Inotuzumab ozogamicin in adult acute lymphoblastic leukemia: Development, current status, and future directions.

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Several clinical trials are investigating InO in combination with low-intensity chemotherapy or other anti-ALL-targeted therapies in the salvage and frontline settings, notably in older adults who often cannot tolerate intensive chemotherapy and tend to have higher-risk disease. InO is also increasingly used to bridge patients to hematopoietic stem cell transplantation (HSCT), in sequence with chimeric antigen receptor T-cell therapy, to eliminate measurable residual disease and to prevent post-HSCT relapse. Veno-occlusive disease/sinusoidal obstruction syndrome is a potential complication of InO treatment, particularly when followed by HSCT. Herein, the authors review the historical development and current status of InO, strategies for mitigating the risk of InO-related veno-occlusive disease/sinusoidal obstruction syndrome, and future directions for InO research and clinical use.

Radiofrequency ablation in patients with obstructive hypertrophic cardiomyopathy: An updated comprehensive review and meta-analysis.

BACKGROUND: Radiofrequency catheter ablation (RFCA) has emerged as a therapeutic option for surgical myectomy and alcohol septal ablation (ASA) in patients with hypertrophic obstructive cardiomyopathy (HOCM), but its efficacy remains unclear. AIM: Due to limited research on RFCA for HCM, there is an ongoing attempt to assess its efficacy and safety. METHODS: PubMed, Embase, and Scopus were systematically searched for studies assessing the efficacy outcomes for patients with HOCM who underwent RFCA. Mean differences (MDs) with 95% confidence intervals (CIs) were computed using a random-effects model and heterogeneity was assessed using I2 statistics. RESULTS: We included 11 studies comprising 470 patients, of whom 34.6% were female. The mean patient age ranged from 43.7 to 60.7 years. During the follow-up after RFCA, there was a significant decrease in the left ventricular outflow tract (LVOT) gradient at rest (MD -60.25 mmHg; 95% CI [-70.53;-59.14 mmHg]; p < 0.01) and during stimulation (MD -83.56 mmHg; 95% CI [-100.36;-66.76 mmHg]; p < 0.01). Moreover, RFCA reduced interventricular septum (IVS) thickness (MD -3.61 mm; 95% CI [-5.64; -1.59 mm]; p = 0.01) and New York Heart Association (NYHA) class (MD -1.46; 95% CI [-1.69; -1.24]; p < 0.01). CONCLUSIONS: In patients with HOCM, RFCA was associated with an improved NYHA class, reduced IVS thickness, and decreased LVOT gradient at rest and with stimulation.

The conundrum of high-grade hydronephrosis with non-obstructive drainage on diuretic renography.

BACKGROUND: Patients with high grade hydronephrosis (HN) and non-obstructive drainage on mercaptoacetyltriglycine (MAG-3) diuretic renography (renal scans) can pose a dilemma for clinicians. Some patients may progress and require pyeloplasty; however, more clarity is needed on outcomes among these patients. OBJECTIVE: Our primary objective was to predict which patients with high-grade HN and non-obstructive renal scan, (defined as T ½ time <20 min) would experience resolution of HN. Our secondary objective was to determine predictors for surgical intervention. STUDY DESIGN: Patients with prenatally detected HN were prospectively enrolled from 7 centers from 2007 to 2022. Included patients had a renal scan with T ½<20 min and Society for Fetal Urology (SFU) grade 3 or 4 at last ultrasound (RBUS) prior to renal scan. Primary outcome was resolution of HN defined as SFU grade 1 and anterior posterior diameter of the renal pelvis (APD) < 10 mm on follow-up RBUS. Secondary outcome was pyeloplasty, comparing patients undergoing pyeloplasty with patients followed with serial imaging without resolution. Multivariable logistic regression was used for analysis. RESULTS: Of the total 2228 patients, 1311 had isolated HN, 338 patients had a renal scan and 129 met inclusion criteria. Median age at renal scan was 3.1 months, 77% were male and median follow-up was 35 months (IQR 20-49). We found that 22% (29/129) resolved, 42% of patients had pyeloplasty (54/129) and 36% had persistent HN that required follow-up (46/129). Univariate predictors of resolution were age≥3 months at time of renal scan (p = 0.05), T ½ time≤5 min (p = 0.09), SFU grade 3 (p = 0.0009), and APD<20 mm (p = 0.005). Upon multivariable analysis, SFU grade 3 (OR = 4.14, 95% CI: 1.30-13.4, p = 0.02) and APD<20 mm (OR = 6.62, 95% CI: 1.41-31.0, p = 0.02) were significant predictors of resolution. In the analysis of decision for pyeloplasty, SFU grade 4 (OR = 2.40, 95% CI: 1.01-5.71, p = 0.04) and T ½ time on subsequent renal scan of ≥20 min (OR = 5.14, 95% CI: 1.54-17.1, p = 0.008) were the significant predictors. CONCLUSIONS: Patients with high grade HN and reassuring renal scan can pose a significant challenge to clinical management. Our results help identify a specific candidate for observation with little risk for progression: the patient with SFU grade 3, APD under 20 mm, T ½ of 5 min or less who was 3 months or older at the time of renal scan. However, many patients may progress to surgery or do not fully resolve and require continued follow-up.

