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Abstract A complex network precisely regulates the cell cycle through the G1, S, G2, and M phases and is the basis for cell division under physiological and pathological conditions. On the one hand, the transition from one phase to another as well as the progression within each phase is driven by the specific cyclin-dependent kinases (CDKs; e.g., CDK1, CDK2, CDK4, CDK6, and CDK7), together with their exclusive partner cyclins (e.g., cyclin A1, B1, D1–3, and E1). On the other hand, these phases are negatively regulated by endogenous CDK inhibitors such as p16ink4a, p18ink4c, p19ink4d, p21cip1, and p27kip1. In addition, several checkpoints control the commitment of cells to replicate DNA and undergo mitosis, thereby avoiding the passage of genomic errors to daughter cells. CDKs are often constitutively activated in cancer, which is characterized by the uncontrolled proliferation of transformed cells, due to genetic and epigenetic abnormalities in the genes involved in the cell cycle. Moreover, several oncogenes and defective tumor suppressors promote malignant changes by stimulating cell cycle entry and progression or disrupting DNA damage responses, including the cell cycle checkpoints, DNA repair mechanisms, and apoptosis. Thus, genes or proteins related to cell cycle regulation remain the main targets of interest in the treatment of various cancer types, including hematologic malignancies. In this context, advances in the understanding of the cell cycle regulatory machinery provide a basis for the development of novel therapeutic approaches. The present article summarizes the pathways as well as their genetic and epigenetic alterations that regulate the cell cycle; moreover, it discusses the various approved or potential therapeutic targets associated with the cell cycle, focusing on hematologic malignancies.

Objective IgG4‐related disease (IgG4‐ RD ) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serologic, radiologic, and pathologic data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4‐ RD . Methods An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology ( ACR ) and the European League Against Rheumatism ( EULAR ). Investigators used consensus exercises, existing literature, derivation and validation cohorts of 1,879 subjects (1,086 cases, 793 mimickers), and multicriterion decision analysis to identify, weight, and test potential classification criteria. Two independent validation cohorts were included. Results A 3‐step classification process was developed. First, it must be demonstrated that a potential IgG4‐ RD case has involvement of at least 1 of 11 possible organs in a manner consistent with IgG4‐ RD . Second, exclusion criteria consisting of a total of 32 clinical, serologic, radiologic, and pathologic items must be applied; the presence of any of these criteria eliminates the patient from IgG4‐ RD classification. Third, 8 weighted inclusion criteria domains, addressing clinical findings, serologic results, radiology assessments, and pathology interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% confidence interval [95% CI ] 97.2–99.8%) and a sensitivity of 85.5% (95% CI 81.9–88.5%). In the second, the specificity was 97.8% (95% CI 93.7–99.2%) and the sensitivity was 82.0% (95% CI 77.0–86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. Conclusion ACR / EULAR classification criteria for IgG4‐ RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiologic, and basic science investigations.

Introduction: Emerging evidence supports that cytogenetic abnormalities (CAs) drive myelomagenesis and heterogeneity (e.g., clinical presentation, response to therapy, and prognosis) of multiple myeloma (MM). Diversity of CAs, including primary (IgH translocations and trisomies) and secondary CAs (copy number abnormalities) argues that MM is not a "single disease". Thus, identification of CAs at diagnosis is essential for risk stratification, guiding treatment, and prognostic estimation in daily practice. However, although frequency, configuration, and significance of CAs have been well documented in the Western countries, this information is lacking in the Asian population. To this end, a multi-center retrospective analysis was carried out to examine epidemiology and prognostic significance of CAs alone or in combination in a cohort of Chinese patients with newly-diagnosed MM (NDMM). Materials and Methods: A total of 1015 NDMM patients who had the baseline information of CAs detected