Long-Term Efficacy and Safety of Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria and High Disease Burden: Real-World Data From Korea

Background@#Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled terminal complement activation. Eculizumab, a monoclonal antibody C5 inhibitor was introduced in Korea in 2009 and has been the standard treatment option for PNH. @*Methods@#This study assessed the long-term efficacy/safety of eculizumab in PNH using real-world data from the Korean Health Insurance Review and Assessment Service. Eighty patients who initiated eculizumab from 2009–2020 were enrolled. @*Results@#At eculizumab initiation, the median age was 51.5 years, lactate dehydrogenase (LDH) 6.8 × upper limit of normal, and granulocyte clone size 93.0%. All patients had at least one PNH-related complication before eculizumab initiation, including renal failure (n = 36), smooth muscle spasm (n = 24), thromboembolism (n = 20), and pulmonary hypertension (n = 15). The median (range) duration of eculizumab treatment was 52.7 (1.0, 127.3) months (338.6 total treated patient-years). Despite high disease activity in the study population before treatment initiation, overall survival was 96.2% and LDH levels were stabilized in most patients during treatment. PNH-related complications at treatment initiation were resolved in 44.4% of patients with renal failure, 95.8% with smooth muscle spasm, 70.0% with thromboembolism, and 26.7% with pulmonary hypertension. Extravascular hemolysis occurred in 28.8% of patients (n = 23; 0.09 per patient-year) and breakthrough hemolysis in 18.8% (n = 15; 0.06 per patient-year). No treatment discontinuation cases related to eculizumab were observed. @*Conclusion@#These data provided evidence for the long-term efficacy and safety of eculizumab in Korean PNH patients with high disease burdens.

Clinical Significance of bZIP In-Frame CEBPA-Mutated Normal Karyotype Acute Myeloid Leukemia / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#We evaluated the characteristics of CCAAT/enhancer-binding protein α (CEBPA) mutations and the significance of a basic leucine zipper in-frame mutation (bZIPin-f) of CEBPA in patients with acute myeloid leukemia with a normal karyotype. @*Materials and Methods@#Based on updated knowledge of CEBPA mutations, we conducted next-generation sequencing analyses in a previously established real-world cohort. @*Results@#Among 78 of a total of 395 patients (19.7%), 50 had bZIPin-f CEBPA, and 28 had non-bZIPin-f CEBPA. In the multivariate analysis, patients with NPM1mut, those with bZIPin-f CEBPA, and those who underwent allogeneic hematopoietic cell transplantation (allo-HCT) had favorable overall survival (OS), but FLT3-ITDmut was a poor prognostic indicator. For relapse-free survival (RFS) and cumulative incidence of relapse, bZIPin-f CEBPA, and allo-HCT were associated with favorable outcomes; FLT3-ITDpos was associated with worse outcomes. In the CEBPA double-mutated group (CEBPAdm), bZIPin-f CEBPA was associated with superior outcomes in terms of OS (p=0.007) and RFS (p=0.007) compared with non-bZIPin-f CEBPA. Of 50 patients with bZIPin-f CEBPA, 36 patients had at least one mutation. When grouped by the presence of mutations in chromatic/DNA modifiers (C), cohesion complex (C), and splicing genes (S) (CCS mutations), CCS-mutated bZIPin-f CEBPA was associated with poor OS (p=0.044; hazard ratio [HR], 2.419) and a trend in inferior RFS (p=0.186; HR, 1.838). @*Conclusion@#Only bZIPin-f CEBPA was associated with favorable outcomes in patients with CEBPAdm. However, some mutations accompanying bZIPin-f CEBPA showed inferior OS; thus, further studies with larger numbers of patients are required for clear conclusions of the significance of bZIPin-f CEBPA.