Replacement of P1 of soybean mosaic virus with P1 of clover yellow vein virus has no impact on virus viability and host specificity.

Potyvirus genomes are expressed as polyproteins that are autocatalytically cleaved to produce 10 to 12 multifunctional proteins, among which P1 is the most variable. It has long been hypothesized that P1 plays role(s) in host adaptation and host specificity. We tested this hypothesis using two phylogenetically distinct potyviruses: soybean mosaic virus (SMV), with a narrow host range, and clover yellow vein virus (ClYVV), with a broader host range. When the full-length P1 cistron of SMV-N was replaced with P1 from ClYVV-No.30, the chimera systemically infected only SMV-N-permissive hosts. Hence, there were no changes in the host range or host specificity of the chimeric viruses. Despite sharing only 20.3% amino acid sequence identity, predicted molecular models of P1 proteins from SMV-N and ClYVV-No.30 showed analogous topologies. These observations suggest that P1 of ClYVV-No.30 can functionally replace P1 of SMV-N. However, the P1 proteins of these two potyviruses are not determinants of host specificity and host range.

Cancer mRNA vaccines: clinical advances and future opportunities.

mRNA vaccines have been revolutionary in terms of their rapid development and prevention of SARS-CoV-2 infections during the COVID-19 pandemic, and this technology has considerable potential for application to the treatment of cancer. Compared with traditional cancer vaccines based on proteins or peptides, mRNA vaccines reconcile the needs for both personalization and commercialization in a manner that is unique to each patient but not beholden to their HLA haplotype. A further advantage of mRNA vaccines is the availability of engineering strategies to improve their stability while retaining immunogenicity, enabling the induction of complementary innate and adaptive immune responses. Thus far, no mRNA-based cancer vaccines have received regulatory approval, although several phase I-II trials have yielded promising results, including in historically poorly immunogenic tumours. Furthermore, many early phase trials testing a wide range of vaccine designs are currently ongoing. In this Review, we describe the advantages of cancer mRNA vaccines and advances in clinical trials using both cell-based and nanoparticle-based delivery methods, with discussions of future combinations and iterations that might optimize the activity of these agents.

Association Between Diagnosis-to-Limb Revascularization Time and Clinical Outcomes in Outpatients With Chronic Limb-Threatening Ischemia: Insights From the CLIPPER Cohort.

BACKGROUND: The extent and consequences of ischemia in patients with chronic limb-threatening ischemia (CLTI) may change rapidly, and delays from diagnosis to revascularization may worsen outcomes. We sought to describe the association between time from diagnosis to endovascular lower extremity revascularization (diagnosis-to-limb revascularization [D2L] time) and clinical outcomes in outpatients with CLTI. METHODS AND RESULTS: In the CLIPPER cohort, comprising patients between 66 and 86 years old diagnosed with CLTI betweeen 2010 and 2019, we used Medicare claims data to identify patients who underwent outpatient endovascular revascularization within 180 days of diagnosis. We described the risk-adjusted association between D2L time and clinical outcomes. Among 1 130 065 patients aged between 66 and 86 years with CLTI, 99 221 (8.8%) underwent outpatient endovascular lower extremity revascularization within 180 days of their CLTI diagnosis. Among patients with D2L time <30 days, there was no association between D2L time and all-cause death or major lower extremity amputation. However, among patients with D2L time >30 days, each additional 10-day increase in D2L time was associated with a 2.5% greater risk of major amputation (hazard ratio, 1.025 [95% CI, 1.014-1.036]). There was no association between D2L time and all-cause death. CONCLUSIONS: A delay of >30 days from CLTI diagnosis to lower extremity endovascular revascularization was associated with an increased risk of major lower extremity amputation among patients undergoing outpatient endovascular revascularization. Improving systems of care to reduce D2L time could reduce amputations.