by FISH at four institutes nationwide were included. According to the IMWG consensus updated in 2016, 1q gain, del(17p), t[4;14], and t[14;16] were defined as high-risk CAs (HRCAs), while another HRCA t[14;20] was not tested routinely in a majority of these patients. In addition, del(1p) and del(13q14) were considered as an adverse CA. According to the mSMART3.0 proposed by Mayo Clinic in 2018, double-hit (DHMM) and triple-hit MM (THMM) were defined as co-occurrence of 2 or >= 3 HRCAs, respectively. The Kaplan-Meier approach was used to estimate progression-free survival (PFS) and overall survival (OS). Results: In this cohort, the median age of 1015 patients was 61 years; 63.5% were male. The type of IgG, light chain, IgA, IgD, non/oligosecretory, IgM, or IgE accounted for 42.9%, 26.2%, 24.5%, 3.4%, 2.5%, 0.4%, and 0.1%, respectively. Del(13q) (46.4%) and 1q gain (46.1%; 3 copies = 73.8%, >= 4 copies = 26.2%) represented the most common CAs, followed by t(4;14) (14.0%), t(11;14) (11.8%), del(1p) (11.5%), del(17p) (9.9%; 20-50% cells = 35.6%, > 50% cells = 64.4%), and t(14;16) (5.1%). While none of these CAs was detected in 23.8% of cases, the frequency of patients who carried 1 - 5 CAs was 31.9%, 28.0%, 13.4%, 2.0%, and 0.9%, respectively. In the 1q+ cases, 36.4% patients carried second CA(s), including del(13q) (61.1%), t(4;14) (20.3%), del(1p) (14.8%), del(17p) (10.7%), t(11;14) (10.4%), and t(14;16) (8.1%). In the del(17p) cases, 57.5% patients had additional CA(s), including del(13q) (75.2%), 1q gain (49.5%), del(1p) (21.6%), t(4;14) (19.6%), t(14;16) (8.7%), and t(11;14) (2.2%). In the cases bearing IgH translocations, 26.0% patients also carried other CA(s), including del(13q) and 1q gain (61.9% for each), and del(17p) (9.3%). In the cases harboring HRCAs, the percentage of patients who carried 1 - 4 HRCAs was 70.2%, 24.8%, 3.7%, and 1.1%, respectively. Overall, 14.3% and 2.9% patients had DHMM or THMM, of whom 65.0%, 18.0%, 12.0%, and 5.0% had 2 - 5 HRCAs, respectively. While there was no significant difference in PFS between the cases carrying 1 and 2 CAs (P = 0.209), the patients who had 3 or more CAs displayed a sharp reduction in median PFS (P = 0.022 and P = 0.003 for 3 vs 1 or 2 CAs). Although multiple CAs was associated with shorter median OS, no statistical significance was observed for each comparison (P > 0.05). However, patients who carried >= 2 HRCAs had significantly shorter median PFS (12.1 months; P = 0.0004) and OS (29.3 months; P = 0.027) than those who had one single HRCA (32.2 and 65.6 months for median PFS and OS). Conclusion: In comparison with the Western countries, the incidence of secondary HRCAs (e.g., 1q gain and del(17p)) is relatively higher in Chinese patients at diagnosis, while the standard-risk CA such as t(11;14) is clearly less frequent. The proportion of Chinese patients who carry multiple CAs (up to 5) or HRCAs appear to be greater as well. In this context, patients carrying two or more HRCAs, so called DHMM or THMM, exhibit significantly worse outcome than those carrying only one HRCA. Together, this study builds up an up-to-date profile of CAs for Chinese patients, which might lay a foundation for revising the criteria for risk stratification and the guideline for treatment that is more feasible and practicable in China. It also provides the information about frequency and configuration of MM-driven CAs, which might be more relevant to the Asian population. Disclosures Kumar: Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Abstract Introduction: Histone lysine methylation, a reversible event dynamically and reciprocally regulated by lysine methyltransferases (KMTs) and demethylases (KDMs), represents one of the major epigenetic mechanisms for regulation of chromatin remodeling and gene expression re-programming. The KDM4 family, which belongs to the Jumonji C (JmjC)-domain-containing proteins (JMJDs), consists of five members, including KDM4A-E that demethylate H3K9me2/3 and/or H3K36me2/3 in a Fe2+- and α-ketoglutarate-dependent manner. KDM4 proteins are involved in various cellular processes such as gene transcription and translation, DNA replication, DNA repair, apoptosis, and stem cell renewal. Notably, increasing evidence implicates KDM4 dysregulation in promoting genomic instabilities and oncogenesis, thereby which is considered as a potential target for emerging cancer epigenetic therapy. Although KDM4A, a member of the KDM4 family, has been widely studied in many solid tumors including breast, prostate, bladder