CREST-UK: Real-world effectiveness, safety and outpatient delivery of CPX-351 for first-line treatment of newly diagnosed therapy-related AML and AML with myelodysplasia-related changes in the UK.

Favourable outcomes with CPX-351 versus conventional 7 + 3 were demonstrated in the pivotal phase III trial in adults aged 60-75 years with newly diagnosed, highrisk/secondary acute myeloid leukaemia (AML). As a complement to the clinical trial and to address important data gaps, the CPX-351 Real-World Effectiveness and SafeTy (CREST-UK; NCT05169307) study evaluated the use of CPX-351 in routine clinical practice in the UK, in 147 patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Best response of complete remission or complete remission with incomplete platelet or neutrophil recovery was achieved by 53% of evaluable patients. Kaplan-Meier median overall survival (OS) was 12.8 months (95% confidence interval 9.2-15.3). Fifty (34%) patients proceeded to haematopoietic cell transplantation (HCT); median OS landmarked from the HCT date was not reached. There were no new safety concerns with CPX-351 identified in CREST-UK. Patients treated with CPX-351 in the outpatient setting spent an average of 24.4, 16.7, 28.2, and 27.7 fewer days on the ward compared with inpatients during first induction, second induction, first consolidation, and second consolidation, respectively. The results from CREST-UK provide valuable insights into the effectiveness, safety, and outpatient delivery of CPX-351 in routine clinical practice in the UK.

Impact of patient demographics on treatment outcomes in AML: a population-based registry in England, 2013-2020.

ABSTRACT: We report 1- and 5-year survival after acute myeloid leukemia (AML) diagnosis and early mortality within 30 days of systemic anticancer therapy (SACT) treatments, using national cancer registry data in England. Patients aged 18 to 99 years diagnosed between 2013 and 2020 were included. Overall survival (OS) was calculated using Kaplan-Meier methodology, and adjusted hazard ratios (aHRs; adjusted for intensity of treatment, age at diagnosis, sex, ethnicity, socioeconomic deprivation, comorbidity, and year of diagnosis) using Cox proportional hazards regression. Odds of 30-day mortality (adjusted odds ratios [aORs], adjusted for aforementioned characteristics), along with performance status and body mass index, were calculated using logistic regression. Among 17 107 patients identified, older age and comorbidity were associated with worse survival. Asian and Black patients had better survival than White patients: 5-year OS of 34.6%, 29.7%, and 17.8%, respectively; aHR of 0.86; (95% confidence interval [CI], 0.77-0.96) Asian vs White, and 0.84 (95% CI, 0.73-0.96) Black vs White. Socioeconomic deprivation was associated with worse survival. Overall, 7906 (46.2%) patients were documented as having received SACT. Thirty-day mortality was lower for patients receiving intensive rather than nonintensive SACT. After adjustment for cofactors, the risk was higher in those treated intensively (aOR, 0.74; 95% CI, 0.60-0.92). We show that ethnicity and socioeconomic status affects outcomes in AML. Further work is needed to understand how these effects may differ in different health care settings, and whether this because of effects on disease biology, responsiveness to treatment, or drug toxicity. Selection of intensive vs nonintensive treatment should be based on individual patient factors, balancing improved long-term survival against higher early mortality.

Capture-based targeted sequencing using a T-cell control in myeloid malignancies and idiopathic cytopenias.

We report on a study of next-generation sequencing in 257 patients undergoing investigations for cytopenias. We sequenced bone marrow aspirates using a target enrichment panel comprising 82 genes and used T cells from paired blood as a control. One hundred and sixty patients had idiopathic cytopenias, 81 had myeloid malignancies and 16 had lymphoid malignancies or other diagnoses. Forty-seven of the 160 patients with idiopathic cytopenias had evidence of somatic pathogenic variants consistent with clonal cytopenias. Only 39 genes of the 82 tested were mutated in the 241 patients with either idiopathic cytopenias or myeloid neoplasms. We confirm that T cells can be used as a control to distinguish between germline and somatic variants. The use of paired analysis with a T-cell control significantly reduced the time molecular scientists spent reporting compared to unpaired analysis. We identified somatic variants of uncertain significance (VUS) in a higher proportion (24%) of patients with myeloid malignancies or clonal cytopenias compared to less than 2% of patients with non-clonal cytopenias. This suggests that somatic VUS are indicators of a clonal process. Lastly, we show that blood depleted of lymphocytes can be used in place of bone marrow as a source of material for sequencing.

A novel algorithmic approach to generate consensus treatment guidelines in adult acute myeloid leukaemia.

