Institutional Research Funding Research Articles

Health care costs and resource utilization among commercially insured adult patients with hemophilia A managed with FVIII prophylaxis in the United States.

BACKGROUND: Standard of care for patients with severe hemophilia A (HA) is life-long prophylaxis with factor VIII (FVIII) concentrate or other hemostatic agents. Published literature highlights a wide range of treatment costs for patients with HA. OBJECTIVE: To estimate average annual health care costs and resource utilization for a cross-section of adult patients managed with FVIII concentrate prophylaxis using recent data from a large US commercial claims database. METHODS: Adult males with 1 or more claim with HA diagnosis, continuous commercial plan enrollment, and 4 or more FVIII prescription dispenses during 12 months were identified from IBM MarketScan Research Database from January 2013 to September 2019, excluding those with FVIII inhibitors, an HIV/AIDS diagnosis, or diagnosis and treatment for hepatitis B or C. Patients were classified as using FVIII prophylaxis if they met any of the following definitions: (1) 6 or more FVIII dispenses, (2) a gap of 60 days or less between dispenses, and (3) at least 273 days supply in the 12-month period. Additionally, subgroups of patients meeting each individual definition were examined, with some patients included in all 3 subgroups. RESULTS: The overall cohort included 411 patients who met 1 or more of the 3 definitions, with a mean age of 28.9 years. Subgroups of 401, 325, and 237 patients met the first, second, and third FVIII prophylaxis definitions, respectively. Per-patient mean (SD) annual all-cause health care costs were $654,571 ($380,762) in the overall cohort and ranged from $650,065 ($382,196) to $759,661 ($387,040) among subgroups. Cost of FVIII concentrate accounted for more than 96% of total costs in the overall cohort and in each subgroup. Cost of FVIII in the overall cohort varied according to type of concentrate, with the highest among patients who were treated with both standard and extended half-life (SHL and EHL) FVIII ($784,945), followed by EHL FVIII only ($708,928), SHL FVIII only ($647,800), and plasma-derived FVIII ($535,614). The most common treatment type was SHL FVIII only (45.7% of all patients). In the overall cohort, the majority had 1 or more outpatient visits (94.9%), while emergency department visits, hospital admissions, and home health visits occurred less frequently (27.0%, 7.1%, and 7.1%, respectively). CONCLUSIONS: Commercially insured patients with HA incur substantial all-cause annual health care costs, with FVIII concentrate accounting for a majority of costs. DISCLOSURES: This study was funded by BioMarin Pharmaceutical Inc, which was involved in the protocol development, analysis plan development, data interpretation, manuscript preparation, and publication decisions. All authors contributed to protocol development, analysis plan development, data interpretation, and manuscript development and maintained control over the final content. Thornburg has received professional fees from BioMarin Pharmaceutical, CSL Behring, Genentech, Novo Nordisk, Sanofi Genzyme, HEMA Biologics, and Spark Therapeutics and institutional research funding from BioMarin Pharmaceutical, Novo Nordisk, and Sanofi Genzyme. Adamski, Cook, and Sendhil are employees of Analysis Group, a consulting company that was contracted by BioMarin Pharmaceutical to conduct this study and develop the manuscript. Vembusubramanian is a former employee of Analysis Group. Hinds, Chen, and Sammon are employees and shareholders of BioMarin Pharmaceutical. Solari is a former employee of BioMarin Pharmaceutical. Garrison has received consulting fees from BioMarin Pharmaceutical and Analysis Group. Croteau has received professional fees from BioMarin Pharmaceutical, Bayer, CSL Behring, HEMA Biologics, and Pfizer and institutional research funding from Novo Nordisk and Spark Therapeutics.

REASSEMBLING TECHNOLOGY TRANSFER IN INDONESIA

This article aims to provide a dynamic picture of the technology transfer process in public research institutions in Indonesia that has been updated by establishing the National Research and Innovation Agency in August 2021. This body is directly under the President of the Republic of Indonesia based on Presidential Regulation number 78 of 2021. During the research period, there was a change in the landscape of technology transfer actors. Some of these changes are in line with the results of the analysis, namely increasing the role of GFRI and research and development agencies under the ministry. This change is referred to as technology transfer reassembly. The arrangement of technology transfer leads to a new form. The research was initiated in October 2017 using the AHP to determine the best institutional arrangement for integrating research. The AHP results show the rank of institutional arrangements from highest to lowest as Government Funded Research Institutes (GFRI) (0.27833), a research division under the Ministerial Office (0.24890), universities (0.17966), private R&D (0.13589) and foreign agencies (0.07214). Government Funded Research Institutes are the top choice of experts for having a significant role in the technology transfer process. The core function of GFRI in the technology transfer system is to plan, conduct and develop technology and they have contributed significantly to the policy-making process by providing information and policy recommendations. This research enriched the application of the recommendations by establishing the National Research and Innovation Agency as the most influential actor in building a national technology transfer system.