cancer, its role in hematopoietic malignancies, including multiple myeloma (MM), remains unknown. Materials and Methods: Human MM cell lines (U266, RPMI8226, H929, OPM-2) were employed. After exposed to hypoxia (or the chemical hypoxia mimetic lactic acid) and anti-MM agents (e.g., bortezomib/Btz), cells were analyzed by flow cytometry, qPCR, Western blot to monitor apoptosis, cell cycle, proliferation (Ki67), DNA double-strand break/DSB (γH2A.X), expression of 1q21 and anti-apoptotic genes, as well as activation of the NF-κB and HIF pathways. The shRNA approach was used to knock down KDM4A for functional evaluation. The findings from in vitro experiments involving cell lines were then validated in primary MM samples to link KDM4A expression to disease progression and therapeutic response. Results: Analysis of the MM genome-wide GEP databases revealed that KDM4A mRNA was significantly up-regulated in MGUS and MM, but not SMM, compared to normal control, as well as in relapsed MM, compared to newly-diagnosed MM. To our surprise, KDM4A expression rather favored overall survival of MM patients, including those carrying 1q21 gain in whom KDM4A expression was indeed lower than those who did not have this high risk cytogenetic abnormality. Moreover, KDM4A expression correlated adversely with expression of 1q21 genes (e.g., CKS1B, MCL1, PSMD4, ARNT). Whereas basal KDM4A protein level was moderately but clearly higher in MM cell lines carrying 1q21 gain or acquired drug resistance than their counterparts, exposure to hypoxia or lactic acid (but not cobalt chloride) resulted in marked KDM4A up-regulation, accompanied by NF-κB and HIF pathway activation. However, while NF-κB inhibition and to a lesser extent ARNT/HIF-1β knockdown led to a robust increase in hypoxia-induced KDM4A expression, shRNA knockdown or pharmacological inhibition of KDM4A triggered NF-κB activation and HIF expression, as well as up-regulated anti-apoptotic proteins (e.g., Mcl-1, TNFAIP3/A20, CKS1B), in association with increased H3K36me3 rather than H3K9me3. Furthermore, KDM4A knockdown or inhibition sharply diminished Btz lethality and overrode hypoxia-mediated cytoprotection. Interestingly, KDM4A knockdown also increased MM cell proliferation, promoted S phase entry, and attenuated Btz-induced DSB. Last, IHC of sequential bone marrow biopsies revealed that while KDM4A protein was relatively low at diagnosis, its level was markedly increased when patients achieved CR and then fell to the baseline low level at relapse. Conclusion: KDM4A/JMJD2A, a lysine demethylase that has been recognized as an pro-oncogenic protein via its epigenetic and/or non-epigenetic properties, is identified for the first time as a potential tumor suppressor in MM, particularly in a high risk subtype carrying 1q21 gain. Whereas KDM4A is expressed in MM and can be further induced by hypoxia that naturally exists in bone marrow niche, it seems to play multiple inhibitory roles in cell growth, cell cycle, DNA repair, and drug resistance by suppressing expression of oncogenic and anti-apoptotic genes (especially 1q21 genes), likely via H3K36me3 demethylation, and antagonizing NF-κB and HIF activation. These findings suggest that in contrast to its pro-oncogenic role in certain solid tumors, KDM4A might instead act as a tumor suppressor in MM. This work was supported by NNSFC (81471165, 81670189, and 81670190). Disclosures Kumar: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract BACKGROUND: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) are observed in approximately 4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia. Ivosidenib (AG-120), an oral, potent, targeted, small-molecule inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for the treatment of patients with mIDH1 MDS. Through inhibition of mIDH1, ivosidenib suppresses the production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from patients with relapsed or refractory (R/R) MDS enrolled in the first-in-human, phase 1, dose escalation and expansion study of ivosidenib in patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Trial enrollment was completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the dose to be tested in expansion. Expansion Arm 3 enrolled patients with mIDH1 advanced hematologic malignancies, including MDS. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR. Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present safety and efficacy data for patients with MDS in expansion Arm 3 and in dose escalation whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 12 patients with MDS (9 from expansion and 3 from escalation) whose starting dose was 500 mg QD. Baseline characteristics for these 12 patients were: 9 men/3 women; median age, 72.5 years (range, 52-78) and 42% were ≥75 years of age; median number of prior therapies, 1 (range, 1-3). As of 10Nov2017, 7 of 12 (58.3%) patients remained on treatment and 5 (41.7%) had discontinued (one for allogeneic stem cell transplantation). The median duration of exposure to ivosidenib was 11.0 months (range, 3.3-31.1). The most common adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were back pain (n=4, 33.3%) and anemia, decreased appetite, diarrhea, dyspnea, fatigue, hypokalemia, pruritus, and rash (n=3, 25.0% each). The majority of these AEs were grade 1-2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome (IDH-DS) was observed in 2 of 12 (16.7%) patients; the events were grade 1 and 2, respectively. Of the 12 patients with MDS receiving ivosidenib 500 mg QD, 5 achieved CR (41.7%; 95% CI 15.2%, 72.3%) and 6 achieved marrow CR (50.0%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median durations of CR and overall response were not estimable at the time of the data cutoff. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for at least 56 days on treatment. Baseline co-occurring mutations and changes in mIDH1 VAF levels on ivosidenib therapy will be presented. CONCLUSION: In patients with mIDH1 R/R MDS, ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS. Disclosures DiNardo: Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Stein:Celgene: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Bayer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Fathi:Takeda: Consultancy, Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Stein:Amgen: Speakers Bureau; Celgene: Speakers Bureau. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Stone:AbbVie: Consultancy; Agios: Consultancy, Research Funding; Cornerstone: Consultancy; Orsenix: Consultancy; Fujifilm: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Ono: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Jazz: Consultancy; Merck: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Orsenix: Other: Advisory board. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership.

Abstract Introduction B progenitor acute lymphoblastic leukemia (B-ALL) is a leading cause of childhood cancer death. Many chimeric genes have been identified and led to a refined classification of B-ALL and tailored therapies. Still, up to 30% of B-ALL cannot be classified into established subtypes, and the outcome for many is poor. Methods To identify novel subtypes of B-ALL, we performed integrative genomic analysis including transcriptome sequencing (RNA-seq) of 1,988 cases from St. Jude, Children's Oncology Group and adult cooperative group studies and analyzed chromosomal rearrangements, gene-expression profiles (GEP), somatic mutations and chromosome-level copy-number alterations. Cases lacking known or putative subtype-defining alterations underwent whole genome sequencing. Effects on proliferation and transformation of novel lesions were assessed by retroviral expression in cell lines and point-mutation knock-in mice using CRISPR/Cas9 genome editing. Results Using integrated genetic alterations and gene expression profiling, we classified 23 B-ALL subtypes (Table and Figure). Three groups included cases with similar GEP as canonical subtypes (ETV6-RUNX1, KMT2A-rearranged, and ZNF384-rearranged), but lacking the expected drivers (e.g., ETV6-RUNX1-like, n=42). Eighteen cases (0.9%) had rearrangements of BCL2, MYC and/or BCL6 showing a distinct GEP; they were mostly adults (n=16) with very poor outcome. These alterations, rarely seen in ALL, are identical to those observed in "double/triple hit" lymphoma, and are of pre-B immunophenotype. Eight cases with tightly clustered GEP comprised a novel subtype defined by IKZF1 N159Y missense mutation. N159Y is in the DNA-binding domain of IKZF1, and is known to perturb IKZF1 function, with distinct nuclear mislocalization and induction of aberrant intercellular adhesion. We identified two subtypes with distinct GEP characterized by PAX5 alterations. One, herein termed PAX5 altered (PAX5alt), comprised 148 (7.4%) cases, was characterized by diverse PAX5 alterations including rearrangements (n=57), sequence mutations (n=46) and/or focal intragenic amplifications (n=8). These PAX5 alterations were found in 73.6% of PAX5alt