Predictors of clinical outcome in myeloproliferative neoplasm, unclassifiable: A Bone Marrow Pathology Group study.

OBJECTIVES: Myeloproliferative neoplasm, unclassifiable (MPN-U, revised to MPN, not otherwise specified in the fifth edition of the World Health Organization classification) is a heterogeneous category of primary marrow disorders with clinical, morphologic, and/or molecular features that preclude classification as a more specific MPN subtype due to stage at diagnosis, overlapping features between MPN subtypes, or the presence of coexisting disorders. Compared with other MPN subtypes, the contribution of the mutational landscape in MPN-U in conjunction with other clinical and morphologic biomarkers to prognosis has been less well investigated. METHODS: We performed a multicenter, retrospective study of MPN-U (94 cases) to better define the clinicopathologic features, genetic landscape, and clinical outcomes, including subgroups of early-stage, advanced-stage, and coexisting disorders. The Dynamic International Prognostic Scoring System (DIPSS) plus scoring system was applied to assess its relevance to MPN-U prognosis. RESULTS: Multivariate analysis demonstrated bone marrow blast count and DIPSS plus score as statistically significant in predicting overall survival. Univariate analysis identified additional potential poor prognostic markers, including abnormal karyotype and absence of JAK2 mutation. Secondary mutations were frequent in the subset analyzed by next-generation sequencing (26/37 cases, 70.3%) with a borderline association between high molecular risk mutations and overall survival. CONCLUSIONS: This study, as one of the largest of MPN-U studies incorporating both clinicopathologic and molecular data, moves toward identification of biomarkers that better predict prognosis in this heterogeneous category.

Acetabular Labral Reconstruction Does Not Demonstrate Superior Biomechanical Properties Compared to Labral Repair or Intact Native Labrum but Is Superior to Labral Excision: A Systematic Review of Cadaveric Studies.

PURPOSE: To systematically review and compare biomechanical properties of labral reconstruction to labral repair, intact native labrum, and labral excision in cadaveric studies. METHODS: A search of the PubMed and Embase databases was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and checklist. Cadaveric studies focused on hip biomechanics related to intact labrum, labral repair, labral reconstruction, labral augmentation, and labral excision were included. Investigated parameters included biomechanical data measures, such as distraction force, distance to suction seal rupture, peak negative pressure, contact area, and fluid efflux. Review articles, duplicates, technique reports, case reports, opinion articles, articles written in a language other than English, clinical studies focusing on patient-reported outcomes, studies performed in animals, and articles with no abstract available were also excluded. RESULTS: Fourteen cadaveric biomechanical studies were included that compared labral reconstruction to labral repair (4 studies), labral reconstruction to labral excision (4 studies); and evaluation of distractive force of the labrum (3 studies), the distance to suction seal rupture (3 studies), fluid dynamics (2 studies), displacement at peak force (1 study), and stability ratio (1 study). Data pooling was not performed because of methodological heterogenicity of the studies. Labral reconstruction did not outperform labral repair in restoring the hip suction seal or any other biomechanical property. Labral repair significantly prevented greater fluid efflux when compared to labral reconstruction. Labral repair and reconstruction improved the distractive stability of the hip fluid seal from the labral tear and labral excision stage, respectively. Furthermore, labral reconstruction demonstrated to have better biomechanical properties than labral excision. CONCLUSIONS: In cadaveric studies, labral repair or intact native labrum was biomechanically more superior than labral reconstruction; however, labral reconstruction can restore acetabular labral biomechanical properties and was biomechanically superior to labral excision. CLINICAL RELEVANCE: In cadaveric models, labral repair outperforms segmental labral reconstruction in preserving the hip suction seal; nonetheless, segmental labral reconstruction biomechanically outperforms labral excision at time 0.

Defining Thresholds and Predictors for Achieving the Patient Acceptable Symptom State for Patient-Reported Outcome Measures After Revision Hip Arthroscopy.

