The Efficacy and Safety of Tandem Transplant Versus Single Stem Cell Transplant for Multiple Myeloma Patients: A Systematic Review and Meta-Analysis.

While high-dose therapy and autologous stem cell transplant (ASCT) remain integral to the primary treatment of newly diagnosed transplant-elble multiple myeloma (MM) patients, the challenge of disease progression persists. The primary objective of this meta-analysis is to evaluate the efficacy and safety of tandem ASCT compared to single ASCT. We conducted a systematic review and meta-analysis of randomized controlled trials and observational studies comparing tandem ASCT with single ASCT in patients with newly diagnosed MM. We searched PubMed, EMBASE, Cochrane Library, and Clinical Trials databases for studies published up to January 2024. The primary outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR), complete response rate (CRR), and treatment-related mortality (TRM). We used a random-effects model to calculate pooled hazard ratios (HRs) and relative risks (RRs) with 95% confidence intervals (CIs). Study quality was assessed using the Cochrane risk of bias tool and Newcastle-Ottawa Scale. Twelve studies involving 5057 patients met the inclusion criteria. Tandem ASCT was associated with a significantly higher CRR compared to single ASCT (HR 1.33, 95% CI 1.03-1.71, I2 = 15%), but no significant differences were observed in PFS (HR 0.75, 95% CI 0.42-1.34, I2 = 14%), OS (HR 0.60, 95% CI 0.33-1.10, I2 = 27%), or the ORR (RR 0.80, 95% CI 0.59-1.08, I2 = 33%). However, tandem ASCT was associated with a significantly higher risk of TRM (RR 1.78, 95% CI 1.00-3.18, I2 = 0%). Tandem ASCT improves the CRR but does not provide significant benefits in terms of PFS, OS, or ORR compared to single ASCT in patients with newly diagnosed MM. Moreover, tandem ASCT is associated with a higher risk of TRM. The decision to pursue tandem ASCT should be made on an individual basis, carefully weighing the potential benefits and risks in light of each patient's unique clinical situation. Future research should focus on identifying patient subgroups most likely to benefit from tandem ASCT and exploring strategies to optimize the efficacy and safety of this approach in the context of novel agent-based therapies.

Chylothorax after chimeric antigen receptor T cell therapy for relapsed and refractory diffuse large B-cell lymphoma: A case report.

RATIONALE: Anti-CD19-targeted chimeric antigen receptor (CAR) T cell therapy is effective in treating relapsed/refractory diffuse large B-cell lymphoma (DLBCL). This therapy is associated with several side effects that can be life-threatening such as cytokine release syndrome (CRS). However, chylothorax associated with CRS after CAR-T therapy has not been reported. PATIENT CONCERNS: A 23-year-old male diagnosed with DLBCL relapsing after autologous peripheral blood stem cell transplantation was treated with anti-CD19-targeted CAR-T cell therapy. After CAR-T cell transfusion, he developed grade 3 CRS includes fever, dyspnea, tachycardia and hypotension. The symptoms of CRS persisted and chest plain film revealed bilateral pleural effusion. DIAGNOSIS: Chylothorax was confirmed by the pleural effusion analysis that triglyceride level was 1061 mg/dL. Bacterial and fungal culture of pleural fluid reported no pathogen was detected. Cytological examination of pleural effusion revealed no malignant cells. INTERVENTIONS: The chylothorax resolved after treatment with intravenous administration of tocilizumab. OUTCOMES: On 30-day follow-up, the patient was in stable clinical condition with complete remission of DLBCL on whole-body positron emission tomography scan. LESSONS: We reported a rare case of CAR-T associated chylothorax in a patient with relapsed and refractory DLBCL. Grade 3 CRS with high interleukin-6 level was presented in our patient. The symptoms of CRS were improved with tocilizumab treatment and the chylothorax resolved later on. It is suggested that high interleukin-6 releases might induce chyle leakage resulting from activations of endothelium and coagulation. Our finding highlights the occurrence of chylothorax during the course of CAR-T cell therapy and the importance of proper monitoring and prompt management of this life-threatening side effect.

Case report: Vaccine-induced immune thrombotic thrombocytopenia complicated by acute cerebral venous thrombosis and hemorrhage after AstraZeneca vaccines followed by Moderna COVID-19 vaccine booster and surgery.

