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Background: All‐trans retinoic acid (ATRA) and arsenic trioxide (ATO) combinations have produced excellent outcomes in patients with standard‐risk acute promyelocytic leukemia (APL). Herein, the authors update their long‐term results with the regimen of ATO‐ATRA and gemtuzumab ozogamicin (GO) in standard‐risk and high‐risk APL. Methods: This was a phase 2 trial of patients with newly diagnosed APL. Induction comprised ATRA 45 mg/m2 and ATO 0.15 mg/kg daily. GO 6–9 mg/m2 was added for high‐risk patients and for standard‐risk patients who developed leukocytosis >10 × 109/L. Consolidation consisted of four courses of ATO‐ATRA, with GO for patients who had PML::RARA persistence. Results: One hundred forty‐six patients (median age, 53.0 years; range, 19.3–83.9 years) were treated, including 106 patients (72.6%) with standard‐risk APL and 40 (27.4%) with high‐risk APL. GO was administered to 68 standard‐risk patients (64.2%) for leukocytosis. The complete remission rate was 93.8% (95% confidence interval [CI], 92.2%–98.5%). Negative measurable residual disease status was achieved in 97.1% of patients who attained complete remission. At a median follow‐up of 61.8 months (95% CI, 4.7–128.4 months), the 5‐year event‐free survival, disease‐free survival, and overall survival rates were 92.4% (95% CI, 87.9%–97.1%), 93.6% (95% CI, 89.5%–97.8%), and 93.1% (95% CI, 88.9%–97.7%), respectively. Induction mortality was 2.7%. The most common severe adverse events were elevated transaminases in 41.0% of patients and infection in 13.7%. There were no cases of veno‐occlusive disease. Conclusions: The combination of ATO‐ATRA and GO was curative in 94% of patients who had APL with a favorable safety profile (ClinicalTrials.gov identifier NCT01409161). [ABSTRACT FROM AUTHOR]

Background. Metabolic dysfunction‐associated steatohepatitis (MASH) has become the leading cause of chronic liver disease, but there has been no approved pharmacotherapy to date. Methods. We used a network analysis approach to delineate protein‐protein interactions that contribute to the transition from steatosis to MASH, in order to identify and target this transition as a potential pharmacotherapeutic strategy. Acyl‐CoA thioesterase 1 (ACOT1) was identified as a critical node in the protein‐protein interaction (PPI) network of the transition from steatosis to MASH in patient samples. ACOT1 overexpression and silencing effects were tested in vivo on C57BL/6 mice exposed to high‐fat diet (HFD) and inoculated with an adenoviral system to modulate ACOT1 expression. Transcriptomic and untargeted lipidomic profiles were performed on the mouse livers. Results. ACOT1 expression was 3‐fold higher in MASH as compared to steatosis. In patient samples, ACOT1 was significantly correlated with the severity of MASH as reflected by the nonalcoholic fatty liver disease score. Experimental validation showed that downregulation of ACOT1 resulted in decreased lipid accumulation and prevention of MASH in vivo. Conversely, upregulation of ACOT1 via an adenoviral vector resulted in development of MASH, whereas control mice only developed steatosis. Lipidomic analysis revealed glycerophospholipids to be especially abundant in MASH accelerated by ACOT1 upregulation. Conclusion. These results suggest that ACOT1 contributes to the transition from steatosis to MASH through modulation of glycerophospholipid accumulation and its potential as a novel therapeutic target in MASH. This trial is registered with NCT02148471. [ABSTRACT FROM AUTHOR]

Background: Genomic profiling is needed to identify actionable alterations in non–small cell lung cancer (NSCLC). Panel‐based testing such as next‐generation sequencing (NGS) is often preferred to interrogate multiple alterations simultaneously. In this study, we evaluate the utility of an RNA‐based NGS assay to detect genomic alterations in NSCLC cytology specimens and compare these results to fluorescence in situ hybridization (FISH) testing. Methods: A retrospective review was performed of 264 NSCLC cytology specimens that were concurrently tested for gene fusions by RNA‐based NGS and ALK, RET, and/or ROS1 by FISH. Results: Genomic alterations were detected in 29 cases by NGS, including ALK, RET, ROS1, NTRK, NUTM1, and FGFR3 fusions and MET exon 14 skipping alterations. Of the 20 cases with ALK, RET, and ROS1 fusions detected by NGS, 16 (80%) were concordant with the corresponding FISH results. Three cases showed discordance, where EML4::ALK (n = 2) and SLC34A2::ROS1 (n = 1) fusions were not detected by the corresponding FISH assay; one case with EZR::ROS1 was inadequate for FISH. No gene fusions were detected in 181 cases by NGS and 54 cases failed testing. The concordance rates for detecting ALK, RET, and ROS1 fusions using NGS and FISH were 97%, 100%, and 99.5%, respectively. Conclusion: RNA‐based NGS can be used to detect gene fusions in NSCLC cytology cases with high concordance with FISH results. However, RNA‐based NGS may have high failure rates and therefore a low threshold for reflexing inadequate cases to an orthogonal testing method is essential for comprehensive genomic profiling. This study explores the use of an RNA‐based next‐generation sequencing assay for detecting genomic alterations in non–small cell lung cancer cytology specimens in comparison to fluorescence in situ hybridization testing. The results have important implications for clinical oncology practice, including selection of biomarkers and biomarker testing workflow, in addition to specimen collection and optimizing the use of cytology samples. [ABSTRACT FROM AUTHOR]

