogeneic Stem Cell Transplant (ASCT) in Patients (Pts) with Relapsed/Refractory (R-R) Acute Lymphoblastic Leukemia (ALL) Treated with Inotuzumab Ozogamicin (INO) in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab (Blina): Results from a Phase 2 Study

Roleof Allogeneic Stem Cell Transplant (ASCT) in Patients (Pts) with Relapsed/Refractory (R-R) Acute Lymphoblastic Leukemia (ALL) Treated with Inotuzumab Ozogamicin (INO) in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab (Blina): Results from a Phase 2 Study

Outcomes of Patients with Myelofibrosis and Favorable Karyotype

Introduction Myelofibrosis (MF) is an aggressive myeloproliferative neoplasm negatively affecting patient's (pts) overall survival (OS). Several clinical and molecular factors, such as anemia, leukocytosis, thrombocytopenia, increased blasts, presence of unfavorable karyotype, or adverse molecular abnormalities (e.g., ASXL1, IDH1/2, SRSF2, EZH2), further worsen outcomes. Pts with favorable karyotype (e.g., diploid, single deletion 13q, or single deletion 20q), are assumed to have comparable and superior outcome, only affected by their clinical features and molecular background. We decided to evaluate how adverse clinical and molecular factors impact OS within this subset of patients. Methods We conducted a retrospective analysis on patients with favorable karyotype and newly diagnosed MF who presented to our institution within the last 20 years. Favorable karyotype was considered according to classification in DIPSS-Plus and MIPSS70v2.0 models. Prognostic models, IPSS, DIPSS, DIPSS-Plus and MIPSS70v.20 were calculated for patients as published. Molecular analysis was performed in some patients using at least 28-gene panel by next generation sequencing (NGS). Categorical variables were compared by Chi-squared test. Univariate analysis for association between variables and outcome was performed with Cox-regression analysis. Overall survival (OS) was estimated using Kaplan-Meier method and calculated from the time of presentation to our institution until the last follow-up or death. Results Among 1002 patients, 741 pts (74%) had diploid karyotype (DP); the remaining patients had single deletion 13q (del13q, n 33), single deletion 20q (n 97), single abnormality of chromosome 1, 9 or minus Y (n 131). Only pts with del13q had inferior OS to all other groups (42 vs ~ 62 months, p 0.001), and therefore we decided to further focus on pts with del13q and DP karyotype. Patients and disease characteristics are detailed in Tables 1 and 2. We did not observe any significant clinical differences between groups. Distribution by prognostic systems; IPSS, DIPSS, DIPSS-Plus and MIPSS10v2.0 is shown in Table 1. IPSS and DIPSS classified more patients with del13q into higher (combined intermediate 2 and high) risks. DIPSS-Plus and MIPSS70v2.0 showed similar distribution of patients into risks in both groups. Forty - two percent (n 87) and 36% (n 4) of patients with DP karyotype and del13q carried at least one high risk molecular mutation (HMR; such as ASXL1, IDH1/2, EZH2, U2AF1/SRSF2/SF3B1), respectively (Table 2). Whilst all applied clinical risk models (IPSS, DIPSS, DIPSS-Plus) appropriately discriminated distinct OS in pts with DP karyotype, only DIPSS-Plus was able to accurately predict distinct OS in those with del13q (Table 3). MIPSS70v2.0 (only patients with NGS panel) did not predict for distinct OS in DP or del13q pts (Table 3). Pts with DP karyotype had superior OS to those with del13q with median OS of 62 and 42 months, respectively (Figure 1), p < 0.001, HR 0.49, 95% CI 0.32-0.78. Although presence of HMR had negative impact on OS in both groups (Figure 2), pts with del13q with HRM had OS of only 15 months (vs 55 months in DP pts with HMR, p < 0.001). Conclusion Patients with MF and del13q appear to have inferior OS than those with diploid karyotype, despite similar clinical features. Impact of molecular abnormalities, especially presence of high-risk mutations, might be underestimated in this group and deserves further investigation. Ongoing research in our center is aimed to provide new evidence on the role of mutations for this karyotypically "favorable" subgroup. Disclosures Verstovsek: CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; ItalPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding. Bose:Kartos Therapeutics: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Celgene Corporation: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pemmaraju:Blueprint Medicines: Honoraria; SagerStrong Foundation: Other: Grant Support; Pacylex Pharmaceuticals: Consultancy; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Cellectis: Research Funding; LFB Biotechnologies: Honoraria; Plexxikon: Research Funding; Daiichi Sankyo: Research Funding; Roche Diagnostics: Honoraria; DAVA Oncology: Honoraria; Celgene: Honoraria; Samus Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Ariad: Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding.

