Singhal, Deepak

Abstract Therapy-related myeloid neoplasm (t-MN), characterized by its association with prior exposure to cytotoxic therapy, remains poorly understood and is a major impediment to long-term survival even in the era of novel targeted therapies due to its aggressive nature and treatment resistance. Previously, cytotoxic therapy–induced genomic changes in hematopoietic stem cells were considered sine qua non in pathogenesis; however, recent research demonstrates a complex interaction between acquired and hereditary genetic predispositions, along with a profoundly senescent bone marrow (BM) microenvironment. We review emerging data on t-MN risk factors and explore the intricate interplay among clonal hematopoiesis, genetic predisposition, and the abnormal BM microenvironment. Significance: t-MN represents a poorly understood blood cancer with extremely poor survival and no effective therapies. We provide a comprehensive review of recent preclinical research highlighting complex interaction among emerging therapies, hereditary and acquired genetic factors, and BM microenvironment. Understanding the risk factors associated with t-MN is crucial for clinicians, molecular pathologists, and cancer biologists to anticipate and potentially reduce its incidence in the future. Moreover, better understanding of the molecular pathogenesis of t-MN may enable preemptive screening and even intervention in high-risk patients.

Background: Wearable device technology has recently been involved in the healthcare industry substantially. India is the world’s third largest market for wearable devices and is projected to expand at a compound annual growth rate of ~26.33%. However, there is a paucity of literature analyzing the factors determining the acceptance of wearable healthcare device technology among low-middle-income countries. Methods: This cross-sectional, web-based survey aims to analyze the perceptions affecting the adoption and usage of wearable devices among the Indian population aged 16 years and above. Results: A total of 495 responses were obtained. In all, 50.3% were aged between 25–50 years and 51.3% belonged to the lower-income group. While 62.2% of the participants reported using wearable devices for managing their health, 29.3% were using them daily. technology and task fitness (TTF) showed a significant positive correlation with connectivity (r = 0.716), health care (r = 0.780), communication (r = 0.637), infotainment (r = 0.598), perceived usefulness (PU) (r = 0.792), and perceived ease of use (PEOU) (r = 0.800). Behavioral intention (BI) to use wearable devices positively correlated with PEOU (r = 0.644) and PU (r = 0.711). All factors affecting the use of wearable devices studied had higher mean scores among participants who were already using wearable devices. Male respondents had significantly higher mean scores for BI (p = 0.034) and PEOU (p = 0.009). Respondents older than 25 years of age had higher mean scores for BI (p = 0.027) and Infotainment (p = 0.032). Conclusions: This study found a significant correlation with the adoption and acceptance of wearable devices for healthcare management in the Indian context.

Abstract Introduction: Therapy-related myeloid neoplasm (t-MN) includes acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) that occur as a complication of DNA-damaging therapies. The World Health Organization recommends considering t-MN as a single entity. Whether t-MDS and t-AML have distinct characteristics and outcomes is not known. The aim of this study was to compare clinicopathological characteristics and outcomes of t-MDS and t-AML. Methods: All patients diagnosed with t-MN based on the World Health Organization criteria were identified. Bone marrow biopsies, cytogenetic, and next-generation sequencing (NGS) were obtained at the treating physician's discretion. Pathogenic/likely pathogenic variants (PV) were called based on the standard criteria. Overall survival (OS) was calculated from the time of t-MN diagnosis until the last follow up using Kaplan-Meier analysis using Wilcoxon test. For survival analysis comparing chemotherapy to best supportive care (BSC) only, patients were censored at the time of allogeneic stem cell transplant (SCT). Multivariate analysis was performed using Cox proportional hazard method and corrected using false discovery rate (FDR). Statistical analysis was performed using JMP (v14.1, SAS Institute) and significance was defined as P<0.05. Results: We identified 554 patients, of which 180 (32.4%), 365 (65.8%), and 9 (1.6%) presented as t-AML, t-MDS, and t-MDS/MPN respectively. t-MDS/MPN patients were excluded from further analysis due to a small number. Clinical and laboratory characteristics of the t-AML and t-MDS cohorts is shown in Table 1. t-AML patients were significantly more anemic and thrombocytopenic at presentation. As expected, t-AML had a higher peripheral blood and BM blast count. There was no difference in proportion of patients with chromosomal abnormalities, though a statistically significantly higher proportion of t-MDS patients had chromosome 5 abnormality, 5q deletion, monosomy 5, chromosome 7 abnormality, monosomy 7 compared to t-AML patients. On other hand, 11q23 (mixed lineage leukemia, MLL) rearrangement was more common in t-AML compared to t-MDS (9.3% vs. 2.8%, P=0.005). A higher proportion of t-MDS patients had PV detected by NGS compared to t-AML (92.9% vs. 85.6%, P=0.038). A higher