Background and aim: Non‐alcoholic steatohepatitis (NASH) is a leading indication for liver transplantation (LT). This study aimed to determine whether living donor LT (LDLT) recipients experienced less recurrent NASH, cirrhosis, and cardiometabolic complications compared to deceased donor LT (DDLT). Method: Patients with LDLT and DDLT for NASH between February 2002 and May 2018 at University Health Network (UHN) were compared. Cox Proportional Hazard model was used to analyze overall survival (OS), Fine and Gray's Competing Risk models were conducted to analyze cumulative incidence of post LT outcomes. Results: One hundred and ninety‐nine DDLTs and 66 LDLTs were performed for NASH cirrhosis. Time and rate of recurrence of NAFLD and NASH were comparable in both groups. Graft cirrhosis was more common in DDLT recipients (n = 14) versus LDLT (n = 0) (p <.0001). Significant fibrosis (Fibrosis ≥ F2) developed in 50 recipients (12 LDLT and 38 DDLT) post LT (DDLT vs. LDLT: HR = 1.00, 95% CI = (.52–1.93), p =.91) and there was no difference in time to significant fibrosis (p =.57). There was no difference in development of post‐transplant diabetes, dyslipidemia, metabolic syndrome, cardiovascular disease, and cancers. LDLT group had better renal function at 10 years (MDRD eGFR of 57.0 mL/min vs. 48.5 mL/min, p =.047). Both groups had a comparable OS (HR = 1.83 (95% CI =.92–3.62), p =.08). Conclusion: Overall, LDLT recipients had significantly better renal function by virtue of having early transplantation in their disease course. LDLT was also associated with significantly less graft cirrhosis, although OS and cardiometabolic outcomes were comparable between LDLT and DDLT. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to develop a prognostic model for survival in older/unfit patients with newly diagnosed acute myeloid leukemia (AML) who were treated with lower‐intensity chemotherapy regimens. Methods: The authors reviewed all older/unfit patients with newly diagnosed AML who received lower‐intensity chemotherapy from 2000 until 2020 at their institution. A total of 1462 patients were included. They were divided (3:1 basis) into a training (n = 1088) and a validation group (n = 374). Results: In the training cohort of 1088 patients (median age, 72 years), the multivariate analysis identified 11 consistent independent adverse factors associated with survival: older age, therapy‐related myeloid neoplasm, existence of previous myelodysplastic syndrome or myeloproliferative neoplasms, poor performance status, pulmonary comorbidity, anemia, thrombocytopenia, elevated lactate dehydrogenase, cytogenetic abnormalities, and the presence of infection at diagnosis, and therapy not containing venetoclax. The 3‐year survival rates were 52%, 24%, 10%, and 1% in favorable, intermediate, poor, and very poor risk, respectively. This survival model was validated in an independent cohort. In a subset of patients in whom molecular mutation profiles were performed in more recent times, adding the mutation profiles after accounting for the effects of previous factors identified IDH2 (favorable), NPM1 (favorable), and TP53 (unfavorable) mutations as molecular prognostic factors. Conclusion: The proposed survival model with lower‐intensity chemotherapy in older/unfit patients with newly diagnosed AML may help to advise patients on their expected outcome, to propose different strategies in first complete remission, and to compare the results of different existing or future investigational therapies. Plain Language Summary: Lower intensity therapy can be considered for older patients to avoid severe toxicities and adverse events.However, survival prediction in AML was commonly developed in patients who received intensive chemotherapy.In this study, we have proposed a survival model to guide therapeutic approach in older patients who received lower‐intensity therapy. The proposed survival model with lower‐intensity chemotherapy in older/unfit patients with newly diagnosed acute myeloid leukemia may help to advise patients on their expected outcome, to propose different strategies in first complete remission, and to compare the results of different existing or future investigational therapies. [ABSTRACT FROM AUTHOR]

Background: ETNK1 mutation has been suggested as a useful tool to support the diagnosis of atypical chronic myeloid leukemia. ETNK1 mutations, however, occur in other myeloid neoplasms. Methods: The authors assessed the clinicopathologic and molecular genetic features of 80 ETNK1‐mutated myeloid neoplasms. Results: Thirty‐seven neoplasms (46%) were classified as myelodysplastic syndrome, 17 (21%) were classified as myelodysplastic/myeloproliferative neoplasm, 14 (18%) were classified as acute myeloid leukemia, and 12 (15%) were classified as myeloproliferative neoplasm. ETNK1 mutations were detected at the first test in 96% of patients, suggesting that ETNK1 mutation is an early event in pathogenesis. ETNK1 mutations represented the dominant clone in 63% of patients and was persistently dominant in 93%. The variant allele frequencies were usually higher in acute myeloid leukemia and increased upon leukemic transformation. ETNK1 mutation was accompanied by coexisting mutations in all patients, with ASXL1 (50%), TET2 (25%), EZH2 (24%), RUNX1 (24%), and SRSF2 (24%) mutations being the most common. Neoplasms with ETNK1 mutations were associated with morphologic dysplasia, increased blasts, myelofibrosis, and noncomplex karyotypes. With a median follow‐up of 16.5 months, 30 patients died, 44 had persistent disease, and four achieved complete remission after stem cell transplantation. Conclusions: ETNK1 mutation is present in various myeloid neoplasms, often as an early event and a dominant clone and always with concurrent mutations. It may play an important role in the pathogenesis and progression of myeloid neoplasms by causing DNA damage and inducing other mutations and genomic instability, and it may serve as a potential therapeutic target. ETNK1 mutation is not disease‐specific and should be interpreted with caution to classify myeloid neoplasms. ETNK1 mutation is not disease‐specific and is associated with dysplasia, increased blasts, myelofibrosis, and noncomplex karyotypes. ETNK1 mutation often represents an early event and a dominant clone, and it has a probable role in leukemogenesis and targeted therapy. [ABSTRACT FROM AUTHOR]