PREDICT: A Multicenter, Prospective, Open-Label, Clinical Study Using a New Risk Score Approach to Assess the Most Appropriate Prophylaxis Regimen to Reach Favorable Outcomes in Hemophilia A, When Switching from Standard-Half-Life Products to Damoctocog Alfa Pegol

PREDICT: A Multicenter, Prospective, Open-Label, Clinical Study Using a New Risk Score Approach to Assess the Most Appropriate Prophylaxis Regimen to Reach Favorable Outcomes in Hemophilia A, When Switching from Standard-Half-Life Products to Damoctocog Alfa Pegol

Relationship between Endogenous, Transgene FVIII Expression and Bleeding Events Following Valoctocogene Roxaparvovec Gene Transfer for Severe Hemophilia A: A Post-Hoc Analysis of the GENEr8-1 Phase 3 Trial

Relationship between Endogenous, Transgene FVIII Expression and Bleeding Events Following Valoctocogene Roxaparvovec Gene Transfer for Severe Hemophilia A: A Post-Hoc Analysis of the GENEr8-1 Phase 3 Trial

Challenges for the sustainability of Brazilian scientific journals and the SciELO Program

Scientific journals play a fundamental role in the development of science. However, in Brazil, there are major challenges for their sustainability, as well as for the sustainability of the SciELO Program. The article reports a worrying scenario of low public funding and lack of strategic planning for long-term funding for scientific publication, contrary to the development of Brazilian journals and the SciELO Program. This scenario places great pressure on journals, with reports of situations of closure of activities, or implementation of fees charged to authors, while bringing financial insecurity to the SciELO Program. The actions taken by Brazilian scientific societies and the position of the Forum of Editors of Public Health Journals are aligned with that of the Advisory Committee of the SciELO Brazil Collection, namely that the publication of scientific journals edited in Brazil is strategic and, therefore, should be fostered through public policies and supported with public financing from the sponsoring institutions and grants from the research funding institutions.

Capitalizing an epidemic: Does voluntary license stabilizes access to patented vaccines and public health crisis?

AbstractThe spread of SARS‐CoV‐2 has paused the entire commercial sector except for the pharmaceutical domain. This highly contagious virus has kept the pharmaceutical domain, and publicly funded research institutions dynamically occupied in the R&D process to achieve the vaccine for the treatment and eradication of the COVID‐19 virus. The key issues are not the incentives for R&D but the accessibility of such vaccines at the ground level amidst voluntary licensing, elliptically, the dilemma encompassing innovations, patent rights, accessibility, and public health emergencies amidst stakeholders with contrasting interests. The voluntary licensing approach promotes a balance between native generic manufactures and international groups yearning to protect their intellectual property (IP) rights while boosting goodwill via better accessibility of such medicine, and concurrently providing pharmaceutical giants a constructive business strategy to set foot in developing markets. Patent rights and more significantly voluntary licensing might have a consequential impact on the public healthcare niche as it would facilitate a grip of patent holders concerning private governance activities over IP‐protected technologies. This paper provides an overview of voluntary licensing and its implications on vaccines in the pandemic.

The Indian Council of World Affairs: Revisiting Formative Points of Institutional History

This commentary recounts the important hallmarks of the institutional history of the Indian Council of World Affairs, one of India’s first publicly funded research institutions. It presents a brief account of its long history since 1943, its career in acquiring prominence, its decline and its revival. This commentary takes off from its recently published institutional history (Raghavan, T., & Mishra, V. [2021]. Sapru House: A story of institution building in world affairs).