BACKGROUND: The Patient Acceptable Symptom State (PASS) after primary hip arthroscopy has been determined; nonetheless, the PASS still needs to be defined for revision hip arthroscopy. PURPOSE: To define minimum 2-year follow-up PASS thresholds for the modified Harris Hip Score (mHHS), Nonarthritic Hip Score (NAHS), Hip Outcome Score-Sports Specific Subscale (HOS-SSS), visual analog scale (VAS) for pain, and International Hip Outcome Tool-12 (iHOT-12) after revision hip arthroscopy, and to identify predictors of achieving the PASS. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Data were prospectively collected and retrospectively reviewed for all patients who underwent revision hip arthroscopy between April 2017 and July 2020. Patients were included if they had baseline and minimum 2-year follow-up scores for the mHHS, NAHS, HOS-SSS, VAS for pain, and iHOT-12. PASS was calculated using the anchor-based method. Receiver operating characteristic curve analysis was used to determine the thresholds for the PASS. A multivariate logistic regression was used to identify predictors for achieving the PASS. RESULTS: A total of 318 patients who underwent revision hip arthroscopy met the inclusion criteria. Of those patients, 292 (91.8%) had baseline and minimum 2-year follow-up. Of this group, 68 patients (72.1% female and 27.9% male; mean age, 32.9 years) answered the PASS anchor question. Achievement PASS rates were 58.8%, 41.2%, 52.9%, 60.3%, and 52.9% for the mHHS, NAHS, HOS-SSS, VAS, and iHOT-12, respectively. The area under the curve (AUC) values for the PASS for mHHS, NAHS, HOS-SSS, VAS, and iHOT-12 were 0.912, 0.888, 0.857, 0.903, and 0.871, respectively, indicating excellent discrimination. The PASS for the mHHS was 76 (sensitivity, 0.809; specificity, 0.905), for the NAHS was 86.3 (sensitivity, 0.660; specificity, 1), for the HOS-SSS was 64.3 (sensitivity, 0.745; specificity, 0.905), for the VAS was 3 (sensitivity, 0.830; specificity, 0.905), and for the iHOT-12 was 64.3 (sensitivity, 0.745; specificity, 0.905). Body mass index (BMI) was identified as a significant predictor of achieving PASS for the NAHS (OR, 0.967; 95% CI, 0.940-0.996; P = .027), as patients with a BMI ≤25.4 had 1.03 times higher odds ratio of achieving PASS for the NAHS. CONCLUSION: After revision hip arthroscopy, the minimum 2-year follow-up PASS thresholds for the mHHS, NAHS, HOS-SSS, VAS for pain, and iHOT-12 were 76, 86.3, 64.3, 3, and 64.3, respectively. The odds ratio of achieving PASS for the NAHS was 1.03 times higher for patients with a BMI ≤25.4.

STAT5B mutations in myeloid neoplasms differ by disease subtypes but characterize a subset of chronic myeloid neoplasms with eosinophilia and/or basophilia.

STAT5B has been reported as a recurrent mutation in myeloid neoplasms (MNs) with eosinophilia, but the overall frequency and importance across a spectrum of MNs are largely unknown. We conducted a multicenter study on a series of 82 MNs with STAT5B mutations detected by next-generation sequencing. The estimated frequency of STAT5B mutation in MNs was low.

Defining the Percent Thresholds for Achieving the Maximum Outcome Improvement of the Modified Harris Hip Score, the Non-Arthritic Hip Score, the Hip Outcome Score-Sports Subscale, the Visual Analog Scale for Pain, and the International Hip Outcome Tool-12 in Revision Hip Arthroscopy at Minimum 2-Year Follow-Up.

PURPOSE: To determine the respective percent thresholds for achieving the maximal outcome improvement (MOI) for the modified Harris Hip Score (mHHS), the Non-Arthritic Hip Score (NAHS), the Hip Outcome Score-Sports Subscale (HOS-SSS), the visual analog scale (VAS) for pain, and the International Hip Outcome Tool-12 (iHOT-12) that were associated with satisfaction following revision hip arthroscopy, and to identify predictors for achieving the MOI. METHODS: An anchor question was provided to patients who underwent revision hip arthroscopy between April 2017 and July 2020. Patients were included for the final analysis if they answered the anchor question and had minimum 2-year follow-up. Receiver operating characteristic analysis was used to determine the thresholds for the percentage of the MOI predictive of satisfaction. A P-value of < .05 was considered significant. RESULTS: In total, 318 patients underwent revision hip arthroscopy. Of those patients, 292 (91.8%) had minimum 2-year follow-up. Of this cohort, 68 answered the anchor question, with 49 (72.1%) female and 19 (27.9%) male patients. The mean age, and body mass index time were 32.9 ± 13 years and 25.4 ± 5.1, respectively. It was determined that 42.1%, 50%, 48.1%, 50%, and 50% of MOI were the thresholds for maximal predictability of satisfaction for mHHS, NAHS, HOS-SS, VAS for pain, and the iHOT-12, respectively. The presence of unaddressed subspine impingement was a significant predictor for achieving the MOI threshold for the VAS (odds ratio 1.40; 95% confidence interval 1.00-1.95; P = 0.0273). CONCLUSIONS: Following revision hip arthroscopy, the percent thresholds for achieving the MOI at a minimum 2-year follow-up for the mHHS, NAHS, HOS-SS, VAS for pain, and iHOT-12 were 42.1%, 50%, 48.1%, 50%, and 50.9%, respectively. Addressing residual subspine impingement was identified as significant positive predictor for achieving the MOI. LEVEL OF EVIDENCE: Level IV, case-series.

