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Introduction While clonal hematopoiesis (CH) can precede the development of AML, preleukemic CH can persist after attaining remission. In rare cases, non-leukemic CH can also emerge after remission. Long-term clonal dynamics of persistent CH or emerging CH (together, post-remission CH) in AML patients during consolidation therapies or maintenance therapies is not well understood. Furthermore, the clinical implications of post-remission CH have not been systematically studied. Since AML patients receive various types of post-remission consolidation therapies, including allogeneic stem cell transplant (allo-SCT), analysis of clonal dynamics of post-remission CH offers unique opportunity to study the response of CH to therapies. Such knowledge may be translated into the development of therapeutic strategy targeting CH. Here, we analyzed multiple longitudinal samples from AML patients after remission and analyzed clonal behavior of post-remission CH during consolidation and maintenance therapies. Methods We studied 164 AML patients who attained complete remission (CR) after induction therapies and analyzed baseline and CR marrow by targeted deep sequencing of 295 genes (median 403x depth). Among the patients who were identified to have post-remission CH, we analyzed multiple longitudinal marrows and tracked clonal dynacmis of post-remission CH. We defined “persistent CH” when patients had mutations that were originally detected in AML and persisted after CR with variant allele frequency (VAF) > 2.5%. On the other hand, we defined “ emerging CH” when the patients had new mutations arising after attaining CR. Results Among the 164 AML patients, 79 (48%) patients were found to have post-remission CH at first CR. Of those, we were able to analyze multiple post-remission marrows in 54 patients (median 6 samples/patient, IQR 4-7.75),of which 44 (66%) had persistent CH and 1 (1.9%) had emerging CH, and 9 (17%) had both. The median age of these 54 patients cohort was 59 (IQR: 51-68). 34 (63%) patients attained CR after intensive chemotherapies (IC, idarubicin with high-dose cytarabine based), whereas 20 (37%) patients received low-intensity chemotherapies as induction (hypomethylating agent [HMA]-based N=3, low dose cytarabine-based N=17). All 34 patients treated with IC induction subsequently received consolidation chemotherapies with high-dose cytarabine (HDAC) regimens for median 2 cycles (IQR 2-3.25). Among the 20 patients treated with low-intensity chemotherapies, all patients received consolidation therapies with HMA-based regimen. A subset of patients received maintenance therapies under clinical trials: lenalidomide (N = 1), venetoclax (N = 2), and nivolumab (N = 1). 29 patients underwent allo-SCT (23 with myeloablative conditioning [MAC], and 6 with reduced-intensity conditioning [RIC]). The most frequently mutated genes for persistent CH were DNMT3A (N = 23), followed by TET2 (N = 17), IDH2 (N = 10), and SRSF2 (N = 10). For emerging CH, we observed emergence of JAK2 (N = 2), RUNX1 (N = 2), TET2 (N = 2), BRAF (N = 1), BCOR (N = 1), TP53 (N = 1), KDM6A (N = 1), and NRAS (N = 1). Longitudinal clonal analysis revealed that post-remission CH persisted in 52 of 54 (96%) patients during consolidation and maintenance therapies. Neither cytarabine based chemotherapies, HMA, venetoclax, lenalidomide, and nivolumab, reduced the VAF of post-remission CH, except in 2 (4%) patients, in which post-remission CH (IDH2 and TET2 mutations) were cleared with high dose cytarabine regimen. Although consolidation or maintenance therapies did not reduce post-remission CH, 17 out of 19 (89.4%) patients who underwent for allo-SCT had clearance of post-remission CH with both MAC and RIC. Overall, post-remission CH did not impact the risk of relapse or overall survival. Furthermore, post-remission CH did not affect long-term blood counts (neutrophil counts, hemoglobin, and platelet counts). Conclusion Post-remission CH persisted long-term in AML patients during consolidation and maintenance therapies without having significant impact on blood counts, relapse, and survival. Therapies with cytarabine-based chemotherapies and HMA did not affect the clonal size of post-remission CH, suggesting that these therapies may not be useful to treat CH in pre-leukemic context either. The novel therapeutic approach is warranted to target CH. Disclosures DiNardo: celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria; agios: Consultancy, Honoraria; medimmune: Honoraria; jazz: Honoraria. Kadia: Bioline RX: Research Funding; Celgene: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AbbVie: Consultancy, Research Funding. Ravandi: Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding. Konopleva: Astra Zeneca: Research Funding; Agios: Research Funding; Ablynx: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Kantarjian: Takeda: Honoraria; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Champlin: Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding; Actinium: Consultancy. Garcia-Manero: Onconova: Research Funding; H3 Biomedicine: Research Funding; Astex: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Merck: Research Funding. Takahashi: Symbio Pharmaceuticals: Consultancy.