Data Science in Decision-Making Processes: A Scientometric Analysis

Purpose: The article concludes on the importance of scientometric analysis to present research areas and directions in data science in order to support decision-making process. Design/Methodology/Approach: Scientometric analysis. Findings: Article is part of scientometric research performed by authors that results in series of two separate papers. The first one described leading researchers and their area of interest who provide significant input into data science development. The current article quantitatively characterizes the literature thematically related to data science issues, particularly in decision-making processes. The scientometric method was used for data content analysis. The Scopus database was chosen as a source database to perform scientometric analysis. The authors identified core business areas where data science tools have been used in decision-making processes. It is also worth noting the correlation between domain areas and funding sources. Practical Implications: Executing scientific analysis can help to identify research directions in data science area. Originality/value: In our study, we showed that a significant increase in the number of scientific articles in the medical field is directly dependent on research funding institutions. The quantitative characteristics and evolution of keywords, which were the subject of the publications, are also presented. Research directions and their evolution over the years are as well indicated.

Meta-analysis of the prevalence of malaria associated with pregnancy in Colombia 2000-2020.

Knowledge about malaria associated with pregnancy is scarce in Latin America, and in Colombia, little is known about the magnitude of this infection. A systematic review was conducted to determine the prevalence of malaria associated with pregnancy (MAP) and each of its three forms: gestational (GM), placental (PM), and congenital (CM) tested using thick blood smear (TBS) and PCR. Also to compare the proportion of cases due to Plasmodium falciparum and Plasmodium vivax in Colombia from the year 2000–2020. We searched in Pubmed, Science Direct, EMBASE, EMCare, Cochrane Library, Scielo, Lilacs, Google Scholar, libraries, and repositories of Colombian universities, to obtain data on prevalence of GM, PM and CM with their respective testing method. We performed a meta-analysis with a random-effects model to obtain pooled prevalence of MAP and its three forms categorized by testing methods (TBS and PCR). We used data from 14 studies (out of 258 screened) contributing 7932, 2506 women for GM and PM respectively, also data on 1143 umbilical cord blood samples, and 899 peripheral blood of neonates. We found prevalence by TBS as, MAP 4.5% (95%CI = 2.9–6.9), GM 5.8% (95%CI = 3.8–8.7), PM 3.4% (95%CI = 1.7–6.7) and CM 1.3% (95%CI = 0.6–3.0). With PCR the prevalence was, MAP 14.4% (95%CI = 7.6–25.5), GM 16.7% (95%CI = 9.0–28.8), PM 11.0% (95%CI = 4.1–26.3) and CM 16.2% (95%CI = 8.2–29.5). The prevalence of submicroscopic infection was 8.5% (95%CI = 3.4–19.7) in GM, 10.1% (95%CI = 3.5–25.5) in PM and 22.0% (95%CI = 13.2–34.3) in CM. Infections by P. vivax was dominant over P. falciparum when tested with TBS, the PCR test gave similar proportions of P. falciparum and P. vivax. This meta-analysis has demonstrated high prevalence of MAP in Colombia, and highlights the urgent need to increase attention of researchers, research funding institutions, government agencies, and health authorities to study and intervene MAP, that has currently been under investigated.

Establishment of CORONET: COVID-19 Risk in Oncology Evaluation Tool to Identify Cancer Patients at Low Versus High Risk of Severe Complications of COVID-19 Infection Upon Presentation to Hospital

Establishment of CORONET: COVID-19 Risk in Oncology Evaluation Tool to Identify Cancer Patients at Low Versus High Risk of Severe Complications of COVID-19 Infection Upon Presentation to Hospital

Developmental biology of Corona vaccine: lipid nanoparticle mRNA-encapsulation, a safe approach

The global pandemic of COVID-19 is progressing rapidly across the world and declared as health emergency. The novel Coronavirus can cause severe lower respiratory tract infections primarily in geriatric, immunocompromised persons, infants and patients with comorbidities, or genetic disorders. Few Emergency Use Authorizations (EAUs) have been granted by FDA and other regulatory bodies with an aim to repurpose the existing approved medicines to fight the disease, and till date no specific treatment methodologies or preventive measures are available. At present, numerous medications which are already approved for other therapeutic indications, as well as the new medications, are undergoing clinical trials for the evaluation of safety and efficacy against COVID-19 infection. These therapeutic ranges include antimalarial, antiviral, steroids, convalescent plasma containing antibodies, and immune modulators, etc. Nevertheless, the primary focus is on preventive care and currently more than hundred potential vaccine candidates are under development by leading biotech companies across the globe which are at different phases of clinical development. Lipid based mRNA delivery, DNA delivery and mAbs are the most advanced technologies being embraced besides whole-virion inactivated vaccine, attenuated live vaccine, non-replicating viral vector-based vaccine, protein single unit vaccine and multiunit vaccine. This review focuses on the current progress in drug delivery systems of COVID-19 vaccine across industries, academics, and government funded research institutes with a special focus on the synthetic mRNA-based lipid nanoparticle (LNP).

