Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial.

This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 (isocitrate dehydrogenase 2) inhibitor, with conventional care regimens (CCRs) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care) and then randomized (1:1) to enasidenib 100 mg per day or CCR. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI). Overall, 319 patients were randomized to enasidenib (n = 158) or CCR (n = 161). The median age was 71 years, median (range) enasidenib exposure was 142 days (3 to 1270), and CCR was 36 days (1 to 1166). One enasidenib (0.6%) and 20 CCR (12%) patients received no randomized treatment, and 30% and 43%, respectively, received subsequent AML-directed therapies during follow-up. The median OS with enasidenib vs CCR was 6.5 vs 6.2 months (HR [hazard ratio], 0.86; P = .23); 1-year survival was 37.5% vs 26.1%. Enasidenib meaningfully improved EFS (median, 4.9 vs 2.6 months with CCR; HR, 0.68; P = .008), TTF (median, 4.9 vs 1.9 months; HR, 0.53; P < .001), ORR (40.5% vs 9.9%; P <.001), HI (42.4% vs 11.2%), and red blood cell (RBC)-TI (31.7% vs 9.3%). Enasidenib safety was consistent with prior reports. The primary study endpoint was not met, but OS was confounded by early dropout and subsequent AML-directed therapies. Enasidenib provided meaningful benefits in EFS, TTF, ORR, HI, and RBC-TI in this heavily pretreated older mutant-IDH2 R/R AML population.

North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC's inaugural meetings are presented herein.

Results of Randomized Controlled Trials of Platelet-Rich Plasma in Lower-Extremity Tendinopathy Are Not Influenced by Industry Sponsorship.

PURPOSE: To determine whether industry affiliation influences the results of randomized controlled trials (RCTs) studying the use of platelet-rich plasma (PRP) for the treatment of patellar or Achilles tendinopathy. METHODS: The PubMed, Scopus, Cochrane, and MEDLINE databases were searched in July 2023 for RCTs investigating PRP for the treatment of patellar or Achilles tendinopathy published between 2009 and July 2023. Industry affiliation was determined by analyzing each study's funding or conflict-of-interest section. Author disclosures were searched in the American Academy of Orthopaedic Surgeons disclosure database and the Centers for Medicare & Medicaid Services open payments database. An industry-affiliated (IA) designation was given if an author had a relevant disclosure or if the company that funded the study manufactured PRP. Otherwise, a non-industry-affiliated (NIA) designation was given. Fisher exact analysis was used to determine whether PRP had a favorable effect, no significant effect, or an unfavorable effect on outcome. RESULTS: Analysis was performed on 22 studies (10 IA and 12 NIA), with 17 studies (77.3%) reporting a conflict of interest or funding for the research, 4 (18.2%) reporting no conflict of interest, and 1 (4.5%) with no reporting. Of the 22 included studies, 8 (36.4%) reported favorable outcomes regarding PRP use and 14 (63.6%) reported no significant effect. Favorable outcomes were found in 4 of the 10 IA studies (40.0%), whereas no significant effect was reported in 6 (60.0%). The 12 NIA studies included 4 (33.3%) with favorable results and 8 (66.7%) with no significant effect. The comparison between industry affiliation and results reported was not statistically significant (P > .999). CONCLUSIONS: The results of RCTs evaluating the use of PRP in lower-extremity tendinopathy were not influenced by industry sponsorship. CLINICAL RELEVANCE: Most biomedical research is funded through industry sponsorship. Although this relation is necessary as technologies are developed, it is important to scrutinize studies for evidence of industry bias to understand how this bias may be affecting study results published in the literature.

Most Major Hospitals Fail to Comply With Federal Price Transparency Regulations.