Background and Aims: Liver fibrosis results from a prolonged wound healing response to continued injury with excessive production of extracellular proteins. In patients with chronic liver disease, the monitoring of liver fibrosis dynamics is of high interest. Whilst markers of fibrogenesis exist, markers of hepatic fibrosis resolution remain an unmet clinical need. Thus, we sought to develop an assay quantifying a circulating proteolytic fragment of cross‐linked type III collagen as a biomarker of fibrolysis, testing its utility in two clinical cohorts of liver fibrosis of distinct aetiology and regressing endotype Methods: We used a monoclonal antibody targeting the C‐telopeptide of type III collagen following C‐proteinase cleavage to develop and validate a neo‐epitope‐specific enzyme‐linked immunosorbent assay (CTX‐III). A potential fibrosis resolution marker, CTX‐III, was measured in two clinical cohorts of patients with obesity‐associated non‐alcoholic fatty liver disease undergoing bariatric surgery or hepatitis C virus infection from a clinical trial study evaluating the anti‐fibrotic effect of farglitazar. Results: CTX‐III was robust and specific for the targeted neo‐epitope with good reproducibility in EDTA plasma. We assessed type III collagen remodelling using a panel of biomarkers, including a type III collagen formation marker (PRO‐C3), degradation (C3M), and CTX‐III (fibrolysis). Net fibrolysis was increased in patients with non‐alcoholic fatty liver disease following bariatric surgery (p <.001). Moreover, net fibrolysis identified spontaneous fibrotic regressors from stable and progressors (p <.05 and p <.001) among hepatitis C virus infection patients. Conclusion: Circulating CTX‐III as a marker of fibrolysis indicates the biomarker's beneficial use in assessing hepatic fibrosis resolution. [ABSTRACT FROM AUTHOR]

Amniotic tissues have been long utilised to treat chronic wounds; however, there are few studies evaluating how the wound microenvironment responds to these therapies. The goal of this study was to evaluate the changes in wounds treated with a hypothermically stored amniotic membrane (HSAM). In this prospective single‐arm study, 15 female patients with venous leg ulcers were treated with HSAM from male donors and standard of care for 12 weeks. Over the course of the study, wound exudate was collected and evaluated using proteomic microarrays. Biopsies were collected during the course of treatment to detect the presence of HSAM tissue. By 4 weeks, 60% of subjects achieved 50% or greater reduction in wound size, and by 12 weeks, 53% of subjects achieved 100% re‐epithelialization. HSAM DNA was detected in 20% of biopsies as determined by the detection TSPY4, indicating HSAM was no longer present within the wound bed approximately 7 days from the last treatment for the majority of wounds. Proteomic analysis of wound exudate found that wounds on a healing trajectory had significantly higher levels of MMP‐10, MMP‐7, and TIMP‐4 and significantly lower levels of CX3CL1, FLT‐3 L, IL‐1ra, IL‐1a, IL‐9, IL‐2, IL‐3, MCP‐1, and TNF‐b compared with other wounds. [ABSTRACT FROM AUTHOR]

Signet Ring Cell (SRC)/Histiocytoid carcinoma of the eyelid is a rare neoplasm that shares histological and immunohistochemical similarities with diffuse gastric cancer and breast lobular carcinoma. The CDH1 gene, which encodes the E-cadherin protein, is the best known gene associated with these tumors. The structural and functional integrity of E-cadherin is regulated by interconnecting molecular pathways which might participate in the development of this disease. Hence, we analyzed the protein expression in key genes in E-cadherin-related pathways associated with primary SRC/Histiocytoid carcinoma of the eyelid. SRC/Histiocytoid carcinoma diagnosed in the eyelid/orbit at MD Anderson Cancer Center from 1990 to 2016 were evaluated. Clinicopathologic findings were studied to confirm the primary site of origin. Immunohistochemical studies for the expression of E-cadherin, β-catenin, c-Myc, Cyclin D1, Src, and p53 were analyzed. Next generation sequencing for the detection of somatic mutations was performed on each tumor with matched normal tissue, examining 50 cancer-related genes. Four primary SRC/Histiocytoid carcinomas of the eyelid were diagnosed in four male patients aged 40-82 years. Immunohistochemically, two tumors with loss of E-cadherin expression had weak β-catenin and low cytoplasmic staining for Src while the other two cases with intact E-cadherin showed strong β-catenin expression and high cytoplasmic expression for Src. Cyclin D1 was focally positive in three cases. Somatic mutations in CDH1, PIK3CA, and TP53 genes were detected in two cases. Our results suggest an abnormality in the convergence of E-cadherin/β-catenin pathways which may promote tumorigenesis by inducing expression of oncogenes such as Cyclin D1 and C-Myc. Mutations in CDH1, PIK3CA, and TP53 genes could induce E-cadherin dysfunction which takes part in the development and progression of this malignancy. [ABSTRACT FROM AUTHOR]