Venetoclax (VEN) Is Active in Chronic Lymphocytic Leukemia (CLL) Relapsed or Refractory to More Than One B-Cell Receptor Pathway Inhibitor (BCRi)

Venetoclax (VEN) Is Active in Chronic Lymphocytic Leukemia (CLL) Relapsed or Refractory to More Than One B-Cell Receptor Pathway Inhibitor (BCRi)

Safety, Efficacy and MRD Negativity of a Combination of Venetoclax and Obinutuzumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia - Results from a Phase 1b Study (GP28331)

Safety, Efficacy and MRD Negativity of a Combination of Venetoclax and Obinutuzumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia - Results from a Phase 1b Study (GP28331)

A Phase 2 Trial of Early Intervention with Ibrutinib in Patients with Asymptomatic, High-Risk CLL

▪Introduction:The current IWCLL guidelines recommend initiation of therapy for progressive, symptomatic disease since studies have yet to demonstrate improved survival with early treatment with chemotherapy. However, available therapeutic options have recently increased significantly, including the development of Bruton's tyrosine kinase inhibitors such as ibrutinib (IB). IB is now approved for both previously untreated and relapsed patients requiring therapy. While IB achieves complete remissions in the minority of relapsed/refractory cases, the drug effects sustained responses, including >20% complete responses in frontline patients, hence providing a rationale for its use earlier in the disease course. Because CLL is associated with profound cellular, humoral and innate immune suppression that worsens with disease progression even in the absence of treatment, patients with CLL respond poorly to routine vaccinations. IB has been shown to reverse disease mediated immune dysfunction partly through Th1 skewing. We sought two test two hypotheses in this study: 1) the safety and efficacy of a defined period of therapy (2 years) of ibrutinib in early stage high risk disease and 2) ability of ibrutinib to improve the efficacy of routine vaccines administered to patients undergoing IB therapy.Methods:This is a single-stage phase II study of IB in previously untreated asymptomatic, genetically high-risk patients with CLL, who did not meet IWCLL treatment criteria. High risk genomics were defined as del(11)(q22.3), del(17)(p13.1), unmutated IGHV, and/or complex karyotype (≥3 cytogenetic abnormalities). Patients were randomized to receive IB 420mg PO daily in 4-week cycles either with the pneumococcal, influenza and TdaP vaccines (Arm A, concurrent) or following vaccination (Arm B, sequential)(see Fig 1). The primary objective of the study is to determine the safety and 2-year progression-free survival of asymptomatic, high-risk CLL patients treated with IB. Secondary objectives include determination of safety and immune responses to vaccines in relation to IB administration along with response characteristics, resistance development and quality-of-life outcomes.Results:Forty-four patients (66% male) have been enrolled on the trial. All patients are high-risk; 91% with unmutated IGHV, 86% with del17p, 66% with del11q, and 76% with complex karyotype. Two patients who progressed on arm B prior to starting therapy with IB are not included in the primary endpoint analysis, and one discontinued because of lung cancer diagnosis 8 months after starting IB. Patients on arms A and B have completed a median of 17 and 15.5 cycles of treatment respectively. Vaccinations in patients with CLL were generally safe and well-tolerated with only 3 patients in Arm B experiencing 5 grade 1 AEs (injection site reactions). There have been no grade 4 toxicities related to IB, and 2 patients have experienced 4 occurrences of grade 3 atrial fibrillation related to IB. Two additional patients experienced 1 episode of grade 3 fever and grade 3 chest pain respectively, which were deemed to be unrelated to IB. No hematologic grade 3 or 4 adverse events were observed. All 41 remaining patients continue IB without evidence of progressive disease. Early treatment with IB was associated with reduction in cancer related stress (p<0.01), anxiety (p=0.004) and improvement in sleep (p=0.02). Patients in Arm A reported a higher decline in anxiety levels as compared to patients in the sequential treatment arm (p=0.04).Conclusion:Treatment of early stage, high risk CLL patients with ibrutinib demonstrates no unexpected safety signals and all patients remain progression free (at median 16 months of follow-up) providing support that this treatment approach is feasible. Earlier IB treatment also results in a decline in stress and anxiety and improvements in sleep compared to patients awaiting treatment. The study is ongoing and updated clinical and vaccine response data will be reported. [Display omitted] DisclosuresJones:Sunesis: Other: Institutional research funding; Abbvie, Pharmacyclics, Genentech, Gilead, Janssen, Merck, and Acerta: Other: Institutional research funding; Genentech, Abbvie, Pharmacyclics, Gilead, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrd:Janssen: Research Funding; Genentech: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding.

