ALBERT

Description: Background Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme responsible for symmetric arginine dimethylation of multiple proteins that impact cell proliferation. Its substrates include proteins involved in mRNA splicing, signal transduction, gene transcription, and DNA repair. PRMT5 overexpression occurs in many cancers and correlates with poor prognosis. GSK3326595 is a potent, specific, and reversible inhibitor of PRMT5 that inhibits proliferation and induces cell death in a broad range of solid and hematologic tumor cell lines. It also exhibits potent anti-tumor activity in vivo in animal models, including in preclinical models of myeloid malignancies. One mechanism of action of GSK3326595 is via inhibition of cellular mRNA splicing and upregulation of tumor suppressor function. Mutations in splicing factors are frequent in myeloid malignancies (including approximately 40% of patients with myelodysplastic syndrome [MDS], and over 60% of patients with chronic myelomonocytic leukemia [CMML]), and further inhibition of mRNA splicing via GSK3326595 may lead to a synthetic lethal phenotype specifically in splicing mutant disease. Study 208809 is the first trial of a PRMT5 inhibitor in participants with myeloid malignancies. Methods Study 208809 is a Phase I/II study to evaluate the safety, tolerability, and clinical activity of GSK3326595 monotherapy in participants with relapsed and refractory MDS, CMML, and hypoproliferative acute myeloid leukemia (AML) that has evolved from an antecedent MDS. Part 1 will identify a tolerated dose and establish preliminary evidence of efficacy in this population. At the end of Part 1, if pre-specified criteria are met, then the study will be expanded with three additional Parts that will be opened in parallel. Part 2A is a Phase II randomized comparison of monotherapy GSK3326595 versus investigator's choice of best available care in participants with relapsed and refractory MDS, CMML, and hypoproliferative AML. Part 2B is a single-arm investigation of safety and efficacy of GSK3326595 plus 5-azacitidine in participants with newly diagnosed high-risk MDS. Part 2C is a single-arm investigation of the safety and efficacy of monotherapy GSK3326595 in participants with relapsed or refractory AML whose tumors harbor mutations in components of the pre-mRNA splicing machinery. All participants enrolled in this study have a diagnosis of MDS, CMML, or AML, with enrollment into each cohort as defined above. Participants are adults with adequate organ function as defined in the protocol. Prior allogeneic transplant is permitted. There are no required biomarkers for enrollment to Parts 1, 2A, and 2B, though central confirmation of pre-mRNA splicing factor mutations will be performed to stratify participants for overall analysis. Enrollment to Part 2C is limited to participants with splicing factor mutations. It is estimated that a maximum of 302 participants will be enrolled in the study, divided as follows: Approximately 41 participants in Part 1, approximately 192 participants in Part 2A, approximately 41 participants in Part 2B, and approximately 28 participants in Part 2C. In Part 1, the primary endpoint is clinical benefit rate, as defined as the percentage of participants achieving a complete remission, complete marrow remission, partial remission (PR), stable disease lasting at least 8 weeks, or hematologic improvement, as per standard criteria. In Part 2A, the primary endpoint is overall survival. In Part 2B and Part 2C, the primary endpoint is overall response rate (ORR), defined as the percentage of participants achieving a PR or better. Samples are collected to evaluate symmetric dimethylated arginine (SDMA), the enzymatic product of PRMT5. This has been demonstrated to be a pharmacodynamic marker of PRMT5 inhibition in plasma and tumor tissue. In addition, participants will be stratified based on the presence or absence of spliceosome mutations and analyzed separately to evaluate the effect of these mutations on clinical activity. As of 1 August 2019, recruitment is ongoing across six centers in the United States and Canada; ten participants have been enrolled, all into Part 1. ClinicalTrials.gov identifier: NCT03614728 Study is funded by GlaxoSmithKline Disclosures Watts: Takeda: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bradley:AbbVie: Other: Advisory Board. Brunner:Novartis: Research Funding; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Papadantonakis:Agios: Consultancy, Honoraria. Abedin:Actinium Pharmaceuticals: Research Funding; Pfizer Inc: Research Funding; Helsinn Healthcare: Research Funding; Agios: Honoraria; Jazz Pharmaceuticals: Honoraria. Baines:GlaxoSmithKline: Employment, Equity Ownership. Barbash:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties, Research Funding. Gorman:GlaxoSmithKline: Employment, Equity Ownership. Kremer:GlaxoSmithKline: Employment, Equity Ownership. Borthakur:Cantargia AB: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Novartis: Research Funding; Oncoceutics: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agensys: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; NKarta: Consultancy; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding.