cases and different alteration types were mutually exclusive. Other PAX5 alterations, including deletions and large-scale amplifications were also assessed using SNP array, but were not enriched in the PAX5alt group. Clinically, PAX5alt pediatric and adult patients had favorable (96.8±3.2%) and intermediate (42.1±10.2%) 5-year overall survival (OS), respectively. The other GEP distinct subtype comprised 44 cases, all with PAX5 P80R missense mutations. In 30 of these cases, PAX5 P80R was homozygous due to deletion of the wild-type (WT) PAX5 allele or copy-neutral loss of heterozygosity. Of the other 14 cases with heterozygous PAX5 P80R mutations, 13 had a second frameshift (n=7), nonsense (n=2) or deleterious missense (n=4) PAX5 mutation. Four of the remaining 1,944 cases also had the PAX5 P80R mutation, but all were heterozygous with preservation of a WT PAX5 allele, consistent with the notion that homozygous or compound heterozygous PAX5 P80R mutation is the hallmark of this subtype. Adult PAX5 P80R cases (n=14) showed better 5-year OS (61.9±13.4%) than those in PAX5alt subtype (42.1±10.2%). To examine the effects of PAX5 P80R on B-cell maturation, WT PAX5, PAX5 P80R, V26G and P34Q were expressed in Pax5-/- lineage-depleted bone marrow cells. Expression of WT PAX5, PAX5 V26G and P34Q resulted in near complete rescue of B cell differentiation; however, expression of PAX5 P80R blocked the differentiation at the pre-pro-B stage of B-cell maturation. Further, Pax5 P80R heterozygous or homozygous mice developed pre-B-ALL with a median latency of 166 and 87 days, respectively, with heterozygous mice acquiring alterations on the second allele. In contrast, Pax5+/- mice, and those harboring G183S mutation observed in familial leukemia, do not spontaneously develop B-ALL. Conclusions These results show the utility of transcriptome sequencing in defining subtypes and founding genetic alterations in B-ALL, provide a revised taxonomy of the disease across the age spectrum, and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis. Disclosures McKay: ImmunoGen Inc.: Employment. Tallman:Orsenix: Other: Advisory board; AROG: Research Funding; BioSight: Other: Advisory board; Cellerant: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Konopleva:Stemline Therapeutics: Research Funding. Relling:Shire Pharmaceuticals: Research Funding. Mullighan:Cancer Prevention and Research Institute of Texas: Consultancy; Amgen: Honoraria, Speakers Bureau; Abbvie: Research Funding; Loxo Oncology: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau.

AbstractBackgroundMolecular studies have tried to address the unmet need for prognostic biomarkers in prostate cancer (PCa). Some gene expression tests improve upon clinical factors for prediction of outcomes, but additional tools for accurate prediction of tumor aggressiveness are needed.MethodsBased on a previously published panel of 23 gene transcripts that distinguished patients with metastatic progression, we constructed a prediction model using independent training and testing datasets. Using the validated messenger RNAs and Gleason score (GS), we performed model selection in the training set to define a final locked model to classify patients who developed metastatic‐lethal events from those who remained recurrence‐free. In an independent testing dataset, we compared our locked model to established clinical prognostic factors and utilized Kaplan‐Meier curves and receiver operating characteristic analyses to evaluate the model's performance.ResultsThirteen of 23 previously identified gene transcripts that stratified patients with aggressive PCa were validated in the training dataset. These biomarkers plus GS were used to develop a four‐gene (CST2, FBLN1, TNFRSF19, and ZNF704) transcript (4GT) score that was significantly higher in patients who progressed to metastatic‐lethal events compared to those without recurrence in the testing dataset (P = 5.7 × 10−11). The 4GT score provided higher prediction accuracy (area under the ROC curve [AUC] = 0.76; 95% confidence interval [CI] = 0.69‐0.83; partial area under the ROC curve [pAUC] = 0.008) than GS alone (AUC = 0.63; 95% CI = 0.56‐0.70; pAUC = 0.002), and it improved risk stratification in subgroups defined by a combination of clinicopathological features (ie, Cancer of the Prostate Risk Assessment‐Surgery).ConclusionOur validated 4GT score has prognostic value for metastatic‐lethal progression in men treated for localized PCa and warrants further evaluation for its clinical utility.