Background: SF3B1 mutations (SF3B1mut) in myelodysplastic syndromes (MDS) frequently involve codon K700E and have a favorable prognosis. The prognostic effect of non‐K700E SF3B1mut is uncertain. Methods: The authors analyzed the clinicopathological features and outcomes of a single‐institution series of 94 treatment‐naive SF3B1mut MDS patients (18%) and 415 treatment‐naive SF3B1wt MDS patients and explored the differences between K700E and non‐K700E SF3B1mut MDS. Results: Fifty‐five patients (59%) carried K700E. Recurrent non‐K700E mutations (39 [41%]) included R625, H662, and K666. Compared with SF3B1mut K700E patients, non‐K700E patients had a lower median absolute neutrophil count (1.8 vs 2.4; P =.005) and were frequently "high" according to the Revised International Prognostic Scoring System (19% vs 4%; P =.031). Non‐K700E MDS was associated frequently with RUNX1 (26% vs 7%; P =.012) and exclusively with BCOR, IDH2, and SRSF2 mutations. A splicing analysis showed the differential distribution of alternatively spliced events and gene expression profiles between K700 and non‐K700E MDS patients. The majority (at least 80%) of SF3B1mut K700E, SF3B1mut non‐K700E, and SF3B1wt patients were treated with hypomethylating agents. Over a median follow‐up of 16 months, SF3B1mut had superior overall survival (OS) in comparison with SF3B1wt in all MDS patients (not reached vs 25.2 months; P =.0003), in patients with low‐grade MDS, and in patients with myelodysplastic syndromes with ring sideroblasts (MDS‐RS). Compared with SF3B1wt, SF3B1mut K700E had superior outcomes in all MDS (median OS, 25 months vs not reached; P =.0001), in low‐grade MDS (median OS, 41.3 months vs not reached; P =.0015), and in MDS‐RS (median OS, 22.3 months vs not reached; P =.0001), but no significant difference was seen between non‐K700E and SF3B1wt MDS. By multivariable analysis, the absence of SF3B1mut K700E mutations was independently associated with the prognosis. Conclusions: This study highlights the importance of the SF3B1 mutation subtype in MDS risk assessment. Lay Summary: Myelodysplastic syndromes (MDS) with SF3B1 mutations are regarded as having a favorable prognosis by both the World Health Organization and the International Working Group for the Prognosis of Myelodysplastic Syndromes.However, this article shows that only MDS patients with SF3B1 K700E mutations have a favorable prognosis (and not MDS patients with SF3B1 mutations involving other codons).This has important implications for refining future MDS subclassification and risk assessment criteria. Myelodysplastic syndromes (MDS) with K700E and non‐K700E SF3B1 mutations show distinct clinicopathological and genomic characteristics, with only SF3B1 K700E mutated MDS showing significantly better overall survival compared to wild‐type MDS. The SF3B1 mutation type is important for MDS risk assessment. [ABSTRACT FROM AUTHOR]

Millions worldwide suffer from chronic wounds challenging clinicians and burdening healthcare systems. Bacteria impede wound healing; however, the diagnosis of excessive bacterial burden or infection is elusive. Clinical signs and symptoms of infection are inaccurate and unreliable. This trial evaluated a novel, point‐of‐care, lateral flow diagnostic designed to detect virulence factors released by the most common bacteria found in chronic wounds. A multicentre prospective cohort clinical trial examined the efficacy of a diagnostic test in detecting bacterial proteases taken from swab samples of chronic venous, arterial, pressure and mixed aetiology chronic wounds. Two hundred and sixty six wounds were included in the analysis of the study. The wounds were tested at the start of the study after which investigators were permitted to use whatever dressings they desired for the next 12 weeks. Healing status at 12 weeks was assessed. The presence of elevated bacterial protease activity decreased the probability of wound healing at 12 weeks. In contrast, a greater proportion of wounds were healed at 12 weeks if they had little or no bacterial protease activity at study start. In addition, the presence of elevated bacterial protease activity increased the time it takes for a wound to heal and increased the risk that a wound would not heal, when compared to the absence of bacterial protease activity. The results of this clinical trial indicate that bacterial protease activity, as detected by this novel diagnostic test, is a valid clinical marker for chronicity in wounds. The diagnostic test offers a tool for clinicians to detect clinically significant bacteria in real time and manage bacteria load before the clinical signs and symptoms of infection are evident. [ABSTRACT FROM AUTHOR]

