ALBERT

Description: Background: The myelodysplastic syndromes (MDS) are associated with shortened overall survival (OS) and inferior quality of life (QOL). Age, degree of comorbidity, MDS risk group, and treatment status are all likely predictors of both outcomes. We aimed to assess the association between treatment status and patient-reported QOL in a large cohort of community-treated MDS patients at the time of presentation to tertiary care, while controlling for the other three factors. Methods: Beginning in 2006, patients with MDS presenting for their first evaluation at Dana-Farber Cancer Institute (DFCI) were enrolled into a clinical database (consent rate 85%). Enrollment included administration of the EORTC QLQ-C30 (Aaronson, JNCI, 1993), a 30-item measure of QOL that includes subscales for global health (higher score better), fatigue (lower score better), and physical function (higher score better). Medical record review was performed to characterize baseline demographic, clinical, and laboratory data. Treatment status included therapies received in the community during the 30 days prior to QOL assessment, as these were most likely to directly impact QOL. Comorbidity was assigned via the Modified Charlson Comorbidity Index (mCCI; Charlson, Journal Clinical Epi, 1994). MDS prognostic group was assigned via the IPSS-R (Greenberg, Blood, 2012). Associations between treatment status and QOL scores were analyzed with separate multivariable linear regressions adjusted for age, sex, comorbidity, and IPSS-R. Results: In total, 287 patients with complete QLQ-C30 data were included, of which 22% were IPSS-R very high risk, 24% high risk, 22% intermediate risk, 26% low risk, and 6% very low risk. The majority of patients (66%) were male, median age was 68 years, and the mCCI was 0 in 40%, 1-2 in 35%, and 3+ in 24%. Relative to very low risk on the IPSS-R, the unadjusted hazard ratios for death were 1.5 for low risk, 2.2 for intermediate risk, 4.9 for high risk, and 7.2 for very high risk (Ptrend

Description: Background:Leukemia cutis (LC) occurs in 10-30% of AML cases and may be a marker of poor prognosis. However, outside of monocytic AML (FAB M4/M5), no clinical or genetic predictors of LC are known. Recently, a number of somatic molecular mutations have been described in AML. Using amplicon-based next-generation sequencing (NGS) of a panel of recurrent, hematologic malignancy-associated mutations, we sought to determine potential molecular markers associated with the development of LC. Methods: A cohort of non-M3 AML patients treated at the University of Pennsylvania was identified in which NGS had been performed on either leukemic blasts obtained during clinical care or from the institutional tissue bank.Average read depth for 33 hematologic malignancy-associated genes was approximately 3000X, minimal depth was 250x, and reporting frequency cutoff for variants was 5%. Mutations were reported as pathogenic or variants of uncertain significance (VUS, further sub-classified internally as likely disease associated, VUS, or likely benign) based on the University’s Center for Personalized Diagnostics (CPD) review of publically available data; only pathogenic or likely disease-associated mutations were included in this analysis. A database maintained by dermatopathology was reviewed to identify cases of leukemia cutis at any time during the disease course. Independent dermatopathology review was obtained for indeterminate cases. Association between presence of each of the 3 most common molecular mutations (FLT3-ITD, DNMT3A, and NPM1) and development of LC was assessed by logistic regression, with adjustment for FAB M4/M5, as appropriate. The association between presence of a molecular mutation in different functional classes (tumor suppressors, activated signaling, chromatin modifiers, transcription factors, splicing machinery) and the development of LC was also assessed. Results:279 adult patients with AML with known molecular genotype were identified. Molecular profile was determined from AML diagnosis in (243, 88%) with the remainder undergoing assessment after prior therapy (relapsed or refractory). 56% were male with median age of 60 years (range 18-87) and median WBC count at diagnosis of 22 K/uL (range 0.4 -388 K/uL; 17% ≥100K/uL). The majority of patients had intermediate cytogenetic risk (12% favorable, 59% intermediate, 23% unfavorable, 6% unknown) and 41% of patients had FAB M4/M5 AML (9% unknown). The three most common mutations were NPM1 (29%), DNMT3A (25%), and FLT3-ITD (23%). NPM1mutations were enriched in patients with FAB M4/M5 AML (41% vs 23%, p=0.003). Leukemia cutis was present in 26 (9%) of patients. NPM1 mutant status was present in 14 of 26 cases of leukemia cutis (OR 3.17, 95% CI 1.40-7.20, p=0.006). No association was detected for LC and the presence of mutant FLT3-ITD (OR 1.27, p=0.613), mutant DNMT3A (OR 1.7, p=0.224), or a mutation in any functional class of AML mutations (all p-values NS). The impact of NPM1 mutant status remained significant after adjustment for association with M4/M5 AML (OR 3.91, p=0.005). As the histologic subtype of AML might modify the association between NPM1 mutations and leukemia cutis, we next examined the impact of NPM1 mutant status on patients with FAB M4/M5 AML and non-M4/M5 AML. Among patients with M4/M5 AML, 10/12 (80%) patients with LC were NPM1 mutant compared to 32/91 (35%) without LC suggesting that the presence of mutated NPM1 was significantly associated with the development of LC (OR 9.22, p=0.006). Among patients with non-M4/M5 AML, 3/9 (33%) of patients with leukemia cutis were NPM1 mutant compared to 32/142 (22.5%) without LC indicating no association in the non-M4/M5 subgroup (OR 1.72, p=0.461). Interestingly, M4/M5 AML was not associated with LC in the NPM1 WT cohort (OR 0.65, p=0.6). Conclusion: Using NGS, we identify a novel association between NPM1 mutation status and the presence of leukemia cutis, particularly within monocytic AML. Confirmation of these observations in a larger dataset is planned. Our data suggest potential cellular effects of NPM1 mutation affecting homing of leukemic blasts to skin and support the World Health Organization’s provisional classification of NPM1-mutated AML as a distinct biologic entity. Disclosures No relevant conflicts of interest to declare.

