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Contains fulltext : 292382.pdf (Publisher’s version ) (Closed access) Myelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria lead to variability in interpretation and interobserver inconsistency in reporting results from the same sets of data. Thus, we convened an international panel of 36 MDS experts and used an established modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes in HR-MDS. Among others, the IWG 2023 criteria include changes in the hemoglobin threshold for complete remission (CR), the introduction of CR with limited count recovery and CR with partial hematologic recovery as provisional response criteria, the elimination of marrow CR, and specific recommendations for the standardization of time-to-event end points and the derivation and reporting of responses. The updated criteria should lead to a better correlation between patient-centered outcomes and clinical trial results in an era of multiple emerging new agents with novel mechanisms of action.

Image super-resolution is a common task on mobile and IoT devices, where one often needs to upscale and enhance low-resolution images and video frames. While numerous solutions have been proposed for this problem in the past, they are usually not compatible with low-power mobile NPUs having many computational and memory constraints. In this Mobile AI challenge, we address this problem and propose the participants to design an efficient quantized image super-resolution solution that can demonstrate a real-time performance on mobile NPUs. The participants were provided with the DIV2K dataset and trained INT8 models to do a high-quality 3X image upscaling. The runtime of all models was evaluated on the Synaptics VS680 Smart Home board with a dedicated edge NPU capable of accelerating quantized neural networks. All proposed solutions are fully compatible with the above NPU, demonstrating an up to 60 FPS rate when reconstructing Full HD resolution images. A detailed description of all models developed in the challenge is provided in this paper., arXiv admin note: text overlap with arXiv:2105.07825, arXiv:2105.08826, arXiv:2211.04470, arXiv:2211.03885, arXiv:2211.05256

目的 探讨Venetoclax联合低剂量阿糖胞苷（LDAC）在不能耐受强化诱导化疗的中国急性髓系白血病（AML）患者中的疗效及安全性。 方法 一项Ⅲ期随机、双盲安慰剂对照试验（VIALE-C）中中国队列的结果。在本项国际临床试验中，入组了不适合接受强化化疗、新诊断为AML的18岁或以上的成人患者。在全球范围内，患者（211例）按2∶1的比例随机分配接受Venetoclax+LDAC或安慰剂+LDAC（28 d为1个周期），在第1～10天接受LDAC。主要研究终点为总生存（OS）；次要研究终点包括缓解率、无事件生存期及不良事件（AE）。 结果 入组15例中国患者（Venetoclax组9例；安慰剂组6例）。中位年龄为72（61～86）岁。与安慰剂组相比，Venetoclax组的死亡风险下降38％（HR＝0.62，95％ CI 0.12～3.07）。对延长6个月随访进行的计划外分析显示，Venetoclax组的中位OS时间为9.0个月，安慰剂组为4.1个月。完全缓解（CR）率与血细胞计数未完全恢复的CR（CRi）率分别为33％（3/9）和0（0/6）。最常见的非血液学AE（Venetoclax组与安慰剂组）为低钾血症（5/9和4/6）、呕吐（4/9和3/6）、便秘（2/9和4/6）和低白蛋白血症（1/9和4/6）。 结论 Venetoclax联合LDAC在中国患者中表现出有意义的疗效和可管理的安全性特征，这与在全球VIALE-C人群中的观察结果一致，使其成为不适合接受强化化疗的新诊断AML患者的一个重要治疗选择。

Most patients with newly diagnosed acute myeloid leukemia (AML) are 65 years or older. The treatment of AML in older patients has been characterized by distinct patient- and disease-related challenges that have impeded the meaningful progress that has been observed in younger patients with AML. Higher rates of comorbidities and frailty contribute to higher rates of treatment-related complications, whereas adverse disease features such as poor-risk genomics and secondary AML are associated with therapeutic resistance and shortened survival. Intensive chemotherapy and allogeneic stem cell transplant, although still considered standard for many newly diagnosed patients with AML, may not be appropriate for a larger subset of older patients with AML. Lower-intensity approaches such as hypomethylating agents have been widely applied for newly diagnosed older and unfit patients with AML, improving tolerability among this subset, but providing more modest response rates. Numerous analyses have attempted to tackle the utility of higher- versus lower-intensity therapy in older AML and identify the factors that can help choose the approach that best optimizes tolerability and efficacy. Recently, a greater understanding of the genomic and biologic heterogeneity of AML has led to better risk stratification and has contributed to the development of specific targeted therapies that are starting to narrow the gap between safety and efficacy. Newly approved agents, such FLT3 (FMS-like tyrosine kinase 3) inhibitors, IDH1 and IDH2 inhibitors, and the BCL2 inhibitor venetoclax, as well postremission maintenance therapy with CC-486 (oral 5-azacitidine), are being systematically incorporated into the evolving treatment of older patients with newly diagnosed AML.