Induction therapy for acute myeloid leukaemia (AML) has changed with the approval of a number of new agents. Clinical guidelines can struggle to keep pace with an evolving treatment and evidence landscape and therefore identifying the most appropriate front-line treatment is challenging for clinicians. Here, we combined drug eligibility criteria and genetic risk stratification into a digital format, allowing the full range of possible treatment eligibility scenarios to be defined. Using exemplar cases representing each of the 22 identified scenarios, we sought to generate consensus on treatment choice from a panel of nine aUK AML experts. We then analysed >2500 real-world cases using the same algorithm, confirming the existence of 21/22 of these scenarios and demonstrating that our novel approach could generate a consensus AML induction treatment in 98% of cases. Our approach, driven by the use of decision trees, is an efficient way to develop consensus guidance rapidly and could be applied to other disease areas. It has the potential to be updated frequently to capture changes in eligibility criteria, novel therapies and emerging trial data. An interactive digital version of the consensus guideline is available.

An open-source, expert-designed decision tree application to support accurate diagnosis of myeloid malignancies.

Accurate, reproducible diagnoses can be difficult to make in haemato-oncology due to multi-parameter clinical data, complex diagnostic criteria and time-pressured environments. We have designed a decision tree application (DTA) that reflects WHO diagnostic criteria to support accurate diagnoses of myeloid malignancies. The DTA returned the correct diagnoses in 94% of clinical cases tested. The DTA maintained a high level of accuracy in a second validation using artificially generated clinical cases. Optimisations have been made to the DTA based on the validations, and the revised version is now publicly available for use at http://bit.do/ADAtool.

Changes in Psychological Status and Health-Related Quality of Life Following Total Shoulder Arthroplasty.

BACKGROUND: There has been little documentation of the effects of total shoulder arthroplasty (TSA) on psychological status and health-related quality of life (HRQoL). We investigated changes in psychological status (depression and anxiety) and HRQoL following TSA and assessed the effect of preoperative psychological status on postoperative clinical and functional outcome. We hypothesized that TSA would improve both psychological status and HRQoL. METHODS: We prospectively enrolled 46 patients undergoing TSA for osteoarthritis. Preoperatively and at 3, 6, and 12 months postoperatively, all of the subjects completed the visual analog scale (VAS) for pain, the American Shoulder and Elbow Surgeons Scale (ASES), the Subjective Shoulder Value (SSV) measure, the Hospital Anxiety and Depression Scale (HADS), and the World Health Organization Quality of Life Scale Abbreviated Version (WHOQOL-BREF). RESULTS: From 3 months after surgery, significant improvement in HADS-depression, HADS-anxiety, and WHOQOL-BREF scores as well as in the other outcome measures of VAS pain score, ASES score, and SSV were observed. The prevalence of depression and anxiety decreased from a rate of 15.2% and 19.5%, respectively, preoperatively to a rate of 6.5% for each at 12 months postoperatively. Preoperative HADS-depression and HADS-anxiety scores did not correlate with any of the clinical and functional outcome measures at 12 months after surgery. CONCLUSIONS: This study showed significant improvement in psychological status and HRQoL as well as in pain and functional ability from 3 months after TSA in patients with osteoarthritis. Preoperative depression and anxiety did not predict poor postoperative outcome. Our findings suggest that TSA offers an excellent chance of improving psychological status and HRQoL. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Comparison of Glenoid Version and Posterior Humeral Subluxation in Patients With and Without Posterior Shoulder Instability.

PURPOSE: To evaluate glenoid version and humeral subluxation on preoperative multiplanar imaging of patients who underwent surgery for posterior glenohumeral instability compared with a matched group of patients who had shoulder surgery for other pathology. METHODS: All patients over a 2-year period who underwent surgery for posterior instability had preoperative magnetic resonance (MR) imaging or MR arthrogram reviewed. Patients undergoing shoulder surgery for reasons other than instability were identified as a control group and matched by sex, laterality, and age. Measurement of glenoid version and percentage of humeral subluxation was performed by 2 reviewers after completing a tutorial. Reviewers were blinded to diagnosis and to whether or not the patients were in the experimental or control group. RESULTS: There were 41 patients in each group. The average glenoid version in the control group was 5.6° of retroversion (standard deviation [SD] 3.0), and the average humeral subluxation was 54% (SD 5.1%). In the experimental group, the average glenoid version was 8.1° of retroversion (SD 5.0). The average humeral subluxation in the experimental group was 56% (SD 6.8%). Student t test revealed a statistically significant difference in glenoid version (P = .009) but not humeral subluxation (P = .25). Intra- and inter-rater reliability was measured by the intraclass correlation coefficient and found to have an excellent Fleiss rating with regard to both measurements. CONCLUSIONS: Glenoid retroversion is significantly increased in patients with symptomatic posterior labral tears compared with a control group. However, there was no statistically significant difference between the groups with regard to posterior humeral subluxation and, therefore, is not a reliable indicator of the presence or absence of symptomatic posterior shoulder instability. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Assessment of painful total shoulder arthroplasty using computed tomography arthrography.