Sotatercept (ACE-011) for Anemia of Myelofibrosis: A Phase 2 Study

Sotatercept (ACE-011) for Anemia of Myelofibrosis: A Phase 2 Study

Long-Term Follow up of a Phase II Study of Guadecitabine (SGI-110) in Patients with Higher-Risk Myelodysplastic Syndrome (MDS)

Long-Term Follow up of a Phase II Study of Guadecitabine (SGI-110) in Patients with Higher-Risk Myelodysplastic Syndrome (MDS)

Urgent Cytoreductive Chemotherapy for Newly Diagnosed Patients with AML Is Safe and Feasible and Facilitates Enrollment on Investigational Clinical Trials

Urgent Cytoreductive Chemotherapy for Newly Diagnosed Patients with AML Is Safe and Feasible and Facilitates Enrollment on Investigational Clinical Trials

Implications of RAS Mutational Status in Subsets of Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) across Therapy Groups

Implications of RAS Mutational Status in Subsets of Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) across Therapy Groups

Combined Ibrutinib and Venetoclax for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL): Focus on MRD Results

Combined Ibrutinib and Venetoclax for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL): Focus on MRD Results

Interim Analysis of the Phase 1b/2 Study of the BCL-2 Inhibitor Venetoclax in Combination with Standard Intensive AML Induction/Consolidation Therapy with FLAG-IDA in Patients with Newly Diagnosed or Relapsed/Refractory AML

Interim Analysis of the Phase 1b/2 Study of the BCL-2 Inhibitor Venetoclax in Combination with Standard Intensive AML Induction/Consolidation Therapy with FLAG-IDA in Patients with Newly Diagnosed or Relapsed/Refractory AML

Phase II Study of Venetoclax Added to Cladribine + Low Dose AraC (LDAC) Alternating with 5-Azacytidine Demonstrates High Rates of Minimal Residual Disease (MRD) Negative Complete Remissions (CR) and Excellent Tolerability in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Phase II Study of Venetoclax Added to Cladribine + Low Dose AraC (LDAC) Alternating with 5-Azacytidine Demonstrates High Rates of Minimal Residual Disease (MRD) Negative Complete Remissions (CR) and Excellent Tolerability in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Clinical Outcomes and Influence of Mutation Clonal Dominance in Oligomonocytic and Classical Chronic Myelomonocytic Leukemia

Clinical Outcomes and Influence of Mutation Clonal Dominance in Oligomonocytic and Classical Chronic Myelomonocytic Leukemia

Clinical Outcomes with Hypomethylating Agents in Patients with Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T); A Case Series

Clinical Outcomes with Hypomethylating Agents in Patients with Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T); A Case Series

Predictors of Early Mortality, Response, and Survival in Newly Diagnosed Acute Myeloid Leukemia (AML) Using a Contemporary Academic Cohort

Predictors of Early Mortality, Response, and Survival in Newly Diagnosed Acute Myeloid Leukemia (AML) Using a Contemporary Academic Cohort

Thrombotic Events and Mortality Risk in Patients Newly Diagnosed with Intermediate- to High-Risk Essential Thrombocythemia in the United States