A Validated Risk Model for Overall Survival in Relapsed/Refractory Chronic Lymphocytic Leukemia Applicable to Patients Treated with Novel Therapies and Standard of Care

Introduction:Several prognostic models for overall survival (OS) in chronic lymphocytic leukemia (CLL) have been developed, but none were derived in a relapsed/refractory (R/R) population or in the context of novel therapies. We therefore used a comprehensive model-building approach to derive and validate a novel risk model for OS in a population of previously treated patients (pts) with CLL who received therapy in randomized phase 3 trials of ibrutinib (IBR) vs standard of care (SOC) and idelalisib (IDELA) vs SOC.Methods:In collaboration with Janssen Pharmaceuticals, Gilead Sciences, and Pharmacyclics, the analysis included pts from 5 multicenter randomized phase 3 trials (n=1866): IBR plus bendamustine-rituximab (BR) vs placebo plus BR (HELIOS: NCT01611090), IBR vs ofatumumab (RESONATE: NCT01578707), IDELA plus BR vs placebo plus BR (Study 115: NCT01569295); IDELA plus rituximab vs placebo plus rituximab (Study 116: NCT01539512); and IDELA plus ofatumumab vs ofatumumab (Study 119: NCT01659021). All pts had a diagnosis of CLL, were previously treated, and required treatment.The model-building dataset(n=969) included pts from HELIOS and RESONATE, and was randomly assigned to the training dataset (n=727) and internal-validation dataset (n=242). The external-validation dataset was an independent pooled cohort from studies 115, 116, and 119 (n=897).We applied univariate and multivariate analyses (MVA) to 28 candidate clinical, laboratory and molecular/genetic prognostic factors to derive the risk model in the training dataset. The primary endpoint was OS. We assessed the need for separate models for novel therapies by interactions with treatment in univariate analyses.We evaluated different cutoffs for dichotomized covariates and for definition of risk groups after the final factors were selected. We fit a Cox regression on the training, internal-validation ,and external-validation datasets using the risk categories as the covariate to test the difference among the groups, and calculated the C-statistic as a measure of discrimination.Results:We proceeded with the development of a single risk score for all pts with R/R CLL, as only one potential prognostic factor (deletion 13q, interaction p value <0.10) demonstrated a differential effect necessitating separate models. Six factors were independently prognostic in the multivariate analysis of OS (p<0.05): β2-microglobubulin (B2M), lactose dehydrogenase (LDH), hemoglobin (HGB), immunoglobulin heavy chain variable region (IGHV) mutational status, number of prior therapies, and time from initiation of last therapy.We excluded number of prior therapies from the final multivariate model, reasoning that its optimal cutoff might change with advances in CLL therapies. IGHV did not remain significant (p=0.0592) in MVA of 5 remaining prognostic factors. Notably, deletion 17p was not independently prognostic for OS.The final risk model consisted of 4 prognostic factors: B2M ≥5 mg/L, LDH elevated, HGB <110 mg/L for women or <120 mg/L for men, and time from initiation of last therapy <24 months. Because hazard ratios of these factors were similar (range, 0.55-0.68) with overlapping confidence intervals, 1 point was assigned to each factor. The resulting score separated pts into low (score 0-1), intermediate (score 2-3), and high risk (score 4) groups.Our risk model was prognostic for OS in the training dataset (log-rank p<0.0001; C-statistic 0.74 [95% CI 0.60-0.85]) and was confirmed in the internal-validation dataset (log-rank p<0.0001; C-statistic 0.79 [95% CI 0.56-0.97]), as well as in the external-validation dataset (log-rank p<0.0001; C-statistic 0.71 [95% CI 0.59-0.81]).Conclusions:We present the first validated risk model for OS in relapsed/refractory CLL in the era of targeted therapies. Our model consists of 4 readily available factors (B2M, LDH, HGB, time from initiation of last therapy) and identifies 3 prognostic groups with significantly different OS. This model reliably identifies high risk pts. Investigators can address this unmet need by designing prospective trials targeting these pts. [Display omitted] DisclosuresDarif:Janssen: Employment, Equity Ownership. Londhe:Janssen: Employment, Equity Ownership. Xing:Gilead: Employment, Equity Ownership. Huang:Gilead: Employment. Lin:Gilead: Employment. Byrd:Acerta Pharma: Research Funding; Genentech: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S; Pharmacyclics: Research Funding; Janssen: Research Funding. Furman:Pharmacyclics: Consultancy, Honoraria; Genentech: Consultancy; Gilead: Consultancy; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Hallek:Abbvie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hillmen:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Celgene: Research Funding. Jones:Sunesis: Other: Institutional research funding; Abbvie, Pharmacyclics, Genentech, Gilead, Janssen, Merck, and Acerta: Other: Institutional research funding; Genentech, Abbvie, Pharmacyclics, Gilead, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sharman:Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Genentech: Research Funding. Ferrante:Janssen: Employment, Equity Ownership. Reddy:Pharmacyclics/Abbvie: Employment, Equity Ownership. Dreiling:Gilead Sciences, Inc.: Employment. Adewoye:Gilead: Employment. Dubowy:Gilead: Employment. Howes:Janssen R&D: Employment, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Equity Ownership. James:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Zelenetz:Celgene: Consultancy; Amgen: Consultancy.