BACKGROUND TP53 mutation (TP53mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193). METHODS Patients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines. RESULTS Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone. CONCLUSIONS Patients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.

Spliceosome mutations (SRSF2, SF3B1, U2AF1, ZRSR2), are encountered in ∼50% of secondary acute myeloid leukemia cases (sAML) and define a molecular subgroup with outcomes similar to sAML in de novo AML patients treated with intensive chemotherapy. Outcomes in patients with spliceosome mutations treated with hypomethylating agents in combination with venetoclax (HMA+VEN) remains unknown. The primary objective was to compare outcomes in patients with spliceosome mutations vs wild-type patients treated with HMA+VEN. Secondary objectives included analysis of the mutational landscape of the spliceosome cohort and assessing the impact of co-occurring mutations. We performed a retrospective cohort analysis of patients treated with HMA+VEN–based regimens at The University of Texas MD Anderson Cancer Center. A total of 119 patients (spliceosome mutated n = 39 [SRSF2, n = 24; SF3B1, n = 8; U2AF1, n = 7]; wild-type, n = 80) were included. Similar responses were observed between spliceosome and wild-type cohorts for composite complete response (CRc; 79% vs 75%, P = .65), and measurable residual disease–negative CRc (48% vs 60%, P = .34). Median overall survival for spliceosome vs wild-type patients was 35 vs 14 months (P = .58), and was not reached; 35 months and 8 months for patients with SRSF2, SF3B1, and U2AF1 mutations, respectively. IDH2 mutations were enriched in patients with SRSF2 mutations and associated with favorable outcomes (1- and 2-year overall survival [OS] of 100% and 88%). RAS mutations were enriched in patients with U2AF1 mutations and associated with inferior outcomes (median OS, 8 months). Comparable outcomes were observed between patients with vs without spliceosome mutations treated with HMA+VEN regimens, with specific co-mutation pairs demonstrating favorable outcomes.

Clonal haematopoiesis (CH) in patients with acute myeloid leukaemia (AML) may persist beyond attaining complete remission. From a consecutive cohort of 67 patients with nucleophosmin 1-mutated (NPM1mut ) AML, we identified 50 who achieved NPM1mut clearance and had parallel multicolour flow cytometry (MFC) and next generation sequencing (NGS). In total, 13 (26%) cleared all mutations, 37 (74%) had persistent CH frequently involving DNA methyltransferase 3α (DNMT3A,70%), tet methylcytosine dioxygenase 2 (TET2, 27%), isocitrate dehydrogenase 2 (IDH2, 19%) and IDH1 (11%). A small number (