Mitochondrial Reactive Oxygen Species Elicit Acute and Chronic Itch via Transient Receptor Potential Canonical 3 Activation in Mice / 神经科学通报·英文版

Mitochondrial reactive oxygen species (mROS) that are overproduced by mitochondrial dysfunction are linked to pathological conditions including sensory abnormalities. Here, we explored whether mROS overproduction induces itch through transient receptor potential canonical 3 (TRPC3), which is sensitive to ROS. Intradermal injection of antimycin A (AA), a selective inhibitor of mitochondrial electron transport chain complex III for mROS overproduction, produced robust scratching behavior in naïve mice, which was suppressed by MitoTEMPO, a mitochondria-selective ROS scavenger, and Pyr10, a TRPC3-specific blocker, but not by blockers of TRPA1 or TRPV1. AA activated subsets of trigeminal ganglion neurons and also induced inward currents, which were blocked by MitoTEMPO and Pyr10. Besides, dry skin-induced chronic scratching was relieved by MitoTEMPO and Pyr10, and also by resveratrol, an antioxidant. Taken together, our results suggest that mROS elicit itch through TRPC3, which may underlie chronic itch, representing a potential therapeutic target for chronic itch.

IDH1/2 mutations in acute myeloid leukemia

The mutational and epigenetic landscape of acute myeloid leukemia (AML) has become increasingly well understood in recent years, informing on biological targets for precision medicine. Among the most notable findings was the recognition of mutational hot-spots in the isocitrate dehydrogenase (IDH) genes. In this review, we provide an overview on the IDH1/2 mutation landscape in Korean AML patients, and compare it with available public data. We also discuss the role of IDH1/2 mutations as biomarkers and drug targets.Taken together, occurrence of IDH1/2 mutations is becoming increasingly important in AML treatment, thus requiring thorough examination and follow-up throughout the clinical course of the disease.

Management of immune thrombocytopenia: 2022 update of Korean experts recommendations

Despite the availability of therapies to treat patients with immune thrombocytopenia (ITP), there is currently little data from randomized trials to assist clinicians in managing patients. The evidence-based guidelines of the Korean Society of Hematology Aplastic Anemia Working Party (KSHAAWP) are intended to support patients and physicians in the management of ITP. Experts from the KSHAAWP discussed and described this guideline according to the current treatment situation for ITP in Korea and finalized the guidelines. The expert panel recommended the management of ITP in adult and pediatric patients with newly diagnosed, persistent, and chronic disease refractory to first-line therapy with minor bleeding. Management approaches include observation and administration of corticosteroids, intravenous immunoglobulin, anti-D immunoglobulin, and thrombopoietin receptor agonists. Currently, evidence supporting strong recommendations for various management approaches is lacking. Therefore, a large focus was placed on shared decision-making, especially regarding second-line treatment.

Mutations in genes affecting DNA methylation enhances responses to decitabine in patients with myelodysplastic syndrome

Background/Aims@#In this study, we tested whether mutations in the methylation pathway genes ten-eleven-translocation 2 (TET2) and DNA methyltransferase gene 3A (DNMT3A) improve the responses of patients with myelodysplastic syndrome (MDS) to decitabine. @*Methods@#We retrospectively sequenced the TET2 and DNMT3A genes from 70 patients diagnosed with de novo MDS between June 2008 and December 2011 and treated with a 5-day regimen of decitabine (290 cycles). We then analyzed treatment outcomes. @*Results@#Patients with hematological improvement survived longer than those without hematological improvement (22.9 months vs. 10.9 months, p = 0.006). Among the 70 patients, 12 (17.1%) carried TET2 or DNMT3A mutations. The baseline characteristics of patients with wild type or mutated genes were similar. Patients with mutations in TET2 or DNMT3A had a higher overall response rate than those with the wild type genes (82.3% vs. 46.6%, p = 0.023). Multivariate analysis demonstrated that the TET2 or DMNT3A mutation status was associated with improved treatment responses and better overall survival among patients receiving decitabine. @*Conclusions@#These results demonstrate that TET2 mutations enhance the treatment response of MDS patients to hypomethylating agents like decitabine.

Effect of Human or Mouse IL-7 on the Homeostasis of Porcine T Lymphocytes

Due to the inconsistent fluctuation of blood supply for transfusion, much attention has been paid to the development of artificial blood using other animals. Although mini-pigs are candidate animals, contamination of mini-pig T cells in artificial blood may cause a major safety concern. Therefore, it is important to analyze the cross-reactivity of IL-7, the major survival factor for T lymphocytes, between human, mouse, and mini-pig. Thus, we compared the protein sequences of IL-7 and found that porcine IL-7 was evolutionarily different from human IL-7. We also observed that when porcine T cells were cultured with either human or mouse IL-7, these cells did not increase the survival or proliferation compared to negative controls. These results suggest that porcine T cells do not recognize human or mouse IL-7 as their survival factor.

