Impact of Prior Inotuzumab Ozogamicin Treatment on Brexucabtagene Autoleucel outcomes in Adults with B-cell ALL.

The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL), particularly the influence off previous InO response and the timing of administration. We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory (r/r) ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO-exposed). InO-exposed patients were more heavily pretreated (p= 0.02) and frequently had active marrow disease pre-apheresis (p= 0.03). Response rate and toxicity profile following brexu-cel were comparable for InO-exposed and InO-naïve; however, consolidation therapy post brexu-cel response was utilized at a higher rate in InO-naïve patients (p= 0.005). With a median follow up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS) (p=0.013) and overall survival (OS) (p=0.006) in univariate analyses; however, prior InO exposure did not influence PFS (HR 1.20, 95%CI, 0.71-2.03) in multivariate models. When InO-exposed patients were stratified according to prior InO response, InO responders had superior PFS (p=0.002) and OS (p<0.0001) relative to InO-refractory. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (p=0.51) and OS (p=0.86) for patients receiving InO as bridging therapy or pre-apheresis. In conclusion, while InO exposure was associated with inferior survival outcomes following brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively impacts brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.

Cost Analysis of Dropless Cataract Surgery Prophylaxis with Intracameral Antibiotics and Subconjunctival Steroids.

PURPOSE: To determine whether dropless, injection-based cataract surgery prophylaxis with intracameral antibiotic and subconjunctival steroid may reduce healthcare system costs and patient out-of-pocket costs compared to topical medication regimens. SETTING: United States national medical expenditures database. DESIGN: Retrospective cost analysis. METHODS: Costs were analyzed for topical ophthalmics from the 2020 Medical Expenditure Panel Survey (MEPS) and for dropless medications from pharmaceutical invoices/catalogs. Main outcomes included system costs, from insurance and patient payments, and out-of-pocket costs for cataract surgery topical and dropless, injection-based prophylactic medication regimens, per eye and nationally. System costs for individual topical medications and same-class dropless, injection-based medications were compared using two-sided, one-sample t-tests. RESULTS: There were 583 prophylactic topical ophthalmic purchases in MEPS. Mean system costs per eye were $76.20 ± SD 39.07 for the lowest cost topical steroid (prednisolone) compared to $4.01 for the lowest cost subconjunctival steroid (triamcinolone acetonide) (p < 0.001). Per eye, the lowest cost dropless, injection-based regimen, at $15.91, results in an $87.99 (84.7%) reduction in overall healthcare costs and a $43.64 (100%) reduction in patient out-of-pocket costs relative to the lowest cost topical regimen ($103.90 ± 43.14 mean system cost and $43.64 ± 37.32 mean out-of-pocket cost per eye). Use of intracameral moxifloxacin and subconjunctival triamcinolone acetonide can reduce annual national healthcare system and out-of-pocket costs up to $450,000,000 and $225,000,000, respectively. CONCLUSIONS: An evidence-based cataract surgery prophylactic medication regimen of intracameral moxifloxacin and subconjunctival triamcinolone acetonide can reduce healthcare system and patient out-of-pocket costs in comparison to various topical regimens.

Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML.

While intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), data from older patients shows that hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remissions among patients with NPM1 mutations. Whether IC or HMA/VEN is superior in patients ≥60 years-old with NPM1-mutant AML is unknown. To compare IC and HMA/VEN, we performed an international, multicenter retrospective cohort study of patients with newly diagnosed, NPM1-mutant AML.We included 221 patients (147 IC, 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR; defined as CR + CR with incomplete count recovery [CRi]) rate was similar for IC and HMA/VEN (cCR: 85% vs. 74%; p=0.067). While OS was favorable with IC in unselected patients compared to HMA/VEN (24-month OS 59% [95% CI: 52-69%] vs. 38% [95% CI 27-55%]; p=0.013), it was not statistically different among patients 60-75 years-old (60% [95% CI 52-70%] vs. 44% [95% CI 29-66%]; p=0.069) and patients who received an allogeneic stem cell transplant (70% [95% CI: 58-85%] vs. 66% [95% CI: 44-100%]; p=0.56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS with IC 65% [95% 56-74%] vs. 40% [95% CI: 26-60%] with HMA/VEN; p=0.009) and without FLT3-ITD mutations might benefit from IC compared with HMA/VEN (24-month OS: 68% [95% CI: 59-79%] vs. 43% [95% CI: 29-63%]; p=0.008). In multivariable analysis, OS was not statistically different for patients treated with IC and HMA/VEN (hazard ratio for death HMA/VEN vs. IC: 0.71; 95% CI: 0.40-1.27; p=0.25).