The inferior cure rate of T-cell acute lymphoblastic leukemia (T-ALL) is associated with inherent drug resistance. The activating NOTCH1 gene mutations have been reported to cause chemoresistance at the stem cell level1. Direct NOTCH1 inhibition has failed in clinical trials due to a narrow therapeutic window but targeting key oncogenic and metabolic pathways downstream of mutated NOTCH1 may offer novel approaches. We previously reported that rapid transformation of thymocytes at the DN3 differentiation stage into preleukemic stem cells (pre-LSC) requires elevated Notch1 in addition to the presence of Scl/Lmo11. Notably, we showed that cellular metabolism of NOTCH1-mutated T-ALLs depends on Oxidative Phosphorylation (OxPhos) and that OxPhos inhibition using the complex I inhibitor IACS-010759 (OxPhos-i) is efficacious in NOTCH1-mutated T-ALL patient derived xenografts (PDXs)2. Here, we investigated the link between NOTCH1-mutated chemoresistance and OxPhos in pre-leukemic and leukemic cells, utilizing comprehensive molecular and functional assays. We hypothesized that chemotherapy aided by OxPhos-i overcomes chemoresistance, depletes LSCs and combats T-ALL. First, we analyzed the role of OxPhos in downstream Notch1 targets at the pre- and leukemic stage considering four stages of thymocyte differentiation (D1-D4), in a mouse model of human T-ALL1. Gene set enrichment analysis (GSEA) implicated increased expression of Notch1 target genes starting at DN1, and OxPhos target genes were the highest-ranked gene set at DN3. Next, activation of Notch1 by its ligand DL4 and inhibition of OxPhos reduced viability of pre-LSCs, indicating that ligand-dependent activation of Notch1 signaling upregulates the OxPhos pathway and sensitizes pre-LSCs to OxPhos-i. To clarify the role of Notch1 signaling, we examined the effect of IACS-010759 on pre-leukemic thymocytes harboring LMO1, SCL-LMO1, NOTCH1, LMO1-NOTCH1 and SCL-LMO1-NOTCH1 with and without DL4 stimulation. We found that in the absence of DL4, only thymocytes harboring the Notch1 oncogene responded to OxPhos-i, whereas all DL4-stimulated thymocytes responded regardless of Notch1 status (Fig. 1a). In addition, at the leukemic stage, we found elevation of the OxPhos pathway driven by oncogenic Notch1 when we compared transcriptomes of SCL-LMO1 induced T-ALL in the presence or absence of the NOTCH1 oncogene. In line with the murine T-ALL NOTCH1 model, we performed transcriptome analysis of two independent T-ALL patient cohorts prior to chemotherapy, COG TARGET ALL (n=263) and AALL1231 (n=75), comparing transcriptomes of NOTCH1-mutated vs NOTCH1-wt T-ALLs. We found co-segregation of NOTCH1 mutations with significant upregulation of OxPhos and TCA cycle genes and downregulation of apoptosis signaling. Aiming to reverse the NOTCH1-controlled anti-apoptotic program and chemoresistance, we next tested the combination of Vincristine, Dexamethasone and L-Asparaginase (VXL) with IACS-010759. When compared to vehicle, OxPhos-i or VXL alone, only the VXL-OxPhos-i treatment caused an energetic crisis indicated by decreased OCR and ECAR (Seahorse), which translated to a profound reduction of viability (CTG, flow cytometry) in T-ALL cell lines (n=9) and primary T-ALL samples (n=5). Additionally, the IACS-VXL combination in vivo resulted in pan-metabolic blockade, which caused metabolic shut-down and triggered early induction of apoptosis in leukemic cells in peripheral blood, spleen and bone marrow (Fig. 1b). Single cell Proteomic analysis (CyTOF) of spleen showed reduced expression of cell proliferation marker -ki67, c-myc, ERK and p38 proteins, and reduction in number of leukemic cells. Finally, this combination therapy resulted in reduced leukemia burden and extension of overall survival across all three aggressive NOTCH1-mutated T-ALL PDX models (p Disclosures Jabbour: Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding. Teachey:Sobi: Consultancy; Amgen: Consultancy; Janssen: Consultancy; La Roche: Consultancy. Rezvani:Takeda: Other: Licensing agreement; GemoAb: Membership on an entity's Board of Directors or advisory committees; Adicet Bio: Membership on an entity's Board of Directors or advisory committees; Virogen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: Educational grant; Affimed: Other: Educational grant; Formula Pharma: Membership on an entity's Board of Directors or advisory committees. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Lorenzi:Precision Pathways: Consultancy. Konopleva:Calithera: Research Funding; Kisoji: Consultancy; AbbVie: Consultancy, Research Funding; Sanofi: Research Funding; Genentech: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Cellectis: Research Funding; Rafael Pharmaceutical: Research Funding; Eli Lilly: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Agios: Research Funding; AstraZeneca: Research Funding; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding; Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Ascentage: Research Funding.

The aim of this review was to determine the utility of home visits by occupational therapists before and after a patient is discharged from an acute care hospital. All relevant published studies were identified by searching the CENTRAL, MEDLINE, EMBASE, Occupational Therapy Systematic Evaluation of Evidence, and WHO International Clinical Trials Registry Platform databases. Randomized controlled trials were included regardless of sex, age, disease, and duration of acute hospitalization. The intervention was predischarge and postdischarge home visits made by an occupational therapist. The primary outcome was the ability to perform activities of daily living at 1 month after the intervention. We identified eight trials (including 1029 patients) that were eligible for inclusion. More than half of the trials had a low risk of bias in random sequence generation, and allocation concealment and the other half had a high risk of bias with regard to blinding of participants. However, the risk of bias in terms of blinding for outcomes assessment was low in more than half the studies. We found that home visits by an occupational therapist in a single study significantly reduced the prevalence of falls but had no significant effects on ability to perform activities of daily living, quality of life, or mood. We could not find adequate evidence to support routine home visits by an occupational therapist in the acute care. In the future, studies with larger sample sizes are needed to validate home visits by occupational therapists in patients after acute care hospitalization.