Effect of Human or Mouse IL-7 on the Homeostasis of Porcine T Lymphocytes

Due to the inconsistent fluctuation of blood supply for transfusion, much attention has been paid to the development of artificial blood using other animals. Although mini-pigs are candidate animals, contamination of mini-pig T cells in artificial blood may cause a major safety concern. Therefore, it is important to analyze the cross-reactivity of IL-7, the major survival factor for T lymphocytes, between human, mouse, and mini-pig. Thus, we compared the protein sequences of IL-7 and found that porcine IL-7 was evolutionarily different from human IL-7. We also observed that when porcine T cells were cultured with either human or mouse IL-7, these cells did not increase the survival or proliferation compared to negative controls. These results suggest that porcine T cells do not recognize human or mouse IL-7 as their survival factor.

Relationship of Circulating Cytomegalovirus Levels Obtained Through Antigenemia Testing and Quantitative PCR Differs Between Children and Adults

No abstract available.

Getting patient blood management Pillar 1 right in the Asia-Pacific: a call for action

Preoperative anaemia is common in the Asia-Pacific. Iron deficiency anaemia (IDA) is a risk factor that can be addressed under patient blood management (PBM) Pillar 1, leading to reduced morbidity and mortality. We examined PBM implementation under four different healthcare systems, identified challenges and proposed several measures: (a) Test for anaemia once patients are scheduled for surgery. (b) Inform patients about risks of preoperative anaemia and benefits of treatment. (c) Treat IDA and replenish iron stores before surgery, using intravenous iron when oral treatment is ineffective, not tolerated or when rapid iron replenishment is needed; transfusion should not be the default management. (d) Harness support from multiple medical disciplines and relevant bodies to promote PBM implementation. (e) Demonstrate better outcomes and cost savings from reduced mortality and morbidity. Although PBM implementation may seem complex and daunting, it is feasible to start small. Implementing PBM Pillar 1, particularly in preoperative patients, is a sensible first step regardless of the healthcare setting.

Comparison of quality of life and depression between hematopoietic stem cell transplantation survivors and their spouse caregivers

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an exhausting process that impacts both the patient and caregiver. METHODS: This was a cross-sectional, HSCT survivor-spouse caregiver matching study to determine quality of life (QoL) and depression among HSCT survivors and their caregivers. QoL and depression were measured with the World Health Organization Quality of Life: Brief Version (26 items) and the 9-item Patient Health Questionnaire, respectively. Data from 97 married couples were analyzed. RESULTS: There were no significant differences in overall QoL and psychological, social, and environmental health between survivors and spouse caregivers (P=0.345, 0.424, 0.415, and 0.253); however, physical QoL was better in the spouse caregiver group (P=0.011). There was no difference in mean depression scale scores (5.3 vs. 5.1, P=0.812) or proportion of severe depression (15.6% vs. 13.7%, P=0.270) between the two groups. We found that family income had a significant impact on overall QoL and environmental health among spouse caregivers (P=0.013 and 0.023), and female gender, co-morbidities, and family income were the important factors associated with depression among spouse caregivers (P=0.007, 0.017 and 0.049). CONCLUSION: This study found that there were no significant differences in QoL or level of depression between HSCT survivors and their spouse caregivers. Family income, gender, and co-morbidities showed significant association with spouse caregiver distress.

Poor Prognostic Implication of ASXL1 Mutations in Korean Patients With Chronic Myelomonocytic Leukemia