Treatment approach and outcomes of patients with accelerated/blast-phase myeloproliferative neoplasms in the current era.

ABSTRACT: Progression of myeloproliferative neoplasms (MPNs) to accelerated or blast phase is associated with poor survival outcomes. Since 2017 there have been several therapies approved for use in acute myeloid leukemia (AML); these therapies have been incorporated into the management of accelerated/blast-phase MPNs (MPN-AP/BP). We performed a multicenter analysis to investigate outcomes of patients diagnosed with MPN-AP/BP in 2017 or later. In total, 202 patients were identified; median overall survival (OS) was 0.86 years. We also analyzed patients based on first-line treatment; the 3 most common approaches were intensive chemotherapy (n = 65), DNA methyltransferase inhibitor (DNMTi)-based regimens (n = 65), and DNMTi + venetoclax-based regimens (n = 54). Median OS was not significantly different by treatment type. In addition, we evaluated response by 2017 European LeukemiaNet AML criteria and 2012 MPN-BP criteria in an effort to understand the association of response with survival outcomes. We also analyzed outcomes in 65 patients that received allogeneic hematopoietic stem cell transplant (allo-HSCT); median OS was 2.30 years from time of allo-HSCT. Our study demonstrates that survival among patients with MPN-AP/BP is limited in the absence of allo-HSCT even in the current era of therapeutics and underscores the urgent need for new agents and approaches.

Molecular ontogeny underlies the benefit of adding venetoclax to hypomethylating agents in newly diagnosed AML patients.

The clinical impact of molecular ontogeny in acute myeloid leukemia (AML) was defined in patients treated with intensive chemotherapy. In a cohort of 314 newly diagnosed AML patients, we evaluated whether molecular ontogeny subgroups have differential benefit of venetoclax (VEN) added to hypomethylating agents (HMA). In secondary ontogeny (n = 115), median overall survival (OS)(14.1 vs. 6.9 months, P = 0.0054), composite complete remission (cCR 61% vs. 18%, P < 0.001) and allogeneic hematopoietic stem cell transplant (alloHCT) (24% vs. 6%, P = 0.02) rates were better in patients treated with HMA + VEN vs. HMA. In contrast, in TP53 AML(n = 111) median OS (5.7 vs. 6.1, P = 0.93), cCR (33% vs. 37%, P = 0.82) and alloHCT rates (15% vs. 8%, P = 0.38) did not differ between HMA + VEN vs. HMA. The benefit of VEN addition in the secondary group was preserved after adjustment for significant clinicopathologic variables (HR 0.59 [95% CI 0.38-0.94], P = 0.025). The OS benefit of HMA + VEN in secondary ontogeny was similar in those with vs. without splicing mutations (P = 0.92). Secondary ontogeny AML highlights a group of patients whose disease is selectively responsive to VEN added to HMA and that the addition of VEN has no clinical benefit in TP53-mutated AML.

Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML.

Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

Tri-ing to decipher trisomy AML.

Lam et al. compared trisomy acute myeloid leukaemia (AML) patients (inclusive of single trisomy, double trisomy or tetrasomy cases) with cytogenetically normal AML to uncover distinguishing molecular and prognostic features of trisomy AML. The study contributes to our understanding of trisomy AML, but the heterogeneity of trisomy subtypes remains a barrier to its study. Commentary on: Lam et al. Distinct karyotypic and mutational landscape in trisomy AML. Br J Haematol 2024;204:939-944.

Immunotherapy for Acute Myeloid Leukemia: Current Trends, Challenges, and Strategies.

BACKGROUND: In the past decade, there have been significant breakthroughs in immunotherapies for B-cell lymphoid malignancies and multiple myeloma, but progress has been much less for acute myeloid leukemia (AML). Nevertheless, challenge begets innovation and several therapeutic strategies are under investigation. SUMMARY: In this review, we review the state of the art in AML immunotherapy including CD33- and CD123-targeted agents, immune checkpoint inhibition, and adoptive cell therapy strategies. We also share conceptual frameworks for approaching the growing catalog of investigational AML immunotherapies and propose future directions for the field. KEY MESSAGES: Immunotherapies for AML face significant challenges but novel strategies are in development.

Domestic Violence-Related Ocular Injuries Among Adult Patients: Data from the Nationwide Emergency Department Sample, 2008-2017.