Orthobiologics as an adjunct in treatment of femoroacetabular impingement syndrome: cell-based therapies facilitate improved postoperative outcomes in the setting of acetabular chondral lesions-a systematic review.

PURPOSE: To evaluate studies utilizing orthobiologics in the management of femoroacetabular impingement syndrome (FAIS) to (1) assess the indications for usage, and (2) analyze patient-reported outcome measures (PROM) following treatment. It was hypothesized that orthobiologics would (1) be utilized for symptomatic FAIS in the setting of labral or chondral pathology, and (2) improve PROM at most recent follow-up. METHODS: The Pubmed, Ovid Medline, Cochrane, and Web of Science databases were searched for clinical studies evaluating orthobiologics [hyaluronic acid (HA), platelet-rich plasma (PRP), or cell-based therapy (CBT) for treatment of FAIS. Exclusion criteria included orthobiologics used in conjunction with cartilage transfer or scaffolding procedures and a primary indication other than FAIS. Data collection included patient demographics, indications, and baseline and most recent PROM. RESULTS: Eleven studies (one level I, four level II, four level III, and two level IV evidence) met inclusion criteria, consisting of 440 patients with mean ages ranging from 32.8 to 47 years. All 11 studies demonstrated an improvement in PROM from baseline to most-recent follow-up. Four studies administered PRP either intraoperatively or the day after surgery as an adjunct to labral repair. CBT was used intraoperatively in the setting of acetabular chondral lesions (three studies) and labral repair (one study). When comparing to a control group at most recent follow-up, three PRP cohorts demonstrated similar PROM (n.s.), while one PRP group exhibited worse visual analog pain scores (2.5 vs. 3.4, p = 0.005) and modified Harris Hip Scores (mHHS) (82.6 vs. 78.7, p = 0.049). The four CBT studies reported favorable results compared to a control group, with a significantly higher mHHS at most recent follow-up or mean improvement from baseline in Hip Outcome Score-Activities of Daily Living (p < 0.05). Three studies reported on HA, which was utilized exclusively in the nonoperative setting. CONCLUSIONS: Intraoperative PRP and CBT have been commonly reported in the setting of hip arthroscopy for labral repairs and acetabular chondral lesions, respectively. The CBT cohorts demonstrated more favorable PROM at most recent follow-up when compared to a control group, though these results should be interpreted with caution due to heterogeneity of orthobiologic preparations. LEVEL OF EVIDENCE: IV.

Increased TIM-3 and galectin-9 serum levels in patients with advanced systemic mastocytosis.

BACKGROUND: Systemic mastocytosis is characterized by expansion of clonal mast cells in various tissues. Several biomarkers with diagnostic and therapeutic potential have recently been characterized in mastocytosis, such as the serum marker tryptase and the immune checkpoint molecule PD-L1. OBJECTIVE: We aimed to investigate whether serum levels of other checkpoint molecules are altered in systemic mastocytosis and whether these proteins are expressed in mastocytosis infiltrates in the bone marrow. METHODS: Levels of different checkpoint molecules were analyzed in serum of patients with different categories of systemic mastocytosis and healthy controls and correlated to disease severity. Bone marrow biopsies from patients with systemic mastocytosis were stained to confirm expression. RESULTS: Serum levels of TIM-3 and galectin-9 were increased in systemic mastocytosis, particularly in advanced subtypes, compared with healthy controls. TIM-3 and galectin-9 levels were also found to correlate with other biomarkers of systemic mastocytosis, such as serum tryptase and KIT D816V variant allele frequency in the peripheral blood. Moreover, we observed expression of TIM-3 and galectin-9 in mastocytosis infiltrates in bone marrow. CONCLUSIONS: Together, our results demonstrate for the first time that serum levels of TIM-3 and galectin-9 are increased in advanced systemic mastocytosis. Moreover, TIM-3 and galectin-9 are expressed in bone marrow infiltrates in mastocytosis. These findings provide a rationale for exploring TIM-3 and galectin-9 as diagnostic markers and eventually therapeutic targets in systemic mastocytosis, particularly in advanced forms.