Vaccine-induced thrombotic thrombocytopenia (VITT) is a well-known complication of adenoviral vector COVID-19 vaccines including ChAdOx1 nCoV-19 (AstraZeneca) and Ad26. COV2.S (Janssen, Johnson & Johnson). To date, only a few cases of mRNA COVID-19 vaccine such as mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech)-induced VITT have been reported. We report a case of VITT with acute cerebral venous thrombosis and hemorrhage after a booster of mRNA-1273 (Moderna) vaccine in a patient previously vaccinated with two doses of the AstraZeneca vaccine. A 42-year-old woman presented with sudden onset of weakness of the right upper limb with focal seizure. She had received two doses of AstraZeneca vaccines and a booster with Moderna vaccine 32 days before presentation. She had also undergone a laparoscopic myomectomy 12 days previously. Laboratory examinations revealed anemia (9.5 g/dl), thrombocytopenia (31 × 103/µl), and markedly elevated d-dimer (>20.0 mg/L; reference value < 0.5 mg/L). The initial brain computed tomography (CT) was normal, but a repeated scan 10 h later revealed hemorrhage at the left cerebrum. Before the results of the blood smear were received, on suspicion of thrombotic microangiopathy with thrombocytopenia and thrombosis, plasmapheresis and pulse steroid therapy were initiated, followed by intravenous immunoglobulin (1 g/kg/day for two consecutive days) due to refractory thrombocytopenia. VITT was confirmed by positive anti-PF4 antibody and both heparin-induced and PF4-induced platelet activation testing. Clinicians should be aware that mRNA-1273 Moderna, an mRNA-based vaccine, may be associated with VITT with catastrophic complications. Additionally, prior exposure to the AstraZeneca vaccine and surgical procedure could also have precipitated or aggravated autoimmune heparin-induced thrombocytopenia/VITT-like presentation.

Incidence and predictors of idiopathic pneumonia syndrome in hematopoietic stem cell transplant patients: a nationwide registry study.

Idiopathic pneumonia syndrome (IPS) is a rare but deadly complication of hematopoietic stem cell transplantation (HSCT). This study characterized the incidence and risk factors for IPS after HSCT in Taiwan. Data from January 2009 to February 2019 was collected from the Taiwan Society of BMT national registry. Forty-three (1.1%) of 3924 HSCT patients who developed IPS were identified. Incidence of IPS was lower in patients who received autologous HSCT than patients who received allogeneic HSCT (0.68% vs 1.44%, P = 0.022). Multivariate analysis showed that use of TBI and intravenous busulfan in the conditioning regimen were each independent predictor of IPS after HSCT. In addition, development of IPS was significantly associated with increased risk of death in the first 120 days post-HSCT (HR, 2.09; 95% CI, 1.08 to 4.05, P = 0.029) and 2 years post-HSCT (HR, 1.65; 95% CI, 1.07 to 2.542, P = 0.023), but not beyond 2 years post-HSCT. However, survival outcomes did not differ significantly between patients with IPS who received autologous versus allogeneic HSCT (P = 0.52). In conclusion, despite the relatively low incidence of post-HSCT IPS in Taiwan, mortality remains high. The results of this study will help to identify high-risk patients for early intervention and guide future therapeutic research.

Unusual bilateral kidney and duodenal plasmablastic lymphoma presentation in an elderly patient: A case report.

The present report described the case of a 71-year-old man who was admitted to the emergency department with a 7-day history of progressive left flank pain and tarry stool. Bedside point-of-care ultrasound of the left kidney showed lobulated ill-defined hypoechoic foci in the perirenal spaces with mild hydronephrosis. Subsequent contrast-enhanced abdominal computed tomography revealed lobulated low-density lesions in the bilateral perirenal space and paraaortic space. The patient was subsequently admitted to the internal medicine department of the hospital. Renal and duodenal biopsies were arranged, and pathology reports were consistent with the findings of plasmablastic lymphoma (PBL). This unusual presentation of flank pain and tarry stool caused by recurrent PBL highlighted that genitourinary or gastrointestinal manifestations could occur in cases of PBL recurrence. The patient received intensive chemotherapy regimens comprising a combination of etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin hydrochloride for aggressive non-Hodgkin's lymphoma to achieve a good response.

Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors.

BACKGROUND: Combination therapy with the administration of GW5074 and sorafenib significantly induced necrotic death in various cancer cells in vivo, as well as prolonging the survival of an animal disease model due to significant suppression of the primary and metastatic lesions. We sought to determine the safety, tolerability, pharmacokinetics, and anti-tumor activity of this co-administration therapy in patients with refractory advanced solid cancers. METHODS: Twelve patients were enrolled. Eligible subjects received different dosages of GW5074 in one of the three dose cohorts (Cohort 1: 750 mg daily, Cohort 2: 1500 mg daily, Cohort 3: 750 mg twice daily) plus 200 mg of sorafenib daily to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) at phase 1. Furthermore, the expression level of phosphorylated DAPKS308 in primary tumor, metastatic tumor, and circulating tumor cells (CTC) were evaluated to investigate the relationship between biomarker and the efficacy profile. RESULTS: Among the 12 enrolled patients in this phase 1 trial, most adverse effects (AE) were grade 1, with two being grade 3. The most frequent AE of all grades were weight loss and hypertension, occurring in 16.7% of participants. Eight patients (66.7%) had the disease controlled by receiving co-administration therapy of GW5074 and sorafenib. GW5074 was found to have poor absorption, as increasing the dosage did not result in a significant increase in the bioavailability of GW5074 in subjects. Furthermore, the expression level of phosphorylated DAPKS308 in tumor and CTCs were correlated with the disease control rate (DCR) and duration of response (DOR). CONCLUSIONS: Co-administration therapy of GW5074 and sorafenib demonstrated a favorable safety profile and showed anti-tumor activity in a variety of tumor types. However, the solubility of GW5074 is not satisfactory. A future phase 2a trial will be carried out using the new salted form that has been proven to be more effective.

NOVEL-1st: an observational study to assess the safety and efficacy of nilotinib in newly diagnosed patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase in Taiwan.

Nilotinib has been approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP). However, the real-world evidence of nilotinib in newly diagnosed untreated Ph+ CML-CP is limited in Taiwan. The NOVEL-1st study was a non-interventional, multi-center study collecting long-term safety and effectiveness data in patients with newly diagnosed and untreated Ph+ CML-CP receiving nilotinib. We enrolled 129 patients from 11 hospitals. Overall, 1,466 adverse events (AEs) were reported; among these, 151 were serious and 524 were nilotinib-related. Common hematological AEs were thrombocytopenia (31.0%), anemia (20.9%), and leukopenia (14.0%); common nilotinib-related AEs were thrombocytopenia (29.5%), anemia (14.7%), and leukopenia (12.4%). Early molecular response, defined as BCR-ABL ≤ 10% at Month 3, was seen in 87.6% of patients. By 36 months, the cumulative rates of complete hematologic response, complete cytogenetic response, major molecular response, molecular response 4.0-log reduction, and molecular response 4.5-log reduction were 98.5, 92.5, 85.8, 65.0, and 45.0%, respectively. Nilotinib is effective and well-tolerated in patients with newly diagnosed Ph+ CML-CP in the real-world setting. Long-term holistic care and a highly tolerable AE profile may contribute to good treatment outcomes in Ph+ CML-CP under first-line treatment with nilotinib.

Epigenetics-Associated Risk Reduction of Hematologic Neoplasms in a Nationwide Cohort Study: The Chemopreventive and Therapeutic Efficacy of Hydralazine.