Physician burnout has been recognized as a public health crisis. However, there is a paucity of burnout studies in the context of medical internship. We assessed the prevalence and relationship between various training characteristics, personal variables, resilience, and coping with burnout in a cross-sectional study involving 837 interns from ten hospitals across Malaysian healthcare system. The instrument package included demographic questions, the Connor–Davidson Resilience Scale, Brief COPE and the Copenhagen Burnout Inventory. A total of 754 (90.1%) interns completed the inventories. We found a high prevalence of personal-related (73.3%), work-related (69.1%), and patient-related (43.4%) burnout among Malaysian interns. Multivariable analysis showed female gender (odds ratio (OR):1.50, 95% confidence interval (CI): 1.02–2.20), prior work experience (OR: 1.56, 95% CI: 1.05–2.30), and irregular spirituality routines (OR: 1.97, 95% CI: 1.30–2.99) were associated with increased odds of personal-related burnout. Irregular spirituality routines (OR: 2.24, 95% CI: 1.49–3.37) were associated with work-related burnout, while living with other people (OR: 1.77, 95% CI: 1.15–2.73) was associated with patient-related burnout. Lower resilience levels and avoidant copings were associated with personal-, work-, and patient-related burnout. Burnout prevalence among interns is high. The findings support the value of individual-targeted alongside organizational-targeted intervention in burnout reduction. As burnout is prevalent in both years of internship training, ongoing burnout prevention and wellbeing measures are deemed necessary.

VIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled (n = 143, venetoclax; n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, similar to 60% of patients had been on study for = 3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy.

Additional file 1. Additional file of Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial.

VIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled (n = 143, venetoclax; n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, ~60% of patients had been on study for ≤6-months. Here, we present an additional 6-months of follow-up of VIALE-C (median follow-up 17.5 months; range 0.1–23.5). Median OS was (venetoclax +LDAC vs. placebo +LDAC) 8.4 vs. 4.1 months (HR = 0.70, 95% CI 0.50,0.99; P = 0.040); a 30% reduction in the risk of death with venetoclax. Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 48.3% vs. 13.2%. Transfusion independence rates (RBC) were 43% vs.19% and median event-free survival was 4.9 vs. 2.1 months (HR = 0.61; 95% CI 0.44,0.84; P = 0.002). These results represent improved efficacy over the primary analysis. Incidence of grade ≥3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.

This study aimed to translate Oldenburg Burnout Inventory (OLBI) into Malay language, and test its response process (face validity) and internal structure (factor structure and internal consistency). To the author’s knowledge, OLBI is not yet validated in Malay language, thus this study aimed to produce a validated Malay version of OLBI (OLBI-M) in order to measure burnout among the healthcare learner population in Malaysia. OLBI has great potentials mainly due to its accessibility and free of any cost to use it, thus might promote more researchers to conduct burnout research in Malaysia. The forward-backward translation was performed as per standard guideline. The OLBI-M was distributed to 32 medical students to assess face validity and later to 452 medical students to assess construct validity. Data analysis was performed by Microsoft Excel, SPSS and AMOS. The face validity index of OLBI-M was more than 0.70. The two factors of CBI-M achieved good level of goodness of fit indices (Cmin/df = 3.585, RMSEA = 0.076, GFI = 0.958, CFI = 0.934, NFI = 0.912, TLI = 0.905) after removal of several items. The composite reliability values of the two factors ranged from 0.71 to 0.73. The Cronbach’s alpha values of the three factors ranged from 0.70 to 0.74. This study shows OLBI-M is a reliable and valid tool to measure burnout in medical students. Future burnout studies in Malaysia are highly recommended to utilize OLBI-M. However, it is crucial for further validity to be carried out to verify the credential of OLBI-M.