Genomic Data Heterogeneity across Molecular Diagnostic Laboratories: A Real-World Connect Myeloid Disease Registry Perspective on Variabilities in Genomic Assay Methodology and Reporting.

Genomic data variability from laboratory reports can impact clinical decisions and population-level analyses; however, the extent of this variability and the impact on the data's value are not well characterized. This pilot study used anonymized genetic and genomic test reports from the Connect Myeloid Disease Registry (NCT01688011), a multicenter, prospective, observational cohort study of patients with newly diagnosed myelodysplastic syndromes, acute myeloid leukemia, or idiopathic cytopenia of undetermined significance, to analyze laboratory test variabilities and limitations. Results for 56 randomly selected patients enrolled in the Registry were independently extracted and evaluated (data cutoff, January 2020). Ninety-five reports describing 113 assay results from these 56 patients were analyzed for discrepancies. Almost all assay results [101 (89%)] identified the sequencing technology applied, and 94 (83%) described the test limitations; 95 (84%) described the limits of detection, but none described the limit of blank for detecting false positives. RNA transcript identifiers were not provided for 20 (43%) variants analyzed by next-generation sequencing and reported by the same laboratory. Of 42 variants with variant allele frequencies ≥30%, 16 (38%) of the variants did not have report text indicating that the variants might be germline. Variabilities and lack of standardization present challenges for incorporating this information into clinical care and render data collation ineffective and unreliable for large-scale use in centralized databases for therapeutic discovery.

Profiling endogenous, environmental, and infectious disease mutational signatures in blastic plasmacytoid dendritic cell neoplasms.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematopoietic disease derived from plasmacytoid dendritic lineage cells. The disease typically shows skin as well as frequent bone marrow and peripheral blood involvement. However, the pathogenesis of this disease is still not well understood. While somatic point mutations and genetic rearrangements have been described in BPDCN, the types and origins of these mutations and relationships to other cancer types is not well understood. MATERIALS AND METHODS: To probe the origins of BPDCN, we analyzed the exome sequence data of 9 tumor-normal pair cases of BPDCN. We utilized SignatureAnalyzer, SigProfiler and a custom microbial analysis pipeline to understand the relevance of endogenous and environmental mutagenic processes. RESULTS: Our results identified a significant tobacco exposure and aging genetic signature as well as signatures related to nucleotide excision repair deficiency, ultra violet (UV) exposure, and endogenous deamination in BPDCN. We also assessed the samples for microbial infectious disease organisms but did not find a link to a microbial etiology. CONCLUSION: The identification of a tobacco exposure and aging genetic signature in patients with BPDCN suggests that environmental and endogenous genetic changes may be central to the oncogenesis of BPDCN.

Guide to the Diagnosis of Myeloid Neoplasms: A Bone Marrow Pathology Group Approach.

OBJECTIVES: The practicing pathologist is challenged by the ever-increasing diagnostic complexity of myeloid neoplasms. This guide is intended to provide a general roadmap from initial case detection, often triggered by complete blood count results with subsequent blood smear review, to final diagnosis. METHODS: The integration of hematologic, morphologic, immunophenotypic, and genetic features into routine practice is standard of care. The requirement for molecular genetic testing has increased along with the complexity of test types, the utility of different testing modalities in identifying key gene mutations, and the sensitivity and turnaround time for various assays. RESULTS: Classification systems for myeloid neoplasms have evolved to achieve the goal of providing a pathology diagnosis that enhances patient care, outcome prediction, and treatment options for individual patients and is formulated, endorsed, and adopted by hematologists/oncologists. CONCLUSIONS: This guide provides diagnostic strategies for all myeloid neoplasm subtypes. Special considerations are provided for each category of testing and neoplasm category, along with classification information, genetic testing requirements, interpretation information, and case reporting recommendations based on the experience of 11 Bone Marrow Pathology Group members.

Transplantation Referral Patterns for Patients with Newly Diagnosed Higher-Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia at Academic and Community Sites in the Connect® Myeloid Disease Registry: Potential Barriers to Care.