Background: In chronic hepatitis B (CHB) viral infection, e antigen positivity (HBeAg+) is associated with high levels of viral replication and infectivity. Furthermore, HBeAg‐positive CHB is associated with a liver disease spectrum ranging from none to severe. Aim: To assess whether the level of circulating HBeAg is associated with different clinical presentations of HBeAg‐positive CHB. Methods: A cross‐sectional analysis was conducted among HBV mono‐infected participants enrolled in Hepatitis B Research Network (HBRN) cohorts to explore clinical and virological associations with quantitative HBeAg (qHBeAg). Results: Among 763 HBeAg+ participants (56% female; 85% Asian; median age 26 years), multivariable median regression modelling significantly associated qHBeAg with liver injury (inverse qHBeAg association with ALT p<.001 and APRI p<.001), and with both race and age (p=0.01). Among Asians, qHBeAg was inversely related to age; a relationship less clear among Blacks and Whites. Among Asians also, median qHBeAg levels were higher among those infected with HBV genotype C versus B (p<0.001), suggesting causal virologic differences. Across all races, median qHBeAg was higher in women (p=.01). Independent of sex, age, race and HBV genotype, qHBeAg was higher in participants with predominant wild‐type versus basal core promoter and/or precore 'stop' viral variants (p<0.001). Conclusion: Lower qHBeAg was observed among HBRN participants with the greatest degree of liver injury independent of demographics and HBV genotype. These data support longitudinal studies to examine the role of qHBeAg in modulating the host immune response and predicting the outcomes of chronic HBV infection. [ABSTRACT FROM AUTHOR]

Background: The use of RNA‐based next‐generation sequencing (NGS) assays to detect gene fusions for targeted therapy has rapidly become an essential component of comprehensive molecular profiling. For cytology specimens, the cell block (CB) is most commonly used for fusion testing; however, insufficient cellularity and/or suboptimal RNA quality are often limiting factors. In the current study, the authors evaluated the factors affecting RNA fusion testing in cytology and the added value of smears in cases with a suboptimal or inadequate CB. Methods: A 12‐month retrospective review was performed to identify cytology cases that were evaluated by a targeted RNA‐based NGS assay. Samples were sequenced by targeted amplicon‐based NGS for 51 clinically relevant genes on a proprietary platform. Preanalytic factors and NGS quality parameters were correlated with the results of RNA fusion testing. Results: The overall success rate of RNA fusion testing was 92%. Of the 146 cases successfully sequenced, 14% had a clinically relevant fusion detected. NGS testing success positively correlated with RNA yield (P =.03) but was independent of the tumor fraction, the tumor size, or the number of slides used for extraction. CB preparations were adequate for testing in 45% cases, but the inclusion of direct smears increased the adequacy rate to 92%. There was no significant difference in testing success rates between smears and CB preparations. Conclusions: The success of RNA‐based NGS fusion testing depends on the quality and quantity of RNA extracted. The use of direct smears significantly improves the adequacy of cytologic samples for RNA fusion testing for predictive biomarkers. Cytology specimens provide a reliable source for RNA‐based next‐generation sequencing fusion assays. The addition of cytology smears significantly improves the testing success rate of cytologic samples for RNA‐based next‐generation sequencing and is an appropriate alternative for cases in which the cell block preparation is inadequate or suboptimal. [ABSTRACT FROM AUTHOR]

Summary: 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 (<1%) of aberrant CD34+ myeloblasts, but immunophenotypically different from original AML blasts [herein referred to as a pre‐leukaemic (PL) phenotype], was detected in 17 (49%) patients with CH, but not in any patients with complete clearance of all mutations (P = 0·0037). A PL phenotype was associated with higher mutation burden (P = 0·005). Persistent IDH2 and serine and arginine‐rich splicing factor 2 (SRSF2) mutations were exclusively observed in PL+ CH+ cases (P = 0·016). Persistent dysplasia was seen exclusively in cases with a PL+ phenotype (29% vs. none; P = 0·04). The PL+ phenotype did not correlate with age, intensity of induction therapy or relapse‐free survival. Post‐remission CH in the setting of NPM1mut clearance is common and may result in immunophenotypic changes in myeloid progenitors. It is important to not misinterpret these cells as AML measurable residual disease (MRD). [ABSTRACT FROM AUTHOR]