BACKGROUND: Molecular genetic abnormalities are observed in over 90% of chronic myelomonocytic leukemia (CMML) cases. Recently, several studies have demonstrated the negative prognostic impact of ASXL1 mutations in CMML patients. We evaluated the prognostic impact of ASXL1 mutations and compared five CMML prognostic models in Korean patients with CMML. METHODS: We analyzed data from 36 of 57 patients diagnosed as having CMML from January 2000 to March 2016. ASXL1 mutation analysis was performed by direct sequencing, and the clinical and laboratory features of patients were compared according to ASXL1 mutation status. RESULTS: ASXL1 mutations were detected in 18 patients (50%). There were no significant differences between the clinical and laboratory characteristics of ASXL1-mutated (ASXL1+) CMML and ASXL1-nonmutated (ASXL1−) CMML patients (all P>0.05). During the median follow-up of 14 months (range, 0–111 months), the overall survival (OS) of ASXL1+ CMML patients was significantly inferior to that of ASXL1− CMML patients with a median survival of 11 months and 19 months, respectively (log-rank P=0.049). An evaluation of OS according to the prognostic models demonstrated inferior survival in patients with a higher risk category according to the Mayo molecular model (log-rank P=0.001); the other scoring systems did not demonstrate a significant association with survival. CONCLUSIONS: We demonstrated that ASXL1 mutations, occurring in half of the Korean CMML patients examined, were associated with inferior survival. ASXL1 mutation status needs to be determined for risk stratification in CMML.

Efficacy of eculizumab in paroxysmal nocturnal hemoglobinuria patients with or without aplastic anemia: prospective study of a Korean PNH cohort

BACKGROUND: Patients with paroxysmal nocturnal hemoglobinuria (PNH) often have concurrent aplastic anemia (AA). This study aimed to determine whether eculizumab-treated patients show clinical benefit regardless of concurrent AA. METHODS: We analyzed 46 PNH patients ≥18 years of age who were diagnosed by flow cytometry and treated with eculizumab for more than 6 months in the prospective Korean PNH registry. Patients were categorized into two groups: PNH patients with concurrent AA (PNH/AA, N=27) and without AA (classic PNH, N=19). Biochemical indicators of intravascular hemolysis, hematological laboratory values, transfusion requirement, and PNH-associated complications were assessed at baseline and every 6 months after initiation of eculizumab treatment. RESULTS: The median patient age was 46 years and median duration of eculizumab treatment was 34 months. Treatment with eculizumab induced rapid inhibition of hemolysis. At 6-month follow-up, LDH decreased to near normal levels in all patients; this effect was maintained until the 36-month follow-up regardless of concurrent AA. Transfusion independence was achieved by 53.3% of patients within the first 6 months of treatment and by 90.9% after 36 months of treatment. The mean number of RBC units transfused was significantly reduced, from 8.5 units during the 6 months prior to initiation of eculizumab to 1.6 units in the first 6 months of treatment, for the total study population; this effect was similar in both PNH/AA and classic PNH. CONCLUSION: This study demonstrated that eculizumab is beneficial in the management of patients with PNH/AA, similar to classic PNH.

Management of immune thrombocytopenia: Korean experts recommendation in 2017

Management options for patients with immune thrombocytopenia (ITP) have evolved substantially over the past decades. The American Society of Hematology published a treatment guideline for clinicians referring to the management of ITP in 2011. This evidence-based practice guideline for ITP enables the appropriate treatment of a larger proportion of patients and the maintenance of normal platelet counts. Korean authority operates a unified mandatory national health insurance system. Even though we have a uniform standard guideline enforced by insurance reimbursement, there are several unsolved issues in real practice in ITP treatment. To optimize the management of Korean ITP patients, the Korean Society of Hematology Aplastic Anemia Working Party (KSHAAWP) reviewed the consensus and the Korean data on the clinical practices of ITP therapy. Here, we report a Korean expert recommendation guide for the management of ITP.

Successful treatment of steroid-refractory immune thrombocytopenia with alemtuzumab

No abstract available.

Myelodysplastic Syndrome (RAEB-II) Development 2 Months after Chemotherapy for a Primary Non-seminomatous Mediastinal Germ Cell Tumor / 대한내과학회지

Here, we report on a 20-year-old patient with a primary nonseminomatous mediastinal germ cell tumor (MGCT) who developed myelodysplastic syndrome (MDS) 2 months following chemotherapy with cisplatin, etoposide, ifosfamide, and paclitaxel. Bone marrow examinations revealed that the MDS was a refractory anemia with excess type II blasts and complex chromosomal abnormalities. With the onset of MDS occurring rapidly following chemotherapy, it is unlikely to have been caused by the therapy. We discuss the association between primary nonseminomatous MGCTs and hematological malignancies, including the possibility of a common clonal origin.