Hematopoietic stem cell transplantation (HCT) is indicated for patients with higher-risk (HR) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Age, performance status, patient frailty, comorbidities, and nonclinical factors (eg, cost, distance to site) are all recognized as important clinical factors that can influence HCT referral patterns and patient outcomes; however, the proportion of eligible patients referred for HCT in routine clinical practice is largely unknown. This study aimed to assess patterns of consideration for HCT among patients with HR-MDS and AML enrolled in the Connect® Myeloid Disease Registry at community/government (CO/GOV)- or academic (AC)-based sites, as well as to identify factors associated with rates of transplantation referral. We assessed patterns of consideration for and completion of HCT in patients with HR-MDS and AML enrolled between December 12, 2013, and March 6, 2020, in the Connect Myeloid Disease Registry at 164 CO/GOV and AC sites. Registry sites recorded whether patients were considered for transplantation at baseline and at each follow-up visit. The following answers were possible: "considered potentially eligible," "not considered potentially eligible," or "not assessed." Sites also recorded whether patients subsequently underwent HCT at each follow-up visit. Rates of consideration for HCT between CO/GOV and AC sites were compared using multivariable logistic regression analysis with covariates for age and comorbidity. Among the 778 patients with HR-MDS or AML enrolled in the Connect Myeloid Disease Registry, patients at CO/GOV sites were less likely to be considered potentially eligible for HCT than patients at AC sites (27.9% versus 43.9%; P < .0001). Multivariable logistic regression analysis with factors for age (<65 versus ≥65 years) and ACE-27 comorbidity grade (<2 versus ≥2) showed that patients at CO/GOV sites were significantly less likely than those at AC sites to be considered potentially eligible for HCT (odds ratio, 1.6, 95% confidence interval, 1.1 to 2.4; P = .0155). Among patients considered eligible for HCT, 45.1% (65 of 144) of those at CO/GOV sites and 35.7% (41 of 115) of those at AC sites underwent transplantation (P = .12). Approximately one-half of all patients at CO/GOV (50.1%) and AC (45.4%) sites were not considered potentially eligible for HCT; the most common reasons were age at CO/GOV sites (71.5%) and comorbidities at AC sites (52.1%). Across all sites, 17.4% of patients were reported as not assessed (and thus not considered) for HCT by their treating physician (20.7% at CO/GOV sites and 10.7% at AC sites; P = .0005). These findings suggest that many patients with HR-MDS and AML who may be candidates for HCT are not receiving assessment or consideration for transplantation in clinical practice. In addition, treatment at CO/GOV sites and age remain significant barriers to ensuring that all potentially eligible patients are assessed for HCT.

Smoking status in acute myeloid leukemia is associated with worse overall survival and independent of prior nonhematopoietic malignancies, cytogenetic abnormalities, and WHO category.

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy with several patient- and disease-associated variables known to impact prognosis. Tobacco smoking is an environmental factor associated with a greater incidence of AML, but there have been limited studies that evaluated smoking toward overall survival. We retrospectively searched for AML cases and collected clinical and diagnostic data for each case. We also used an independent next-generation sequencing (NGS) data set to assess for a distinct mutational signature associated with smoking. When stratified by smoking status, there was a greater number of males, patients aged ≥60 years, and patients with ≥2 comorbidities within the smoking category (P < .05). Survival analysis demonstrated decreased survival probability in the smokers, male smokers, smokers with 1 other comorbidity, and smokers without a prior history of nonhematopoietic malignancy (P < .05) as compared to nonsmokers. Smoking was associated with a decrease in survival within the World Health Organization categories of AML, not otherwise specified (AML NOS; P = .035) and AML with recurrent genetic abnormalities (AML RGA; P = .002). Multivariate analysis showed that patients who were smokers had a greater hazard ratio than nonsmokers after adjusting for the other covariates. Our findings demonstrated that smoking was independently associated with decreased overall survival after adjusting for other potentially confounding factors. In addition, our results suggest that a mutational signature can be recognized using NGS data in a subset of AML patients who smoke.

Myeloid sarcoma with NPM1 mutation may be clinically and genetically distinct from AML with NPM1 mutation: a study from the Bone Marrow Pathology Group.