BACKGROUND: Although several epigenetic drugs have been reported to have therapeutic efficacy for some hematologic neoplasms (HNs) in clinical trials, few achieved disease-free survival benefit. The traditional drug discovery pathway is costly and time-consuming, and thus, more effective strategies are required. We attempted to facilitate epigenetic drug repositioning for therapy of HNs by screening the Human Epigenetic Drug Database (HEDD) in the web, conducting a bench-work cytotoxicity test and a retrospective nationwide cohort study prior to a clinical trial. METHODS: Four FDA-approved epigenetic drugs with antitumor properties and completion of clinical phase II trials were selected from HEDD. Hydralazine (HDZ) and valproate (VAL) among the four were selected with higher cytotoxicity to HN cells, no matter whether carrying the JAK2V617F mutation or not. Both of them were chosen for a cohort study using the Longitudinal Health Insurance Database (LHID) 2000-2015 (N = 1,936,512), a subset of the National Health Insurance Research Database (NHIRD, N= 25.68 millions) in Taiwan. RESULTS: In the initial cohort, HDZ or VAL exposure subjects (11,049) and matching reference subjects (44,196) were enrolled according to maximal daily consumption (300/2,100 mg per day of HDZ/VAL). The HN incidence in HDZ and VAL exposure groups reduced from 4.97% to 3.90% (p <.001) and 4.45% (p = .075), respectively. A further cohort study on HDZ at a lower range of the WHO defined daily dose (<34 mg per day) and HN incidence of HDZ exposure subjects (75,612) reduced from 5.01% to 4.16% (p = 1.725 × 10 -18) compared to the reference subjects (302,448). CONCLUSIONS: An association of a chronically prescribed HDZ, even prescribed low dose, with reduction of overall incidence rate and in most subgroups of HN was observed in our study. Repositioning HDZ for HN management may be feasible. This is the first nationwide cohort study of the epigenetics-associated risk evaluation of overall HN in the existing literature, showing an effective method with a wider scope to inform contemporary clinical trials of epigenetic drugs in the future.

Evolution of congenital haemophilia care in Taiwan.

Haemophilia care in Taiwan has come a long way over the past 35 years, from the absence of specialised haemophilia treatment centres before 1984 to the establishment of treatment centers in the majority of medical centers, the listing of haemophilia as a catastrophic illness with full treatment reimbursement by the Taiwan National Health Insurance (NHI), and the implementation of full NHI coverage for prophylaxis therapy. This has led to outcome improvements such as reduced bleed-related morbidity and mortality, fewer viral infections, and enhanced overall multi-modality care. Most people with haemophilia (PWH) are now able to live normal, active lives. Early diagnosis has improved through increased awareness, physician education, and prenatal diagnosis; while comprehensive care, including state of the art rehabilitation and orthopaedic management for haemophilic arthropathy, eradication therapy for chronic hepatitis C, and better treatments for human immunodeficiency virus, allows PWH to enjoy a better quality of life and improved survival. Efforts are now being made to raise prophylaxis rates through full NHI reimbursement and the use of extended half-life recombinant factor products. Overall, Taiwan has made great strides in haemophilia care and we would like to share these experiences for the benefit of all healthcare providers involved in haemophilia care.

Aberrantly reduced expression of miR-342-5p contributes to CCND1-associated chronic myeloid leukemia progression and imatinib resistance.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with the Philadelphia chromosome, and the current standard of care is the use of tyrosine kinase inhibitors (TKI). However, some patients will not achieve a molecular response and may progress to blast crisis, and the underlying mechanisms remain to be clarified. In this study, next-generation sequencing was used to explore endogenous miRNAs in CML patients versus healthy volunteers, and miR-342-5p was identified as the primary target. We found that miR-342-5p was downregulated in CML patients and had a significant inhibitory effect on cell proliferation in CML. Through a luciferase reporter system, miR-342-5p was reported to target the 3'-UTR domain of CCND1 and downregulated its expression. Furthermore, overexpression of miR-342-5p enhanced imatinib-induced DNA double-strand breaks and apoptosis. Finally, by analyzing clinical databases, we further confirmed that miR-342-5p was associated with predicted molecular responses in CML patients. In conclusion, we found that both in vivo and in vitro experiments and database cohorts showed that miR-342-5p plays a key role in CML patients, indicating that miR-342-5p may be a potential target for future CML treatment or prognostic evaluation.

Cerebral Venous Sinus Thrombosis, Pulmonary Embolism, and Thrombocytopenia After COVID-19 Vaccination in a Taiwanese Man: A Case Report and Literature Review.