Description: Chronic neutrophilic leukemia (CNL), atypical chronic myeloid leukemia (aCML), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are a group of rare and heterogeneous myeloid disorders. There is strong morphologic resemblance among these distinct diagnostic entities as well as a lack of specific molecular markers and limited understanding of disease pathogenesis, which has made diagnosis challenging in certain cases. The treatment has remained empirical, resulting in dismal outcomes. We, therefore, performed whole-exome and RNA sequencing of these rare hematologic malignancies and present the most complete survey of the genomic landscape of these diseases to date. We observed a diversity of combinatorial mutational patterns that generally do not cluster within any one diagnosis. Gene expression analysis reveals enrichment, but not cosegregation, of clinical and genetic disease features with transcriptional clusters. In conclusion, these groups of diseases represent a continuum of related diseases rather than discrete diagnostic entities.

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: BACKGROUND: Effective and well tolerated treatment options for patients with relapsed acute myelogenous leukemia (AML) are limited. Birinapant is a small molecule, peptidomimetic of second mitochondrial-derived activator of caspases (SMAC) that selectively targets Inhibitor of Apotosis proteins (IAPs) resulting in tumor cell apoptosis and inactivation of NF-kB. SMAC mimetics represent a novel class of anti-tumor agents and birinapant has been explored as a single agent and in combination with chemotherapy in trials in solid tumors. Based on pre-clinical response observed in a mouse model with AML, we developed an investigator initiated Phase I clinical trial using single agent birinapant in pts with relapsed AML and high risk myelodysplastic syndrome (MDS). METHODS: Eligible pts were 〉18 years old with non-M3 relapsed or refractory AML or high risk MDS refractory to a hypomethylating agent. A standard 3+3 dose escalation was planned using single agent birinapant at increasing dose levels and frequency. Subjects who did not complete at least one cycle of therapy (4 wks) or experience a dose limiting toxicity (DLT) were replaced. The primary endpoint was safety and determination a maximum tolerated dose (MTD). Secondary endpoints included pharmacokinetic (PK) and pharmacodynamics (PD) analysis as well as disease response. RESULTS: From 12/2011 to 05/2014, 20 subjects were enrolled at the Hospital of the University of Pennsylvania and received at least one dose of study drug, 1 had MDS, 19 had AML (9 with antecedent MDS). The median age was 75 (range 36 to 80). The median number of prior treatments was 2 (range 1 to 5) and 11 patients required hydroxyurea during study treatment. No other concurrent chemotherapy was permitted. Several dose levels were tested varying the dose (17mg/m2, 22mg/m2 and 26mg/m2) and frequency (weekly, twice weekly (BIW) and 3 times weekly (TIW)) for 3 out of 4 wk cycles. Evaluable subjects have stayed on study drug for