PURPOSE: To present hospital compliance with federal price transparency regulations for sports medicine procedures. METHODS: Online price estimator and machine-readable files were recovered for U.S. News and World Report's top 100 orthopaedic hospitals. From June to November 2023, compliance and monetary values were recorded for each of Centers for Medicare and Medicaid Services price transparency regulations. Price estimator data were assessed on the basis of hospital placement in the bottom and top 50 of the 100 institutions under review, as well as by region (Northeast, South, Midwest, West). Statistical analyses included 2-sample t tests and Kruskal-Wallis tests. RESULTS: In total, 95% of hospitals had a price estimator tool for both subacromial decompression (Current Procedural Terminology [CPT] code 29826) and meniscectomy (CPT code 29881). Only 38% were compliant with all regulations for subacromial decompression and 39% for meniscectomy; the remaining did not list minimum or maximum procedure charges. Higher-ranked hospitals were significantly more likely to charge a greater cash price for subacromial decompression and meniscectomy (P = .040 and P = .009, respectively). Compliance with machine-readable file reporting was poor, with less than 20% meeting requirements for each CPT code. Reported prices varied greatly by hospital. CONCLUSIONS: This study demonstrates that U.S. News and World Report's top 100 orthopaedic hospitals exhibit poor overall compliance with federal price transparency regulations for sports medicine procedures. Most often they lack full compliance by not reporting minimum or maximum charges as part of their price estimator tool or do not report procedure prices in their machine-readable files. Hospitals also exhibit wide variation in prices reported for specific procedures. CLINICAL RELEVANCE: Consumer price transparency continues to be an important goal in health care, as it allows patients to make informed decisions when selecting appropriate treatment options and providers. To realize the full benefits of price transparency, hospitals should address areas of improvement.

Randomized controlled trials in the shoulder arthroplasty literature rarely include key demographic and socioeconomic patient data.

BACKGROUND: It is well known that socioeconomic and demographic variables can greatly affect health outcomes. Previous studies across medical and surgical subspecialties have demonstrated that these variables are frequently under-reported in randomized controlled trials (RCTs). No such study currently exists that examines rates of reporting of sociodemographic variables in shoulder arthroplasty RCTs. This study aims to present these rates and explore the impact of failing to report socioeconomic variables in shoulder arthroplasty RCTs. METHODS: The PubMed database was queried for the term shoulder arthroplasty. Sixty-five RCTs from the past 10 years were identified for inclusion from 5 high-impact orthopedic surgery journals. Each RCT was analyzed for patient age and sex or gender as well as the following sociodemographic variables: race, ethnicity, insurance status, income, work status, and education. It was also noted whether each of the above variable was mentioned in the results section of the article. Data were presented in a descriptive fashion as well as analyzed using χ2 and Fisher exact tests where appropriate. RESULTS: From 2014 to 2023, the 65 shoulder arthroplasty RCTs published reported age in 40 of 65 (61.5%) in their results sections and 61 of 65 (93.8%) in any section. Sex or gender was reported in 27 of 65 (41.5%) in their results sections and 61 of 65 (93.8%) in any section. No articles included any sociodemographic variables in the results section. Reporting rates for sociodemographic variables in any section were as follows: race, 6 of 65 (9.2%); ethnicity, 5 of 65 (7.7%); work status, 4 of 65 (6.2%); and insurance status, 1 of 65 (1.5%). No studies included income or education of the enrolled patients. There was no difference in reporting sociodemographic variables by journal (P = .45) or by year of publication (P = .57). However, no study prior to 2020 included any sociodemographic variable (0 of 27, 0%), whereas from 2020 onward 6 studies included at least 1 (6 of 38, 15.8%). Sociodemographic variables were reported significantly less frequently than age and sex or gender (P = .001). DISCUSSION: Our study found sociodemographic variables are rarely reported in shoulder arthroplasty RCTs, whereas age and sex or gender are reported with great frequency. In order to understand the results of shoulder arthroplasty RCTs, apply their findings to the care of our patients, and address health disparities, we must ensure these studies include patient sociodemographic data.

Perioperative intravenous dexamethasone use is not associated with periprosthetic joint infection or wound healing complications following shoulder arthroplasty.