Background: Isocitrate dehydrogenase (IDH1 and IDH2) mutations commonly co‐occur with FMS‐like tyrosine kinase 3 (FLT3) mutations in patients with acute myeloid leukemia (AML). Methods: The authors reviewed cases of patients with FLT3‐internal tandem duplication (FLT3‐ITD)–mutated AML with concurrent IDH mutations diagnosed between January 2011 and December 2018. Results: A total of 91 patients with FLT3‐ITD and IDH1 or IDH2 "double‐mutated" AML were identified; 36 patients had concurrent FLT3‐ITD/IDH1 mutations (18 in the frontline and 18 in the recurrent and/or refractory [R/R] setting) and 55 patients had concurrent FLT3‐ITD/IDH2 mutations (37 in the frontline and 18 in the R/R setting). FLT3 and/or IDH inhibitors (FLT3Is and/or IDHIs) were given as a single agent or in combination with cytotoxic chemotherapy (CCT) or low‐intensity therapy (LIT). Rates of complete remission (CR) plus CR with incomplete count recovery (CRi) with the use of CCT and FLT3Is were 100% and 64%, respectively, in patients in the frontline and R/R settings. CCT with IDHIs was given in 2 frontline patients and both achieved a CR. LIT with FLT3Is in the frontline and R/R settings demonstrated CR and CRi rates of 67% and 28%, respectively. Single‐agent FLT3Is and IDHIs demonstrated limited activity with a CR and/or CRi rate of 14% in patients with disease in the R/R setting. Conclusions: The combination of FLT3I‐based therapy with CCT or LIT appeared to be effective in both the frontline and R/R settings among patients with FLT3‐ITD/IDH co‐mutated disease. Fewer patients with double‐mutated disease received CCT or LIT with IDH1/2 inhibitor in the frontline setting; however, high response rates also were noted with this approach. Lay Summary: The prognostic influence of FMS‐like tyrosine kinase 3–internal tandem duplication (FLT3‐ITD) and isocitrate dehydrogenase (IDH) co‐mutation status on outcomes in patients with acute myeloid leukemia receiving an FLT3 inhibitor, non–FLT3/IDH inhibitor–based regimens, or an IDH inhibitor is unclear. This is an important clinical question because multiple targeted therapies for FLT3 and IDH1/2 mutations have become available.The results of the current study demonstrated that a combination of a FLT3 inhibitor with cytotoxic chemotherapy or low‐intensity therapy appears to be an effective approach in patients with FLT3‐ITD/IDH co‐mutated disease in both the frontline and recurrent and/or refractory settings.Fewer dual‐mutated patients received cytotoxic chemotherapy or low‐intensity therapy with an IDH1/2 inhibitor in the frontline setting; however, excellent responses also were observed with this approach. The combination of FMS‐like tyrosine kinase 3 (FLT3) inhibitor–based therapy with high‐intensity and/or intermediate‐intensity conventional cytotoxic chemotherapy or low‐intensity regimens appears to be effective in patients with FLT3–internal tandem duplication (FLT3‐ITD) and/or isocitrate dehydrogenase (IDH) (FLT3‐ITD/IDH) co‐mutated acute myeloid leukemia in both the frontline and recurrent and/or refractory settings. Patients with FLT3‐ITD/IDH2 acute myeloid leukemia generally are younger and their disease is associated with improved overall survival compared with patients with FLT3‐ITD/IDH1–mutated disease in both the frontline and recurrent and/or refractory settings. [ABSTRACT FROM AUTHOR]

Background: Despite the well-defined role of minimal residual disease (MRD) monitoring by real-time quantitative polymerase chain reaction (RT-PCR) for RUNX1/RUNX1T1 and CBFB-MYH11 transcripts in core binding factor (CBF) acute myeloid leukemia (AML) after intensive chemotherapy, there has been a paucity of data assessing the utility of MRD monitoring at and after allogeneic hematopoietic stem cell transplantation (HSCT).Methods: Patients with CBF AML who underwent HSCT in complete remission (first or second) from January 2007 through December 2018 were included in this analysis.Results: MRD by polymerase chain reaction at HSCT was assessed in 50 of 76 patients, and 44 (88%) had evidence of MRD (MRDpos). MRDpos patients had 3-year overall survival (OS) and leukemia-free survival (LFS) rates of 69.3% and 66.3%, respectively. Six MRD-negative patients had 3-year OS and LFS rates of 100% and 100%, respectively. Thirty-five of the 70 evaluable patients (50%) had a day +100 MRD assessment by RT-PCR, and 14 (40%) were MRDpos. The presence of MRD by RT-PCR on day +100 was not associated with lower estimates of LFS (75% vs 82.2%; P = .3) but was associated with a higher relapse incidence, although the difference did not reach statistical significance (27.6% vs 9.7%; P = .2).Conclusions: Durable complete remissions can be achieved in patients with CBF AML with HSCT even if they are MRDpos by RT-PCR at HSCT. The clinical impact of frequent MRD monitoring for identifying a group at high risk for early relapse and then for determining the best time point for therapeutic interventions to prevent impending relapse warrants investigation in prospectively designed clinical trials. [ABSTRACT FROM AUTHOR]

Background: Dasatinib is a second-generation tyrosine kinase inhibitor that, when used as frontline therapy, produces more and faster cytogenetic and molecular responses compared with imatinib. The authors report the long-term follow-up from the first study using dasatinib as initial therapy for chronic-phase chronic myeloid leukemia.Methods: Between November 2005 and August 2014, patients were randomly assigned to receive 100 mg daily or 50 mg twice daily. After June 2009, all patients started with 100 mg daily.Results: With a median follow-up of 6.5 years, 94 of 149 treated patients (63%) were still receiving dasatinib on study. The median patient age was 48 years (interquartile range, 37-55 years), and 9% of patients had a high risk Sokal risk score. The cumulative complete cytogenetic response rate at 11 years was 92.6%, the major molecular response (MR) rate was 88.2%, and the MR4.5 rate (indicating a ≥4.5-log reduction in BCR-ABL1 transcripts) was 79.5%. The median time to a major MR and MR4.5 was 6 and 23 months, respectively. A sustained MR4.5 (≥2 years) was achieved in 82 patients (55%). The 10-year overall survival, transformation-free survival, event-free survival, and failure-free survival rates were 89%, 95%, 86%, and 65%, respectively. Univariate analysis showed that the achievement of a complete MR was associated with improved overall survival. The most common reasons for treatment discontinuation were toxicity and elective discontinuation. The most common treatment-emergent grade 3 and 4 adverse events were fatigue, thrombocytopenia, and infections.Conclusions: After this long-term follow-up, dasatinib continues to show an excellent safety profile and produces rapid cytogenetic responses and MRs, durable deep MRs, and excellent long-term survival outcomes in patients with chronic-phase chronic myeloid leukemia. [ABSTRACT FROM AUTHOR]