Description: Abstract 103 Post-transplantation lymphoproliferative disorder (PTLD) is a heterogeneous group of lymphoid neoplasms arising in immunosuppressed organ transplant recipients. While it has long been known that reduction of immunosuppression (RI) is an effective therapy, previous reports on RI alone are of limited value due to small numbers of patients. We analyzed the efficacy, safety and predictors of response to therapy in a series of 162 organ transplant recipients diagnosed with PTLD at the University of Pennsylvania between 1988 and 2008. We analyzed clinical and pathological characteristics, response to therapy, graft outcome and survival of patients treated with RI alone as initial therapy for PTLD in comparison to patients who were treated with other therapies. We used logistic regression to identify predictors of response, and Cox regression to identify predictors of survival, in patients treated with RI. We identified 67 patients who were treated with RI alone and additional 30 patients who were treated with complete surgical excision of a localized lesion followed by adjuvant RI. We compared these patients with 51 evaluable patients who were treated with other modalities upfront. The overall response rate to RI alone was 45% (CR 37%, PR 8%). Sixty percent of the patients required additional therapy for failure or relapse, but of patients who experienced a complete response, only 17% later required therapy for relapsed disease. The most common second-line therapies were rituximab (40%), followed by chemotherapy (39%) and radiotherapy (15%). Forty percent of patients had an acute rejection episode. Five patients were re-transplanted successfully without recurrence of PTLD. In the group of patients who were treated with adjuvant RI following surgery, only 13% relapsed. Median survival was 44 months for RI alone (not reached for adjuvant RI). Lack of bulky disease, multiple previous allografts and younger age predicted better response to RI by univariate analysis. Notably, EBV status, pathological subtype and type of transplanted organ were not associated with significant differences in response to RI. A step-wise multivariate logistic regression analysis confirmed that older age and bulky disease were independent predictors of RI failure. Survival analysis was done on patients treated with RI alone and separately on our entire cohort of 153 evaluable patients, validating traditional prognostic factors such as B symptoms, visceral involvement (liver), abnormal LDH and anemia (Table 1). To conclude, in our large, single-center series, RI resulted in responses in 45% of patients, with many patients cured. Although graft rejection was common, it was manageable in some patients and re-transplantation was feasible in others. The strongest predictors of response to RI are younger age and lack of bulky disease. These findings support the use of RI alone as initial therapy for PTLD. Disclosures: No relevant conflicts of interest to declare.

Description: Key Points High-dose daunorubicin benefits AML patients with favorable and intermediate cytogenetics and with FLT3-ITD, NPM1, and DNMT3A mutations. High-dose daunorubicin is required for the favorable impact of the NPM1 mutation in AML.

Description: Key Points Over the last decade, allogeneic HCT has been increasingly administered in the United States to adults aged 70 and older with hematologic malignancies. Allogeneic transplant outcomes were reasonable; high comorbidity and ablative conditioning regimens were associated with inferior outcomes.