Numerous Cochrane Reviews (CRs) in the field of physiotherapy have been published, but their conclusiveness has not been investigated. The purpose of this study was to provide an overview and describe the conclusiveness of evidence from CRs regarding physiotherapy. We conducted a systematic search using the Cochrane Database of Systematic Reviews in the Cochrane Library from 2008 through 2017 in the field of physiotherapy, the Physical Rehabilitation Evidence Database, and the CRs list on the Cochrane Rehabilitation website. Reviewers extracted the following data: year of publication, editorial group, number of articles meeting the criteria, number of patients enrolled, conclusiveness, and need for additional studies. Linear regression was used to determine whether the percentage of conclusive reviews was affected by the year of publication. Reviewers found 283 CRs in the field of physiotherapy, and only 16 (5.7%) of which were conclusive. The number of trials and participants enrolled in conclusive reviews were significantly higher than those in inconclusive reviews (P < 0.001). The percentage of conclusive reviews was significantly correlated with year of publication (P = 0.03). Almost all reviews recognized the need for additional studies. Most CRs in physiotherapy are inconclusive, and most emphasize the need for further research. The ability of a Cochrane Review to reach a conclusion is affected by the cumulative patient sample size and number of trials included in the analysis.

Patients with immunodeficiency or immunosuppression are at risk of developing a lymphoproliferative disorder (LPD). Methotrexate (MTX) is an iatrogenic cause of LPD, which in up to 50% cases occurs in extranodal sites. The occurrence of MTX-related LPD with osteonecrosis of the jaw (ONJ) has rarely been reported. Moreover, there are no clear diagnostic criteria and treatment strategies for management of these lesions. In the present cases, discontinuing MTX and debridement of the necrotic bone were effective. This report describes 3 cases of MTX-related LPD in patients with longstanding rheumatoid arthritis (RA) who presented with ONJ. The first patient was a 74-year-old man with RA who had received treatment with MTX for 7 years before presenting with ONJ and submental lymphadenopathy. The second patient was a 79-year-old woman who had been treated for 21 years with MTX and who presented with ONJ. The third patient was a 67-year-old man who had been treated with MTX for more than 15 years. In all 3 cases, biopsy, histology, and immunohistochemistry using a panel of lymphoid markers (Epstein-Barr virus [EBV], CD79a, CD20, PAX-5, CD3, and CD30) resulted in the diagnosis of EBV-driven T-cell, B-cell, and Hodgkin-like LPD. All 3 patients recovered after cessation of MTX and surgical debridement. Biopsy examination, diagnostic immunohistochemistry using lymphoid immune markers, and imaging studies using computed tomography, magnetic resonance imaging, and positron-emission tomographic computed tomography were useful for the correct diagnosis of this condition.