Background: Nilotinib is a potent, second-generation inhibitor of BCR-ABL1 tyrosine kinase and has been approved as frontline and salvage therapy for patients with chronic-phase chronic myeloid leukemia (CP-CML).Methods: In this single-institution, phase 2 study, 122 patients with newly diagnosed CP-CML received nilotinib 400 mg twice daily. The median follow-up on study was 78.3 months (interquartile range, 58.4-96.5 months).Results: Fifty-six percent of patients remained on therapy at the last follow-up. Both the complete cytogenetic response rate and the major molecular response (MR) rate were 91%. Seventy-five percent and 59% of patients achieved a ≥4.5-log reduction in BCR-ABL1 transcripts (MR4.5) and a sustained MR4.5 beyond 2 years, respectively. The estimated event-free survival and overall survival rates at 5 years were 89% and 93%, respectively, and the corresponding rates at 10 years were 85% and 88%, respectively. Treatment discontinuation due to toxicity occurred in 19% of patients, mostly because of cardiovascular events (10%) and biochemical abnormalities (6%). The top 3 nonhematologic toxicities were rash (55%), elevated bilirubin (57%), and elevated aminotransferases (48%). Hematologic toxicity was transient and mild. Ischemic cardiovascular adverse events occurred in 8% of patients. Four patients (3%) progressed to accelerated or blast phase while on therapy, and 7 patients (6%) died on study.Conclusions: The current data confirm the long-term efficacy of nilotinib 400 mg twice daily in patients with CP-CML. A majority of patients can achieve sustained MR4.5. [ABSTRACT FROM AUTHOR]

Background: The impact of the allelic burden of ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia (AML).Methods: The authors assessed bone marrow aspirates from 421 patients with newly diagnosed AML using next-generation sequencing for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations, defined as the presence of mutations in ASXL1, DNMT3A, JAK2, TET2, or TP53 with a minimum variant allele frequency (VAF) of 5%.Results: A total of 71 patients (17%) had ASXL1 mutations, 104 patients (25%) had DNMT3A mutations, 16 patients (4%) had JAK2 mutations, 82 patients (20%) had TET2 mutations, and 86 patients (20%) had TP53 mutations. Among patients with each mutation, the median VAF of ASXL1 was 34.31% (range, 1.17%-58.62%), the median VAF of DNMT3A was 41.76% (range, 1.02%-91.66%), the median VAF of JAK2 was 46.70% (range, 10.4%-71.7%), the median VAF of TET2 was 42.78% (range, 2.26%-95.32%), and the median VAF of TP53 was 45.47% (range, 1.15%-93.74%). The composite complete response rate was 60%, and was 77% in patients with AML with and without ASXL1, DNMT3A, JAK2, TET2, or TP53 mutations, respectively (P = .006); the median overall survival was 11 months and 27 months, respectively (P < .001). Multivariate analysis identified age; an antecedent history of dysplasia; white blood cell count; adverse cytogenetic risk; previous treatment with an FLT3 inhibitor; and the VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations by next-generation sequencing as prognostic factors for overall survival.Conclusions: The VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations is associated with worse prognosis in patients with newly diagnosed AML. [ABSTRACT FROM AUTHOR]

Adult T‐cell acute lymphoblastic leukemia (T‐ALL) is a heterogeneous group of acute leukemias that account for about one third of all cases of Philadelphia chromosome (Ph)‐negative ALL. Recently, a molecular classifier using the mutational status of NOTCH1, FBXW7, RAS, and PTEN (NFRP) has been shown to distinguish low‐ vs high‐risk groups in adult T‐ALL patients treated using the Berlin‐Frankfurt‐Münster ALL protocol. However, it is unknown if this molecular classifier can stratify adult T‐ALL patients treated with hyper‐CVAD ± nelarabine. We identified a relatively small cohort of 27 adults with T‐ALL who were uniformly treated with hyper‐CVAD ± nelarabine with available mutational analysis at time of diagnosis. The most commonly mutated genes in this group were NOTCH1 (52%), NRAS (22%), DNMT3A (19%), KRAS (15%), and TP53 (7%). The NFRP molecular classifier failed to stratify overall survival (OS; P =.84) and relapse‐free survival (RFS; P =.18) in this cohort. We developed a new stratification model combining K/NRAS and TP53 mutations as high‐risk factors and showed that mutations in these genes predicted poorer OS (P =.03) and RFS (P =.04). While the current study is limited by cohort size, these data suggest that the NFRP molecular classifier might not be applicable to adult T‐ALL patients treated with hyper‐CVAD ± nelarabine. RAS/TP53 mutation status, however, was useful in risk stratification in adults with T‐ALL. [ABSTRACT FROM AUTHOR]