Objective: Coronavirus disease (COVID-19) vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but fatal complication observed within 2 weeks of adenovirus-vectored vaccination. Case Report: A 52-year-old male patient, with a family history of autoimmune diseases, presented with a new onset of worsening headache with nausea and vomiting post-vaccination. The patient was diagnosed with VITT based on laboratory findings demonstrating thrombocytopenia, elevated D-dimer, and dural sinus thrombosis identified on neuroimaging. The patient was successfully treated with high-dose immunoglobulin, steroids, and non-heparin anticoagulants, without any neurologic sequelae. Finally, a confirmatory test with anti-platelet factor 4 antibody was strongly positive. Conclusion: Physicians should be vigilant when treating patients presenting with new-onset thunderclap headache, progressive worsening headache, and awakening headache accompanied by nausea or vomiting after vaccination, even if no definite clinical neurological deficits are identified. Emergency laboratory test results for demonstrating elevated D-dimer levels, decreased platelet count, and neuroimaging correlation are integral for diagnosis and must be the standard protocol. Treatment with non-heparin anticoagulants, high-dose intravenous immunoglobulin, and steroids that halt or slow the immune-mediated prothrombotic process should be initiated immediately. Considering the high mortality rate of VITT, treatment should be initiated prior to confirmatory test results.

Uracil-tegafur vs fluorouracil as postoperative adjuvant chemotherapy in Stage II and III colon cancer: A nationwide cohort study and meta-analysis.

ABSTRACT: We conducted a population-based cohort study enrolling patients with Stage II and III colon cancer receiving postoperative adjuvant chemotherapy with uracil and tegafur (UFT) or fluorouracil (5-FU) from the Taiwan National Health Insurance Research Database from 2000 to 2015. The outcomes of the current study were disease-free survival (DFS) and overall survival (OS). Hazard ratios (HRs) were calculated by multivariate Cox proportional hazard regression models. We compared our effectiveness results from the literature by meta-analysis, which provided the best evidence. Severe adverse events were compared in meta-analysis of reported clinical trials. In the nationwide cohort study, UFT (14,486 patients) showed DFS similar to postoperative adjuvant chemotherapy (adjusted HR 1.037; 95% confidence interval [CI] 0.954-1.126; P = .397) and OS (adjusted HR 0.964; 95% CI 0.891-1.041; P = .349) compared with the 5-FU (866 patients). Our meta-analysis confirmed the similarity of effectiveness and found the incidence of leucopaenia was statistically significantly reduced in UFT (risk ratio 0.12; 95% CI 0.02-0.67; I2 = 0%). Through our analysis, we have confirmed that UFT is a well-tolerated adjuvant therapy choice, and has similar treatment efficacy as 5-FU in terms of DFS and OS in patients with Stage II and III colon cancer.

Does Hemophilia Increase Risk of Adverse Outcomes Following Total Hip and Knee Arthroplasty? A Propensity Score-Matched Analysis of a Nationwide, Population-Based Study.

BACKGROUND: End-stage hemophilic arthropathy is the result of recurrent joint hemarthrosis. Although total hip arthroplasty (THA) and total knee arthroplasty (TKA) can reduce severe joint pain and improve functional activity, controversy remains regarding outcomes after THA and TKA among patients with hemophilia. This study evaluated the risk of adverse outcomes of hemophilia patients who underwent THA and TKA. METHODS: This retrospective cohort study was conducted using data from the National Health Insurance Research Database. Patients who had hemophilia and underwent THA and TKA between 2000 and 2015 were identified. A total of 121 patients with hemophilia and 194,026 patients without hemophilia were included. Through propensity score matching, patients with hemophilia were matched at a 1:4 ratio to patients without hemophilia. Multivariable regression analysis was used to control for confounding variables and compare the risk of postoperative complications and mortality, differences in length of stay, and cost of care for the hospital. RESULTS: After propensity score matching and multivariate regression analysis, the adjusted hazard ratio of postoperative transfusion for hemophilia patients was 5.262 (95% confidence interval [CI] = 3.044-26.565, P < .001) in THA group and 6.279 (95% CI = 3.246-28.903, P < .001) in TKA group, when compared with the control group. Patients with hemophilia had longer length of hospital stay (THA group: 95% CI, 1.541-2.669, P < .001; TKA group: 95% CI, 1.568-2.786; P < .001) and higher total hospital charges (THA group: 95% CI, 3.518-8.293, P < .001; TKA group: 95% CI, 3.584-8.842; P < .001) compared to patients without hemophilia. Hemophiliacs had a higher yet nonsignificant 1-year infection rate (8.11% vs 3.38%, P = .206) in the THA group. There were no differences between the rates of 30-day and 90-day complications, 1-year infection, reoperation and mortality between the hemophilia and nonhemophilia groups. CONCLUSION: Hemophilia patients have higher rates of postoperative transfusion, hospital costs, and increased length of stay. There is an appreciable clinical difference in 1-year infection rates following THA but our analysis was limited by the small sample size. Other postoperative complications and mortality rates were comparable. Patients with hemophilia should be counseled that infection rate maybe as high as 8% following THA. Further investigation is needed to develop prophylactic and effective methods to decrease the rates of transfusions and associated adverse outcomes in hemophilia patients undergoing THA and TKA.

