Cardiac glycoside ouabain efficiently targets leukemic stem cell apoptotic machinery independent of cell differentiation status.

BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by an accumulation of immature leukemic myeloblasts initiating from leukemic stem cells (LSCs)-the subpopulation that is also considered the root cause of chemotherapy resistance. Repurposing cardiac glycosides to treat cancers has gained increasing attention and supporting evidence, but how cardiac glycosides effectively target LSCs, e.g., whether it involves cell differentiation, remains largely unexplored. METHODS: Digoxin, a user-designed digitoxigenin-α-L-rhamnoside (D6-MA), and ouabain were tested against various human AML-derived cells with different maturation phenotypes. Herein, we established two study models to specifically determine the effects of cardiac glycosides on LSC death and differentiation-one allowed change in dynamics of LSCs and leukemic progenitor cells (LPCs), while another maintained their undifferentiated status. Regulatory mechanisms underlying cardiac glycoside-induced cytotoxicity were investigated and linked to cell cycle distribution and apoptotic machinery. RESULTS: Primitive AML cells containing CD34+ LSCs/LPCs were very responsive to nanomolar concentrations of cardiac glycosides, with ouabain showing the greatest efficiency. Ouabain preferentially induces caspase-dependent apoptosis in LSCs, independent of its cell differentiation status, as evidenced by (i) the tremendous induction of apoptosis by ouabain in AML cells that acquired less than 15% differentiation and (ii) the higher rate of apoptosis in enriched LSCs than in LPCs. We sorted LSCs and LPCs according to their cell cycle distribution into G0/G1, S, and G2/M cells and revealed that G0/G1 cells in LSCs, which was its major subpopulation, were the top ouabain responders, indicating that the difference in ouabain sensitivity between LSCs and LPCs involved both distinct cell cycle distribution and intrinsic apoptosis regulatory mechanisms. Further, Mcl-1 and c-Myc, which were differentially expressed in LSCs and LPCs, were found to be the key apoptosis mediators that determined ouabain sensitivity in AML cells. Ouabain induces a more rapid loss of Mcl-1 and c-Myc in LSCs than in LPCs via the mechanisms that in part involve an inhibition of Mcl-1 protein synthesis and an induction of c-Myc degradation. CONCLUSIONS: Our data provide new insight for repurposing cardiac glycosides for the treatment of relapsed/refractory AML through targeting LSCs via distinct cell cycle and apoptosis machinery. Video Abstract.

Simplified predictive scores for thrombosis and bleeding complications in newly diagnosed acute leukemia patients.

BACKGROUND: Bleeding and thrombotic complications are the leading causes of death in acute leukemia patients. The Conventional International Society of Thrombosis and Haemostasis Disseminated Intravascular Coagulation (ISTH DIC) scoring system is utilized to assess DIC diagnoses in various conditions. Nevertheless, limited studies have tested the system's accuracy in predicting thrombo-hemorrhagic events in individuals with acute leukemia. This study aimed to (1) validate the ISTH DIC scoring system and (2) propose a new Siriraj Acute Myeloid/Lymphoblastic Leukemia (SiAML) bleeding and thrombosis scoring system for thrombohemorrhagic risk assessment in acute leukemia. METHODS: We conducted a retro-prospective observational study of newly diagnosed acute leukemia patients between March 2014 and December 2019. We recorded thrombohemorrhagic episodes within 30 days postdiagnosis and DIC profiles, including prothrombin time, platelet level, D-dimer, and fibrinogen. The sensitivities, specificities, positive and negative predictive values, and areas under receiver operating characteristic curves for the ISTH DIC and SiAML scoring systems were calculated. RESULTS: In all, 261 acute leukemia patients were identified: 64% with acute myeloid leukemia, 27% with acute lymphoblastic leukemia, and 9% with acute promyelocytic leukemia. Overall bleeding and thrombotic events were 16.8% and 6.1%, respectively. With a cutoff of 5 for the ISTH DIC score, the sensitivity and specificity for bleeding prediction were 43.5% and 74.4%, respectively, while the corresponding values for thrombotic prediction were 37.5% and 71.8%, respectively. D-dimer > 5000 µg FEU/L and fibrinogen ≤ 150 mg/dL were significantly associated with bleeding. A SiAML-bleeding score was calculated using these factors, with a sensitivity and specificity of 65.2% and 65.6%, respectively. Conversely, D-dimer > 7000 µg FEU/L, platelet > 40 × 109/L, and white blood cell level > 15 × 109/L were significant variables related to thrombosis. Using these variables, we established a SiAML-thrombosis score with a sensitivity and specificity of 93.8% and 66.1%, respectively. CONCLUSIONS: The proposed SiAML scoring system might be valuable for prognosticating individuals at risk for bleeding and thrombotic complications. Prospective validation studies are needed to verify its usefulness.