Multivariate Efficacy Analysis of a Randomized, Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

Multivariate Efficacy Analysis of a Randomized, Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

Comparison of Survival Outcomes in Elderly Acute Myeloid Leukemia Patients (Age ≥ 70) When Treated with Azacitidine or Decitabine As an Initial Treatment Modality

BackgroundTherapeutic options for patients age ≥70 years with acute myeloid leukemia (AML) are limited and comprised mainly of hypomethylating agents (HMAs) including azacitidine (AZA) and decitabine (DEC) or clinical trials. Given a lack of direct comparisons between these agents, we aimed to explore clinical outcomes in older AML patients treated with AZA vs DEC.MethodsWe analyzed 983 patients with AML, age ≥ 70 years, treated at Moffitt Cancer Center between 1995 and 2016. Response rates and overall survival (OS) were compared among patients treated with azacitidine (AZA) or decitabine (DEC). The Kaplan Meier method was used for survival analysis and the log-rank test was used to determine significance (p-value ≤0.05). The World Health Organization (WHO) criteria were used to define complete response (CR) and complete response with incomplete hematologic recovery (CRi).ResultsOut of 983 patients analyzed, we identified 256 patients who were treated with HMA. Twenty four patients were excluded from the analysis due to prior treatment with HMA for non-AML diagnoses, yielding a cohort of 232 patients who were HMA naïve. The median age of all patients was 76 years (range 70-91) and 64% were male. The cohort included 108 patients (46.6%) with secondary AML and 124 patients (53.4%) with de novo AML. DEC was used in 72 patients (31%) and the remaining 156 patients (67%) received AZA as a frontline treatment. Response rates (CR + CRi) were similar in both AZA and DEC treated patients (24% vs. 30%, respectively, p=0.456). Median OS was 16.2 months (mo) in the AZA cohort vs 11.5 mo in the DEC cohort (p=0.331). Per European LeukemiaNet (ELN) cytogenetic risk classification for AML, patients with favorable-risk cytogenetics (FRC) comprised 1.92% and 0% of all patients treated with AZA or DEC, respectively. Patients with intermediate-risk cytogenetics (IRC) comprised 56.41% and 54.17%, respectively; and patients with poor-risk cytogenetics (PRC) comprised 34.6% and 34.72%. respectively. Median OS in the IRC patients was 20.5 mo in the AZA cohort vs 16.5 mo in the DEC cohort (p=0.638). The median OS in PRC patients treated with AZA was 11.5 mo compared to 7 mo with DEC (p=0.019) (Figure1A). Upon further refinement of PRC cohort into those harboring a monosomal karyotype (MK) vs a non-monosomal karyotype (NMK), the NMK patients treated with AZA (n=32) had a superior median OS of 13.6 mo compared to 6.8 mo with DEC (n=16) (p=0.0459) (Figure 1B). Such superiority was not observed in MK patients (8.3mo with AZA vs. 10.6 mo with DEC (p=0.490)).ConclusionsThese data suggest that overall survival in elderly AML patients (age ≥70) is not impacted by the choice of HMAs. However, patients with poor risk cytogenetics had a significantly longer OS when treated with AZA vs DEC, most apparent in poor-risk patients harboring a non-monosomal karyotype. Studies to molecularly characterize this poor-risk AML subgroup in relation to azanucleoside efficacy are warranted. [Display omitted] DisclosuresSallman:Celgene: Research Funding. Padron:Incyte: Honoraria, Research Funding. Komrokji:Celgene: Honoraria; Novartis: Honoraria, Speakers Bureau. Sweet:Pfizer: Consultancy; Otsuka: Consultancy; Ariad: Consultancy, Speakers Bureau; Incyte: Research Funding; Karyopharm: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Lancet:BioSight: Consultancy; Bio-Path Holdings: Consultancy; Janssen: Consultancy; Erytech: Consultancy; Novartis: Consultancy; Pfizer: Other: Institutional research funding, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Boehringer Ingelheim: Consultancy.