Background: Hypomethylating agents (HMA) are well established standard of care for patients (pts) with higher-risk MDS (HR-MDS). However, approximately half of the pts do not respond to HMA therapy and most of the responders eventually lose response (HMA failure). There is no standard of care for pts after HMA failure and median overall survival (OS) post HMA failure is around 6 months (Jabbour et al. 2015). While the mutational landscapes and their role in prognosis are increasingly becoming apparent in pts with HR-MDS at diagnosis, mutational profiles at the time of HMA failure and their impact on clinical outcomes are not well understood. Here, using samples collected from a global Phase 3 trial randomizing HR-MDS pts post HMA failure to I.V. rigosertib (RGS) or physician's choice (PC) (INSPIRE: NCT02562443), we analyzed the landscape of driver mutations in HR-MDS after HMA failure and investigated the association with the clinical outcomes. Since RGS is a non-ATP-competitive small molecule RAS mimetic (Athuluri-Divakar 2016), the study also offered an opportunity to test the hypothesis whether HR-MDS pts with oncogenic RAS pathway mutations benefit from RGS. Methods: HR-MDS pts after HMA failure were randomized 2:1 to RGS or PC. All pts failed to respond to or progressed on prior HMA therapy. Bone marrow samples or peripheral blood samples were collected at the time of trial screening. Genomic DNA was sequenced by the targeted capture deep sequencing of 295 genes (median 500x). Results: 372 pts were enrolled in INSPIRE trial (248 to RGS and 124 to PC). The median age of the trial participants was 73 (range: 40-85). All pts were previously treated and with an HMA with the median duration of prior HMA therapy of 6.7 months. 64% and 28% of the pts were classified as IPSS-R very high risk or high risk, respectively, at the time of randomization. Among the 372 participants, DNA sequencing of pre-treatment samples was performed in 188 pts (51% of the participants, N = 122 in RGS arm, N = 66 in PC arm). The most frequently identified driver mutations involved ASXL1 (36%) followed by RUNX1 (24%), TET2 (23%), STAG2 (22%) and TP53 (21%). Mutations in splicing pathway genes were found in 36% of the pts. Oncogenic RAS pathway mutations were detected in 15% of the pts (NRAS = 3 %, KRAS = 2%, CBL = 4%, NF1 = 5%, PTPN11 = 3%, and 1% had multi-hit mutations). Compared to the previously untreated MDS pts (N = 446, Papaemmanuil et al. Blood 2013), mutations in ASXL1 (36% vs. 18%, P < 0.0001), BCOR (9% vs. 3%, P = 0.002), CEBPA (4% vs. 0.2%, P = 0.001), NF1 (5% vs. 0.9%, P = 0.003), RUNX1 (25% vs. 11%, P < 0.0001), STAG2 (22% vs. 5%, P < 0.0001), TP53 (21% vs. 6%, P < 0.0001), and IDH1/2 (13% vs. 7%, P =0.016) were significantly more enriched in pts with HMA failure, whereas mutations in SF3B1 (7% vs. 37%, P < 0.0001), TET2 (23% vs. 35%, P = 0.006), and splicing pathway genes (36% vs. 68%, P < 0.0001) were significantly less frequent in HMA failure pts. These results are consistent with the high-risk profiles of HMA failure pts. Frequency of oncogenic RAS pathway mutations were similar between HMA failure and previously untreated MDS pts (15% vs. 13%, P = 0.612). Correlation analysis between the types of HMA failure and gene mutations showed that TP53 mutations were significantly enriched in pts who relapsed after initial response to HMA (P = 0.001), whereas oncogenic RAS pathway mutations were significantly enriched in pts who progressed during the HMA therapy (P = 0.03). Overall, RGS did not significantly improve the overall survival (OS) of HMA failure pts compared to PC. Survival difference between RGS arm and PC arm was not observed in any subgroups stratified by the gene mutations. The only subgroup that showed improved OS with RGS compared to PC was pts with RAEB-t (median OS 7.5 vs. 3.9 months, P = 0.049). Of note, among pts with oncogenic RAS pathway mutations, no survival difference was observed between RGS and PC arms. Conclusion: High-risk gene mutations, such as TP53, ASXL1, RUNX1, and STAG2 (Ogawa. Blood 2019). were significantly enriched in MDS pts with HMA failure, suggesting their role in HMA resistance and disease progression. Identifying the mutations present de novo and with HMA failure offers the opportunity to determine prognosis based on these mutations as well as potential strategies to target these mutations with new medical entities. Disclosures Takahashi: GSK: Consultancy; Celgene/BMS: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Rigosertib for MDS patients after HMA failure

Background/Aim World population has been aging and oral-maxillofacial trauma of geriatric population is expected to increase. The aim of this study was to analyze the characteristic features of oral-maxillofacial trauma in the geriatric population. Materials and methods Data from 127 patients aged 65 years old or older, who were treated for oral-maxillofacial trauma at the Department of Oral and Maxillofacial Surgery, Hirosaki University, from 2000 to 2014, were retrospectively analyzed. The data from 292 patients aged 20–64 years was used as a comparison. Results Oral-maxillofacial trauma in the geriatric population had been increasing over 15-year period. The male to female ratio was 1.05:1 in the older group and 2.3:1 in the younger group. In the older group, 117 patients (92.1%) had one or more underlying systemic diseases, and 16 (12.6%) had suffered injuries in association with acute medical disorders. The most common injuries in the older group were bone fractures (46.5%). The ratio of fractures in the older group was lower than in the younger group (69.2%). Trauma in the older group most frequently occurred because of falls from a standing height or lower (52.0%), and the mandible was the most common site of fracture (74.6%). A conservative form of treatment for maxillofacial fractures was most commonly (86.4%) chosen for the older group, while surgical treatment was most commonly in the younger group (55.0%). Conclusion Oral-maxillofacial trauma in the geriatric population shows characteristic features in terms of etiology, patterns, and treatment modalities. This article is protected by copyright. All rights reserved.