BACKGROUND: Perioperative intravenous (IV) dexamethasone is commonly used in lower extremity total joint arthroplasty to manage postoperative pain and nausea/vomiting, and recent studies have demonstrated that its use may lower rates of acute postoperative medical complications. However, there is limited information regarding the safety and efficacy of IV dexamethasone in patients undergoing total shoulder arthroplasty (TSA). Additionally, there is concern surrounding corticosteroid use prior to surgery as preoperative corticosteroid injections have been associated with adverse outcomes after TSA, including periprosthetic joint infection (PJI) and revision surgery. Thus, the purpose of this study was to evaluate the effect of perioperative IV dexamethasone on 90-day rates of PJI, wound complications, and medical complications after TSA. METHODS: The Premiere national hospital database was used to identify adult patients undergoing elective TSA between 2016 and 2020; patients were excluded if they were under 18 years old, were undergoing revision TSA, or had a prior proximal humerus open reduction internal fixation procedure. Patients who did and did not receive perioperative IV dexamethasone were then compared in both univariate and multivariate analyses. A Bonferroni correction was utilized to adjust for multiple comparisons. The primary end point was risk of acute infectious complications within 90 days of surgery, including PJI and wound infection/dehiscence. Secondary end points included acute pulmonary, renal, and thromboembolic complications. RESULTS: A total of 135,333 patients underwent TSA during the study period; 61.2% underwent reverse total shoulder arthroplasty, 33.8% underwent anatomic total shoulder arthroplasty, and 5.0% underwent hemiarthroplasty. From 2016 to 2020, perioperative IV dexamethasone use increased by 135%. Multivariate analysis revealed that patients who received perioperative IV dexamethasone did not have increased odds of PJI, superficial wound infection, or wound dehiscence (P = .15-.47) but did have decreased odds of sepsis (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.55-0.81) and other medical complications such as urinary tract infection and acute kidney injury. Additionally, there was a trend towards decreased 90-day hospital readmission (OR 0.88, 95% CI 0.81-0.96, P = .003). CONCLUSIONS: Perioperative IV dexamethasone was not associated with increased risk of acute infectious and wound healing complications. Moreover, patients who received perioperative IV dexamethasone had decreased odds of medical complications and trended toward lower rates of 90-day hospital readmission. The results of this study support the safety of perioperative IV dexamethasone use in patients undergoing elective TSA.

Evaluation of spin in reviews of biodegradable balloon spacers for massive irreparable rotator cuff tears.

HYPOTHESIS: Clinical studies are often at risk of spin, a form of bias where beneficial claims are overstated while negative findings are minimized or dismissed. Spin is often more problematic in abstracts given their brevity and can result in the misrepresentation of a study's actual findings. The goal of this study is to aggregate primary and secondary studies reporting the clinical outcomes of the use of subacromial balloon spacers in the treatment of massive irreparable rotator cuff tears to identify the incidence of spin and find any significant association with study design parameters. MATERIALS AND METHODS: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Independent searches were completed on 2 databases (PubMed and Embase) for primary studies, systematic and current concepts reviews, and meta-analyses and the results were compiled. Two authors independently screened the studies using a predetermined inclusion criteria and aggregated data including titles, publication journals and years, authors, study design, etc. Each study was independently assessed for the presence of 15 different types of spin. Statistical analysis was conducted to identify associations between study characteristics and spin. RESULTS: Twenty-nine studies met the inclusion criteria for our analysis, of which 10 were reviews or meta-analyses and 19 were primary studies. Spin was identified in every study except for 2 (27/29, 93.1%). Type 3 spin, "Selective reporting of or overemphasis on efficacy outcomes or analysis favoring the beneficial effect of the experimental intervention" and type 9 spin, "Conclusion claims the beneficial effect of the experimental treatment despite reporting bias" were most frequently noted in our study, both observed in 12/29 studies (41.4%). Date of publication, and adherence to Preferred Reporting Items for Systematic Reviews and Meta-Analyses or "The International Prospective Register of Systematic Reviews" were study characteristics associated with a higher rate of certain types of spin. There was a statistically significant association between disclosure of external study funding source and the presence of spin type 4, but none of the other forms of spin. CONCLUSION: Spin is highly prevalent in the abstracts of primary studies, systematic reviews, and meta-analyses discussing the use of subacromial balloon spacer technology in the treatment of massive irreparable rotator cuff tears. Our findings revealed that spin in the abstract tended to favor the balloon spacer intervention. Further efforts are required in the future to mitigate spin within the abstracts of published manuscripts.

Outcomes of multiligament knee injury treated with versus without internal brace suture augmentation.