Bortezomib therapy in a real-world setting in patients with relapsed or refractory multiple myeloma.

Bortezomib is a proteasome inhibitor, approved for treating newly diagnosed and relapsed multiple myeloma (MM). This realworld, multicenter, observational, non-interventional study of bortezomib was designed to collect and analyze prospective data in Taiwanese patients with relapsed or refractory MM. The primary endpoints included clinical effectiveness outcomes (disease response, disease progression [PD], time-to-response, time-toprogression, response duration, and overall survival [OS]). Secondary endpoints were safety and healthcare resource utilization. Total 100 patients (median [range] age 64.9 [37.0-85.5] years) were enrolled; 47 patients completed the study. Of the withdrawn patients (n=53), there were 48 deaths (PD-related death: n=35, adverse events [AEs]-related: n=12, other reason: n=1), and 5 due to loss to follow-up. Four patients in Cycle 1, 6 patients each in Cycle 2 and 5, 7 in Cycle 3, 10 patients in Cycle 4, 5 patients in Cycle 6, and 3 patients each in Cycle 7 and 8 achieved overall response during the study. Time-to-response was 4.68 months (95%CI: 3.2, NE) and response duration was 10.08 months (95%CI: 2.3, 28.6). Median OS was 9.8 months (95%CI: 3.8, 13.7), and median time-to-progression was 11.3 months (95%CI: 6.2, 20.2). Most common non-hematological AEs were diarrhea (n=32) and hypoesthesia (n=25); most common hematological AE was thrombocytopenia (n=18). Efficacy and safety profile of bortezomib in Taiwanese patients with MM was similar to global and other Asian population. Study provides a critical insight on use of bortezomib in realworld clinical practice, which can be helpful for Taiwanese healthcare providers' decision-making processes.

The incidence and risk factors of hepatic veno-occlusive disease after hematopoietic stem cell transplantation in Taiwan.

Hepatic veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). We conducted this study to investigate the incidence and risk factors of hepatic VOD for patients receiving HSCT in Taiwan. We retrospectively analyzed the data from a nationwide registry for patients receiving HSCT, which was collected by the Taiwan Society of Blood and Marrow Transplantation. The data collection period was from 2009 to 2014. A total 2345 patients were reviewed and 39 patients among them were diagnosed as having hepatic VOD. The cumulative incidence of hepatic VOD in the whole cohort of 2345 patients was 1.66%. In multivariate analysis, disease diagnosis of myelodysplastic syndrome, chronic HCV infection, condition regimens of bulsulfan intravenously administered, and antithymocyte immunoglobulin were independent factors to predict higher risk of hepatic VOD. The overall mortality rate for patients with hepatic VOD was 79%. Patients with hepatic VOD had significant worse survival outcomes when compared with those without hepatic VOD (P = 0.00063). In conclusion, although the incidence is low, hepatic VOD remains a serious complication after HSCT in Taiwan. The findings of this study could be the basis for developing prophylactic or early treatment strategies for hepatic VOD.

Long-term safety and efficacy of deferasirox in patients with myelodysplastic syndrome, aplastic anemia and other rare anemia in Taiwan.