Failure of treatment-free remission after a prolonged deep molecular response in patients with chronic myeloid leukemia.

Patients with chronic myeloid leukemia in chronic phase (CML-CP) can have a normal life expectancy when treated with the BCR::ABL1 tyrosine kinase inhibitors. In recent years, treatment discontinuation and treatment-free remission (TFR) emerged as the new goal of therapy in patients with CML-CP. Deep and sustained molecular remissions for more than 3 to 5 years are associated with higher chances of a successful TFR. However, although uncommon, some patients may still experience molecular or hematological relapse after treatment discontinuation, even after a prolonged duration of remission. In this case series, we report the outcome of four patients with CML-CP who were treated with tyrosine kinase inhibitors and achieved a deep molecular response for ≥8 years, but eventually experienced disease relapse after treatment discontinuation. We discuss the importance of regular monitoring after treatment discontinuation as well as future strategies to increase the chances of TFR in patients with CML-CP.

Exploring the impact of high-energy diets on cattle: Insights into subacute rumen acidosis, insulin resistance, and hoof health.

Cattle lameness remains a significant concern, causing economic losses and compromising animal welfare. Claw horn lesions have been identified as a major cause of lameness in dairy cows, but their correlation with high-energy diets and ruminal acidosis remains unclear. Hence, the primary objective of this study was to assess the effects of a high-starch diet and a conventional diet on the rumen environment, acute-phase proteins, and metabolic alterations, with a particular focus on insulin resistance and the consequent implications for the histology of the hooves in Holstein steers. A total of 16 animals were divided into the high-starch (HS; 37% starch) and conventional (CON; 16.8% starch) groups. Glucose tolerance tests (GTT), blood analyses, rumen fluid analyses, and histological evaluations of the hoof tissue were conducted over a 102-d experimental period. The HS group showed a lower ruminal pH than the CON group, and with values indicating SARA. The plasma glucose and IGF-1 concentrations were higher in the HS group, suggesting an anabolic state. Both groups exhibited an increase in the insulin area under the curve (AUC) after the GTT on d 102. Histological analysis of the hooves showed a reduction in the length and width of the epidermal lamella in both groups. We found a significant negative correlation between the insulin AUC and the length and width of the epidermal lamella. Because both groups were similarly affected, the hypothesis that histological alterations were caused by the experimental diets still needs confirmation. Additionally, the development of SARA was not essential for the observed histological changes in the hoof. Further studies are warranted to thoroughly investigate the role of insulin and IGF-1 imbalances in claw health.

Iguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in multiple inflammatory and non-inflammatory diseases, including liver injury induced by acetaminophen (APAP) overdose. Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug's mode of inhibition has not been fully investigated. METHODS: We conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614. We also performed in vivo experiments testing the efficacy of T-614 in a murine model of acetaminophen toxicity. We analyzed survival in lethal APAP overdose with and without T-614 and using two different dosing schedules of T-614. We also examined MIF and MIF inhibition effects on hepatic hydrogen peroxide (H2O2) as a surrogate of oxidative stress in non-lethal APAP overdose. RESULTS: Kinetic analysis was consistent with a non-competitive type of inhibition and an inhibition constant (Ki) value of 16 µM. Crystallographic analysis revealed that T-614 binds outside of the tautomerase active site of the MIF trimer, with only the mesyl group of the molecule entering the active site pocket. T-614 improved survival in lethal APAP overdose when given prophylactically, but this protection was not observed when the drug was administered late (6 h after APAP). T-614 also decreased hepatic hydrogen peroxide concentrations during non-lethal APAP overdose in a MIF-dependent fashion. CONCLUSIONS: T-614 is an allosteric inhibitor of MIF that prevented death and decreased hepatic hydrogen peroxide concentrations when given prophylactically in a murine model of acetaminophen overdose. Further studies are needed to elucidate the mechanistic role of MIF in APAP toxicity.

Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL.