Here we report a case of localized AL amyloidosis of the tongue that caused discomfort and tissue mass in the mid-dorsal surface of the tongue. A 70-year-old woman became aware of discomfort and tissue mass in the mid-dorsal surface of the tongue. Biopsy of the lesion was performed in 2010, and pathological examination suggested amyloidosis. A gradual increase in size of the tongue lesion was seen during clinical follow-up. Second biopsy of the tongue lesion was performed in October 2013, and the pathological diagnosis was amyloidosis. The patient was referred to our hospital for definitive diagnosis. Extensive examination excluded systemic involvement, and localized primary amyloidosis was diagnosed. The lesion was surgically resected and no clinical progression to systemic amyloidosis or local recurrence has been observed during 2 years of follow-up. In English literature, 25% of patients with systemic amyloidosis show macroglossia related to tongue amyloidosis, and there was no consensus for management of localized tongue amyloidosis. Some reports indicated there was no case of localized amyloidosis progressing to the systemic form. On the other hand, there were some reports that amyloidosis of mucosal sites in the head and neck was associated with underlying malignancy. Careful regular follow-up for this disease is thus necessary. Because therapeutic principles are different between localized tongue amyloidosis and oral amyloidosis related to systemic form, oral surgeons must investigate systemic involvement in cases like this.

INTRODUCTION: NPM1 mutations (NPM1mut) occur in ∼30% of acute myeloid leukemia (AML) and frequently co-occur with mutations in other genes including those attributed to clonal hematopoiesis (CH) including DNMT3A and TET2, among others. CH mutations may persist beyond attaining NPM1mut-negative remission. Persistent CH may be associated with immunophenotypic alterations in myeloid progenitors detected by flow cytometry (FC) which poses an interpretive challenge in assessment of measurable residual disease (MRD) by FC. The aim of this study was to characterize the immunophenotypic alterations associated with persistent CH in the setting of NPM1mut clearance and to determine their possible clinical or biologic significance. METHODS: The cohort included 67 consecutive patients (pts) with NPM1mut AML treated at our institution between 01/2017 and 11/2019. FC assessment for MRD was performed an eight-color panel using FACSCanto II instruments (BD Biosciences, San Diego, CA) with a sensitivity of 10-3 to 10-4. Whole bone marrow (BM) DNA was interrogated for mutations with an 81-gene myeloid next-generation sequencing (NGS) panel using an Illumina MiSeq sequencer (Illumina, Inc., San Diego, CA, USA) with a sensitivity: 1% variant allelic frequency (VAF). RESULTS: Pts included 26 men and 41 women with a median age of 64 (range, 19-84) years with newly diagnosed NPM1mut AML. AML blasts had the following immunophenotype at baseline: promyelocytic-like phenotype (CD34-, CD117+, HLA-DR-) in 18 (27%), aberrant myeloid CD34-/CD117+/HLA-DR+ in 15 (22%), aberrant myeloid CD34+ in 13 (19%), myelomonocytic in 11 (16%), and monocytic in 10 (15%) cases. All pts had additional co-mutations at baseline (Fig 1). The most frequently co-mutated genes were DNMT3A (58%) FLT3 (51%), TET2 (27%), IDH2 (24%), PTPN11 (19%), IDH1 (18%), NRAS (16%), and SRSF2 (12%). Pts were treated with intensive (35;52%) and non-intensive induction regimens (32; 48%) (Fig 1); 22 (33%) received an allogeneic hematopoietic stem cell transplant as post-remission consolidation. We compared FC and NGS results in follow-up samples in pts achieving NPM1mut negative remission with adequate data available for comparison (n=50). 13 (26%) pts cleared all mutations whereas 37 (74%) had persistent CH. The most common mutations in the setting of residual CH involved DNMT3A (70%), TET2 (27%), IDH2 (19%) and IDH1 (11%). Among 37 pts with residual CH, 19 (51%) had no phenotypic alterations detected by FC while 17 (49%) had myeloid progenitors with alterations in intensity of antigen expression (increased CD13, CD123, CD117 and/or decreased CD38) or deviation from normal maturation but not diagnostic for AML MRD (herein referred to as pre-leukemic (PL) phenotype); 1 sample was MRD+ by FC. Mutation VAF of ≥5% was significantly more common (p=0.008) in cases with FC PL+ (100%) vs cases with normal FC phenotype (63%). IDH2 and SRSF2 mutation were exclusively observed in PL+CH+ cases with the former being statistically significant when compared with the FC-normal group (p=0.016). PL phenotype by FC did not correlate with intensity of induction therapy (41% treated with intensive regimens vs 59% non-intensive). The CH+/PL+ cohort had more pts ≥60 yrs old (67%) but the difference was not significant. There was no significant association between PL+ and residual mutation count. Presence of PL+ phenotype was not associated with a shorter relapse-free survival (RFS) (median not reached for both groups). CONCLUSIONS: Post-remission clonal hematopoiesis in the setting of NPM1mut clearance is common, and may result in immunophenotypic changes in myeloid progenitors, posing interpretive challenges for MRD assessment by FC. These alterations may be attributable to specific CH characteristics, such as IDH2 and SRSF2 mutations and VAF, but are not associated with a shorter RFS and thus should not be interpreted as residual AML or considered a high-risk attribute. Additional studies in other AML subtypes are warranted to further delineate these changes and their clinical significance. Figure 1 Disclosures DiNardo: Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Takeda: Honoraria; Jazz: Honoraria; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; Astellas: Research Funding. Kadia:JAZZ: Honoraria, Research Funding; Ascentage: Research Funding; Astra Zeneca: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Novartis: Honoraria; Cyclacel: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Research Funding; Abbvie: Honoraria, Research Funding; Cellenkos: Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Konopleva:Sanofi: Research Funding; Eli Lilly: Research Funding; AstraZeneca: Research Funding; Rafael Pharmaceutical: Research Funding; Amgen: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Kisoji: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ascentage: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Cellectis: Research Funding; Agios: Research Funding; Ablynx: Research Funding. Kantarjian:Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Ascentage: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Ravandi:Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding.