OBJECTIVE: Patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemia require chronic blood transfusions which can lead to iron overload and subsequent excess iron-mediated complications. Intensive iron chelation with deferasirox could remove excess iron and can alleviate these events; however, the long-term safety and efficacy in Chinese population are not clearly characterized. This study examined the long-term efficacy and safety of deferasirox in a real-world setting in Taiwan. METHODS: This observational, non-interventional, single-arm, multi-center, phase IV study was designed to collect the safety and clinical information about patients who were treated with deferasirox according to investigator's judgment and in accordance with the general clinical practice. RESULTS: From 2009 to 2011, patients with MDS (N = 38), AA (N = 23), and other rare anemias (N = 18) were enrolled. The mean deferasirox exposure was 17.7 ± 4.02 mg/kg/day. The most common drug-related AEs were skin disorders (32.9%) and gastrointestinal disorders (30.4%), while grade 3-4 AEs were rare (5.1%). In the overall patient population, deferasirox effectively decreased serum ferritin levels at 1 year (P = 0.0154) and 3 years (P = 0.0424) from the baseline. Upon the use of deferasirox, 32.9% patients showed erythroid response and 16.7% patients had platelet response. CONCLUSIONS: For patients with MDS, AA, and other rare anemias, the AEs observed in this 3-year surveillance study with deferasirox were mostly mild or moderate. In addition, the hematological response rate was higher than that in the EPIC study, which primarily enrolled Caucasian patients.

The clinical impact of the novel tumor marker DR-70 in unresectable gastric cancer patients.

BACKGROUND: Gastric cancer tumor markers, such as carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA 19-9), have been applied in clinical practice to screen or monitor treatment responses. However, their sensitivity and specificity are unsatisfactory. Therefore, we assessed the novel tumor marker DR-70 and evaluated its performance in screening and response monitoring. METHODS: The study included newly diagnosed patients with advanced gastric cancer from March 2012 to October 2015. We measured the DR-70, CEA, and CA 19-9 levels at the time of enrollment. The patients subsequently underwent chemotherapy. We followed-up the patients every 3 months; DR-70 levels and abdominal computed tomography scans were re-evaluated and repeated, respectively, at each follow-up. The correlation between treatment response and DR-70 level after chemotherapy was analyzed. The overall survival and progression-free survival rates were also evaluated. RESULTS: A total of 51 patients with gastric cancer were enrolled. Most (82.4%) had metastatic disease. At enrollment, the sensitivity of DR-70 in our study group was 78.4%, compared with 52.9% and 43.1% for CEA and CA 19-9, respectively. When we used the three tumor markers together, the sensitivity increased to 80.4%. We observed a correlation between treatment response and DR-70 level after chemotherapy. No difference in either overall survival or progression-free survival was observed between the DR-70 positive and negative groups. However, a trend toward poorer overall survival was observed for the high DR-70 group, although this was not statistically significant. CONCLUSION: DR-70 is a powerful tool not only for screening unresectable gastric cancer but also for treatment response evaluation.

Safety and efficacy of nilotinib in routine clinical practice in patients with chronic myeloid leukemia in chronic or accelerated phase with resistance or intolerance to imatinib: results from the NOVEL study.

BACKGROUND: Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), is approved for the treatment of patients with chronic myeloid leukemia (CML) in many countries, including Taiwan. Though a number of controlled clinical trials have demonstrated the safety and efficacy of nilotinib, studies assessing the safety and efficacy of nilotinib in routine clinical practice are limited. METHODS: The current study was an open-label, single-arm study conducted across 12 centers in Taiwan in adult patients with CML in chronic or accelerated phase with confirmed Ph+ chromosome (or BCR-ABL) and resistant or intolerant to one or more previous TKIs. The primary objective was to collect the long-term safety data in patients treated with nilotinib 400 mg, twice daily for up to 2 years. RESULTS: The study enrolled 85 patients with CML, including 76 in the chronic phase (CML-CP) and 9 in the accelerated phase (CML-AP). Overall, 1166 adverse events (AEs) were reported in 80 patients (94.1%), of which 70 AEs (6%) in 28 patients (32.9%) were serious and 336 AEs (28.8%) reported in 60 patients (70.6%) were drug-related. Common drug-related AEs were thrombocytopenia (21.2%), increased alanine aminotransferase (21.2%) and pruritus (17.7%). Of the 85 patients, 19 switched from imatinib due to intolerance - AEs were resolved in 16 of these 19 patients (84.2%). By 24 months, the cumulative rates of complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0 (BCR-ABL1IS ⩽0.01%) and MR4.5 (BCR-ABL1IS ⩽0.0032%) were 75.3, 56.8, 16.2 and 7.4%, respectively. Patients with CML-CP at baseline had higher overall survival (OS) and progression-free survival (PFS) than those with CML-AP. CONCLUSION: This is the first study that demonstrated that nilotinib is effective and well-tolerated in patients resistant or intolerant to imatinib in the real-world setting in Taiwan, reflecting effective management of CML by physicians under routine clinical practice in Taiwan.