Description: Background: Aurora kinases play essential roles in regulating cell division, and increased expression has been noted in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We previously conducted a phase I study of alisertib combined with "7+3" induction chemotherapy in untreated patients with AML, and found the combination to have an adverse event profile similar to 7+3 alone, with promising efficacy, particularly for patients with high-risk disease, such as those who were older, with high-risk molecular features, or with secondary AML. These patients collectively have a historically grim prognosis, with an approximate rate of remission, in trials, of 45%. CPX-351, a liposomal daunorubicin-cytarabine product, was recently approved for use in secondary AML after it was demonstrated to be superior to 7+3 induction, with a median survival of 9.6 months versus 5.9 months among older patients, in a phase 3 trial. We recently completed accrual to a phase II study of alisertib plus induction chemotherapy in patients with untreated, high-risk AML. Methods: Patients were eligible if they had AML defined by WHO 2016 and either an adverse-risk karyotype (European Leukemia Net Guidelines), secondary (post-MDS/MPN) AML, therapy-related AML, or age ≥ 65 vears. We used a Simon two-stage design, assuming a null composite remission rate (complete remission [CR] and CR with incomplete count recovery [CRi]) of 45%. Patients could be enrolled prior to cytogenetic classification, but those without adverse-risk karyotype who lacked other eligibility criteria were removed before day 8 and replaced. All patients received continuous infusion cytarabine 100mg/m2 on days 1-7 [D1-7] and idarubicin 12mg/m2 [or daunorubicin 60mg/m2] D1-3 (7+3). On D8 through D15, alisertib at 30mg BID orally (PO) was administered. All underwent a mid-induction marrow biopsy to assess for residual disease, which if present, was treated with 5+2 re-induction without alisertib. Following remission, patients could receive up to 4 consolidation cycles with cytarabine (3g/m2 BID D1,3,5 for age

Description: Introduction: Survival among patients diagnosed with chronic myeloid leukemia (CML) has markedly improved with the advent of tyrosine kinase inhibitors. Nonetheless, access to care, including medication cost and adherence, may be barriers to therapeutic effectiveness. We performed a population-based analysis to determine if insurance status at the time of CML diagnosis influenced patient outcomes. Methods: We used the Surveillance, Epidemiology, and End Results Program (SEER) database (November 2014 submission) to identify patients age 15 or older, diagnosed with CML between 2007 and 2012 (SEER ICD-O3 recodes 9863 and 9875). We included patients with documented insurance status at diagnosis and categorized them as either private insurance, Medicaid coverage, or uninsured. We excluded patients with unknown insurance status at diagnosis. The primary outcome was overall survival according to insurance status. We performed a stratified analysis looking at patients age 15-64 and patients 65 or older; we did not include uninsured patients over age 65 in the analysis (n=16) due to Medicare eligibility. Covariates of interest in multivariable analysis included age at diagnosis, race, ethnicity, sex, and marital status at diagnosis. Overall survival was compared by log-rank test and estimated by the method of Kaplan and Meier. P-values were significant to the 2-sided 0.05 level. Results: 5784 patientswere diagnosed with CML between 2007 and 2012 and had insurance status documented at diagnosis. Of patients age 15-64, uninsured and Medicaid patients were younger, more often non-white race and Hispanic ethnicity, and less often married (Table 1). Over age 65, Medicaid patients were more often female, non-white race and Hispanic ethnicity, and less often married. Median follow up was 32 months. Among patients age 15 to 64, being uninsured or having Medicaid was associated with worse survival compared to insured patients (5-year OS uninsured 72.7%, Medicaid 73.1%, insured 86.6%, p

Description: Acute myeloid leukemia with chromosomal alterations impacting the core binding factor transcription complex (CBF-AML), specifically t(8;21) and inv(16), are associated with a greater responsiveness to cytarabine-based chemotherapies and a more favorable prognosis. The latter has been primarily gleaned from outcomes of large clinical trials of AML. However, to date, there is limited population-based outcomes data on CBF-AML. We therefore performed an epidemiologic retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database to assess survival trends for CBF-AML at the population level between 2000 and 2010. Patients and Methods Patients with a diagnosis of CBF-AML between 2000 and 2010 were identified using the SEER 18 registries database. We included patients with a diagnosis code of inv(16)/t(16;16) AML (Code 9871) or t(8;21) AML (Code 9896) diagnosed between January 2000 and December 2010. Patients were divided into cohorts based on age at diagnosis: 15-44 years old, 45-64 years old, 65-74 years old, and 75-84 years old. Disease incidence