7529 Background: Clonal Hematopoiesis may persist following complete remission (CR) in patients with acute myeloid leukemia (AML) but does not necessarily indicate residual AML and may represent persistence of pre-leukemic stem cells. Post-remission CH identified by NGS has not been systemically studied in parallel with measurable residual disease (MRD) detection by flow cytometric immunophenotyping (FCI). Methods: We studied bone marrow sample from AML patients at baseline and CR by targeted deep NGS of 295 genes (median 403x depth) and compared the results to FCI. Measurable residual disease (MRD) detection by FCI was performed by comparing the phenotype at CR to baseline and by detection of leukemia associated immunophenotype (LAIP) and derivation from normal (DFN) (sensitivity: 0.1%). Post-CR CH was defined as presence of mutations originally detected in AML with variant allele frequency > 2.5%. FCI results were categorized into 4 groups: a) AML MRD negative by LAIP or DFN b) AML MRD+ (similar to baseline) c) AML MRD+ (different from baseline), d) Negative for AML MRD, but aberrant phenotype suggestive of pre-leukemic cells. We correlated FCI and NGS results. Results: 101 patients were included in the study. 45 (45%) had persistent post-CR clonal hematopoiesis; 23 (51%) had phenotypic alterations detected by FCI including AML MRD+ in 18 (40%) and pre-leukemic cells in 5 (10%). Among patient with no detectable mutations by NGS (n = 56; 55%), 14 (25%) had FCI aberrancies including AML MRD+ in 4 (7%) and pre-leukemic cells in 10 (18%). CH was significantly more common in samples with residual phenotypic aberrancies detected by FCI (p = 0.004). There was no significant correlation between FCI group d and persistent CH (p = 0.4). Persistent ASXL1 (p = 0.024, OR = 7.2 ) and RUNX1 (p = 0.016; OR = 17.3) mutations were significantly associated with FCI abnormalities. The correlation coefficient between FCI abnormalities and RUNX1 mutations inferred from a Bayesian network structure was 0.66. Conclusions: NGS and FCI are complementary in evaluating post treatment disease status in AML. Post CR-CH is associated with phenotypic abnormalities that either represent residual AML or pre-leukemic cells. The latter may not have the same prognostic implications as AML MRD; however, the association with outcome needs to be elucidated. Single cell DNA sequencing technologies may be helpful in more accurately deciphering the association of individual gene mutations and their contribution to phenotypic aberrations.