Effects of prone positioning on ARDS outcomes of trauma and surgical patients: a systematic review and meta-analysis.

BACKGROUND: Prone position is an option for rescue therapy for acute respiratory distress syndrome. However, there are limited relevant data among trauma and surgical patients, who may be at increased risk for complications following position changes. This study aimed to identify the benefits and risks of proning in this patient subgroup. METHODS: Follow the PRISMA 2020, MEDLINE and EMBASE database searches were conducted. Additional search of relevant primary literature and review articles was also performed. A random effects model was used to estimate the PF ratio, mortality rate, mechanical ventilator days, and intensive care unit length of stay using Review Manager 5.4.1 software. RESULTS: Of 1,128 studies, 15 articles were included in this meta-analysis. The prone position significantly improved the PF ratio compared with the supine position (mean difference, 79.26; 95% CI, 53.38 to 105.13). The prone position group had a statistically significant mortality benefit (risk ratio [RR], 0.48; 95% CI, 0.35 to 0.67). Although there was no significant difference in the intensive care unit length of stay, the prone position significantly decreased mechanical ventilator days (-2.59; 95% CI, -4.21 to -0.97). On systematic review, minor complications were frequent, especially facial edema. There were no differences in local wound complications. CONCLUSIONS: The prone position has comparable complications to the supine position. With its benefits of increased oxygenation and decreased mortality, the prone position can be considered for trauma and surgical patients. A prospective multicenter study is warranted.

Direct oral anticoagulants versus low-molecular-weight heparins for the treatment of acute venous thromboembolism in patients with gastrointestinal cancer: a systematic review and meta-analysis.

BACKGROUND: The association between gastrointestinal (GI) cancer and a high incidence of venous thromboembolism (VTE) is well known. Previous randomized controlled studies demonstrated that direct oral anticoagulants (DOACs) effectively treat cancer-associated thrombosis (CAT). However, some DOACs appeared to increase the risk of bleeding, particularly in patients with GI malignancies. Therefore, the current systematic review and meta-analysis were conducted to evaluate the safety and efficacy of DOACs in GI cancer-associated thrombosis. METHODS: Two investigators individually reviewed all studies that compared DOACs and low-molecular-weight heparins (LMWHs) in GI cancer-associated thrombosis and were published in MEDLINE and EMBASE before February 2022. The effect estimates and 95% confidence intervals (CIs) from each eligible study were combined using the Mantel-Haenszel method. RESULTS: A total of 2226 patients were included in the meta-analysis. The rates of major bleeding in the DOAC and LMWH groups were not significantly different (relative risk [RR]: 1.31; 95% CI: 0.84-2.04; P = 0.23; I2 = 41%). However, the rate of clinically relevant nonmajor bleeding (CRNMB) was significantly higher in the DOAC group (RR: 1.76; 95% CI: 1.24-2.52; P = 0.002; I2 = 8%). The risks of recurrent VTE in the groups did not significantly differ (RR: 0.72; 95% CI: 0.49-1.04; P = 0.08; I2 = 0%). CONCLUSIONS: The current data suggest that treatment of GI cancer-associated thrombosis with DOACs significantly increases the risk of CRNMB. However, the risk of major bleeding was not significantly different. The efficacy of DOACs for preventing recurrent VTE in GI cancer was comparable to that of LMWHs. TRIAL REGISTRATION: INPLASY202180113 .

Genetic alterations in Thai adult patients with acute myeloid leukemia and myelodysplastic syndrome-excess blasts detected by next-generation sequencing technique.

