국내 Human Research Protection Program 도입 과정과 발전 방향에 대한 고찰

The Human Research Protection Program (HRPP) includes all subject protection activities and entities involved in the process of planning, reviewing, and conducting clinical research and it ultimately aims that research can be conducted ethically and scientifically while protecting the rights and welfare of research subjects. At the beginning of its introduction in Korea, it was settled down by adopting the United States HRPP, especially the form of AAHRPP element and regulations. However, regulations and operating forms of HRPP have been changed according to the Korean domestic research environment. Actually, all the Korean institutions are adopted the Korean HRPP guidelines that have been officially announced by the Ministry of Food and Drug Safety in Korea. Recently, Korean domestic laws such as the "Advanced Regenerative Biology Act" or "In Vitro Diagnostic Medical Device Act" have been dramatically innovated and our research environment becomes to be more complicated. Therefore, the development of a suitable Korean HRPP model considering the Korean research environment is strongly demanded. For the early settle down of the Korean HRPP model, the positive incentive method should be applied, when the HRPP is operated and/ or properly operated. These improvements in the Korean HRPP environment will eventually lead to the appropriate protection of subjects who are participating in human clinical research and the quality improvement of clinical research.ope

Acquired Hemophilia A

Acquired hemophilia A is rare but fatal bleeding disorder caused by an autoantibody against factor VIII. Acquired hemophilia A is more prevalent in the elderly patients and associated with other underlying diseases such as autoimmune disorders, malignancies, pregnancy, infection and several drugs. The bleeding pattern of acquired hemophilia A is quite different from that of congenital hemophilia A. Thus, acquired hemophilia A should be suspected in the presence of bleeding with sudden onset, often severe, which occurs spontaneously or after minor trauma, following invasive procedures or surgical interventions in patients without a personal or family history of bleeding. The main goal of the treatment for acquired hemophilia A should be the control of bleeding with the use of bypassing agents and the eradication of autoantibodies with the use of immunosuppressive agents. Because the remained level of factor VIII is not correlated with the risk of fatal bleeding, appropriate hemostatic management should be applied in patients with clinically significant bleeding regardless of the level of factor 8 or the inhibitor level of factor VIII. Because current recommendations for acquired hemophilia A are developed mainly based on the retrospectively available data, larger multicenter prospective trials should be conducted for developing appropriate treatments.ope

Treatment outcome and prognostic factors of Korean patients with chronic lymphocytic leukemia: a multicenter retrospective study

Background/aims: Compared with Western countries, chronic lymphocytic leukemia (CLL) rarely occurs in Asia and has different clinical characteristics. Thus, we aimed to evaluate the clinical characteristics, treatment outcomes, and prognostic significance of Korean patients with CLL. Methods: We retrospectively analyzed 90 patients with CLL who had received chemotherapy at 6 centers in Korea between 2000 and 2012. Results: Compared with Western patients with CLL, Korean patients with CLL express lambda (42.0%) and atypical markers such as CD22 and FMC7 (76.7% and 40.0%, respectively) more frequently. First-line chemotherapy regimens included chlorambucil (n = 43), fludarabine and cyclophosphamide (FC) (n = 20), fludarabine (n = 13), rituximab-FC (n = 4). The remaining patients were treated with other various regimens (n = 10). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 79.3% and 28.1%, respectively. Multivariate analyses showed that hyperleukocytosis (≥ 100 × 103/μL), extranodal involvement, and the Binet C stage were significant negative prognostic factors for OS (hazard ratio [HR] 4.75, p = 0.039; HR 21.6, p = 0.002; and HR 4.35, p = 0.034, respectively). Cytogenetic abnormalities including complex karyotypes (≥ 3), del(11q), and del(17) had a significantly adverse impact on both OS and PFS (p < 0.001 and p = 0.010, respectively). Conclusion: Initial hyperleukocytosis, extranodal involvement, complex karyotype, del(17) and del(11q) need to be considered in the risk stratification system for CLL.ope