was calculated, as were early mortality rates, defined as death within 1 month. Overall survival (OS) was estimated using the method of Kaplan and Meier. Cox regression was performed to estimate predictors of survival by specific CBF-AML type, age cohorts, race/ethnicity, gender, year of diagnosis, number of primary malignancies, and residence. Results We identified 777 patients with a new diagnosis of CBF-AML between 2000 and 2010. The incidence of CBF-AML increased with advancing age (ages 15-44, 0.06 per 100,000 people; ages 45-64, 0.13; ages 65-74, 0.25; ages 75-84, 0.28). Median OS for all patients was 22 months, and the combined 3-year OS was 44.3% (Fig. 1). Median OS increased from 16 months during the period encompassing 2000 and 2002 to 25 months during the period from 2006 to 2008 (p=0.002) (Fig. 2). The rate of early death was 13%, which increased with age (15-44 5%, 45-64 10%, 65-74 20%, 75-84 33%; P

Description: Abstract 1484 Introduction: Acute Myeloid Leukemia (AML) is more common among patients over the age of 60, who also historically have a poorer prognosis. It is unclear which patients will benefit most from intensive chemotherapy; prognostic factors have been identified to risk-stratify these patients, but tend to consider characteristics specific to the disease such as cytogenetics [Lancet 2010; 376: 2000–08], and may not account for patient comorbidities that preceded the diagnosis of AML. Increased body mass index (BMI) has been associated with an increased incidence of various malignancies, including AML [The Oncologist 2010; 15: 1083–1101], and is increasingly prevalent among the general population. We sought to determine whether patient BMI at time of AML diagnosis is related to overall survival among patients older than age 60. Methods: We performed a retrospective chart review of all patients diagnosed at Massachusetts General Hospital with records available in the electronic medical record between January 1, 1992 and May 1, 2011. Patients were identified using billing codes and pathology records and underwent chart review to confirm a diagnosis of AML. Patients were included in this review if they had a pathologically-confirmed new diagnosis of AML, were older than age 60 at the time of diagnosis, and were given cytarabine-based induction chemotherapy. We collected past medical history, presenting labs, patient cytopathology, weight, and height at diagnosis. Overall survival (OS) was estimated using the Kaplan-Meier method, with 95% confidence intervals calculated using Greenwood's formula. We then performed a stepwise multivariable Cox regression analysis, pre-specifying that a variable had to be significant at the 0.3 level before it could be entered into the model, while a variable in the model had to be significant at the 0.05 level for it to remain in the model. Results: We identified 152 patients with AML diagnosed after the age of 60. The median age was 68 years (range 60–87); 54% of patients were male, and 86% were white. Patient disease was identified as de novo in 50%, and secondary in 50%. Cytogenetics, when available (86.2% of patients), were most commonly normal (37.5%) or poor risk (34.2%); only 1.3% of patients were good risk. The median OS for all patients was 269 days (95% CI 217–323). The 60 day OS for all patients was 83% (95% CI 77–89%). Using the log-rank test to perform a univariate analysis, worsened OS was associated with increased age (P=0.024); body mass index (BMI) 〈 27, the median BMI in our cohort, (P=0.011); presence of coronary artery disease (CAD) (P=0.042); and with cytogenetics (P=0.013). The multivariable analysis of the Cox proportional-hazards model found that the hazard rate for death was increased with older age (HR 1.53, P=0.027, 95% CI 1.05–2.24), lower BMI 〈 27 (HR 1.93, P=0.002, 95% CI 1.28–2.92) and cytogenetics (P

Description: Introduction: Acute myeloid leukemia (AML) is more frequent among older patients in the United States (US), with a median age at diagnosis of 67 years old. A recent case series of AML patients from India reported a median age at diagnosis of 40 years old, suggesting that the pathogenesis of AML may differ between these populations (British Journal of Haematology 2015;170:110). In this study, we examined whether differences exist in the age at diagnosis, cytogenetic risk, and overall survival (OS) of White and South Asian patients diagnosed with AML in the US. Methods: We used the 1973-2012 Surveillance, Epidemiology, and End Results Program (SEER) database to identify adults, age 20 years or older, diagnosed with AML between 2000 and 2012. We included patients with documented race/ethnicity and known age at diagnosis. We compared age at diagnosis, cytogenetic risk, and OS according to White or South Asian race/ethnicity, based on patient surname as defined by SEER. We stratified age at diagnosis into age groups, defined as 20-24, 25-34, 35-44, 45-54, 55-64, and 〉65 years old, to compare the White and South Asian populations. Using the 2012 US Census population age distributions, we directly standardized the distribution of age at diagnosis of AML in SEER, weighted according to the age distribution of the total White and South Asian populations in the US. We categorized SEER-reported cytogenetic profiles as having favorable or adverse prognosis based on accepted definitions. We compared cytogenetic risk and OS between White and South Asian populations according to stratified age group at diagnosis. Differences in age at diagnosis were calculated using the Mann-Whitney test. OS was compared by the Log-rank test and estimated by the method of Kaplan and Meier. P-values