Several molecular aberrations affect the prognosis of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with excess blasts (EB). This study aimed to determine the incidence and clinical impact of molecular genetic aberrations in Thai patients with AML and MDS-EB, detected by the next-generation sequencing (NGS) technique. This prospective, observational study was conducted between 2018 and 2020 on newly diagnosed Thai AML or MDS-EB patients aged above 15 years. NGS was performed using a custom amplicon-based targeted enrichment assay for 42 genes recurrently mutated in myeloid neoplasms. The molecular results were correlated with baseline patient and disease characteristics as well as outcomes. Forty-nine patients were enrolled in this study. The median age was 56 years (interquartile range [IQR], 44-64), with nearly equal proportions of males and females. The median number of mutations was 3 (IQR, 2-4). The most frequent alterations were FLT3 internal tandem duplications (ITD) (28.6%), DNMT3A (24.5%), and WT1 (22.4%) mutations. FLT3-ITD was more frequent in the de novo AML group than in the MDS/secondary AML group, whereas in the MDS/secondary AML group, ASXL1, ETV6, and SRSF2 mutations were more frequent. Patients aged greater than 65 years and patients with mutated TP53 were more likely to have inferior overall survival from multivariate analysis. FLT3-ITD was the most common mutation among newly diagnosed Thai AML patients. TP53 mutation and advanced age were independent adverse factors for survival outcome. The genetic landscapes of AML patients vary between national populations. Thai Clinical Trials Registry identifier: TCTR20190227003.

A systematic review and meta-analysis of the prevalence of thrombosis and bleeding at diagnosis of Philadelphia-negative myeloproliferative neoplasms.

BACKGROUND: Philadelphia (Ph) chromosome-negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematopoietic stem cell clonal diseases. Most patients with MPN are asymptomatic at diagnosis although some of them suffer from constitutional symptoms. Thrombosis and bleeding can also be one of the initial manifestations although the reported prevalence varied considerably across the studies. This systematic review and meta-analysis was conducted with the aims to better understand the prevalence and characteristics of thrombosis and bleeding among patients with newly-diagnosed MPN. METHODS: Using a search strategy that included the terms for myeloproliferative neoplasms, thrombosis, and bleeding, two investigators independently searched for published articles indexed in the MEDLINE and EMBASE databases from inception to August 2018. The pooled prevalence was calculated using the DerSimonian-Laird random-effects model with a double arcsine transformation. RESULTS: A total of 29 cohort studies (8 prospective and 21 retrospective) with 13,436 patients with MPN were included into this meta-analysis. At diagnosis, the pooled prevalence of overall thrombosis among patients with MPN was 20.0% (95% CI, 16.6-23.8%; I2 96%), with the pooled prevalence of arterial thrombosis of 16.2% (95% CI, 13.0-20.0%; I2 95%) and the pooled prevalence of venous thrombosis of 6.2% (95% CI, 4.9-7.8%; I2 89%). Common thrombotic events included cerebrovascular disease/transient ischemic attack, coronary heart disease, and deep venous thrombosis. The pooled prevalence of hemorrhagic complications among patients who were newly diagnosed with MPN patients was 6.2% (95% CI, 5.0-7.8%; I2 85%). Common sites of bleeding included gastrointestinal, mucosal, and cutaneous bleeding. CONCLUSIONS: Thrombosis and bleeding are common initial manifestations of MPN. Investigations for MPN should be considered for patients who present with unexplained thrombosis or abnormal bleeding.

Correction to: High incidence of invasive fungal infection during acute myeloid leukemia treatment in a resource-limited country: clinical risk factors and treatment outcomes.

Incorrect family name of Warissara Jutidamrongphan.

High incidence of invasive fungal infection during acute myeloid leukemia treatment in a resource-limited country: clinical risk factors and treatment outcomes.