Bone marrow vascular niches sustain hematopoietic stem cells (HSCs) and are drastically remodeled in leukemia to support pathological functions. Acute myeloid leukemia (AML) cells produce angiogenic factors, which likely contribute to this remodeling, but anti-angiogenic therapies do not improve AML patient outcomes. Using intravital microscopy, we found that AML progression leads to differential remodeling of vasculature in central and endosteal bone marrow regions. Endosteal AML cells produce pro-inflammatory and anti-angiogenic cytokines and gradually degrade endosteal endothelium, stromal cells, and osteoblastic cells, whereas central marrow remains vascularized and splenic vascular niches expand. Remodeled endosteal regions have reduced capacity to support non-leukemic HSCs, correlating with loss of normal hematopoiesis. Preserving endosteal endothelium with the small molecule deferoxamine or a genetic approach rescues HSCs loss, promotes chemotherapeutic efficacy, and enhances survival. These findings suggest that preventing degradation of the endosteal vasculature may improve current paradigms for treating AML.

Introduction: The academic life of medical students can be considered as psychological toxic. Abouthalf of United States medical students experience burnout and more than 25% experience depression.This study aimed to determine the prevalence of burnout among medical students in a Malaysianmedical school and its associated factors. Methods: This is a cross sectional study of 452 medicalstudents from Universiti Sains Malaysia (USM). Copenhagen Burnout Inventory was distributedvia Google Forms through Facebook Messenger. Ethical approval was obtained from the HumanResearch Ethics Committee USM. Data were collected via Google Sheets. Each respondent onlysubmitted one Google Form as no resubmission link was provided once completed Google Form wassubmitted. Result: The prevalence of burnout among USM medical students was 67.9%. Personalburnout was the highest (81.6%), followed by work-related burnout (73.7%) and client-relatedburnout (68.6%). The analysis showed that regardless of year of study, gender and ethnicity (all P >0.05), USM medical students were vulnerable to burnout. Conclusion: The prevalence of burnoutamong USM medical students was high and the most prevalent type of burnout was personal burnout.Therefore, burnout among medical students should be a concern and must be addressed to preventsubsequent unwanted consequences.

By listening to the stories of chronically homeless patients and the community leaders who care deeply about them, I learned a tremendous amount about how our current health system is ill-equipped to address many patient needs, especially the social determinants of health. I learned how powerful it is to talk to patients outside of the hospital in humanizing them and influencing our own attitudes and biases. Given medical students’ limited exposure to homeless patients outside of the hospital, partnering with community hotspotting and housing-first initiatives is a valuable experience for changing future physician attitudes towards the homeless and learning a tremendous amount about our health and social support systems.

PurposeThe aim of this paper is to propose an approach to international market segmentation that identifies meaningful cross‐national consumer segments, which focuses on airline passengers in the NAFTA market.Design/methodology/approachA conjoint analysis is used to evaluate consumers' preferences for six flight attributes: price, in‐flight service, number of stops before destination, on‐time performance, frequent flyer programme, and country of airline. A cluster analysis based on the relative importance scores of each of the six flights attributes then identifies five segments that prioritize similar product attributes within each country.FindingsA representative sample of 4,787 airline passengers from the three countries reveal that price is the most important attribute for consumers from the USA and Canada, while on‐time performance is the most important attribute for Mexican consumers. A cluster analysis identifies five segments that prioritize similar product attributes within each country. It is also found that there are five cross‐national consumer segments in the NAFTA market that are homogeneous in terms of consumer preferences but heterogeneous in terms of relative group size and demographic variables.Research limitations/implicationsThe study is based on a purposive sample, which limits the ability to generalize to the whole population with any known degree of precision.Practical implicationsThe research produces practical operational information on each segment that is translatable into strategy, specifically in terms of positioning, promotion, and targeting of the airline service.Originality/valueThe paper sheds light on the nature of cross‐national segmentation in the NAFTA air passengers market and the resulting cross‐national segmentation will be highly relevant for international marketing management.

The driving forces behind the exponential growth in mobile cellular network traffic have fundamentally shifted from the steady increase in demand for conventional "connection-centric" communications, such as phone calls and text messages, to the explosion of "content- centric" communications, such as video streaming and content sharing. The Cisco Visual Networking Index projects that video traffic will amount to 72 percent of global mobile data traffic by 2019. The mobile cellular network architectures of today are, however, still designed with a connection-centric communication mindset. Moreover, the myriad technological advances proposed for beyond fourth generation (4G) and 5G mobile networks still mostly focus on capacity increase, which is fundamentally constrained by the limited radio spectrum resources as well as the diminishing investment efficiency for operators, and therefore will always lag behind the growth rate of mobile traffic. It can be argued that the logjam in cellular networks cannot be addressed by improving connection capability alone, but instead must be tackled by fundamentally addressing the underlying ineffectiveness of the current communication architecture for massive content delivery.