Cherubism is a rare genetic disorder and the majority of patients with cherubism are children. The aim of this study was to determine if analysis of mutations in the SH3BP2 gene using collected blood could distinguish cherubism from other similar diseases and might therefore replace the current extensive and invasive methods of diagnosis of cherubism with a minimally invasive method. Exon 9 of the SH3BP2 gene of a child with cherubism and of the child's parents was sequenced using PCR of the genomic DNA of collected leucocytes. The patient's lesions were analyzed radiographically. Biopsied lesions of the patient were histopathologically analyzed. The genomic DNA analysis indicated that the exon 9 sequence of the child and that of its mother, but not its father, was mutated. The combined radiographic and histopathological analyses suggested cherubism. In conclusion, sequencing of mutations in exon 9 of the SH3BP2 gene can diagnose cherubism and may therefore replace the combined extensive and more invasive methods previously required for such diagnosis.

Oral mucositis (OM) is a painful complication of radiation therapy (RT) for head and neck cancer. OM can compromise nutrition, require opioid analgesics and hospitalization for pain control, and lead to interruption of treatment. Severe oral mucositis appears inevitable in superselective intra-arterial chemotherapy concurrent with radiotherapy (SSIACRT), requiring management of OM for the patient. The objective of this study was to assess the utility of professional oral health care (POHC) for the management of OM in patients undergoing SSIACRT. Thirty-three patients were enrolled in this study. The first 17 patients underwent SSIACRT before we created an oral management team, and thus did not receive POHC. The remaining 16 patients received POHC. Fever duration, duration of oral feeding difficulty, opioid usage, duration of opioid administration, duration of hospitalization, and number of hospital days from the end of irradiation to discharge were compared between these two groups. Median total dose of morphine during SSIACRT, median number of hospital days from end of irradiation to discharge, and duration of hospitalization all differed significantly between groups (P

We report the case of a 3-month-old female infant who presented with a cystic swelling in the left side of the oral floor (i.e., a congenital ranula). Observation was initially carried out because of the patient's poor general condition. A puncture was performed twice because the ranula enlarged gradually and caused difficulty with sucking during follow-up. Despite being punctured, the ranula recurred again and resulted in difficulty with sucking. Therefore, we performed marsupialization of the ranula under general anesthesia. There was no sign of recurrence for 4 years after marsupialization.

A penetrating injury by a foreign body is comparatively common in the oral and maxillofacial region. On the other hand, injury to the temporomandibular joint (TMJ) by a foreign object is very rare. The TMJ is an anatomically narrow space surrounded by hard bony processes. An unusual case of trauma with severe trismus caused by a foreign body that impaled the TMJ is reported. A 55-year-old man presented with a 5 × 1-cm laceration to the right cheek caused by a flying object propelled during the use of a lawn mower. The edge of the foreign body had a metallic wire, which became imbedded in the wound. His jaw opening was severely limited. Computed tomography revealed that the foreign body was 3 mm in diameter and was impaled on the articular capsule. The object was successfully removed, and the wound and interior of the TMJ were irrigated. Rehabilitation of mouth opening was started on postoperative day 3. On day 9, mouth opening had improved to 35 mm, and he was discharged. After 1 year, mouth opening was 45 mm with no sign of any TMJ disorders.

Background. Distant metastasis is considerably more frequent in superselective intra-arterial chemoradiotherapy than other radical treatments for advanced oral cancers. However, there is no evidence supporting such claim. The purpose of this study was to report our experience in superselective intra-arterial chemoradiotherapy and conventional surgical management with particular focus on distant metastasis. Methods. One hundred seventy-two patients with oral squamous cell carcinoma in stages III and IV were included in this study. Retrospective analysis for DM rates and background between surgical management and superselective intra-arterial chemoradiotherapy was performed. Results. Distant metastasis developed clinically was detected in 24 out of 141 patients (17.0%) treated surgically and in 6 out of 31 patients (19.4%) treated with superselective intra-arterial chemoradiotherapy. There was no significant difference in the rate of distant metastasis between the 2 groups. Comparison of patients in both groups with and without distant metastasis revealed no differences in age, T classification, N classification, and treatment effect. Neck recurrence was the only significant risk factor for distant metastasis. Conclusion. No significant difference was found in the rate of distant metastasis between patients treated with surgical treatment and superselective intra-arterial chemoradiotherapy, and additional effort is needed to reduce the risk of distant metastasis.

This is a report of creative and technical considerations in building a participatory sound performance The SINE WAVE ORCHESTRA stay. In this performance, the participants one by one leave their own sine wave in the performance space. These sine waves form a mutually interfering sound space while the sound field of a room changes during the performance.