PURPOSE: To investigate domestic violence (DV)-related ocular injuries among adult emergency department (ED) patients in the US. METHODS: This was a retrospective, cross-sectional study of patients with a diagnosis of DV and diagnosis of ocular injury in the Nationwide Emergency Department Sample (NEDS) from 2008-2017. We identified patient- and hospital-level variables associated with DV-related ocular injuries. We calculated annual incidence rates using US Census data. Adjusting for inflation using the Consumer Price Index, we calculated mean and total charges. RESULTS: From 2008-2017, there were 26,215 ED visits for ocular injuries related to DV with an average incidence of 1.09 per 100,000 adult population (female patients, 84.5%; mean age [SE], 34.3 [0.2]). DV-related ocular injuries were most prevalent among patients in the lowest income quartile (39.1%) and on Medicaid (37.4%). Most ED visits presented to metropolitan teaching (55.4%), non-trauma (46.7%), and south regional (30.5%) hospitals. The most common ocular injury was contusion of eye/adnexa (61.1%). The hospital admission rate was 5.2% with a mean hospital stay of 2.9 [0.2]. The inflation-adjusted mean cost for medical services was $38,540 [2,310.8] per encounter with an average increase of $2,116 per encounter, annually. The likelihood of hospital admission increased for patients aged ≥60 years old, on Medicare, and with open globes or facial/orbital fractures (all p < .05). CONCLUSION: Contusion of the eye/adnexa was the most common ocular injury among patients with DV-related ED visits. To better facilitate referrals to social services, ophthalmologists should utilize DV screenings, especially towards women and patients of less privileged socioeconomic status.

Shifts in ophthalmic care utilization during the COVID-19 pandemic in the US.

BACKGROUND: Healthcare restrictions during the COVID-19 pandemic, particularly in ophthalmology, led to a differential underutilization of care. An analytic approach is needed to characterize pandemic health services usage across many conditions. METHODS: A common analytical framework identified pandemic care utilization patterns across 261 ophthalmic diagnoses. Using a United States eye care registry, predictions of utilization expected without the pandemic were established for each diagnosis via models trained on pre-pandemic data. Pandemic effects on utilization were estimated by calculating deviations between observed and expected patient volumes from January 2020 to December 2021, with two sub-periods of focus: the hiatus (March-May 2020) and post-hiatus (June 2020-December 2021). Deviation patterns were analyzed using cluster analyses, data visualizations, and hypothesis testing. RESULTS: Records from 44.62 million patients and 2455 practices show lasting reductions in ophthalmic care utilization, including visits for leading causes of visual impairment (age-related macular degeneration, diabetic retinopathy, cataract, glaucoma). Mean deviations among all diagnoses are 67% below expectation during the hiatus peak, and 13% post-hiatus. Less severe conditions experience greater utilization reductions, with heterogeneities across diagnosis categories and pandemic phases. Intense post-hiatus reductions occur among non-vision-threatening conditions or asymptomatic precursors of vision-threatening diseases. Many conditions with above-average post-hiatus utilization pose a risk for irreversible morbidity, such as emergent pediatric, retinal, or uveitic diseases. CONCLUSIONS: We derive high-resolution insights on pandemic care utilization in the US from high-dimensional data using an analytical framework that can be applied to study healthcare disruptions in other settings and inform efforts to pinpoint unmet clinical needs.

The COVID-19 pandemic disrupted healthcare services globally, including eye care in the United States. Using a US eye disease database, we measured how the pandemic impacted patient visits for 261 eye diagnoses by comparing actual visit volumes for each diagnosis with what would have been expected without the pandemic. We identified groups of conditions with similar changes in visit levels and examined whether these shifts were related to characteristics of the diagnoses studied. We found extended decreases in patient presentations for most eye conditions, with greater reductions for less severe diagnoses, and with anomalies and differences in this trend across diagnosis categories and pandemic sub-periods. This highlights areas of potentially unmet need in vision care arising from the pandemic.

Epidemiologic trends of domestic violence-related ocular injuries among pediatric patients: data from the Nationwide Emergency Department Sample 2008-2017.