proportion of t-MDS patients had PV in TP53 (37.6% vs. 21.4%, P=0.004) and ASXL1 (23% vs. 11.7%, P=0.016) genes; whereas a higher proportion of t-AML patients had PV in RAS (18.9% vs. 9.1%, P=0.013) and WT1 (8.1% vs. 2.9%, P=0.05) genes. One hundred twenty-eight (35%) of 365 t-MDS patients progressed to t-AML. The presence of any chromosomal abnormality at t-MDS diagnosis predicted a higher risk of transformation to t-AML (χ 2 3.9, P=0.03). t-AML patients had a significantly shorter OS compared to t-MDS (9.2 vs. 19.7 months, P<0.0001, Figure A). This difference persisted when stratified by no disease modifying therapies (BSC only) 2 vs. 17 months (P<0.0001, Figure B), as well as among those who received at least one line of chemotherapy (14 vs. 24.6 months, P<0.001). Finally, a higher proportion of patients with t-AML underwent SCT and there was a trend towards improved survival for t-AML patients (vs. t-MDS 52.9 vs. 20.7 months, P=0.07) from the time of transplant. Multivariate analysis for OS performed to control for all the variables that were different at presentation (except for blast count), showed that t-MDS (as opposed to t-AML) phenotype at diagnosis, and undergoing SCT were independent predictors of improved survival (Table 2). Conclusion: t-MDS and t-AML have distinct clinical, cytogenetic, and genetic features at presentation. In the absence of disease modifying therapies, t-AML is a more aggressive phenotype, consistently associated with a shorter survival. Even after controlling adverse risk features, t-AML phenotype had a shorter survival compared to t-MDS. Figure 1 Figure 1. Disclosures Litzow: AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Therapy related myeloid neoplasm (t-MN) is a rare but devastating complication of cytotoxic therapy used for management of unrelated malignancy or autoimmune diseases. Therapeutic options for t-MN are limited and although hypomethylating agents (HMA) are frequently used, the benefit of it in t-MN is unclear. There are no prospective trials of HMA in t-MN and published experience is based on retrospective analysis of small number of cases (n=42 to 54). The aim of this study was to assess the efficacy of HMA therapy in t-MN patients and evaluate predictors for it. Methods: t-MN patients managed with first line HMA therapy were analyzed. This study was approved by the participating institutional review board. Criteria for inclusion were a pathologically confirmed diagnosis of t-MN based on WHO 2016 criteria, age >18 years, and ≥1 cycle of decitabine or azacitidine. Patient characteristics were summarized by frequency (percentage). Overall survival was calculated from the time of starting azacitidine to last follow up or death date using Kaplan-Meier analysis. Multivariable analysis was performed using Cox proportional hazard model. Statistical analysis was performed using R program and significance was defined as P<0.05. Results: Of the 554 t-MN patients analyzed, 184 (33%) patients were treated with HMA as the first line therapy and were included in the study. Median age at t-MN diagnosis was 70 (IQR 64-75) years and 112 (60%) patients were male. At the time of diagnosis, 84% (n=154) and 16% (n=30) patients were classified as t-MDS and t-AML and 47% (87/184) and 46% (49/107) of the evaluable patients had complex karyotype and TP53 somatic mutations (TP53 Mut) respectively. Azacitidine (n=145, 79%) was most frequently used HMA followed by decitabine (n=39, 21%). Median survival of the whole cohort since t-MN diagnosis was 13.2 months. At the time of analysis further treatment details were available for 78 patients and outcome of these patients were compared with primary MDS (p-MDS) and oligoblastic AML managed at the same institute. Completion of six-cycles of HMA (50% vs. 62%; P=0.07) and overall response rate (47 vs. 50%, P=0.22) was not significantly different between t-MN and p-MDS. However, median OS of t-MN was significantly poor compared to p-MDS (10 vs. 20 months, P=0.0004; Figure 1A). In t-MN patients treated with HMA as the first-line agent, median OS was significantly shorter in t-AML compared to t-MDS (7 vs.10 months, P=0.04; Figure 1B). Median OS was significantly shorter in patients with TP53 Mut and complex karyotype (Figure 1C-D). In Cox proportional hazard analysis, t-AML and complex karyotype were independently associated with poor outcome. Conclusion: This study demonstrates significantly poor outcome of t-MN patients treated with HMA therapy as first line. The outcome is particularly poor in t-AML and patients with complex karyotype and TP53 Mut. Hence there is urgent need for clinical trials of novel therapies for t-MN. Figure 1 Figure 1. Disclosures Sharplin: Kite Gilead: Honoraria; Novartis: Other: Travel Support. Ross: Keros Therapeutics: Consultancy, Honoraria; Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: It has been known for approximately 19 years that germline mutations in RUNX1, lead to familial platelet disorder with predisposition to myeloid malignancy (FPD-MM, OMIM 601399). Since that time researchers have identified a broad range of different RUNX1 mutations, in over 100 families. In large families, the diagnosis of malignancy shows variable penetrance among family members with the same mutation; some carriers of RUNX1 mutations do not develop malignancy. The causes of this heterogeneity are currently not known, complicating counselling and risk analysis for individual carriers. Recent advances