PURPOSE: To compare the postoperative outcomes between Internal Brace (IB) and non-IB patients who underwent surgical management of multiple-ligament knee injuries (MLKI). METHODS: Patients who underwent surgical management of MLKI at two institutions between 2010 and 2020 were identified and offered participation in the study via the collection of postoperative functional outcomes for MLKI; Lysholm Knee score, Multiligament Quality of Life (ML-QOL), Patient-Reported Outcomes Measurement Information System (PROMIS) computer adaptive testing (CAT), Pain Interference (PI), Physical Function (PF), and Mobility instruments (MI). The postoperative outcomes and reoperation rates were compared between the IB group and non-IB group. RESULTS: One hundred and twenty-six patients were analyzed; 89 were included in the IB group (31.5% female; age 35.6 ± 1.4 years), and 37 were included in the non-IB group (25.7% female; age 38.8 ± 2.4 years). Mean follow-up time of the entire cohort was 37.9 ± 4.7 months [IB: 21.8 + 1.63; non-IB: 76.4 ± 6.2, p < 0.001). The IB group achieved similar PROMIS CAT [PROMIS Pain (51.8 + 1.1 vs. 52.1 + 1.6, p = 0.8736), Physical Function (46.6 + 1.2 vs. 46.4 + 1.8, p = 0.9168), Mobility (46.0 + 1.0 vs. 43.7 + 1.6, p = 0.2185)], ML-QOL [ML-QOL Physical Impairment (36.6 + 2.5 vs. 43.5 ± 4.2, p = 0.1485), Emotional Impairment (42.5 + 2.9 vs. 48.6 ± 4.6, p = 0.2695), Activity Limitation (34.5 + 2.8 vs. 36.2 ± 4.3, p = 0.7384), Societal Involvement (39.1 + 3.0 vs. 41.7 + 4.2, p = 0.6434)] and Lysholm knee score (64.9 + 2.5 vs. 60.4 + 4.0, p = 0.3397) postoperatively compared the non-IB group, but the differences were not significant. CONCLUSION: In this cohort of patients with MLKI treated with versus without IB, outcomes and reoperation rates trended toward favoring IB, but the study was not sufficiently powered to reach statistical significance. Internal bracing could be useful in the management of MLKI. In the future, matched patient cohorts with more patients are warranted to further evaluate the clinical impact of the internal brace in MLKI.

Psychological mobile app for patients with acute myeloid leukemia: A pilot randomized clinical trial.

BACKGROUND: Patients with acute myeloid leukemia (AML) experience a substantial decline in quality of life (QoL) and mood during their hospitalization for intensive chemotherapy, yet few interventions have been developed to enhance patient-reported outcomes during treatment. METHODS: We conducted a pilot randomized trial (ClinicalTrials.gov identifier NCT03372291) of DREAMLAND, a psychological mobile application for patients with a new diagnosis of AML who are receiving intensive chemotherapy. Patients were randomly assigned to DREAMLAND or usual care. DREAMLAND included four required modules focused on: (1) supportive psychotherapy to help patients deal with the initial shock of diagnosis, (2) psychoeducation to manage illness expectations, (3) psychosocial skill-building to promote effective coping, and (4) self-care. The primary end point was feasibility, which was defined as ≥60% of eligible patients enrolling and 60% of those enrolled completing ≥60% of the required modules. We assessed patient QoL (the Functional Assessment of Cancer Therapy-Leukemia), psychological distress (the Hospital Anxiety and Depression Scale and the Patient Health Questionnaire-9), symptom burden (the Edmonton Symptom Assessment Scale), and self-efficacy (the Cancer Self-Efficacy Scale) at baseline and at day 20 after postchemotherapy. RESULTS: We enrolled 60 of 90 eligible patients (66.7%), and 62.1% completed ≥75% of the intervention modules. At day 20 after chemotherapy, patients who were randomized to DREAMLAND reported improved QoL scores (132.06 vs. 110.72; p =.001), lower anxiety symptoms (3.54 vs. 5.64; p = .010) and depression symptoms (Hospital Anxiety and Depression Scale: 4.76 vs. 6.29; p = .121; Patient Health Questionnaire-9: 4.62 vs. 8.35; p < .001), and improved symptom burden (24.89 vs. 40.60; p = .007) and self-efficacy (151.84 vs. 135.43; p = .004) compared with the usual care group. CONCLUSIONS: A psychological mobile application for patients with newly diagnosed AML is feasible to integrate during hospitalization for intensive chemotherapy and may improve QoL, mood, symptom burden, and self-efficacy.

Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study.

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.

Multisite 11-year experience of less-intensive vs intensive therapies in acute myeloid leukemia.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

Acute Myeloid Leukemia, Version 3.2023, NCCN Clinical Practice Guidelines in Oncology.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Chemotherapy Resistance in B-ALL with Cryptic NUP214-ABL1 Is Amenable to Kinase Inhibition and Immunotherapy.