Description: Abstract 1041 Introduction Granulocytic Sarcoma (GS), also known as chloroma or myeloblastoma, is a rare neoplasm composed of immature myeloid cells occurring in any extramedullary organ, most commonly in the lymph node and soft tissue. It can occur as an isolated lesion, or in conjunction with a diagnosis of acute myeloid leukemia (AML), myeloproliferative disorder (MPD) or myelodysplastic syndrome (MDS). GS has been generally associated with more aggressive disease and a poor prognosis. Although it has been described in the literature in small case series, the clinical characteristics and prognosis of patients with GS associated with AML, MDS, MPD or as an isolated lesion have not been thoroughly described. We therefore studied our institutional experience of granulocytic sarcoma to gain further insight into the clinical features and associations of this disease. Methods We conducted a retrospective medical record review of patients who presented with GS to Massachusetts General Hospital from 1994 through 2011. In total, 35 patients with GS were identified. Kaplan Meier method was used to estimate overall survival (OS). OS was defined as the duration from the time of diagnosis of GS to date of death; patients still alive at the time of analysis were censored. Patients were categorized into three groups for analysis depending on the presence of bone marrow disease: primary (isolated) GS, GS associated with AML, and GS associated with MDS or MPD. Result Of 35 patients with GS, 20 (57%) were associated with a diagnosis of AML, 10 (29%) presented with either MDS or MPD, and 5 (14%) presented with primary GS. Of the AML-associated GS, 13 occurred concurrently with AML at diagnosis and 7 presented as AML relapse. Of the 10 cases of GS with either MDS or MPD, one patient presented with MDS and 9 with MPD. The median age of all patients was 57 years old; 19 of 35 patients were female. Median white blood count (WBC) was 4.6 (th/cmm) (IQR 3.5–8.8) for patients with AML-associated GS and 20.2 (th/cmm) (IQR 9.7–61) for those with MDS/MPD-associated GS. One year survival was 10% (95% CI 0.5 – 35.8%) in MDS/MPD associated GS, 49.5% (95% CI 26.5 – 68.9%) in AML associated GS, and 60% (95% CI 12.6 to 88.2%) in primary GS. The most common area of involvement in patients with AML-associated GS was the nervous system (22%). In contrast, among patients with MPD/MDS-associated GS, the most commonly involved site was bone (45%) (Table 1). 63% of all patients had one site of involvement with GS at presentation. The most common presenting symptom was pain either caused by a mass or lymphadenopathy. Cytogenetics were normal for the majority of patients. Interestingly, however, one AML patient and one patient with primary GS presented with a 9;22 translocation, two AML presented with other cytogenetic abnormalities involving chromosome 9 (t(9;11)(p22;q23) & add(9)(q34)), and three others, including one with primary GS, displayed abnormalities at chromosome 11, specifically 11q23 (Table 2). Conclusions With this study, we provide a single institution experience of granulocytic sarcoma, a rare manifestation of myeloid neoplasms. Interestingly, we found variable presentation with different patterns of site involvement and white blood counts in patients with GS associated with AML and in those with GS associated with MPD/MDS. Additionally, certain karyotypic abnormalities were over-represented in patients with GS, including t(9;22) and translocations involving chromosome 11q23. Finally, in our small series, patients with a diagnosis of GS associated with MPD/MDS had worsened outcomes compared to those with AML-associated GS or primary GS. Larger, prospective studies are needed to better and more fully assess outcomes in these patients. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Myelodysplastic syndromes (MDS) comprise a broad spectrum of hematologic malignancies with varying clinical courses; although most deaths are attributed to MDS, many patients will die of other attributable causes, independent of or potentially augmented by their underlying cancer. Cardiovascular (CV) disease is a frequently attributed cause of death in these patients, and may be influenced by CV care patterns in a patient's county of residence. Patients who live in counties with worse CV outcomes may be at greater risk of CV complications and death. We sought to determine whether regional quality of CV care in the US, measured by the rate of CV death in a county, impacts the cumulative incidence of death attributed to CV disease among MDS patients. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database from the National Cancer Institute to identify patients, age 15 and older, with a new diagnosis of MDS between 2001 and 2011. We identified 29,571 patients with a known age at diagnosis and follow-up, for whom MDS was the first cancer diagnosed in SEER. We grouped patients into lower risk disease (RA, RT, RN, and RARS), intermediate risk disease (MDS-unclassified, del(5q), RCMD, and t-MDS) and higher risk disease (RAEB and RAEB-T) according to SEER classifications. The incidence of a given cause of death (COD) was estimated by the cumulative incidence method identifying each COD as competing risks using R statistical software, and tested using the Gray test. We identified population rates of CV-specific mortality, according to the National Center for Health Statistics and available through SEER*Stat, in all counties with at least one MDS diagnosis over the study period. If the rate of death due to cardiovascular disease in a county was below the 25th percentile, then the CV performance was considered "good", if above the 75th percentile then the CV performance was considered "poor", and all others were considered "intermediate." Patients with MDS were grouped into a county CV performance quartile according to the rate of CV death in that county at the time of diagnosis. Results: The median age at diagnosis was 76 years (range 15-109) and the patients were 54% male. Patients were divided among lower risk (21%), intermediate risk (66%), and higher risk MDS (13%). Cause of death was reported for 29,344 patients. 602 counties had 1 diagnosis of MDS between 2001 and 2011, 599 of which reported overall CV mortality rates. A total of 15,856 MDS patients (54%) lived in counties with good CV performance (less than or equal to the 25th percentile of CV mortality) during the study period, while 11,845 (40%) lived in counties with intermediate CV performance, and 1817 (6%) lived in poor CV performance counties. MDS patients living in poor CV performance counties had a cumulative incidence of death attributed to cardiovascular disease of 7.2% at 12 months, compared to 4.8% and 5.1% among intermediate and good CV performance counties, respectively (p=0.0001). Death attributed to MDS was 15.7%, 15.6%, and 14.5% at 12 months for patients living in good, intermediate, and poor CV performance counties, respectively (Table 1). When looking specifically at MDS risk groups, it appeared that county CV performance had a greater impact on patients with intermediate and higher risk MDS (Table 1). Patients with higher risk MDS living in poor CV performance counties had a 12-month cumulative incidence of death due to CV disease of 9.3% compared to 4.2% and 3.6% in good and intermediate CV performance counties (p

Description: Background The diagnosis of acute myeloid leukemia (AML) is associated with a poor prognosis, particularly for patients older than age 65 and those with relapsed or refractory disease. Little is known about the specific location where AML patients die and how disease status, therapeutic management, and symptoms influence the place of death. Methods We conducted a retrospective descriptive analysis of consecutive patients with AML who died at our institution between January 2007 and December 2012. In addition to place of death, the variables of interest included: disease status at death, previous transplant, prior chemotherapy, presence of a dedicated caregiver, gender, and age at diagnosis. Disease status was classified as: new diagnosis, active disease, relapsed, or in remission. A new diagnosis was defined as a diagnosis within the prior 30 days. Active disease was defined as disease beyond 30 days and without prior remission. Medical records were reviewed to identify whether palliative care service was consulted, and the range of symptoms reported during the last two weeks of life. Categorical variables were compared among groups using chi-square and continuous variables with the Kruskal Wallis test. Results We identified 166 patients with AML. The majority of study patients were white (90%) and male (55%) with a median age of 69 years (range 21-94 years). Disease was characterized as de novo AML (49%), therapy related (14%), secondary to antecedent myelodysplasia (29%) or other hematologic disease (8%). The median time from diagnosis to death was 5.5 months (range 0.7-50.4). The majority (82%) had active AML at time of death. Other causes of death included transplant related complications (8%), sepsis (4%), bleeding (2%), or other (4%) causes. Palliative care consultation occurred in 35% of the cases. The consults typically were late in the course of illness with the median time from initial consult to time of death of 8 days (range 0-122 days). Information on the location of death was available for 154 patients, of whom, 23 (15%) died in inpatient hospice, 41 (27%) at home, 48 (31%) died while hospitalized in a non-ICU bed and 42 (27%) died in either the Intensive Care Unit or Emergency Department (ED). Location of death was significantly associated with disease status at death (p〈 0.0001, Figure 1), prior anthracycline/cytarabine based induction therapy (p=0.01), social support/dedicated caregiver (p=0.05), and age at diagnosis (p