ABSTRACT: Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of the response and resistance to InO. Pre- and post-InO-treated patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO-relapsed tumor samples, but not in refractory samples (0/16). There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included epitope loss (protein truncation and destabilization) and epitope alteration. Two CD22 mutant cases were post-InO hyper-mutators resulting from error-prone DNA damage repair (nonhomologous/alternative end-joining repair, or mismatch repair deficiency), suggesting that hypermutation drove escape from CD22-directed therapy. CD22-mutant relapses occurred after InO and subsequent hematopoietic stem cell transplantation (HSCT), suggesting that InO eliminated the predominant clones, leaving subclones with acquired CD22 mutations that conferred resistance to InO and subsequently expanded. Acquired loss-of-function mutations in TP53, ATM, and CDKN2A were observed, consistent with a compromise of the G1/S DNA damage checkpoint as a mechanism for evading InO-induced apoptosis. Genome-wide CRISPR/Cas9 screening of cell lines identified DNTT (terminal deoxynucleotidyl transferase) loss as a marker of InO resistance. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. Our findings highlight the importance of defining the basis of CD22 escape and eradication of residual disease before HSCT. The identified mechanisms of escape from CD22-targeted therapy extend beyond antigen loss and provide opportunities to improve therapeutic approaches and overcome resistance. These trials were registered at www.ClinicalTrials.gov as NCT01134575, NCT01371630, and NCT03441061.

Inotuzumab in Older Patients with Newly Diagnosed Acute Lymphoblastic Leukemia-A Podcast.

Older patients with acute lymphoblastic leukemia (ALL) have historically had poor outcomes (5-year survival rate, 20%) with standard intensive and dose-adjusted chemotherapy regimens, due to a high incidence of adverse biologic features including high-risk cytogenetics, presence of TP53 mutations, and poor tolerance to intensive therapy. Thus, there is an unmet medical need in this patient population. Inotuzumab ozogamicin is a humanized antibody-drug conjugate that targets CD22-positive leukemic blasts. It is approved for the treatment of relapsed or refractory ALL and has been shown to be effective and tolerable in older patients. Several ongoing trials in older patients with newly diagnosed ALL have yielded encouraging data with inotuzumab ozogamicin in induction alone and in combination with low-intensity chemotherapy. In this podcast, the authors summarize and highlight some of the recent findings on the use of inotuzumab ozogamicin as induction therapy for older adults with newly diagnosed ALL.

Targetable genetic abnormalities in patients with acute myeloblastic leukemia across age groups.

Incidence of potential targetable genetic abnormalities by age in AML.

Safety and long-term survival results of the addition of inotuzumab ozogamicin to the conditioning regimen of allogeneic stem cell transplantation: A single-center phase 1,2 trial.

Here we report on the first prospective study evaluating the safety and long-term survival when an escalating dose of inotuzumab ozogamicin (INO) (0.6, 1.2, or 1.8 mg/m2 on day 13) was added to one alkylator-containing conditioning regimen in patients with relapsed CD22 (+) lymphoid malignancies who were candidates for hematopoietic stem cell transplantation (HSCT). Twenty-six patients were enrolled. Six (23%) of these patients entered the phase 1 study: four were treated at an INO dose of 0.6 mg/m2 and two at dose of 1.2 mg/m2. None of these patients experienced dose-limiting toxicities. The remaining 20 (77%) patients entered the phase 2 part of the study at the maximum dose of 1.8 mg/m2. One patient developed VOD; this patient had received nivolumab immediately before HSCT while simultaneously experiencing hyperacute graft-vs-host disease (GVHD). Treatment-related mortality (TRM) at 5 years was 12%. With a median follow-up of 48.7 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 84% and 80%, respectively. Compared with a historical cohort who received same conditioning for HSCT but without INO (n = 56), the INO group showed no significant differences in incidence of liver toxicity, engraftment time, TRM, or risk of acute GVHD. Patients with lymphoma who received INO had a trend for a better 5-year OS (93% versus 68%) and PFS (93% versus 58%) than those in the control group. In conclusion, our results showed that INO is safe with no increased risk of VOD when combined with one alkylator-containing regimen of HSCT.

Expanded specific T cells to hypomutated regions of the SARS-CoV-2 using mRNA electroporated antigen-presenting cells.