Introduction Relatively little is known about the processing changes that support treatment-induced recovery in aphasia. Visual-world eyetracking has been used to detail language processing deficits in aphasia (Meyer, Mack, & Thompson, 2012; Mirman, Yee, Blumstein, & Magnuson, 2011), and may be useful for detecting processing changes that result from treatment. However, the test-retest reliability of eyetracking has not been fully established. One previous study suggested that eyetracking is a reliable measure of lexical access (Farris-Trimble & McMurray, 2013). However, that study used a large number of trials (n=640), which may be impractical in treatment research. Additionally, no previous studies have examined the reliability of eyetracking for sentence comprehension tasks. The present study tested the reliability of eyetracking for lexical and sentence comprehension tasks, using a practical number of trials. Method Unimpaired college-aged adults (n=21) participated in eyetracking experiments testing lexical access and sentence comprehension, in two sessions one week apart. In the lexical access experiment (n=30 trials), participants viewed arrays of four objects and heard a noun matching one object. In the sentence comprehension task (n=48 trials), participants viewed two drawings with reversed participant roles and listened to an active or passive sentence (e.g. The dog is chasing the cat/The cat is being chased by the dog). Participants were instructed to click on the picture that matched the auditory stimuli. Eye data were analyzed in time windows in which a rise in fixations to the target picture was observed: 300-800 ms from word onset in the lexical access experiment, and 0-500 ms from verb offset in the sentence comprehension experiment. Eye fixation patterns were modeled using mixed effects empirical logit regression, with maximal fixed and random effects. These models tested for effects of test session at the group level. To test for reliability of individual eye fixation patterns, participant-specific parameters from each test session were entered into intraclass correlations (ICCs). Results See Figure. In both experiments, no significant effects of session (main effects or interactions with other variables) were observed at the group level (p’s > 0.05). For both experiments, moderately strong correlations were observed in the rise of fixations to the target picture within individuals across sessions (lexical access: ICC(2,1) = 0.531; p = 0.007; sentence comprehension: ICC(2,1) = 0.582, p = 0.002). Discussion The results indicate that eyetracking is a reliable measure of the latency of lexical access and sentence comprehension, even with a limited number of trials. Therefore, this method may prove useful for investigating lexical access and sentence comprehension changes as a result of treatment for aphasia. Figure 1. Proportion of fixations to the target picture across sessions in (a) lexical access and (b) sentence comprehension trials. Vertical lines indicate windows for statistical analyses.

In this phase 2 study, the authors evaluated the efficacy, safety, and tolerability of the Aurora B kinase inhibitor barasertib compared with low-dose cytosine arabinoside (LDAC) in patients aged ≥ 60 years with acute myeloid leukemia (AML).Patients were randomized 2:1 to receive either open-label barasertib 1200 mg (as a 7-day intravenous infusion) or LDAC 20 mg (subcutaneously twice daily for 10 days) in 28-day cycles. The primary endpoint was the objective complete response rate (OCRR) (complete responses [CR] plus confirmed CRs with incomplete recovery of neutrophils or platelets [CRi] according to Cheson criteria [also requiring reconfirmation of CRi ≥21 days after the first appearance and associated with partial recovery of platelets and neutrophils]). Secondary endpoints included overall survival (OS) and safety.In total, 74 patients (barasertib, n = 48; LDAC, n = 26) completed ≥1 cycle of treatment. A significant improvement in the OCRR was observed with barasertib (35.4% vs 11.5%; difference, 23.9%; 95% confidence interval, 2.7%-39.9%; P .05). Although the study was not formally sized to compare OS data, the median OS with barasertib was 8.2 months versus 4.5 months with LDAC (hazard ratio, 0.88; 95% confidence interval, 0.49-1.58; P = .663). Stomatitis and febrile neutropenia were the most common adverse events with barasertib versus LDAC (71% vs 15% and 67% vs 19%, respectively).Barasertib produced a significant improvement in the OCRR versus LDAC and had a more toxic but manageable safety profile, consistent with previous studies.