BCR-ABL1 kinase inhibitors have improved the prognosis of Philadelphia-chromosome-positive (Ph+)-acute lymphoblastic leukemia (ALL). Ph-like (or BCR-ABL1-like) ALL does not express BCR-ABL1 but commonly harbors other genomic alterations of signaling molecules that may be amenable to therapy. Here, we report a case with a NUP214-ABL1 fusion detected at relapse by multiplexed, targeted RNA sequencing. It had escaped conventional molecular work-up at diagnosis, including cytogenetic analysis and fluorescence in situ hybridization for ABL1 rearrangements. The patient had responded poorly to initial multi-agent chemotherapy and inotuzumab immunotherapy at relapse before the fusion was revealed. The addition of dasatinib targeting NUP214-ABL1 to inotuzumab resulted in complete molecular remission, but recurrence occurred rapidly with dasatinib alone. However, deep molecular remission was recaptured with a combination of blinatumomab and ponatinib, so he could proceed to allotransplantation. This case illustrates that next-generation sequencing approaches designed to discover cryptic gene fusions can benefit patients with Ph-like ALL.

Implementation and Clinical Adoption of Precision Oncology Workflows Across a Healthcare Network.

BACKGROUND: Precision oncology relies on molecular diagnostics, and the value-proposition of modern healthcare networks promises a higher standard of care across partner sites. We present the results of a clinical pilot to standardize precision oncology workflows. METHODS: Workflows are defined as the development, roll-out, and updating of disease-specific molecular order sets. We tracked the timeline, composition, and effort of consensus meetings to define the combination of molecular tests. To assess clinical impact, we examined order set adoption over a two-year period (before and after roll-out) across all gastrointestinal and hepatopancreatobiliary (GI) malignancies, and by provider location within the network. RESULTS: Development of 12 disease center-specific order sets took ~9 months, and the average number of tests per indication changed from 2.9 to 2.8 (P = .74). After roll-out, we identified significant increases in requests for GI patients (17%; P < .001), compliance with testing recommendations (9%; P < .001), and the fraction of "abnormal" results (6%; P < .001). Of 1088 GI patients, only 3 received targeted agents based on findings derived from non-recommended orders (1 before and 2 after roll-out); indicating that our practice did not negatively affect patient treatments. Preliminary analysis showed 99% compliance by providers in network sites, confirming the adoption of the order sets across the network. CONCLUSION: Our study details the effort of establishing precision oncology workflows, the adoption pattern, and the absence of harm from the reduction of non-recommended orders. Establishing a modifiable communication tool for molecular testing is an essential component to optimize patient care via precision oncology.

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML.

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. METHODS: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. RESULTS: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%). CONCLUSIONS: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).

Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia.

Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.

Correlation of p53 immunohistochemistry with TP53 mutational status and overall survival in newly diagnosed acute myeloid leukaemia.

AIMS: TP53-mutated acute myeloid leukaemia (AML) is associated with an adverse prognosis and poor response to traditional chemotherapy regimens. Next-generation sequencing (NGS) is considered the gold standard method to determine TP53-mutational status; however, molecular assays are costly and time-consuming. In contrast, immunohistochemistry (IHC) can be performed within 1 day of biopsy. We sought to determine an optimal threshold of staining with p53 IHC to predict TP53-mutational status. METHODS AND RESULTS: We identified 142 consecutive patients with newly diagnosed AML with concurrent NGS analysis diagnosed between 2019 and 2020. All cases were stained for p53 IHC and images were scored for the percent of strongly stained p53+ cells by a combination of manual counting and image analysis. We then correlated percent positive staining with mutational status and clinical outcomes. We determined that a threshold of ≥7% strongly stained cells by p53 IHC correlated with the presence of a TP53 mutation with a sensitivity of 67%, specificity of 100%, positive predictive value of 100% and negative predictive value of 90%. TP53 mutation and the presence of ≥7% staining by IHC were associated with shorter overall survival by univariate analysis (P < 0.01). CONCLUSION: If the limitations of this study are carefully considered, our findings suggest that p53 protein expression as evaluated by IHC could be used to rapidly predict TP53-mutational status with high specificity and assist in risk stratification in newly diagnosed AML.

Relationship Between Longitudinal Coping Strategies and Outcomes in Patients With Acute Myeloid Leukemia.