Background Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) associated with an increased risk of thrombotic events (TEs), which represent a substantial cause of mortality in this population. There is limited contemporary, real-world evidence exploring the effect of TEs on mortality in patients with ET. The aim of this analysis was to compare risk of mortality among patients newly diagnosed with intermediate- or high-risk ET who experienced a TE vs those who did not experience a TE. Study Design and Methods All data from the Medicare Fee-for-Service (FFS) claims database (Parts A/B/D) from January 2010-December 2017 were used to identify patients with an ET diagnosis (all intermediate or high risk based on cohort age ≥65 years) with ≥1 inpatient or ≥2 outpatient claims. The index date was the date of the first qualifying ET claim. Patients with an ET diagnosis, use of hydroxyurea, or use of ruxolitinib within 12 months before the index date and patients with a myelofibrosis diagnosis during the study period were excluded. A minimum of 12 months of continuous medical and pharmacy enrollment pre-index was required. The study sample was categorized into TE and non-TE groups based on the occurrence of any of the following events during follow-up: deep vein thrombosis, pulmonary embolism, ischemic stroke, acute myocardial infarction, transient ischemic attack, peripheral arterial thrombosis, or superficial thrombophlebitis. TEs were evaluated from the index date to the end of follow-up. Cox regression analyses with time-varying effects were used to assess mortality risk among patients with ET with post-index TE as a time-dependent variable, stratified by pre-index TE, and adjusting for patient demographic characteristics and comorbid conditions. Results A total of 143,588 Medicare FFS beneficiaries with a diagnosis of ET met the study inclusion criteria; median age was 76.0 years, 68.1% were female, and 84.2% were white. Pre-index TE was reported in 37,284 patients (26.0%). In the follow-up period, 49,497 patients (34.5%) had a TE and 94,091 patients (65.5%) did not have a TE. In the comparison between the TE vs non-TE groups, the median (range) age (77 [65-107] vs 75 [65-110] years, respectively), mean (SD) Charlson comorbidity index score (4.8 [3.5] vs 3.8 [3.5]), and percentage of patients with a history of bleeding (27.0% vs 22.2%), anemia (64.7% vs 55.9%), or a cardiovascular event (45.8% vs 33.5%) were higher (Table 1). The median time from ET diagnosis to first TE in the follow-up period was 2.8 months for all patients, 0.5 months for patients with pre-index TE, and 8.0 months for those without pre-index TE. The most common types of first TE in the follow-up period were ischemic stroke (37.3%), acute myocardial infarction (23.2%), and transient ischemic attack (22.6%). The risk of mortality was increased for patients who experienced a TE compared with those who did not (hazard ratio [HR; 95% CI], 11.2 [10.6-11.8]; P<0.001), including for both those with pre-index TE (HR [95% CI], 9.3 [8.6-10.1]; P<0.001) and those without pre-index TE (HR [95% CI], 15.4 [14.2-16.8]; P<0.001). Conclusions In this contemporary, real-world analysis, approximately one-third of patients with newly diagnosed intermediate- to high-risk ET experienced a TE. Elderly patients with ET who experienced a TE had an approximately 11-fold increased risk of mortality vs those who did not experience a TE, highlighting a continued unmet need in this population. Further efforts are needed to better define and mitigate TE risk in patients with ET, particularly in those with prior TE. Disclosures Pemmaraju: Daiichi Sankyo: Research Funding; Cellectis: Research Funding; Plexxikon: Research Funding; Blueprint Medicines: Honoraria; AbbVie: Honoraria, Research Funding; Samus Therapeutics: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Roche Diagnostics: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; MustangBio: Honoraria; Celgene: Honoraria; DAVA Oncology: Honoraria; SagerStrong Foundation: Other: Grant Support. Gerds:Gilead Sciences: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; AstraZeneca/MedImmune: Consultancy; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy, Research Funding; Pfizer: Research Funding. Yu:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Parasuraman:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Shah:Avalere Health: Current Employment. Xi:Incyte Corporation: Other: Avalere Health is a paid consultant of Incyte Corporation; Avalere Health: Current Employment. Kumar:Incyte Corporation: Other: Avalere Health is a paid consultant of Incyte Corporation; Avalere Health: Current Employment. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Verstovsek:CTI Biopharma Corp: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding.

Characteristics and Outcome of Myelofibrosis Patients on Long-Term Ruxolitinib Therapy (≥3 years)

Characteristics and Outcome of Myelofibrosis Patients on Long-Term Ruxolitinib Therapy (≥3 years)