Effect of NPM1 Mutation on Prognosis and Therapeutic Efficacy in Patients Aged ≥70 Years with Acute Myeloid Leukemia

IntroductionMutations in nucleophosmin (NPM1) in the presence of a normal karyotype in acute myeloid leukemia (AML) typically portend a favorable outcome and are present in approximately 28-35% of patients; however, its prognostic importance and effect on chemotherapy sensitivity is unclear in elderly patients (age ≥ 70). To this end, we investigated the impact of NPM1 mutation (NPM1+) on clinical outcomes in a large cohort of AML patients aged ≥ 70 years.MethodsWe analyzed an institutional database of 983 AML patients aged ≥ 70 years treated between 1995 and 2016. Response rates and overall survival (OS) were compared between NPM1+ and wildtype NPM1 (NPM1-) patients, with a focus on presence or absence of FLT3-ITD mutation (FLT3+ or FLT3-). The Kaplan Meier method was used for survival analysis and the log-rank test was used to determine significance (p-value ≤0.05). The World Health Organization (WHO) criteria were used to define complete response (CR) and complete response with incomplete hematologic recovery (CRi). Categorical data were analyzed by Fisher exact test and all calculated p-values are two-tailed.ResultsOf the 983 patients, 321 patients had NPM1 tested at diagnosis and a mutation was detected in 39 (12.1%) patients. Baseline characteristics of both NPM1+ and NPM1- cohorts are described in Figure 1A. Frequency of de novo AML was higher in NPM1+ vs NPM1- cohorts (76.9% vs. 41.5%, p<0.0001) and rate of antecedent hematological malignancy (AHM) was higher in the NPM1- cohort (51.1% vs. 20.5%, p=0.0005). Frequency of European LeukemiaNet (ELN) defined poor risk cytogenetics (PRC) was greater in NPM1- cohort compared to NPM1+ (38.0% vs. 5.1%, p<0.0001). Presence of FLT3+ was significantly higher in NPM1+ cohort (17.9% vs. 7.4%, p=0.039). More patients were treated with intensive chemotherapy (IC) in the NPM1+ cohort vs the NPM1- cohort (61.5% vs 35.8%, p=0.003), whereas the rate of hypomethylating agent (HMA) use was similar between the 2 cohorts.A trend toward improved median overall survival (OS) was observed in the NPM1+ compared to the NPM1- cohort (12 mo vs 8.9 mo, p=0.078). However, patients with NPM1+/FLT3- genotype had superior OS compared to all other genotypes (15.5 mo vs 8.9 mo, p=0.0481 (Figure 1B). A higher rate of CR/CRi was noted in the NPM1+ group vs the NPM1- group (63.6% vs 32.9%, p=0.001). Amongst patients with intermediate-risk cytogenetics, the rate of CR/CRi was 62.5% in the NPM1+ group vs 38.7% in the NPM1- group (p=0.018).ConclusionOur data suggest that NPM1 mutation in older adults (aged ≥70 years) with AML, while less commonly encountered than in younger patients, retains prognostic importance and impacts response to treatment. The NPM1+ group had a lower incidence of baseline adverse prognostic factors (e.g. PRC, AHM), a high rate of response to therapy, and a trend toward superior survival, particularly in the NPM1+/FLT3- cohort. Although these findings should be validated in a larger cohort, our data suggest that the NPM1+ elderly AML patients represent a unique subgroup that warrants further study to optimize outcomes. [Display omitted] DisclosuresSallman:Celgene: Research Funding. Padron:Incyte: Honoraria, Research Funding. Komrokji:Celgene: Honoraria; Novartis: Honoraria, Speakers Bureau. Sweet:Novartis Pharmaceuticals: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Consultancy; Karyopharm: Consultancy, Research Funding; Otsuka: Consultancy; Incyte: Research Funding. Lancet:BioSight: Consultancy; Erytech: Consultancy; Bio-Path Holdings: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Pfizer: Other: Institutional research funding, Research Funding; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Boehringer Ingelheim: Consultancy.