BACKGROUND: Invasive fungal infection (IFI) causes high morbidity and mortality during acute myeloid leukemia (AML) treatment. Interventions to prevent fungal infection, including air filtration systems and antifungal prophylaxis, may improve outcomes in this group of patients. However, they are expensive and therefore inapplicable in resource-limited countries. The benefit of antifungal therapy is also dependent on the local epidemiology. That led us to conduct the study to evaluate the characteristics and impact of IFI in AML patients without prophylaxis in our setting. METHODS: Clinical data from patients with AML who have been treated with chemotherapy without antifungal prophylaxis were retrieved during a 5-year period at Thailand's hematology referral center. Incidence and risk factors of IFI and outcomes of patients were evaluated. RESULTS: Among 292 chemotherapy courses, there were 65 (22.3%) episodes of IFI. Of those, 10 (15.4%) were proven, 19 (29.2%) were probable, and 36 (55.4%) were categorized as being possible IFI. Molds were the most commonly observed causative pathogens (93.1%). The incidence of probable/proven IFI was highest during first induction (20.5%), followed by second induction (6.1%), and consolidation (2.7%). A long duration of neutropenia, old age, and low serum albumin were the strongest predictors of IFI. Compared with patients who had no IFI, patients with probable/proven IFI had a longer length of hospital stay and higher in-hospital mortality. Patients with proven IFI had a significantly worse outcome at 1 year. CONCLUSIONS: These results suggest the change in health policy to implement IFI preventive measures to improve outcomes of AML treatment.

Risk of febrile neutropenia among patients with multiple myeloma or lymphoma who undergo inpatient versus outpatient autologous stem cell transplantation: a systematic review and meta-analysis.

BACKGROUND: Outpatient autologous stem cell transplantations (ASCTs) in multiple myeloma and lymphoma patients have been shown to reduce the overall costs and improve the quality of life relative to inpatient ASCTs. This systematic review and meta-analysis was performed with the aim of comprehensively comparing the risk of febrile neutropenia developing in ASCT outpatients and inpatients who have multiple myeloma or lymphoma. METHODS: To be eligible for the meta-analysis, studies needed to be either randomized, controlled studies or cohort studies. They also need to have two groups of patients with multiple myeloma or lymphoma who underwent ASCT, with the treatment being provided to one group in an outpatient setting and to the other on an inpatient basis. The studies had to report our primary outcome of interest, the rate of febrile neutropenia after stem cell infusion, for both groups. The Mantel-Haenszel method was used to pool the effect estimates and 95% confidence intervals of each study. RESULTS: From 9 eligible studies, a total of 1940 patients were included in the meta-analysis. Contrary to conventional concerns, the patients who underwent the outpatient ASCT had a significantly lower risk of developing febrile neutropenia than those admitted for ASCT, with a pooled odds ratio (OR) of 0.44 (95% confidence interval [CI]: 0.29-0.65; p < 0.0001; I2 = 52%). The risk of septicemia was also significantly lower for the outpatients than the inpatients, with a pooled OR of 0.40 (95% CI: 0.16-0.97; p = 0.04; I2 = 23%). Additional analyses found that the odds of having grade 2-3 mucositis and transplant-related mortality were numerically lower for the outpatient group, although the pooled result was not statistically significant. The odds of surviving at 2-3 years was also numerically higher for the ASCT outpatients, but the difference did not reach statistical significance. CONCLUSIONS: This study found a significantly lower odds of developing febrile neutropenia and septicemia among patients with multiple myeloma and lymphoma who received an outpatient ASCT than among those who had an inpatient ASCT.

Transient adrenal insufficiency in diffuse large B cell lymphoma patients after chemotherapy with short-course, high-dose corticosteroids.

Data on the rate of adrenal insufficiency (AI) in patients receiving short-course and high-dose corticosteroids are limited. In this study, we aimed to determine the incidence of AI in newly diagnosed, diffuse large B cell lymphoma (DLBCL) patients after receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [or prednisolone] (R-CHOP/CHOP) regimen. We enrolled newly diagnosed DLBCL patients who were scheduled to receive 6-8 cycles of R-CHOP/CHOP regimen. One-microgram adrenocorticotropic hormone (ACTH) stimulation tests were performed at the study entry and 3 weeks after each cycle of chemotherapy (CMT). AI was defined by a peak-stimulated serum cortisol of less than 18 µg/dL. For patients who had AI after completing a course of CMT, 1-µg ACTH stimulation tests were carried out at 60 and 90 days after the last CMT cycle to assess the duration of hypothalamic-pituitary-adrenal (HPA) axis recovery. Ten DLBCL patients were included in this study, with a total of 84 1-µg ACTH stimulation tests. Their mean age was 52 years. AI occurred in 3 out of the 10 patients (30%). The first occurrence of AI was after the third CMT cycle, and the incidence was highest after the fifth cycle. Adrenal function recovered completely 3 to 5 weeks after completing the course of CMT, except for 1 patient, whose HPA axis suppression persisted 90 days after the last CMT cycle. Receiver operating characteristic (ROC) analysis revealed that a basal cortisol level of < 8.7 µg/dL was predictive of AI, with a sensitivity and specificity of 80% and 72.2%, respectively. Transient HPA axis suppression can occur in DLBCL patients receiving R-CHOP/CHOP regimen. We strongly encourage careful observation and examination for potential adrenal insufficiency in such patients, particularly after the fifth cycle of chemotherapy.

High proportion of TAFRO syndrome in Thai adult Castleman's disease patients: a 10-year experience.

Castleman's disease (CD) is a rare lymphoproliferative disorder, and its prevalence in Thailand is not known. This 10-year period study investigated the prevalence of CD in Thailand, and the clinical characteristics and outcomes of Thai CD patients, with special focus on the existence and prevalence of TAFRO syndrome. TAFRO syndrome is defined as CD with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. Thirty-three CD patients diagnosed and treated at Siriraj Hospital during January 2007 to December 2016 were included. The prevalence of CD was 1.4 per 1,000,000 patients/10 years. Median age was 46 years, with slight female predominance. Six patients were assigned to the TAFRO group. A high proportion of TAFRO syndrome (18.2%) was found among Thai adult CD patients. In addition to routine TAFRO diagnostic criteria, significantly lower hemoglobin and albumin levels were observed in the TAFRO group than in the non-TAFRO group. Treatment outcomes of CD patients were complete remission (52%), stable disease (30%), and death (13%). Three-year overall survival in the non-TAFRO group and TAFRO group was 88 and 50%, respectively. While most CD patients had a good prognosis, severe cases with TAFRO syndrome had poor outcome.

Intracranial Hemorrhage in Patients with Hematologic Disorders: Prevalence and Predictive Factors.

BACKGROUND: Intracranial hemorrhage (ICH) is an uncommon complication in patients with hematologic disorders although high fatality rates have been shown in these patients. At present, no epidemiological data regarding ICH in patients with hematologic disorders has been collected and/or reported in Thailand. OBJECTIVE: The purpose of this study was to determine the incidence of ICH in hospitalized patients with hematologic disorders and to identify predictive factors associated with ICH in these patients. MATERIAL AND METHOD: The medical records of all patients with hematologic disorders admitted to Siriraj Hospital (Bangkok, Thailand) between January 2002 and September 2011 were reviewed. Patients with ICH were identified and factors associated with ICH were investigated using a retrospective case-control design. RESULTS: Of 9,62 patients identified with hematologic disorders, ICH was diagnosed in 106 (1.1%). The ICH rate was higher in acute myeloid leukemia (AML) patients than in patients with other hematologic malignancies (4.29% vs. 0.78%; p<0. 001) and higher in aplastic anemia (AA) patients than in patients with other benign hematologic disorders (4.00% vs. 0.97%; p<0.001). Cortical hemorrhage was the main presentation in all hematologic disorders, with a single lesion in the parietal area as the most common site. The overall mortality rate was 85% with most patients succumbing within two days of onset. The independent predictors of ICH were hyperleukocytosis and a low platelet count in AML patients, and ecchymosis, upper gastrointestinal hemorrhage, hematuria, and a low platelet count in AA patients. CONCLUSION: AML and AA patients had the highest risk of ICH compared with other hematologic disorders and several predictive factors for ICH were identified.

Organomegalies as a predictive indicator of leukemia cutis in patients with acute myeloid leukemia.

BACKGROUND: Leukemia cutis (LC) is an extramedullary acute myeloid leukemia (AML) infiltrate. No previous study has described the clinical characteristics and outcomes of Thai patients diagnosed with AML with LC. MATERIALS AND METHODS: We conducted a 7-year retrospective case-control study on Thai AML patients at Siriraj Hospital from November 2013 to July 2020. Patients were divided into LC and non-LC groups. Initial clinical presentations and laboratory findings were examined to identify LC-associated factors. Overall survival (OS) and relapse-free survival (RFS) were assessed. Pathological tissues underwent re-evaluation to validate the LC diagnoses. RESULTS: The study included 159 patients in a 2:1 ratio (106 non-LC and 53 LC). The LC group had a mean ± SD age of 54.3 ± 15.5 years; females were predominant. Three-fifths of the LC patients had intermediate-risk cytogenetics; 20.4% had an adverse risk, and 10.2% had a favorable risk. Most were classified as AML-M4 and AML-M5. Leukemic nodules were the primary finding in 58.5% of the cases, mainly on the legs. In the multivariate analysis of predictive factors associated with LC, organomegalies, specifically hepatomegaly, and lymphadenopathy, remained significant factors associated with LC [OR 4.45 (95%CI 1.20, 16.50); p = 0.026 and OR 5.48 (95%CI 1.65, 18.20); p = 0.005], respectively. The LC group demonstrated a significantly reduced OS (log-rank test p = 0.002) (median OS of 8.6 months vs. 32.4 months). RFS was considerably lower in the LC group (log-rank test p = 0.001) (median duration of 10.3 months vs. 24.4 months in the non-LC). CONCLUSIONS: AML patients who developed LC tended to experience notably poorer prognoses. Therefore, it is imperative to consider aggressive treatment options for such individuals. The presence of organomegalies in AML patients serves as a strong predictor of the possible occurrence of LC when accompanied by skin lesions.

Infliximab in neurosarcoidosis: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the clinical outcomes and relapse rates in neurosarcoidosis patients administered infliximab. METHODS: A systematic review was conducted using the MEDLINE, EMBASE, SCOPUS, and Cochrane Library databases. The search included studies from their inception to March 2023. We included case-series studies with at least 10 neurosarcoidosis patients undergoing any treatment type. Studies were also required to report at least one of the following outcomes: response rate, overall survival rate, or relapse rate. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A random-effects model facilitated the analysis of proportional treatment outcomes. Study quality was evaluated using the modified Newcastle-Ottawa quality assessment scale, while a funnel plot helped detect any publication bias. RESULTS: Seven studies comprising 237 patients with neurosarcoidosis were included in the analysis. Of these patients, 184 (77.6%) received treatment with infliximab. The pooled proportion of patients showing clinical improvement after infliximab treatment was 0.74 (95% CI 0.64-0.84, I2 = 49.73%). Relapse rates, derived from four studies, stood at 0.38 (95% CI 0.22-0.55, I2 = 56.92%). Most studies reported successful tapering or cessation of corticosteroid dosage in patients receiving infliximab. Adverse effects were reported in 52 (29.4%) patients, of which 39 out of 54 events (72.2%) were linked to infections. INTERPRETATION: Infliximab demonstrated potential improvement in clinical outcomes for patients with refractory neurosarcoidosis and showed potential for reducing the dosage of concurrent corticosteroids. However, a degree of relapse was observed, with infections being the primary concern for adverse events.

First-line immunosuppressive therapies for acquired hemophilia A: A 25-year cohort experience and network meta-analysis.

Acquired hemophilia A (AHA) presents a significant bleeding risk. Management involves bleeding control and immunosuppressive therapy (IST) to eliminate inhibitors. This study, encompassing a retrospective cohort of 76 newly diagnosed AHA patients (1997-2022), evaluated IST outcomes such as complete remission (CR), relapse, and mortality rates, alongside influencing factors. Supplementing these findings, a systematic review and network meta-analysis compared CR and relapse rates across ISTs, sourcing from Embase, Scopus, and ScienceDirect up to November 2023. In our cohort, demarcated by a 20 Bethesda-unit titer threshold, cyclophosphamide plus prednisolone (CP; n = 64) was the predominant initial IST. Lower inhibitor levels significantly correlated with higher CR rates (86.8 % vs 62.2 %; P = .014) and showed an odds ratio of 0.26 for CR (P = .021). Median relapse-free survival (RFS) extended to 37.13 months, significantly enhanced by CP (hazard ratio, 0.24; 95 % confidence interval, 0.10-0.60; P = .002). Our network meta-analysis, including 1476 CR and 636 relapse patients, indicated CP and rituximab-based ISTs significantly outperformed steroid monotherapy in terms of CR and lower relapse rates (risk differences of 0.15 and -0.13/-0.15, respectively; P < .05), without significant differences between CP and rituximab. Moreover, adding rituximab to the front-line treatment did not produce superior outcomes compared to the CP regimen alone, positioning CP as a viable first-line choice, particularly where rituximab is less accessible. The consideration of IST toxicity remains critical in treatment decisions.