This is Part 2 of a Feature Topic (FT) series covering the convergence of communications, caching, and computing for next generation wireless mobile networks. The design and engineering philosophy of modern wireless networks is witnessing a fundamental shift from being "connection-centric" to being "content-centric". This FT aims to provide a comprehensive overview of recent progress in the theoretical foundation, architectural advances, modeling/analytics, protocol engineering, and prototyping of content-centric mobile networks. The response to our Call for Papers was overwhelming, with a total of 54 articles submitted by leading researchers and practitioners from around the world. Following a rigorous review process, Part 1 of this FT series, containing 12 articles, appeared in the August issue of IEEE Communications Magazine. The following additional six papers are selected to be included in Part 2 of the series.

7032 Background: Enasidenib (ENA) is an oral inhibitor of mutant-IDH2 (mIDH2) proteins. In the phase 3 IDHENTIFY trial, ENA improved event-free survival (EFS), overall response, and complete remission rate vs conventional care regimens (CCR) ( P < 0.01 for all) in patients (pts) ≥ 60 years of age with m IDH2 R/R AML with 2 or 3 prior treatments (Tx) (DiNardo 2021). Pt-reported HRQoL was a secondary trial endpoint. Methods: IDHENTIFY is an open-label, randomized trial (NCT02577406). Pts were preselected to a CCR (SC azacitidine, intermediate- or low-dose Ara-C, or supportive care) and then randomized 1:1 to ENA 100 mg/d or CCR in 28-d cycles. Key HRQoL endpoints were mean changes from baseline (CFB) overall and by clinical response in the Global Health Status/QoL, Physical Functioning, Role Functioning, Fatigue, and Dyspnea domains of the EORTC QLQ-C30 questionnaire, and in EQ-5D-5L utility index (UI) and visual analogue scale scores. The QLQ-C30 and EQ-5D-5L were assessed on D1 of each Tx cycle (C) and at end of Tx. Minimally important differences (MIDs) in CFB scores within or between Tx arms were based on accepted thresholds. Sensitivity analysis using imputed data on CFB was conducted using pattern mixture modeling. Results: HRQoL-evaluable cohorts included 118/158 (74.7%) pts in the ENA arm and 80/161 (49.7%) in the CCR arm; 40 ENA pts and 81 CCR pts were not evaluable due to missing data at baseline (BL; 22 ENA and 51 CCR) and/or at ≥1 post-BL visit (26 ENA and 69 CCR). Pts ineligible for HRQoL analyses had lower response rates and worse EFS and overall survival than HRQoL-evaluable pts. Overall QLQ-C30 completion rates in the ENA and CCR arms were 79% and 65%, respectively ( P < 0.001). While there was no meaningful improvement or worsening from BL (ie, exceeding MID) within either Tx arm in the key QLQ-C30 domains, scores worsened during initial Tx cycles and then improved with continued Tx. Mean EQ-5D-5L scores also worsened during early cycles in both Tx arms, with meaningful UI deterioration in the ENA arm from C2 through C7. However, between-group comparisons showed no consistent differences between ENA and CCR in mean CFB. Sensitivity analysis with imputation of missing CFB data showed worsened HRQoL compared with non-imputed data in the CCR arm but not with ENA. In the ENA arm, clinical responders reported relatively stable mean HRQoL scores over time, and non-responders showed no meaningful differences in CFB vs the CCR arm. Conclusions: HRQoL measures tended to worsen during early cycles in both Tx arms and gradually improved with continued Tx. Data should be interpreted with caution as only approximately one-half of pts in the CCR arm were HRQoL-evaluable. ENA improved clinical efficacy measures vs CCR without compromising HRQoL in older pts with R/R AML. Clinical trial information: NCT02577406.