BACKGROUND: This study assessed the accuracy of computed tomography (CT) arthrography when evaluating glenoid component stability in the setting of postarthroplasty shoulder pain. METHODS: We retrospectively reviewed all patients presenting to the clinic during a 5.5-year period to identify those with a painful shoulder arthroplasty more than 1 year after the index procedure. We excluded reverse and hemiarthroplasty procedures, patients with a clearly identifiable cause for pain, such as rotator cuff insufficiency or gross component loosening as seen on plain radiographs, and those with culture-positive aspiration. There were 14 patients with suspected glenoid component loosening but inconclusive plain radiographs. Each of the 14 patients underwent a CT arthrogram that was evaluated by the senior author (J.J.P.W.) for the presence or absence of contrast material underneath the polyethylene component. Operative reports and surgical videos from subsequent arthroscopy were reviewed to assess glenoid component stability as determined by direct arthroscopic visualization. RESULTS: CT arthrography suggested glenoid component loosening in 8 of 14 patients (57.1%), and arthroscopic inspection identified loosening in 10 of 14 patients (71.4%). In 3 of 10 patients (30%), CTA suggested a well-fixed glenoid component, but gross loosening was identified during arthroscopy. In this study, CTA yielded a sensitivity of 70%, a specificity of 75%, a positive predictive value of 87.5%, and a negative predictive value of 50.0%. CONCLUSION: CTA had a low negative predictive value (50%), and therefore, the prediction of component stability based on the absence of contrast between the glenoid component and the bone-cement interface does not always reflect true stability.

Effects of ACL reconstruction surgery on muscle activity of the lower limb during a jump-cut maneuver in males and females.

We compared muscle activity of the quadriceps, hamstring, and gastrocnemius muscles when ACL-intact (ACL(INT)) and ACL-reconstructed (ACL(REC)) male and female subjects performed a jump-cut task. Surface electromyography sensors were used to evaluate time to peak muscle activity and muscle activity ratios. Rectus femoris (RF) and vastus medialis (VM) peak timing was 71 and 78 ms earlier in ACL(INT) than in ACL(REC) subjects, respectively. Biceps femoris (BF) peak timing was 90 ms earlier in ACL(INT) than in ACL(REC) subjects and 75 ms earlier in females than in males. Medial gastrocnemius (MG) muscle peak timing was 77 ms earlier in ACL(INT) than in ACL(REC) subjects. Lateral gastrocnemius (LG) and MG muscle peak times were 106 ms and 87 ms earlier in females than in males, respectively. The RF, VM, BF, and MG peaked later in ACL(REC) than in ACL(INT) subjects. There was evidence suggesting that the loading phase quadriceps:hamstring (quad:ham) muscle activity ratio was greater in ACL(REC) than in ACL(INT) subjects. Finally, the injury risk phase quad:ham muscle activity ratio was 4.8 times greater in females than in males. In conclusion, differences exist in muscle activity related to ACL status and sex that could potentially help explain graft failure risk and the sex bias.

Review of eprodisate for the treatment of renal disease in AA amyloidosis.

Secondary (AA) amyloidosis is a multisystem disorder complicating chronic infections or inflammatory diseases. It is characterized by extracellular deposit of fibrils composed of fragments of serum amyloid A (SAA), an acute phase reactant protein. The kidney is the most frequent organ involved, manifesting as progressive proteinuria and renal impairment. Attenuation of the level of circulating SAA protein by treating the underlying inflammatory condition remains the primary strategy in treating AA amyloidosis. However, at times, achieving adequate control of protein production can prove difficult. In addition, relapse of renal function often occurs rapidly following any subsequent inflammatory stimulus in patients with existing amyloidosis. Recently there has been an interest in finding other potential strategies targeting amyloid deposits themselves. Eprodisate is a sulfonated molecule with a structure similar to heparan sulfate. It competitively binds to the glycosaminoglycan-binding sites on SAA and inhibits fibril polymerization and amyloid deposition. Recent randomized clinical trial showed that it may slow down progressive renal failure in patients with AA amyloidosis. However confirmatory studies are needed and results of a second Phase III study are eagerly awaited to clarify whether or not eprodisate has a place in treating renal amyloid disease.