Description: Genes encoding the alpha (GNAS) and beta (GNB1) subunits of the heterotrimeric G-protein complex are recurrently mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Alterations in G-protein coupled receptors can affect signaling via the PI3K/AKT/mTOR and RAS/MAPK pathways, suggesting that GNB1/GNAS mutations may function similarly to mutations in RAS and tyrosine kinases in myeloid disease progression. However, unlike RAS mutations, GNB1/GNAS mutations are among the most commonly affected genes in clonal hematopoiesis of indeterminate potential (CHIP), suggestive of a distinct functional role in myeloid disease initiation. We evaluated 6343 unique patients who received gene panel sequencing at our institution as part of a diagnostic evaluation of known or suspected hematologic malignancy. We identified 68 patients that had at least 1 sample with a mutation in GNB1 (N =42), GNAS (N=24) or both (N=2) (Figure 1). Twenty-six patients had multiple samples (range 2-10) obtained at serial timepoints during the course of progression and treatment. GNB1 mutations affected codon 57 (K57E/M/N/T) in 38 out of 42 cases; the remaining were G53E, D76G, I81V, and K89R. GNAS mutations affected codon 201 (R201H/C) in 23 out of 24 cases. Forty patients had active myeloid neoplasms [AML (N=10), MDS (N=13), MPN (N=11), MDS/MPN (N=5), BPDCN (N=1)]. The distribution of myeloid diagnoses was similar among patients with GNB1 or GNAS mutations. Analysis of serial samples showed that GNB1/GNAS mutations were frequently acquired at the time of leukemic transformation and clinical progression. Among 5 patients with secondary AML, 2 patients acquired GNB1/GNAS mutations at the time of transformation from MDS to AML, and 3 patients were found to have GNB1/GNAS mutations in high-risk MDS prior to subsequent transformation to AML. After induction chemotherapy for AML, two patients had expanded or newly acquired GNB1 mutations at time of treatment failure. Notably, 15 out of the 40 (37.5%) patients with active myeloid disease had co-mutations in the MPN-associated genes JAK2, CALR, and MPL. Eleven of these patients had a clinical diagnosis of MPN, including myelofibrosis (n=5), essential thrombocytosis (n=3), polycythemia vera (n=2), and systemic mastocytosis (n=1). In the context of underlying oncogenic kinase alterations including JAK2 V617F, GNB1 mutations have been shown to promote resistance to kinase inhibitors in vitro. Fourteen out of fifteen patients had no history of ruxolitinib therapy, suggesting that these mutations arise during the course of disease progression in the absence of therapeutic selection pressures. The impact of GNB1/GNAS mutations on the clinical response to JAK inhibitors has not been evaluated. Twenty-eight patients in the cohort (41%) had no evidence of active myeloid disease, including 14 patients with a lymphoid malignancy [mature B-cell neoplasms (n=8), mature T cell neoplasms (n=3), plasma cell neoplasms (n=2), acute lymphoblastic leukemia (n=1)], 6 patients with AML in complete remission, and 8 patients without a clinical diagnosis of hematologic malignancy. Four of the AML patients had a GNAS or GNB1 mutation that was newly acquired or persistent at the time of complete remission following induction chemotherapy. All 4 patients underwent allogeneic stem cell transplant (HSCT) based on disease risk at diagnosis and are alive with median follow up of 2.5 years. In 1 patient, a new GNB1 mutation was identified immediately after HSCT in the context of 100% donor chimerism, suggesting donor-engrafted CHIP. All 8 patients without hematologic malignancy were evaluated for cytopenias or cytoses at the time of the identification of the GNB1/GNAS mutation. GNB1 and GNAS are recurrently mutated in diverse clinical and genetic contexts. In patients with active myeloid disease, MPN-associated mutations were common and GNB1/GNAS mutations were newly acquired at the time of clinical progression, suggesting a functional role similar to other gene mutations that activate mitogenic signaling pathways. However, many GNB1 and GNAS mutations are seen as sole mutations in the absence of active myeloid disease, suggesting that unlike other signaling mutations they can drive initiation of clonal hematopoiesis. The diverse clinical spectrum of patients with GNB1/GNAS mutations suggests that these mutations have distinct, context dependent effects in hematopoietic cells. Disclosures Kim: Aushon Biosciences: Consultancy; LabCorp, Inc.: Consultancy; Papgene, Inc: Consultancy. Lane:N-of-one: Consultancy; Stemline Therapeutics: Research Funding.

Description: Background: Socioeconomic status (SES) and other non-disease (social and demographic) characteristics are known to predict overall survival (OS) in children with acute lymphoblastic leukemia (ALL) (Petridou et al. Ann Oncol 2015). Less is known about the impact of these factors on survival of adults with ALL. We studied which non-biological risks impact OS in adults with Philadelphia chromosome negative (Ph negative) ALL, with emphasis on the impact of SES on survival. Methods: We assembled data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER-18) registry from 2000 to 2014. This registry covers 27.8% of the US population. We identified patients 18-69 years old diagnosed with Ph negative ALL between 2000-2012 using ICD-O-3 codes. We merged data with the Federal Information Processing Standards county codes and designated patients as metropolitan or non-metropolitan based on state and country 2013 rural-urban continuum codes. We assigned county-level median household income using the Census American Community Survey (www.census.gov). Descriptive statistics were calculated for age at diagnosis, sex, race/ethnicity, marital status, insurance status,median household income, and status with respect to the 200% of the federal poverty line (FPL). We stratified the population by age: 18-39 years (adolescent and young adult, or AYA, cohort) and 40-69 years (adult cohort). We also identified 3 eras of interest: 2000 to 2003, 2004 to 2007, and 2008 to 2012. Multivariable Cox proportional hazards (PH) regression assessed predictors of OS, with separate models for AYAs and adults. Analyses were performed using SAS. Results: In total, 5,858 patients met criteria for analysis. Median age was 41.4 years (25-75th%: 26.9-54.8), with 45.8%patients in the AYA cohort. 57.8% of patients were male, and half were non-Hispanic white (50.8%). Over 90% of all patients lived in metropolitan counties. One-third (35%) of patients lived below the 200% FPL. Median household income was $55,901 (25-75th%: $51,389-67,677). 49% of patients had missing data about insurance, so we omitted this variable from analysis. ALL lineage was B cell in 57%, T-cell in 10%, and unspecified in 33% of cases. 52% were married overall with more AYAs (61.3%) not married compared to older adults (34%). In Cox regression model for AYAs, higher median income was associated with better OS (HR=0.95 for every $10,000 above national household income, p=0.03). We also found that later era of diagnosis (2008-2012 vs. 2000-2003) was associated with better OS (HR=0.70, p