Background Clot perviousness in large vessel occlusion has been shown to be associated with improved recanalization outcomes with mechanical thrombectomy and intravenous thrombolysis. Objective To evaluate the association between clot perviousness based on thrombus attenuation increase (TAI) on CT, and histologic composition of clots in acute ischemic stroke (AIS). Methods A retrospective review was completed of patients with AIS secondary to large vessel occlusion, non-contrast CT (NCCT) and CT angiography (CTA) images, and histologic analysis of the retrieved clot. TAI was measured by subtracting clot attenuation on NCCT from the attenuation on CTA. Up to 3 regions of interest (ROIs) were evaluated on each clot; the average attenuation was used for analysis if multiple ROIs were assessed. Pervious clots were defined as TAI ≥10 Hounsfield units (HUs); impervious clots had TAI <10 HU. Histopathologic analyses of clots were assessed for relative compositions of red blood cells (RBCs), white blood cells (WBCs), fibrin, and platelets/other. Results 57 patients were included. Pervious clots were more likely to be RBC rich (p=0.04); impervious clots were more likely to be fibrin and WBC rich (p=0.01 for both). Pervious clots also had greater RBC density than impervious clots (49.8% and 33.0%, respectively; p=0.006); fibrin density of pervious clots was lower than that of impervious clots (17.8% and 23.2%, respectively; p=0.02). Conclusion Clot perviousness, assessed on NCCT and CTA imaging, is associated with higher RBC density and lower fibrin density, offering a possible explanation for the higher rates of successful thrombectomy and favorable clinical outcome seen in such patients.

Background:Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ∼4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia (AML). Ivosidenib (IVO; AG‐120) is an oral, potent, targeted inhibitor of the mutant IDH1 protein (mIDH1) that is approved for the treatment of adults with mIDH1 relapsed or refractory (R/R) AML. Through inhibition of mIDH1, IVO suppresses production of the oncometabolite 2‐hydroxyglutarate, leading to clinical responses via differentiation of malignant cells.Aims:To report safety and efficacy data from patients with R/R MDS enrolled in the first‐in‐human, phase 1, dose escalation and expansion study of IVO in patients with mIDH1 advanced hematologic malignancies (NCT02074839).Methods:This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of IVO. Enrollment was completed on May 8, 2017. In dose escalation, patients received single‐agent IVO orally (dose range, 200–1200 mg daily) in 28‐day cycles. The MTD was not reached and 500 mg QD was selected as the dose for expansion. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR (mCR) according to International Working Group 2006 criteria for MDS. Exploratory biomarker assessments included baseline co‐occurring mutations (next‐generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02–0.04%).Results:Baseline characteristics of the 12 patients with R/R MDS who received 500 mg IVO once daily were: 9 men/3 women; median age 72.5 years (range 52–78), and 42% were ≥75 years of age; median number of prior therapies 1 (range 1–3). As of Nov 2, 2018, 3 of 12 (25.0%) patients remained on treatment; 9 (75.0%) had discontinued (one for allogeneic stem cell transplantation). Median duration of exposure to IVO was 11.4 months (range 3.3–42.5). Adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were diarrhea, fatigue, back pain, rash (n = 4 each, 33.3%), anemia, urinary tract infection, decreased appetite, hypokalemia, arthralgia, dyspnea, pruritus, and hypotension (n = 3 each, 25.0%). No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome was observed in 1 of 12 (8.3%) patients (grade 2). Electrocardiogram QT prolonged was reported in 2 of 12 patients (17%; grade 1 in 1 patient and grade 2 in 1 patient). Five of 12 patients achieved CR (41.7%; 95% CI 15.2%, 72.3%), 1 achieved PR (8.3%), and 5 achieved mCR (41.7%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median duration of CR was not estimable (NE) at the time of datacutoff and the median duration of response was 21.4 months (95% CI 2.3, NE). At 12 months, 60.0% of patients remained in CR. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for ≥56 consecutive days on treatment. Baseline co‐occurring mutations and changes in mIDH1 VAF levels will be presented.Summary/Conclusion:In patients with mIDH1 R/R MDS, IVO monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of IVO as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS.