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.

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.

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.

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.

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.

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.

Clinical Outcomes of Acute Myeloid Leukemia Patients Harboring the RUNX1 Mutation: Is It Still an Unfavorable Prognosis? A Cohort Study and Meta-Analysis.

Acute myeloid leukemia (AML) with mutated RUNX1 (RUNX1mut) is considered to have an unfavorable prognosis. However, recent studies have reported comparable survival outcomes with wild-type RUNX1 (RUNX1wt). To assess the clinical outcomes of AML with and without RUNX1mut, we performed a prospective cohort study and systematic review and meta-analysis. The study enrolled 135 patients (27 with RUNX1mut; 108 with RUNX1wt). There were no significant differences in the median OS and RFS of the RUNX1mut and RUNX1wt groups (9.1 vs. 12.2 months; p = 0.268 and 7.8 vs. 14.6 months; p = 0.481, respectively). A subgroup analysis of de novo AML patients with intermediate-risk cytogenetics showed similar outcomes. Our meta-analysis pooled data from 23 studies and our study. The complete remission rate was significantly lower in the RUNX1mut group (pooled odds ratio: 0.42). The OS, RFS, and event-free survival rates also favored the RUNX1wt group (pooled risk ratios: 1.36, 1.37, and 1.37, respectively). A subgroup analysis of de novo AML patients with intermediate-risk cytogenetics demonstrated nearly identical OS and RFS outcomes. This study confirms that patients with AML and RUNX1mut had poor prognoses. Nonetheless, in de novo AML with intermediate-risk cytogenetics, the survival outcomes of both groups were comparable.

Characteristics and Outcomes of Secondary Acute Myeloid Leukemia and Acute Myeloid Leukemia With Myelodysplasia-Related Changes: Multicenter Study From the Thai Acute Leukemia Study Group.

BACKGROUND: Secondary acute myeloid leukemia (sAML) and AML with myelodysplasia-related changes (AML-MRC) both result in dismal outcomes. This retrospective study aimed to determine whether these features are poor prognostic factors independent of older age and adverse cytogenetics, which are commonly associated with a poor prognosis. METHODS: The characteristics and real-world outcomes of sAML and AML-MRC from the Thai AML registry database were investigated. RESULTS: From a total of 992 newly diagnosed AML patients, 315 (31.8%) patients were classified into sAML or AML-MRC subtypes. Older age, low white blood cell (WBC) count, low bone marrow blast, and adverse cytogenetic risk were commonly present in sAML and AML-MRC compared to de novo AML. Complete remission after 7 + 3 induction therapy occurred in 42.3% of patients with sAML or AML-MRC and 62.4% of de novo AML (P < .001). The median overall survival (OS) of sAML, AML-MRC, and de novo AML were 6.9, 7.0, and 12.2 months, respectively (P < .001). The independent prognostic factors for inferior OS were older age, intermediate-risk or adverse-risk cytogenetics, WBC count > 100 × 109/L, poor performance status, and a subgroup of AML-MRC with the morphologic criteria of multilineage dysplasia (AML-MRC-M). In addition, sAML, AML-MRC, and a WBC count > 100 × 109/L were pre-treatment prognostic factors associated with poor relapse-free survival (P = .006, P = .017, and P < .001, respectively). CONCLUSION: Both sAML and AML-MRC are independently associated with poor outcomes in Thai patients. Our study supports AML-MRC-M as an adverse prognostic factor for OS.

Comparison of Three Doses of Cytarabine Consolidation for Intermediate- and Adverse-risk Acute Myeloid Leukemia: Real World Evidence From Thai Acute Myeloid Leukemia Registry.

BACKGROUND: Intermediate or high doses of cytarabine (IDAC or HiDAC) were recommended as postremission chemotherapy for acute myeloid leukemia (AML). This retrospective study investigated the real-world outcomes of 3-different cytarabine doses from the multicenter Thai AML registry database. PATIENTS AND METHODS: The intermediate- and adverse-risk AML patients (N = 258) who achieved complete remission and proceeded to single-agent cytarabine consolidation were enrolled. RESULTS: The median relapse-free survival (RFS) using IDAC 1.5 g/m2, high-dose cytarabine (HiDAC) 2 g/m2, and HiDAC 3 g/m2 were 12.6, 11.7, and 13 months, respectively. The median overall survival (OS) using IDAC 1.5 g/m2, HiDAC 2 g/m2, and HiDAC 3 g/m2 were 34.9, 22.7, and 23.7 months, respectively. No significant difference in RFS and OS was detected between the 3 doses. Secondary AML, white blood cell > 100×109/L and the adverse-risk AML were independent prognostic factors for inferior survival (P= .008, P < .001, P= .014). Patients who completed 3 to 4 cycles of consolidation had significantly superior RFS and OS (P< .001, P< .001). Febrile neutropenia occurred in 72.9% of IDAC, 73.8% of HiDAC 2 g/m2, and 78.1% of HiDAC 3 g/m2 without statistical significance. However, the incidence of septic shock was significantly higher after HiDAC 3 g/m2 compared to IDAC regimen (8% vs. 3%, P= .037). CONCLUSION: IDAC is an appropriate regimen for postremission chemotherapy for intermediate- and adverse-risk AML. The higher dosing levels may not produce any benefits to patients and may increase incidence of septic shock. The number of consolidation cycles may impact on survivals rather than the intensity of cytarabine.

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 .

Author's response to the commentary: Neuromyelitis optica complicating COVID vaccinations and additional case reports.

Our article Newly diagnosed neuromyelitis optica spectrum disorders following vaccination: Case report and systematic review had instigated a critique that there were more cases of post-COVID-19-vaccination NMOSD. Indeed, after the systematic review was performed in July 2021, many reports have been published, and we have seen two new patients at our center as well. However, Finsterer's question on the subclinical activity of NMOSD prior to vaccination, although an interesting notion, was debatable. NMOSD is a relapsing disease with severe attacks. Investigations in our patients did not reveal robust evidence of prior subclinical attacks so far.

Comparison of Clinical Characteristics and Genetic Aberrations of Plasma Cell Disorders in Thailand Population.

Multiple myeloma is an incurable malignancy of plasma cells resulting from impaired terminal B cell development. Almost all patients with multiple myeloma eventually have a relapse. Many studies have demonstrated the importance of the various genomic mutations that characterize multiple myeloma as a complex heterogeneous disease. In recent years, next-generation sequencing has been used to identify the genomic mutation landscape and clonal heterogeneity of multiple myeloma. This is the first study, a prospective observational study, to identify somatic mutations in plasma cell disorders in the Thai population using targeted next-generation sequencing. Twenty-seven patients with plasma cell disorders were enrolled comprising 17 cases of newly diagnosed multiple myeloma, 5 cases of relapsed/refractory multiple myeloma, and 5 cases of other plasma cell disorders. The pathogenic mutations were found in 17 of 27 patients. Seventy percent of those who had a mutation (12/17 patients) habored a single mutation, whereas the others had more than one mutation. Fifteen pathogenic mutation genes were identified: ATM, BRAF, CYLD, DIS3, DNMT3A, FBXW7, FLT3, GNA13, IRF4, KMT2A, NRAS, SAMHD1, TENT5C, TP53, and TRAF3. Most have previously been reported to be involved in the RAS/MAPK pathway, the nuclear factor kappa B pathway, the DNA-repair pathway, the CRBN pathway, tumor suppressor gene mutation, or an epigenetic mutation. However, the current study also identified mutations that had not been reported to be related to myeloma: GNA13 and FBXW7. Therefore, a deep understanding of molecular genomics would inevitably improve the clinical management of plasma cell disorder patients, and the increased knowledge would ultimately result in better outcomes for the patients.

Maintenance With Hypomethylating Agents After Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis.

INTRODUCTION: Hypomethylating agents (HMAs) seem to have a range of properties favorable to post-allogeneic hematopoietic stem cell transplantation (allo-SCT) maintenance in acute myeloid leukemia (AML) patients. MATERIALS AND METHODS: The Embase, MEDLINE, and Cochrane Central Register of Controlled Trials databases were independently searched by two investigators to identify relevant studies published inception to 18 November 2021. These trials compared HMA maintenance to observation following allo-SCT for AML or myelodysplastic syndrome. RESULTS: The meta-analysis eligibility criteria were fulfilled by 14 studies. The overall survival and relapse-free survival of the HMA maintenance group were superior to the observation group, with a pooled risk ratio (RR) of 1.38 and 1.46, respectively. Moreover, the cumulative incidence of relapse was significantly lower in those who received HMAs. The HMA group also had lower non-relapse mortality compared with the observation group. Overall, the incidences of grades III-IV acute graft-vs.-host disease (GVHD) and chronic GVHD did not differ in both groups. However, when looking specifically at those receiving decitabine maintenance, the rate of chronic GVHD seemed to be lower compared with observation alone. CONCLUSIONS: The current systematic review and meta-analysis illustrated that AML and MDS patients receiving HMA maintenance after allo-SCT had better outcomes in regards to OS, RFS, NRM, CIR as well as a reduced incidence of chronic GVHD.

Newly diagnosed neuromyelitis optica spectrum disorders following vaccination: Case report and systematic review.

INTRODUCTION: The pathogenesis of neuromyelitis optica spectrum disorder (NMOSD) has been vigorously illustrated, but triggers of the disease remain unclear. Viral infection and vaccination have been observed to precede certain cases of NMOSD. Amidst the Coronavirus disease 2019 (COVID-19) pandemic, mass vaccination takes place across the globe. We report two cases of newly diagnosed NMOSD following COVID-19 vaccination and systematically review previous reports. METHOD: Searching of Ovid MEDLINE and EMBASE databases was done using predefined search terms related to NMOSD and vaccination. Duplicates were removed. Newly diagnosed NMOSD cases fulfilling the 2015 International Panel for NMO Diagnosis criteria with symptoms presenting between 2-30 days after vaccination were included. Data on age, sex, comorbidity, vaccine name, type, and dose number, duration from vaccination to symptom onset, clinical phenotype(s), MRI findings, CSF profiles, severity of attack, initial and maintenance treatment, number of relapses after vaccination, and clinical outcomes were extracted using a standardized table and compared. RESULT: Ten cases of postvaccination NMOSD were identified. Patients aged between 15-46 years old. Nine patients (90%) presented with transverse myelitis and 3 (30%) with optic neuritis. The mean duration from vaccination to clinical onset was 8.2 days (median 9 days). Five patients (50%) tested positive for aquaporin 4 (AQP4) antibody. One patient had a family history of NMOSD. Three-fourths of AQP4-IgG seropositive patients with myelopathy had short transverse myelitis. The reported vaccines included CoronaVac, ChAdOx1 nCoV-19, yellow fever, quadrivalent influenza, H1N1 influenza, quadrivalent human papillomavirus, Japanese encephalitis, rabies, and recombinant hepatitis B virus together with tetanus-diphtheria-pertussis vaccines. All patients received high-dose steroids for initial treatment and 2 received additional therapeutic plasma exchange. Maintenance therapy was given in 4 patients. Five patients (50%) experienced no subsequent relapses within the follow-up period ranging between 3-34 months. Almost all patients returned to baseline functional status. DISCUSSION: The temporal relationship between vaccination and onset of symptoms suggests that vaccine might be a trigger of NMOSD. Genetic predisposition could be a risk factor for postvaccination NMOSD as there are evidences of family history and presence of an associated HLA allele. The prevalence of short-segment transverse myelitis seems to be higher than in typical cases of NMOSD, but the natural history is otherwise similar. All patients received acute treatment with high-dose corticosteroids, most with excellent response. Long-term immunomodulation therapy should be initiated for relapse prevention. Limitations of this study are lack of some relevant data, precision of temporal relationship, and the small number of reports. CONCLUSION: Postvaccination NMOSD is a rare condition that can occur with various types of vaccines. The short temporal relationship between vaccination and onset of NMOSD and the history of NMOSD in one patient's sibling indicate that vaccine might be a trigger for genetically predisposed individuals.

The efficacy of low-dose warfarin initiation (3 mg versus 5 mg) in newly diagnosed venous thromboembolism patients among a population with a high prevalence of warfarin-sensitive haplotype of the VKORC1 gene: a randomized controlled trial.

OBJECTIVES: The fact that a lower warfarin maintenance dose is required by Asian populations is well-known. Currently, the American College of Chest Physicians recommends commencing warfarin at a dose between 5 and 10 mg for venous thromboembolism (VTE). However, the optimal initiating dose in Asians is unknown. This study aimed to evaluate the efficacy of a 3 mg versus a 5 mg of warfarin initiating dose and a corresponding nomogram in patients with VTE. METHODS: Eligible patients were randomized to receive 3 mg or 5 mg per day warfarin for the first 2 days of treatment. The subsequent dose was adjusted according to the warfarin nomogram. The primary outcome was the number of patients who achieved an INR 2.0-3.0 within 8 days. RESULTS: Fifty-six patients were enrolled. There was no significant difference in baseline characteristics between the groups. Seventeen (60.7%) patients in the 3-mg group and 22 (78.6%) patients in the 5-mg group achieved a therapeutic INR within 8 days (p = 0.146). However, there were significantly more patients in the 5-mg group who achieved the target INR on day 5 (53.6% vs 25.0%, p = 0.029). Furthermore, VKORC1-1639G > A was associated with an increased likelihood to achieve the target INR within 5 days (OR 3.81, 95%CI 1.19-12.16, p = 0.021). CONCLUSIONS: The efficacy of a 3 mg warfarin starting dose with subsequent dose adjustment was similar to that of 5 mg on day 8 after warfarin initiation. However, a 5 mg initiating dose resulted in more patients who achieved therapeutic INR on day 5.

A Comparison of the Clinical Outcomes of Haploidentical Transplantation and Other Graft Sources in Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis.

BACKGROUND: Most likely due to the availability of potential stem cell sources, there appears to be a growing usage of haploidentical (haplo) donors for cases of acute lymphoblastic leukemia involving high-risk features or relapse. PATIENTS AND METHODS: This study compared the outcomes of stem cell transplantations (SCTs) using haplo and other stem cell sources, namely, matched sibling donors (MSDs), matched unrelated donors (MUDs), and cord blood transplantations (CBTs). Literature searches were conducted of the MEDLINE and Embase databases from inception to December 2020. RESULTS: Twenty-eight studies were examined (17 retrospective and 11 prospective). There were no significant differences in the overall survival of haplo and those of the other stem-cell sources. For haplo versus matched donor (MSD or MUD), the pooled odds ratio (OR) was 0.94 (95% CI, 0.79-1.12; I2, 22%); while for haplo versus CBT, the OR was 1.24 (95% CI, 0.78-1.96; I2, 28%). The cumulative relapse incidence was significantly higher for MSD than haplo (OR, 0.69; 95% CI, 0.48-0.99; I2, 48%). Both grade II-IV acute and long-term graft-versus-host disease (GVHD) were significantly higher for haplo than MSD (OR, 1.78; 95% CI, 1.15-2.74; I2, 28%; and OR, 1.33; 95% CI, 1.00-1.77; I2, 14%, respectively). The other clinical outcomes did not demonstrate any statistical differences. CONCLUSION: The outcomes of patients treated with haplo-SCT appear comparable with those of the SCTs using other sources. The higher probability of developing GVHD supports the need for a novel method to harness T-cell alloreactivity.