Dilated cardiomyopathy with Graves disease in a young child

Graves disease (GD) can lead to complications such as cardiac arrhythmia and heart failure. Although dilated cardiomyopathy (DCMP) has been occasionally reported in adults with GD, it is rare in children. We present the case of a 32-month-old boy with DCMP due to GD. He presented with irritability, vomiting, and diarrhea. He also had a history of weight loss over the past few months. On physical examination, he had tachycardia without fever, a mild diffuse goiter, and hepatomegaly. The chest radiograph showed cardiomegaly with pulmonary edema, while the echocardiography revealed a dilated left ventricle with an ejection fraction (EF) of 28%. The thyroid function test (TFT) showed elevated serum T3 and decreased thyroid stimulating hormone (TSH) levels. The TSH receptor autoantibody titer was elevated. He was diagnosed with DCMP with GD; treatment with methylprednisolone, diuretics, inotropics, and methimazole was initiated. The EF improved after the TFT normalized. At follow-up several months later, although the TFT results again showed evidence of hyperthyroidism, his EF had not deteriorated. His cardiac function continues to remain normal 1.5 months after treatment was started, although he still has elevated T3 and high TSH receptor antibody titer levels due to poor compliance with drug therapy. To summarize, we report a young child with GD-induced DCMP who recovered completely with medical therapy and, even though the hyperthyroidism recurred several months later, there was no relapse of the DCMP.

Dilated cardiomyopathy with Graves disease in a young child

Graves disease (GD) can lead to complications such as cardiac arrhythmia and heart failure. Although dilated cardiomyopathy (DCMP) has been occasionally reported in adults with GD, it is rare in children. We present the case of a 32-month-old boy with DCMP due to GD. He presented with irritability, vomiting, and diarrhea. He also had a history of weight loss over the past few months. On physical examination, he had tachycardia without fever, a mild diffuse goiter, and hepatomegaly. The chest radiograph showed cardiomegaly with pulmonary edema, while the echocardiography revealed a dilated left ventricle with an ejection fraction (EF) of 28%. The thyroid function test (TFT) showed elevated serum T3 and decreased thyroid stimulating hormone (TSH) levels. The TSH receptor autoantibody titer was elevated. He was diagnosed with DCMP with GD; treatment with methylprednisolone, diuretics, inotropics, and methimazole was initiated. The EF improved after the TFT normalized. At follow-up several months later, although the TFT results again showed evidence of hyperthyroidism, his EF had not deteriorated. His cardiac function continues to remain normal 1.5 months after treatment was started, although he still has elevated T3 and high TSH receptor antibody titer levels due to poor compliance with drug therapy. To summarize, we report a young child with GD-induced DCMP who recovered completely with medical therapy and, even though the hyperthyroidism recurred several months later, there was no relapse of the DCMP.

Predictive Factors of Mortality in Population of Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): Results from a Korean PNH Registry

Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive, systemic, life-threatening disease, characterized by chronic uncontrolled complement activation. A retrospective analysis of 301 Korean PNH patients who had not received eculizumab was performed to systematically identify the clinical symptoms and signs predictive of mortality. PNH patients with hemolysis (lactate dehydrogenase [LDH] > or = 1.5 x the upper limit of normal [ULN]) have a 4.8-fold higher mortality rate compared with the age- and sex-matched general population (P < 0.001). In contrast, patients with LDH < 1.5 x ULN have a similar mortality rate as the general population (P = 0.824). Thromboembolism (TE) (odds ratio [OR] 7.11; 95% confidence interval [CI] (3.052-16.562), renal impairment (OR, 2.953; 95% CI, 1.116-7.818) and PNH-cytopenia (OR, 2.547; 95% CI, 1.159-5.597) are independent risk factors for mortality, with mortality rates 14-fold (P < 0.001), 8-fold (P < 0.001), and 6.2-fold (P < 0.001) greater than that of the age- and sex-matched general population, respectively. The combination of hemolysis and 1 or more of the clinical symptoms such as abdominal pain, chest pain, or dyspnea, resulted in a much greater increased mortality rate when compared with patients with just the individual symptom alone or just hemolysis. Early identification of risk factors related to mortality is crucial for the management of PNH. This trial was registered at www.clinicaltrials.gov as NCT01224483.

Two Cases of Acute Lymphoblastic Leukemia with an e1a3 BCR-ABL1 Fusion Transcript

No abstract available.