Characteristics comparisons of bacteremia in allogeneic and autologous hematopoietic stem cell-transplant recipients with levofloxacin prophylaxis and influence on resistant bacteria emergence.

BACKGROUND: The aim of this study was to compare the risk factors and clinical outcomes of bacteremia in allogeneic and autologous hematopoietic stem cell transplant (allo-HSCT and auto-HSCT) recipients with levofloxacin prophylaxis during the early period after transplantation. METHODS: Characteristics of bacteremia within 45 days after transplantation between allo-HSCT and auto-HSCT recipients who received levofloxacin prophylaxis between January 2005 and December 2014 were retrospectively reviewed. RESULTS: Of 105 HSCT recipients included in this study, 55 (52.4%) received an allo-HSCT and 50 (47.6%) received an auto-HSCT. Twenty-five patients (23.8%) with HSCT developed 28 episodes of bacteremia. Of these 25 bacteremia patients, 15 received an allo-HSCT, while 10 received an auto-HSCT. The occurrence of Grade 3-4 graft-versus-host disease and longer engraftment duration were associated with bacteremia in allo- and auto-HSCT recipients (p = 0.001 and p = 0.002, respectively). Auto-HSCT recipients with bacteremia had a longer hospital stay after transplantation, while allo-HSCT recipients with bacteremia had an increased 45-day mortality rate as compared with those without bacteremia (p = 0.014 and p = 0.013, respectively). All 14 Gram-negative blood isolates in this study were resistant to fluoroquinolone. CONCLUSION: Levofloxacin prophylaxis in HSCT recipients is associated with the emergence of fluoroquinolone-resistant Gram-negative bacteria. The risk factors and clinical outcomes of bacteremia differ between allo- and auto-HSCT recipients, and these differences should be taken into account when designing strategies to prevent bacteremia.

Efficacy, safety, and pharmacokinetics of subcutaneous azacitidine in Taiwanese patients with higher-risk myelodysplastic syndromes.

AIM: Clinical and pharmacokinetic effects of azacitidine in higher-risk myelodysplastic syndromes were established in mainly Caucasian populations. Because of inter-ethnic genotype variability of drug-metabolizing enzymes, it is important to evaluate azacitidine in populations expected to use the drug. METHODS: In this single-arm study, Taiwanese patients with higher-risk myelodysplastic syndromes received azacitidine 75 mg/m2 /day for 7 days/28-day cycle for up to six cycles. Response-evaluable patients had baseline and cycle 6 marrow assessments. Clinical outcomes are compared descriptively with those from a phase 3 study comprising mainly Caucasian patients (N = 179). Pharmacokinetics in a subgroup of Taiwanese patients are descriptively compared with a historical control of North American patients (N = 45). RESULTS: Median age of Taiwanese patients (N = 44) was 64 years (range 36-90), and 46% had poor cytogenetics. Median number of azacitidine cycles was six (1-6). No response-evaluable patient (n = 33) achieved complete or partial remission; however, 22 patients (50%) achieved hematologic improvement, 12 of 32 patients attained RBC transfusion independence and 7 of 18 attained platelet transfusion independence. Most common grade 3-4 treatment-emergent adverse events were neutropenia (52%) and leukopenia (39%). Pharmacokinetic profiles were similar for Taiwanese (N = 12) and North American (N = 45) patients. Maximum plasma concentration was higher in Taiwanese patients; however, mean azacitidine exposure was within the range for North American patients. CONCLUSION: These data confirm the safety and efficacy of azacitidine in Taiwanese patients with higher-risk myelodysplastic syndromes. Clinical outcomes were generally comparable with those for Caucasian patients. No meaningful differences in azacitidine pharmacokinetics were observed for Taiwanese patients, and no initial dose adjustment is necessary.