PURPOSE: To study the epidemiology of all domestic violence (DV)-related ocular injuries among pediatric emergency department (ED) patients in the United States. METHODS: This is a retrospective, cross-sectional study of isolated children (<18 years of age) with a diagnosis of DV and primary or secondary diagnosis of ocular injuries in the Nationwide Emergency Department Sample, 2008-2017. We calculated annual incidence of DV-related ocular injuries and prevalence by demographic variables, including age, sex, and income quartile. Median charges, median length of inpatient hospital stay, and factors associated with hospitalization were also measured. RESULTS: From 2008 to 2017, there were 4,125 ED encounters, with an average incidence of 0.56 per 100,000 population (males, 50.0%; mean age [SE], 9.2 [0.3]). Patients in the lowest income quartile (42.6%) and with Medicaid insurance (63.2%) were the most prevalent. The most common known perpetrator was a family member (29.4%). Most ED encounters took place at southern regional (28.6%), metropolitan teaching (67.1%) and designated trauma hospitals (57.8%). Contusion of the eye/adnexa and being struck by or against an object were the most common ocular diagnosis and known mechanism of injury, respectively. An estimated 12.4% of patients were admitted with a median hospital stay of 4 (IQR, 2-6). Median charges during the study period were $27,415.10 (IQR, $13,142.70-$54,454.90). CONCLUSIONS: DV-related ocular injuries were most prevalent among patients with a low socioeconomic status. Given the historical underreporting of DV, future studies are warranted to identify more specific social determinants of health that contribute to such presentations.

Transition to Reusable Surgical Gowns at a Hospital System.

This quality improvement study investigates the feasibility of transitioning back to reusable surgical gowns at a US tertiary hospital system and projected corresponding cost savings and solid waste reduction.

Measurable Residual IDH1 before Allogeneic Transplant for Acute Myeloid Leukemia.

Measurable residual disease (MRD) in adults with acute myeloid leukemia (AML) in complete remission is an important prognostic marker, but detection methodology requires optimization. The persistence of mutated NPM1 or FLT3-ITD in the blood of adult patients with AML in first complete remission (CR1) prior to allogeneic hematopoetic cell transplant (alloHCT) has been established as associated with increased relapse and death after transplant. The prognostic implications of persistence of other common AML-associated mutations, such as IDH1, at this treatment landmark however remains incompletely defined. We performed testing for residual IDH1 variants (IDH1m) in pre-transplant CR1 blood of 148 adult patients undergoing alloHCT for IDH1-mutated AML at a CIBMTR site between 2013-2019. No post-transplant differences were observed between those testing IDH1m positive (n=53, 36%) and negative pre-transplant (overall survival: p = 0.4; relapse: p = 0.5). For patients with IDH1 mutated AML co-mutated with NPM1 and/or FLT3-ITD, only detection of persistent mutated NPM1 and/or FLT3-ITD was associated with significantly higher rates of relapse (p = 0.01). These data, from the largest study to date, do not support the detection of IDH1 mutation in CR1 blood prior to alloHCT as evidence of AML MRD or increased post-transplant relapse risk.

Incidence and predictors of anthracycline-related left ventricular dysfunction in acute myeloid leukemia.

INTRODUCTION: Anthracycline-related left ventricular dysfunction (ARLVD) is a concern in patients with acute myeloid leukemia (AML) undergoing anthracyclinecontaining induction chemotherapy. However, the incidence of ARLVD in the modern era of routine pretreatment left ventricular ejection fraction (LVEF) echocardiographic assessment, as well as the clinical and genetic predictors of ARLVD are not well understood. METHODS: Consecutive adult patients with AML receiving anthracycline-containing induction chemotherapy at the Dana-Farber Cancer Institute from 2014 to 2022 were studied. Inclusion criteria included availability of a pre and post chemotherapy echocardiogram to assess the LVEF, pre-treatment LVEF > 50 %, as well as comprehensive diagnostic next generation sequencing assessing for the presence of myeloid mutations. The primary endpoint was the incidence of ARLVD defined as LVEF < 50 % post-induction. RESULTS: Out of 419 patients meeting inclusion criteria, 34 (8%) patients developed ARLVD. Among the 122/419 patients who did not undergo planned allogeneic stem cell transplantation (allo-SCT), ARLVD was the deciding factor for ineligibility in 4 patients (1%). Baseline cardiovascular comorbidities (hypertension, diabetes mellitus, hyperlipidemia, smoking and coronary artery disease) and cumulative anthracycline dose were not predictive of post-induction ARLVD. However, the presence of a JAK2 mutation (but not other myeloid mutations) was associated with an increased risk of ARLVD in multivariable analysis (OR 8.34, 95 % CI 1.55-39.3, p = 0.007). DISCUSSION: In a group of AML patients with normal LVEF prior to anthracycline-containing induction chemotherapy, ARLVD was infrequent and did not commonly preclude post-remission allo-SCT consolidation. Genetic predictors of ARLVD require further investigation in a larger patient cohort.

Financial Health of Private Equity-Backed Groups: Perspectives From Eye Care.