Myeloid sarcoma (MS) is currently considered equivalent to de novo acute myeloid leukemia (AML); however, the relationship between these entities is poorly understood. This retrospective multi-institutional cohort study compared 43 MS with NPM1 mutation to 106 AML with NPM1 mutation. Compared to AML, MS had more frequent cytogenetic abnormalities including complex karyotype (p = .009 and p = .007, respectively) and was enriched in mutations of genes involved in histone modification, including ASXL1 (p = .007 and p = .008, respectively). AML harbored a higher average number of gene mutations (p = .002) including more frequent PTPN11 mutations (p < .001) and mutations of DNA-methylating genes including DNMT3A and IDH1 (both p < .001). MS had significantly shorter overall survival (OS) than AML (median OS: 44.9 vs. 93.2 months, respectively, p = .037). MS with NPM1 mutation has a unique genetic landscape, and poorer OS, compared to AML with NPM1 mutation.

First study comparing genetic profiles of MS and AML with a common disease-defining lesion.NPM1^Mut MS may be genetically distinct from NPM1^Mut AML.NPM1^Mut MS may have inferior overall survival compared to NPM1^Mut AML.

Triple-Negative Primary Myelofibrosis: A Bone Marrow Pathology Group Study.

Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm driven by canonical gene mutations in JAK2, CALR, or MPL in >80% of the cases. PMF that lacks these canonical alterations is termed triple-negative PMF (TN-PMF). The pathologic and genetic characteristics of TN-PMF compared with those of conventional PMF with canonical driver mutations (DM-PMF) have not been well studied. We aimed to identify clinicopathologic and molecular genetic differences between patients with TN-PMF (n = 56) and DM-PMF (n = 89), all of whom fulfilled the 2016 World Health Organization diagnostic criteria for PMF. Compared with the control group, patients in the TN-PMF group were more likely to have thrombocytopenia and less likely to have organomegaly. The bone marrow in patients with TN-PMF showed fewer granulocytic elements and more frequent dyserythropoiesis. Cytogenetic analysis showed a higher incidence of trisomy 8. Targeted next-generation sequencing revealed a lower frequency of ASXL1 mutations but enrichment of ASXL1/SRSF2 comutations. Our findings demonstrated several clinicopathologic and molecular differences between TN-PMF and DM-PMF. These findings, particularly the observed mutation profile characterized by a higher frequency of ASXL1 and SRSF2 comutation, suggest that at least a subset of TN-PMF may be pathogenetically different from DM-PMF, with potential prognostic implications.

Clinicopathologic and Molecular Analysis of Normal Karyotype Therapy-Related and De Novo Acute Myeloid Leukemia: A Multi-Institutional Study by the Bone Marrow Pathology Group.

PURPOSE: Therapy-related acute myeloid leukemias (t-AML) are a heterogenous group of aggressive neoplasms that arise following exposure to cytotoxic chemotherapy and/or ionizing radiation. Many therapy-related myeloid neoplasms (t-MN) are associated with distinct chromosomal aberrations and/or TP53 alterations, but little is known about the clinicopathologic and molecular features of normal karyotype t-AML (NK-t-AML) and whether this t-MN subtype is distinctly different from NK de novo AML (NK-dn-AML). METHODS: This multi-institutional study by the Bone Marrow Pathology Group retrospectively evaluated clinicopathologic and molecular characteristics of 335 patients with NK-AML, comprising 105 t-AML and 230 dn-AML cases. RESULTS: Patients with t-AML compared with dn-AML exhibit significantly shorter overall survival (OS; median months: 17.6 v 44.2; P < .0001) and relapse-free survival (RFS; median months: 9.1 v 19.2; P = .0018). Frequency of NPM1, FLT3, KRAS, and GATA2 mutations were significantly different in NK-t-AML compared with NK-dn-AML (NPM1 35% v 49%; P = .0493; FLT3 23% v 36%; P = 0494; KRAS 12% v 5%; P = .0465; GATA2 9% v 2% P = .0105), while TP53 mutations were rare. Patients with t-AML more often stratified into intermediate or adverse 2017 ELN genetic risk groups. Favorable ELN risk predicted favorable OS (hazard ratio [HR], 0.4056; 95% CI, 0 to 0.866; P = .020) and RFS (HR, 0.355; 95% CI, 0 to 0.746; P = .006). Among all patients with NK-AML, stem-cell transplant and favorable ELN risk both significantly affected RFS, while therapy-relatedness and age had a borderline significant impact on OS (HR, 1.355; 95% CI, 0.975 to 1.882; P = .070). CONCLUSION: To our knowledge, this is the largest study to date to comprehensively evaluate NK-t-AML and provides a framework that may inform our understanding of NK-t-AML disease biology and could potentially help guide therapeutic management and improved disease classification in t-MNs that lack cytogenetic aberrations.