Genetic alterations in myeloid sarcoma among acute myeloid leukemia patients: insights from 37 cohort studies and a meta-analysis.

Introduction: Variations in mutation rates among acute myeloid leukemia (AML) patients with myeloid sarcoma (MS) underscore the need for a thorough examination. This meta-analysis was conducted to fill the information gap concerning mutation frequencies in AML patients presenting with MS. Materials and methods: This study included retrospective and prospective cohorts. It examined genetic alterations in AML patients with and without MS across all age groups. The search strategy employed terms such as "acute myeloid leukemia," "extramedullary," "granulocytic sarcoma," "myeloid sarcoma," and "leukemic cutis" in the EMBASE, MEDLINE, and Scopus databases. Excluded from the study were reviews, case reports, and case series with fewer than 10 cases. Statistical analyses were performed with Review Manager 5.4 software. Results: The primary analysis incorporated data from 37 cohorts involving 5646 diagnosed AML patients and revealed a 17.42% incidence of MS. The most prevalent mutation among AML patients with MS was FLT3-ITD, with a pooled prevalence of 17.50% (95% CI 12.60% to 22.50%; I2 82.48%). The dominant fusion gene was RUNX1::RUNX1T1, displaying a pooled prevalence of 28.10% (95% CI 15.10% to 41.20%; I2 96.39%). In comparison, no significant intergroup differences were observed for NPM1, FLT3-ITD, KIT, and IDH2 mutations. Interestingly, the CEBPA mutation exhibited protective effects for MS patients, with an odds ratio of 0.51 (95% CI 0.32 to 0.81; I2 0%). Conversely, the NRAS mutation was associated with an increased risk of MS development, with an odds ratio of 5.07 (95% CI 1.87 to 13.73; I2 0%). Conclusion: This meta-analysis sheds light on the prevalence of genetic mutations in AML patients with MS, providing insights into the unique characteristics of the mutations and their frequencies. These discoveries are crucial in informing therapeutic and prognostic decisions for individuals with myeloid sarcoma.

Is it time for class I recommendation for sodium-glucose cotransporter-2 inhibitors in heart failure with mildly reduced or preserved ejection fraction?: An updated systematic review and meta-analysis.

Background: In heart failure with reduced ejection fraction (HFrEF), sodium-glucose cotransporter-2 (SGLT2) inhibitors were demonstrated to lower cardiovascular mortality (CV death) and hospitalization for heart failure (HHF); however, the advantages of SGLT2 inhibitors in heart failure with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF) are less clear. SGLT2 inhibitors were reported to enhance quality of life (QoL) in HFmrEF or HFpEF patients; however, the findings among studies are inconsistent. Objective: To conduct an updated systematic review and meta-analysis of recent data to assess the effect of SGLT2 inhibitors on cardiovascular outcomes and QoL in patients with HFmrEF or HFpEF. Method: Three databases were searched for studies that evaluated SGLT2 inhibitors and their effect on cardiovascular outcomes, including CV death, HHF, all-cause death, and the composite outcome of CV death, HHF, and urgent visit for heart failure (HF), and patient QoL (Kansas City Cardiomyopathy Questionnaire [KCCQ] score compared to baseline, and increase in KCCQ score ≥ 5 points) that were published during January 2000-August 2022. The meta-analysis was performed using the inverse variance method and random-effects model. INPLASY registration: INPLASY202290023. Results: Sixteen studies (9 recent RCTs) were included, and a total of 16,710 HFmrEF or HFpEF patients were enrolled. SGLT2 inhibitors significantly reduced composite cardiovascular outcome (CV death/HHF/urgent visit for HF; pooled hazard ratio [HR]: 0.80, 95% confidence interval [95%CI]: 0.74-0.86) and HHF alone (HR: 0.74, 95%CI: 0.67-0.82), but there was no significant reduction in CV death alone (HR: 0.93, 95%CI: 0.82-1.05). Benefit of SGLT2 inhibitors for decreasing CV death/HHF was observed across all subgroups, including left ventricular ejection fraction (LVEF) range, diabetes status, New York Heart Association functional class, and baseline renal function. For total HHF, SGLT2 inhibitors conferred benefit in both LVEF 50-60% (HR: 0.64, 95%CI: 0.54-0.76), and LVEF >60% (HR: 0.84, 95%CI: 0.71-0.98). Significant change was observed in the KCCQ-clinical summary score compared to baseline (mean difference: 1.33, 95%CI: 1.31-1.35), and meaningful improvement in QoL was shown across all 3 types of increase in KCCQ score ≥ 5 points. Conclusion: This study demonstrates the benefits of SGLT2 inhibitors for improving cardiovascular outcomes and QoL in HFmrEF or HFpEF patients.

Effects of different types of allogeneic hematopoietic stem cell transplantation donors on Philadelphia chromosome-positive acute lymphoblastic leukemia during the tyrosine kinase inhibitor era: A systematic review and meta-analysis.

BACKGROUND: Matched donor (MD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the preferred choice of treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) patients who have achieved complete remission. This systematic review and meta-analysis was conducted to investigate the effects of allo-HSCTs from different donor types for Ph+ ALL patients who received tyrosine kinase inhibitors (TKIs). METHODS: Studies in EMBASE and MEDLINE between inception and December 2020 were identified using search terms related to "Ph+ ALL" and "HSCT." Eligible studies were studies with Ph+ ALL patients who received a TKI and allo-HSCT. The primary outcomes of interest-the overall survival (OS) or relapse-free survival (RFS)-needed to be reported. The Mantel-Haenszel method was used to combine the effect estimates and associated 95% confidence intervals (CIs) of each donor type. RESULTS: Fourteen cohort studies were identified for the meta-analysis. Haploidentical (HID)-HSCT for Ph+ ALL patients resulted in a superior RFS to MD-HSCT, with a pooled odds ratio (OR) of 1.57 (95% CI, 1.05-2.32; I2 = 0%). However, HID-HSCT and MD-HSCT had comparable OS. Furthermore, HID-HSCT group had a significantly lower relapse rate than MD-HSCT group. On the other hand, the risks of graft-versus-host disease (GvHD) were higher for HID-HSCT and pooled OR of chronic GvHD rate. The OS and RFS of matched sibling-HSCT, matched unrelated-HSCT, and cord blood-HSCT were comparable with those of HID-HSCT. CONCLUSION: This systematic review and meta-analysis showed that HID-HSCT is as effective as MD-HSCT in Ph+ ALL patients.

Does leukocytosis remain a predictive factor for survival outcomes in patients with acute promyelocytic leukemia receiving ATRA plus a chemotherapy-based regimen? A prospective multicenter analysis from TALWG.

INTRODUCTION: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with a unique clinical presentation and prognosis. This study aimed to investigate the epidemiology, clinical characteristics, treatments, and clinical outcomes of Thai APL patients dominantly treated with all-trans-retinoic acid (ATRA) combined with a chemotherapy-based therapy. METHODS: This was an eight-year prospective, observational study from nine academic hospitals in the Thai Acute Leukemia Working Group (TALWG) of the Thai Society of Hematology, which included newly diagnosed Thai APL patients, aged 18 years or older. The web-based registration collected baseline charateristic, and clinical outcomes. RESULTS: From 992 newly diagnosed AML patients, 79 APL patients were enrolled in this study. Almost all subjects were de novo APL (94.9%), while the others were therapy-related APL. The commonest clinical presentation was disseminated intravascular coagulation (38%). One-third of the patients were categorized as high risk according to the initial WBC. Almost all patients received ATRA combined with idarubicin regimen. The complete response rate was as high as 95.7%, which translated into excellent four-year overall survival (OS) (75.6%) and four-year leukemia-free survival (LFS) (75.4%). The multivariate analysis demonstrated that the older age and WBC count >20 × 109/L conferred a significantly unfavorable OS with the hazard ratios of 3.03 (95% confidence interval [CI]: 1.14-8.05) and 4.18 (95%CI: 1.69-10.35), respectively. Similarly, these two parameters remained independent of the poor prognosis factors for LFS. CONCLUSION: This report confirmed that APL had a favorable prognosis. However, advanced age and high WBC count >20 × 109/L contributed to a worse outcome. ABBREVIATIONS: APL; acute promyelocytic leukemia; ATRA; all-transretinoic acid; CR; complete remission; DS; differentiation syndrome; ECOG; Eastern Cooperative Oncology Group; ED; early death; HR; hazard ratio; IQR; interquartile range; LFS; leukemia-free survival; OS; overall survival; WBC; white blood cell.