BACKGROUND: Patients with acute myeloid leukemia (AML) face an abrupt life-threatening illness and experience immense physical and psychological symptoms. However, no data describe how patients with AML cope longitudinally with their illness or the relationship between longitudinal coping and outcomes. METHODS: We conducted a secondary analysis of longitudinal data from 160 patients with high-risk AML enrolled in a supportive care intervention trial to describe coping strategies longitudinally across the illness course. We used the Brief COPE questionnaire, the Hospital Anxiety and Depression Scale, the Post-Traumatic Stress Disorder (PTSD) Checklist-Civilian Version, and the Functional Assessment of Cancer Therapy-Leukemia to measure coping strategies, psychological distress, and quality of life (QoL) at baseline and at weeks 2, 4, 12, and 24 after diagnosis. Electronic health records were used to assess healthcare utilization and end-of-life (EoL) outcomes, and multivariate analyses were used to assess the relationship between coping and outcomes. RESULTS: Longitudinal utilization of approach-oriented coping strategies was significantly associated with less distress (anxiety: ß, -0.18; P<.001; depression symptoms: ß, -0.42; P<.001; PTSD symptoms: ß, -0.60; P<.001) and better QoL (ß, 2.00; P<.001). Longitudinal utilization of avoidant coping strategies was significantly associated with greater distress (anxiety: ß, 0.64; depression symptoms: ß, 0.54; PTSD symptoms: ß, 2.13; P<.001 for all) and worse QoL (ß, -4.27; P<.001). Although the use of approach-oriented and avoidant coping strategies was not significantly associated with hospitalization, chemotherapy administration, or hospice use in the last 30 days of life, approach-oriented coping was associated with lower odds of ICU admissions (odds ratio, 0.92; P=.049). CONCLUSIONS: Longitudinal use of approach-oriented coping strategies was associated with less psychological distress, better QoL, and a lower likelihood of ICU admission, suggesting a possible target for supportive oncology interventions. Coping strategies did not impact EoL outcomes, and further research is needed to elucidate which patient factors impact EoL decision-making.

Design of the VIALE-M phase III trial of venetoclax and oral azacitidine maintenance therapy in acute myeloid leukemia.

Prevention of relapse is a major therapeutic challenge and an unmet need for patients with acute myeloid leukemia (AML). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in AML cells. When combined with azacitidine, it leads to prolonged overall survival and rapid, durable remissions in treatment-naive AML patients ineligible for intensive chemotherapy. VIALE-M is a randomized, double-blind, two-arm study to evaluate the safety and efficacy of venetoclax in combination with oral azacitidine (CC-486) as maintenance therapy in patients in complete remission with incomplete blood count recovery after intensive induction and consolidation therapies. The primary end point is relapse-free survival. Secondary outcomes include overall survival, minimal residual disease conversion and improvement in quality-of-life. Trial Registration Number: NCT04102020 (ClinicalTrials.gov).

Evaluation of spin in systematic reviews and meta-analyses of superior capsular reconstruction.

BACKGROUND: Small, preliminary studies and the systematic reviews on superior capsular reconstruction (SCR) that collate data are at increased risk spin. This study's primary objective was to identify, describe, and account for the incidence of spin in systematic reviews of SCR. This study's secondary objective was to characterize the studies in which spin was identified to determine whether identifiable patterns of characteristics exist among studies with spin. METHODS: This study was conducted per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using a predetermined protocol. A search was conducted on the PubMed and Embase databases for systematic reviews and meta-analyses on SCR. Screening and data extraction were conducted independently by 2 authors. Each included study's abstract was assessed for the presence of the 15 most common types of spin, with full texts reviewed during cases of disagreement or for clarification. General data that were extracted included study title, authors, publication year, journal, level of evidence, study design, funding source, reported adherence to PRISMA guidelines, preregistration of the study protocol, and primary and secondary outcome measures. Full texts were used in the assessment of study quality per AMSTAR 2. RESULTS: We identified 53 studies during our search, of which 17 met the inclusion criteria. At least 1 form of spin was observed in all 17 studies. The most common types of spin were type 5 ("The conclusion claims the beneficial effect of the experimental treatment despite a high risk of bias in primary studies") and type 9 ("Conclusion claims the beneficial effect of the experimental treatment despite reporting bias"), both of which were observed in 11 studies (11 of 17, 65%). A statistically significant association between lower level of evidence and type 5 ("The conclusion claims the beneficial effect of the experimental treatment despite a high risk of bias in primary studies") was observed (P = .0175). A statistically significant association was also found between more recent year of publication and the spin category misleading interpretation (P = .0398), and between lower AMSTAR 2 score and type 13 ("Failure to specify the direction of the effect when it favors the control intervention") (P = .0260). No other statistical associations between other study characteristics were observed. CONCLUSION: Spin is highly prevalent in abstracts of SCR systematic reviews and meta-analyses. An association was found between the presence of spin and lower level of evidence, year of publication, and AMSTAR 2 ratings.