Summary: This study correlated somatic mutation results and known prognostic factors with time‐to‐first treatment (TTFT) in 384 treatment‐naïve (TN) chronic lymphocytic leukaemia (CLL) patients to help determine disease‐specific drivers of early untreated CLL. CLL DNA from either peripheral blood or bone marrow underwent next generation targeted sequencing with a 29‐gene panel. Gene mutation data and concurrent clinical characteristics, such as Rai/Binet stage, fluorescence in situ hybridisation (FISH), ZAP70/CD38, karyotype and IGHV mutation, status were analysed in univariable and multivariable analyses to identify associations with TTFT. TTFT was defined as time from diagnosis to initial treatment. In univariable analyses, mutated ATM (P < 0·001), NOTCH1 (P < 0·001) and SF3B1 (P = 0·002) as well as unmutated IGHV (P < 0·001), del(11q) (P < 0·001) and trisomy 12 (P < 0·001) by hierarchal FISH and advanced Rai (P = 0·05) and Binet (P < 0·001) stages were associated with shorter TTFT. Importantly, del(17p), mutated TP53 and complex karyotype were not associated with shorter TTFT. In a reduced multivariable analysis, mutated ATM (P < 0·001) and unmutated IGHV status (P < 0·001) remained significant, showing their importance in early leukaemogenesis. High‐risk prognostic markers such as del(17p), mutated TP53 and complex karyotype, were not correlated with TTFT, suggesting that these abnormalities have limited roles in early disease progression but are more important in relapsed CLL. [ABSTRACT FROM AUTHOR]

Background: The addition of midostaurin to induction chemotherapy improves survival in younger patients with newly diagnosed, FLT3-mutated acute myeloid leukemia (AML). Sorafenib is a potent multikinase inhibitor with efficacy when given as monotherapy. The authors investigated whether the addition of sorafenib to intensive induction chemotherapy improves outcomes in patients with FLT3-internal tandem duplication (ITD)-mutated AML.Methods: In total, 183 patients who were newly diagnosed with FLT3-ITD-mutated AML between February 2001 and December 2017 were identified. Of these, 79 patients (43%) underwent intensive chemotherapy with the addition of sorafenib, and 104 (57%) received intensive chemotherapy alone. Propensity score matching identified 42 patients in each cohort.Results: The overall response rate was 98% in the sorafenib cohort and 83% in the intensive chemotherapy cohort (P = .057). The median follow-up was 54 months. The median event-free survival was 35 months in the sorafenib cohort and 8 months in the intensive chemotherapy cohort (P = .019), and the median overall survival was 42 and 13 months, respectively (P = .026). With censoring at the time of allogeneic stem cell transplantation, the median event-free survival was 31 and 8 months in the sorafenib and intensive therapy cohorts, respectively (P = .031), and the median overall survival was not reached and 10 months, respectively (P = .001). Multivariate Cox proportional hazards models confirmed that treatment with sorafenib was a favorable prognostic factor (P = .009; hazard ratio, 0.558; 95% CI, 0.360-0.865).Conclusions: The addition of sorafenib improves survival in patients with FLT3-ITD-mutated AML regardless of whether they undergo allogeneic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Background: Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase the risk of atherosclerotic heart disease. Comorbidities significantly impact the prognosis of patients with myelodysplastic syndromes (MDS). The objective of this study was to determine the association and impact of CHIP mutations with comorbidities in patients with MDS.Methods: This retrospective analysis of 566 consecutive patients with MDS was conducted at The University of Texas MD Anderson Cancer Center from August 2013 to December 2016. The 27-item Adult Comorbidity Evaluation (ACE-27) scale was used to assess the severity of comorbid conditions. Next-generation sequencing was used to detect the presence of CHIP mutations in bone marrow aspirates. Spearman correlations and logistic regression analyses were used to determine the association between mutations and comorbidities.Results: Mutations in the genes tet methylcytosine dioxygenase 2 (TET2), ASXL transcriptional regulator 1 (ASXL1), DNA methyltransferase 3α (DNMT3A), Janus kinase 2 (JAK2), and tumor protein 53 (TP53) were noted in 20%, 18%, 9%, 2%, and 21% of patients, respectively. Patients with DNMT3A and JAK2 mutations had higher likelihoods of a prior history of myocardial infarction (odds ratio, 2.62; P = .03) and veno-occlusive disease (odds ratio, 6.48; P = .02), respectively. TP53 mutation was associated with a prior history of malignancy. Patients with TET2 mutation had no association with any comorbidity. A prognostic model including the revised International Prognostic Scoring System classification, the ACE-27 score, and TP53 mutation status (the I-RAT model) predicted median overall survival.Conclusions: In patients with MDS, the presence of CHIP-associated mutations is associated with comorbidities. DNMT3A and JAK2 mutations were associated with higher likelihoods of prior myocardial infarction and thrombotic events. There was no association between comorbidity and TET2 mutation. Incorporating the revised International Prognostic Scoring System classification with the ACE-27 and TP53 mutation status improved outcome prediction in patients with MDS. [ABSTRACT FROM AUTHOR]