The COVID-19 pandemic has caused about seven million deaths worldwide. Preventative vaccines have been developed including Spike gp mRNA-based vaccines that provide protection to immunocompetent patients. However, patients with primary immunodeficiencies, patients with cancer, or hematopoietic stem cell transplant recipients are not able to mount robust immune responses against current vaccine approaches. We propose to target structural SARS-CoV-2 antigens (i.e., Spike gp, Membrane, Nucleocapsid, and Envelope) using circulating human antigen-presenting cells electroporated with full length SARS-CoV-2 structural protein-encoding mRNAs to activate and expand specific T cells. Based on the Th1-type cytokine and cytolytic enzyme secretion upon antigen rechallenge, we were able to generate SARS-CoV-2 specific T cells in up to 70% of unexposed unvaccinated healthy donors (HDs) after 3 subsequent stimulations and in 100% of recovered patients (RPs) after 2 stimulations. By means of SARS-CoV-2 specific TCRß repertoire analysis, T cells specific to Spike gp-derived hypomutated regions were identified in HDs and RPs despite viral genomic evolution. Hence, we demonstrated that SARS-CoV-2 mRNA-loaded antigen-presenting cells are effective activating and expanding COVID19-specific T cells. This approach represents an alternative to patients who are not able to mount adaptive immune responses to current COVID-19 vaccines with potential protection across new variants that have conserved genetic regions.

Cytogenetic and Molecular Associations with Outcomes in Higher-Risk Myelodysplastic Syndromes Treated with Hypomethylating Agents plus Venetoclax.

PURPOSE: Hypomethylating agents (HMA) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood. EXPERIMENTAL DESIGN: We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan-Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or the Cox proportional hazards model (for OS and EFS) were used to identify associations between clinical, cytogenetic, and molecular factors and outcomes. RESULTS: A total of 80 patients (52 HMA-naïve, 28 HMA-failure) were included. ORR was 90% in HMA-naïve and 57% in HMA-failure. Median OS was 28.2 and 8.3 months in HMA-naïve and HMA-failure, respectively. Median EFS was 17.9 and 5.5 months in HMA-naïve and HMA-failure, respectively. In addition, 24/52 (46%) of the HMA-naïve and 3/28 (11%) of the HMA-failure patients proceeded to allogeneic stem cell transplantation (SCT). Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutations, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes. CONCLUSIONS: Knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from venetoclax.

A Review of the Therapeutic Role of Bosutinib in Chronic Myeloid Leukemia.

The development of the BCR::ABL1 tyrosine kinase inhibitors (TKIs) has transformed Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) from a fatal disease to an often-indolent illness that, when managed effectively, can restore a life expectancy close to that of the normal population. Bosutinib is a second-generation TKI approved for adults with Ph-positive CML in chronic phase, accelerated phase, or blast phase that is resistant or intolerant to prior therapy, and for newly diagnosed Ph-positive chronic phase CML. This review details the efficacy of bosutinib for the treatment of CML in the first- and second-line settings, as well as in third- and later-line settings for high-risk patients resistant or intolerant to at least 2 TKIs. It also outlines bosutinib studies that provide evidence for dose-optimization strategies that can be used to improve efficacy and effectively manage adverse events. The studies that provide evidence for specific patient populations benefiting particularly from bosutinib dose-optimization strategies are also discussed. The well-established, long-term side-effect profile and the potential to make dose adjustments with bosutinib make it an appropriate treatment option for patients with CML. Bosutinib has demonstrated a positive impact on health-related quality of life and an important role in the long-term treatment of patients with CML.

Vaccines: a promising therapy for myelodysplastic syndrome.

Myelodysplastic neoplasms (MDS) define clonal hematopoietic malignancies characterized by heterogeneous mutational and clinical spectra typically seen in the elderly. Curative treatment entails allogeneic hematopoietic stem cell transplant, which is often not a feasible option due to older age and significant comorbidities. Immunotherapy has the cytotoxic capacity to elicit tumor-specific killing with long-term immunological memory. While a number of platforms have emerged, therapeutic vaccination presents as an appealing strategy for MDS given its promising safety profile and amenability for commercialization. Several preclinical and clinical trials have investigated the efficacy of vaccines in MDS; these include peptide vaccines targeting tumor antigens, whole cell-based vaccines and dendritic cell-based vaccines. These therapeutic vaccines have shown acceptable safety profiles, but consistent clinical responses remain elusive despite robust immunological reactions. Combining vaccines with immunotherapeutic agents holds promise and requires further investigation. Herein, we highlight therapeutic vaccine trials while reviewing challenges and future directions of successful vaccination strategies in MDS.