Accurate classification of acute myeloid leukaemia (AML) has become increasingly reliant on molecular characterisation of this blood cancer. Throughout Australia and New Zealand massively parallel sequencing (MPS) is being adopted by diagnostic laboratories for the routine evaluation of patients with AML. This technology enables the surveying of many genes simultaneously, with many technical advantages over single gene testing approaches. However, there are many variations in wet and dry lab MPS procedures, which raises the prospect of discordant results between laboratories. This study compared the results obtained from MPS testing of ten diagnostic AML bone marrow aspirate samples sent to eight participating laboratories across Australasia. A reassuringly high concordance of 94% was observed with regard to variant detection and characterisation of pathogenicity. The level of discordance observed, although low, demonstrates the need for ongoing assessment of concordance between diagnostic testing laboratories through quality assurance programs. Refereed/Peer-reviewed

Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy and bone marrow transplantation, overall survival remains poor. Sphingosine kinase 1 (SPHK1) generates the bioactive lipid sphingosine 1- phosphate (S1P) and has established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers. The role and targeting of SPHK1 in primary AML, however, has not been previously investigated. HereweshowthatSPHK1is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death inAMLcell lines, primary AML patient blasts, and isolated AML patient leukemic progenitor/stem cells, with negligible effects on normal bone marrow CD34 + progenitors from healthy donors. Furthermore, administration of SPHK1 inhibitors to orthotopic AML patient-derived xenografts reduced tumor burden and prolonged overall survival without affecting murine hematopoiesis. SPHK1 inhibition was associated with reduced survival signaling from S1P receptor 2, resulting in selective down regulation of the prosurvival protein MCL1. Subsequent analysis showed that the combination of BH3 mimetics with either SPHK1 inhibition or S1P receptor 2 antagonism triggered synergistic AML cell death. These results support the notion that SPHK1 is a bona fide therapeutic target for the treatment of AML. Refereed/Peer-reviewed

Sonya M. Diakiw, Michelle Perugini, Chung H. Kok, Grant A. Engler, Nik Cummings, Luen Bik To, Andrew H. Wei, Ian D. Lewis, Anna L. Brown, Richard J. D’Andrea

The prognosis of older patients with acute myelogenous leukemia is generally poor. The interleukin-3 receptor alpha-chain (CD123) is highly expressed on the surface of acute leukemia cells compared with normal hematopoietic stem cells. CSL362 is a fully humanized, CD123-neutralizing monoclonal antibody containing a modified Fc structure, which enhances human natural killer cell antibody-dependent cell-mediated cytotoxicity. Six continuous acute myelogenous leukemia xenografts established from patient explants and characterized by cell and molecular criteria, produced progressively lethal disease 42-202 days after transplantation. CSL362 alone reduced engraftment of one of four and three of four acute myelogenous leukemia xenografts in the bone marrow and peripheral organs, respectively. A cytarabine and daunorubicin regimen was optimized using this model to identify potentially synergistic interactions with CSL362. Cytarabine/daunorubicin improved the survival of mice engrafted with four of four acute myelogenous leukemia xenografts by 31-41 days. Moreover, CSL362 extended the survival of cytarabine/daunorubicin-treated mice for two of two acute myelogenous leukemia xenografts, while augmentation of natural killer cell-deficient NSG mice with adoptively transferred human natural killer cells improved survival against a single xenograft. Interestingly, this enhanced CSL362 efficacy was lost in the absence of chemotherapy. This study shows that acute myelogenous leukemia xenografts provide a platform for the evaluation of new therapeutics, simulating complex in vivo interactions, and that the in vivo efficacy of CSL362 supports continued clinical development of this drug. Refereed/Peer-reviewed

The protein kinase activity of PI3K phosphorylates specific serine residues in growth factor receptors to promote cell survival; these events are constitutively activated in some leukemias., The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K), promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML) cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF) receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting such pathways in cancer., Author Summary The ability of cells to survive in the absence of proliferation (cell division), differentiation (cell maturation) or activation allows tissues to maintain cell populations that are poised for rapid responses to damage, infections, or other physiological demands. While this “survival-only” response is fundamental to all physiological processes, the underlying mechanisms are not understood. Many growth factors are potent regulators of cell survival through their ability to bind specific cell surface receptors, which in turn activate specialized enzymes called kinases. Phosphoinositide 3-kinase (PI3K) is a dual specificity kinase that is known to be involved in cell survival and malignant transformation, and it is able to phosphorylate both lipid and protein substrates. While the PI3K lipid kinase activity has been extensively studied, the functional significance of its protein kinase activity remains unclear. Here we show that PI3K protein kinase activity can directly phosphorylate growth factor receptors on human hematopoietic (blood) cells to promote a “survival-only” response. We further show that the protein kinase activity of PI3K can be hijacked to result in uncontrolled growth factor receptor phosphorylation and the deregulated survival of leukemic cells. Our studies provide the first evidence that the protein kinase activity of PI3K can control cell survival and that this activity may be deregulated in cancer.