BACKGROUND: In private equity (PE) buyouts of medical practices, it is common for the PE firm to raise significant levels of debt in order to finance the purchase. This debt is subsequently shouldered by the acquired practice(s). There remains a scarcity of literature quantifying the effect of PE acquisition on the subsequent financial performance of eye care practices. We aim to identify and characterize debt valuations of ophthalmology and optometry private equity-backed group (OPEG) practices, which serve as an indicator of practice financial performance. METHODS: A cross-sectional study from March 2017 to March 2022 was conducted using business development company (BDC) quarterly/annual filings to the Securities and Exchange Commission (SEC). The 2021 BDC Report was used to identify all BDCs actively filing annual reports (Form 10-Ks) and quarterly reports (Form 10-Qs) in the United States in 2021. The public filings of BDCs lending to OPEGs were searched from the inception of the OPEG's debt instrument in a BDC's portfolio and the amortized cost and fair value of each debt instrument were tabulated. A panel linear regression was used to evaluate temporal changes in OPEG valuations. RESULTS:  A total of 2,997 practice locations affiliated with 14 unique OPEGs and 17 BDCs were identified over the study period. Debt valuations of OPEGs decreased by 0.46% per quarter over the study period (95% CI: -0.88 to -0.03, P = 0.036). In the COVID-19 pre-vaccine period (March 2020 to December 2020), there was an excess (additional) 4.93% decrease in debt valuations (95% CI: -8.63 to -1.24, P = 0.010) when compared to pre-pandemic debt valuations (March 2017 to December 2019). Effects of COVID-19 on valuations stabilized during the pandemic post-vaccine period (February 2021 to March 2022), with no change in excess debt valuation compared to pre-pandemic baseline (0.60, 95% CI: -4.59 to 5.78, P = 0.822). There was an increase in practices that reported average discounted debt valuations from 20 practices (1.6%) associated with one OPEG to 1,213 practices (40.5%) associated with nine OPEGs (including 100% of newly acquired practices), despite the stabilization of COVID-19-related excess (additional) debt. CONCLUSIONS: Debt valuations of eye care practices have declined significantly post-PE investment from March 2017 to March 2022, suggesting that the financial health of these groups is volatile and vulnerable to economic contractions such as the COVID-19 pandemic. Eye care practice owners must consider long-term financial risks and impacts of subsequent patient care when selling their practice to a private equity group. Future research should assess the impact of secondary transactions of OPEGs on the financial health of practices, practitioner lifestyle, and patient outcomes.

Heel-selfie for visualization and documentation of heel pressure ulcers.

"heel-selfie" is a method for examination and documentation of heel ulcers, particularly in patients with significant morbidity and impaired mobility. Images can be electronically saved and also be shared with caregivers.

Spectrum From Clonal Hematopoiesis to Myelodysplastic Neoplasm/Syndromes and Other Myeloid Neoplasms.

ABSTRACT: Clonal hematopoiesis (CH) confers a high risk of aging-related diseases and hematologic malignancy. There are still significant knowledge gaps in identifying high-risk patients with CH and managing such patients. In this review, we focus on 3 areas: (1) the natural history of CH; (2) the risks of progression of CH, including CH of indeterminate potential, clonal cytopenia of undetermined significance, and therapy-related CH, to myeloid malignancy; and (3) the challenges and unmet needs of CH management and research.

Epidemiology and Pathogenesis of Myelodysplastic Syndrome.

ABSTRACT: Myelodysplastic syndrome (MDS) is a clonal disorder characterized by ineffective hematopoiesis and variable cytopenias with a considerable risk of progression to acute myeloid leukemia. Epidemiological assessment of MDS remains challenging because of evolving classification systems, but the overall incidence in the United States is estimated to be approximately 4 per 100,000 and increases with age. The sequential accumulation of mutations drives disease evolution from asymptomatic clonal hematopoiesis (CH) to CH of indeterminate potential, clonal cytopenia of unknown significance, to frank MDS. The molecular heterogeneity seen in MDS is highly complex and includes mutations of genes involved in splicing machinery, epigenetic regulation, differentiation, and cell signaling. Recent advances in the understanding of the molecular landscape of MDS have led to the development of improved risk assessment tools and novel therapies. Therapies targeting the underlying pathophysiology will hopefully further expand the armamentarium of MDS therapeutics, bringing us closer to a more individualized therapeutic approach based on the unique molecular profile of each patient and eventually improving the outcomes of patients with MDS. We review the epidemiology of MDS and the newly described MDS precursor conditions CH, CH of indeterminate potential, and CCUS. We then discuss central aspects of MDS pathophysiology and outline specific strategies targeting hallmarks of MDS pathophysiology, including ongoing clinical trials examining the efficacy of these therapeutic modalities.