Defining Acute Myeloid Leukemia Ontogeny in Older Patients

BackgroundAML in elderly patients (pts) is associated with poor outcomes and often arises from antecedent hematological disorders (AHD), classified as secondary AML (sAML). The primary objective of this study was to validate the use of somatic mutations to determine AML ontogeny in the elderly population (>70yo) in order to better distinguish de novo AML (pAML) versus sAML and their distinct outcomes.MethodsUtilizing the AML Database at Moffitt Cancer Center, we identified elderly pts with AML who had next generation sequencing (NGS) of up to 54 genes obtained at the time of diagnosis. Pts were divided into pAML or sAML based on prior history of AHD. Pts were then classified into 4 groups based on somatic mutation signature as suggested by Lindsley et al (Blood, 26 Feb 2015 x Vol125): group 1 (pAML) for pts with CBF rearrangements, 11q23/MLL gene rearrangements and NPM1 mutation (MT); group 2 (sAML) for those with SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 MT; group 3 for any pts who harbored TP53 MT; and group 4 as not otherwise specified (NOS).ResultsWe identified 178 AML pts ≥ 70 years of age. The median overall survival (OS) was 9.4 months (mo). Based on clinical criteria, 95 pts were classified as pAML (no AHD) with a median OS of 11.2 mo and 82 pts were classified as sAML (prior AHD) with a median OS 5.1 mo (p=.21). Utilizing AML cytogenetic risk stratification only 4 pts met the criteria for good risk, 109 pts intermediate risk, and 57 pts poor risk. The median OS was 22.4,15.4, and 4 mo respectively (p<0.001).Based on the molecular signature proposed by Lindsley et al, 8 pts were classified as pAML, 72 pts sAML, 28 pts had TP53 MT, and 70 pts were classified as NOS. The median OS was 22.4,14, 2.8, and 11.2 mo respectively for the 4 proposed groups based on molecular signature (p <0.001).Clinical versus molecular classification was discordant where 25% of pts (n=2) classified as pAML by molecular signature had a history of AHD while 44% of pts (n=32) classified molecularly as sAML had no prior AHD. In TP53 MT and NOS categories, 37% (n=28) and 43% (n=70) of pts had AHD, respectively.There was no difference in outcome based on first line therapy with hypomethylating agent (HMA) or intensive chemotherapy among any of the groups.ConclusionsMolecular annotation of elderly AML patients by NGS reclassifies a significant proportion of patients as sAML. Pts molecularly categorized as sAML have worse outcomes than pts categorized as pAML, regardless of AHD history. Pts with TP53 MT are a distinct group who have particularly poor outcomes. [Display omitted] DisclosuresSallman:Celgene: Research Funding. Padron:Incyte: Honoraria, Research Funding. Sweet:Incyte: Research Funding; Otsuka: Consultancy; Pfizer: Consultancy; Karyopharm: Consultancy, Research Funding; Ariad: Consultancy, Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Lancet:Celgene: Consultancy; Erytech: Consultancy; Janssen: Consultancy; Jazz Pharmaceuticals: Consultancy; BioSight: Consultancy; Bio-Path Holdings: Consultancy; Boehringer Ingelheim: Consultancy; Novartis: Consultancy; Pfizer: Other: Institutional research funding, Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria.

Subanalysis of Patients with Secondary Acute Myeloid Leukemia (sAML) with Refractory Anemia with Excess of Blasts in Transformation (RAEB-t) Enrolled in a Phase 3 Study of CPX-351 Versus Conventional 7+3 Cytarabine and Daunorubicin

Subanalysis of Patients with Secondary Acute Myeloid Leukemia (sAML) with Refractory Anemia with Excess of Blasts in Transformation (RAEB-t) Enrolled in a Phase 3 Study of CPX-351 Versus Conventional 7+3 Cytarabine and Daunorubicin