Two Cases of Chickenpox Developed from an Immunocompromised Patient with Localized Herpes Zoster

Varicella zoster virus causes chickenpox, which is highly contagious, at primary infection and herpes zoster at reactivation. The varicella zoster virus may be more contagious and cause serious outbreaks in immunocompromised patients. There are some reports of outbreaks of chickenpox in patients with herpes zoster. Here, we describe a case of localized herpes zoster occurring in an immunocompromised patient during hospitalization in a specialized ward for immunocompromised patients. This episode resulted in two newly developed, hospital-acquired cases of chickenpox. If we had isolated the index patient who had localized herpes zoster immediately, the two cases of chickenpox could have been prevented. Therefore, patients with localized herpes zoster should be isolated in wards with immunocompromised patients.ope

Limited benefits of thalidomide and dexamethasone maintenance after autologous stem cell transplantation in newly diagnosed multiple myeloma patients: a prospective phase II multi-center study in Korea

Although the clinical outcome of newly diagnosed multiple myeloma has improved with maintenance therapy, maintenance with novel agents is not always available depending on medical expenses or drug accessibility. We intended to investigate the efficacy and toxicity of thalidomide/dexamethasone maintenance in Korean patients. In this multicenter phase 2 study, patients with newly diagnosed myeloma who underwent induction chemotherapy followed by autologous stem cell transplantation (ASCT) were enrolled to receive maintenance treatment of 100mg thalidomide daily for 28 days and 40mg dexamethasone daily for 4 days each cycle. Maintenance was given up to 12 cycles. The primary endpoint was a 1-year event free survival (EFS) rate. It was assumed that EFS at 1-year would be 91% with thalidomide and 1-year EFS below 82% would be of no effect. A total of 43 patients were consecutively enrolled (median age, 58 years [range, 34 - 65]; male, n = 31). With a median follow-up duration of 17.3 months (range, 1.1 - 32.2), EFS at 1 year was 65.1% (95% confidence interval [CI], 48.9 - 77.3). PFS and OS at 1 year was 85.6% (95% CI, 70.7 - 93.3) and 90.4 (95% CI, 76.3 - 96.3), respectively. In terms of side effects, 39 patients (90.7%) experienced adverse events (AEs) of any grade, and 14 patients (32.6%) experienced grade 3 or 4 adverse events. 15 patients (34.9%) failed to complete 12 cycles of maintenance, and the most common reason for premature termination was AEs (n = 6). In Korean patients the benefits of thalidomide maintenance does not seem to outweigh the toxicity of thalidomide, especially in high-risk MM. Considering the long clinical course of MM, preservation of quality of life and finances might be more beneficial for subsequent MM treatment.ope

Multicenter retrospective analysis of patients with chronic lymphocytic leukemia in Korea

Background: Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in Western countries but is rare in the East Asian countries. Due to its rarity and the lack of feasible novel agents and laboratory prognostic tools, there are limited data on the clinical outcomes of this disease in Asia. To clarify the current treatment status, we performed a multicenter retrospective analysis of patients with CLL in Korea. Methods: The medical records of 192 eligible patients between 2008 and 2019 were reviewed for clinical characteristics, treatment courses, and outcomes. The first-line treatment regimens of the patients included in this analysis were as follows: fludarabine/cyclophosphamide/ rituximab (FCR) (N=117, 52.7%), obinutuzumab plus chlorambucil (GC) (N=30, 13.5%), and chlorambucil monotherapy (N=24, 10.8%). Results: The median progression-free survival (PFS) was 55.6 months, and the average 2-year PFS rate was 80.3%. PFS was not significantly different between the patients receiving FCR and those receiving GC; however, chlorambucil treatment was associated with significantly inferior PFS (P <0.001). The median overall survival was 136.3 months, and the average 5- and 10-year OS rates were 82.0% and 57.4%, respectively. Conclusion: This is one of the largest studies involving Korean patients with CLL. Although the patients had been treated with less favored treatment regimens, the outcomes were not different from those reported in Western studies.ope

Comparison of treatment strategies for patients with intestinal diffuse large B-cell lymphoma: surgical resection followed by chemotherapy versus chemotherapy alone.