in genetic sequencing technology applied by many FPD-MM research groups around the world have highlighted their value in understanding the somatic genetic changes that are associated with development of malignancies in germline RUNX1 mutation carriers. Collectively this information could lead to powerful insights essential for more precise risk assessment, monitoring, and therapeutic intervention. Specifically, a growing catalogue of somatic mutations associated with germline RUNX1 malignancy offers the opportunity for informed monitoring of asymptomatic RUNX1 carriers for additional high-risk somatic mutations, in turn providing the possibility for early therapeutic intervention to arrest the leukemic process. The challenge in advancing these goals for FPD-MM is the relative rarity of the disorder in individual populations. Global data sharing in a highly interactive FPD-MM research community offers a solution to this problem that benefits all patients world-wide. Aims: To create a global RUNX1 network through identifying and contacting researchers and clinicians with known and novel germline RUNX1 families, seeking their collaboration to share genomics data. To create a RUNX1.db portal to collectively house and analyse genomics data from germline RUNX1 carriers, with associated phenotype and clinical information, such that researchers have an ongoing means by which to combine their data with those generated by other groups around the world. Methods: RUNX1 network : Through existing collaborative networks, a systematic review of the literature, and referrals from initial contacts, we have identified a global network of researchers managing FPD-MM cases and families. RUNX1.db: We have adapted a custom-built variant analysis platform, VariantGrid, that is a visual web application and database designed to help scientists manage and analyse DNA variants that can be used to aggregate and analyse multiple datasets. Results: Preliminary analysis of aggregated data from the literature suggests there are features of germline RUNX1 syndrome that can be ascertained. These include frequent somatic mutation of RUNX1 in malignancy development, as well as mutations in genes associated with clonal hematopoiesis that may precede development of overt leukemia. This analysis also suggests that different types of germline RUNX1 mutations may be associated with different combinations of somatic mutations in the tumour. To further this analysis, we have identified over 70 groups internationally that either manage RUNX1 families or have identified potential germline carriers through genomics initiatives. This represents a large and growing resource for both scientific studies and clinical programs to benefit individuals with FPD-MM. Many of these groups have generated NGS data sets from patient samples which will be available for analysis through this portal. Further details and activities of the network, and results from the genomics aggregation database will be presented. Conclusion: We have created a global RUNX1 network, aggregated their data, and generated a RUNX1.db genomics portal for the continuous curation of genomics data from germline RUNX1 carriers. A preliminary analysis has already identified specific features of germline RUNX1 mutated malignancies that have clinical importance. Ongoing scientific and clinical studies through the RUNX1 network will enhance the power of aggregated data analysis, with RUNX1.db providing a central link, driving new insights that benefit patients. Disclosures Natsoulis: Imago BioSciences, Inc.: Consultancy, Equity Ownership. Guzman:Cellectis: Research Funding. DiNardo:Bayer: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Agios: Consultancy; Medimmune: Honoraria; Abbvie: Honoraria. Borate:Novartis: Consultancy; Agios: Consultancy. Wei:Amgen: Honoraria, Other: Advisory committee, Research Funding; Pfizer: Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Research Funding; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau. Dokal:MRC, Bloodwise, Telomerase Activator Sciences: Research Funding; The Gary Woodward Dyskeratosis Congenita Trust: Membership on an entity's Board of Directors or advisory committees; Action Medical Research, European School of Haematology: Membership on an entity's Board of Directors or advisory committees; Barts and The London School of Medicine and Dentistry, Queen Mary University of London,: Employment, Research Funding; Telomerase Activator Sciences: Research Funding; Barts and The London, Queen Mary University of London: Employment; Gary Woodward Dyskeratois Congenita Trust: Membership on an entity's Board of Directors or advisory committees. Hiwase:Novartis: Research Funding; Celgene: Research Funding. Branford:Cepheid: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kramer:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Daiichi Sankyo: Consultancy. Owen:Merck: Honoraria; Teva: Honoraria; AbbVie: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding. Fitzgibbon:Epizyme: Consultancy, Research Funding; Gilead: Consultancy. Rienhoff:Imago BioSciences, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kurokawa:Astellas Pharma: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Eizai: Research Funding; MSD: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Takeda Pharmaceutical: Research Funding; Otsuka Pharmaceutical: Research Funding; Teijin Pharma: Research Funding; Chugai Pharmaceutical: Research Funding.