The aim of this retrospective cohort study was to analyze the impact of surgery on the outcomes and qualities of life (QOL) in patients with intestinal diffuse large B-cell lymphoma (DLBCL). We assessed 345 patients with either localized or disseminated intestinal DLBCL and compared them according to treatment: surgical resection followed by chemotherapy versus chemotherapy alone. In patients with localized disease (Lugano stage I/II), surgery plus chemotherapy yielded a lower relapse rate (15.3%) than did chemotherapy alone (36.8%, P < .001). The 3-year overall survival rate was 91% in the surgery plus chemotherapy group and 62% in the chemotherapy-alone group (P < .001). The predominant pattern in the chemotherapy group was local relapse (27.6%). When rituximab was used with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), there was no improvement of the outcomes in patients treated with primary surgical resection. The QOL of patients who underwent surgery and chemotherapy was lower than chemotherapy alone, but its difference was acceptable. Multivariate analysis showed that surgical resection plus chemotherapy was an independent prognostic factor for overall survival. Surgical resection followed by chemotherapy might be an effective treatment strategy with acceptable QOL deterioration for localized intestinal DLBCL. This study was registered at www.clinicaltrials.gov as #NCT01043302ope

Combination treatment of copanlisib and gemcitabine in relapsed/refractory PTCL (COSMOS): an open-label phase I/II trial

Background: Current treatment options for peripheral T-cell lymphomas (PTCLs) in the relapsed/refractory setting are limited and demonstrate modest response rates with rare achievement of complete response (CR). Patients and methods: This phase I/II study (NCT03052933) investigated the safety and efficacy of copanlisib, a phosphatidylinositol 3-kinase-α/-δ inhibitor, in combination with gemcitabine in 28 patients with relapsed/refractory PTCL. Patients received escalating doses of intravenous copanlisib on days 1, 8, and 15, administered concomitantly with fixed-dose gemcitabine (1000 mg/m2 on days 1 and 8) in 28-day cycles. Results: Dose-limiting toxicity was not observed in the dose-escalation phase and 60 mg copanlisib was selected for phase II evaluation. Twenty-five patients were enrolled in phase II of the study. Frequent grade ≥3 adverse events (AEs) included transient hyperglycemia (57%), neutropenia (45%), thrombocytopenia, (37%), and transient hypertension (19%). However, AEs were manageable, and none were fatal. The overall response rate was 72% with a CR rate of 32%. Median duration of response was 8.2 months, progression-free survival was 6.9 months, and median overall survival was not reached. Combination treatment produced a greater CR rate in patients with angioimmunoblastic T-cell lymphoma than those with PTCL-not otherwise specified (55.6% versus 15.4%, respectively, P = 0.074) and progression-free survival was significantly longer (13.0 versus 5.1 months, respectively, P = 0.024). In an exploratory gene mutation analysis of 24 tumor samples, TSC2 mutation was present in 25% of patients and occurred exclusively in responders. Conclusion: The combination of copanlisib and gemcitabine is a safe and effective treatment option in relapsed/refractory PTCLs and represents an important new option for therapy in this rare group of patients.ope

Efficacy and Safety of CT-P10 Versus Rituximab in Untreated Low-Tumor-Burden Follicular Lymphoma: Final Results of a Randomized Phase III Study

Introduction: This double-blind, parallel-group, active-controlled phase III trial (NCT02260804) assessed CT-P10 and rituximab safety and efficacy in patients with previously untreated low-tumor-burden follicular lymphoma (LTBFL), including after a single switch from rituximab to CT-P10. Patients and methods: LTBFL patients were randomized (1:1) to receive CT-P10 or rituximab (375 mg/m2 intravenously; day 1 of 4 7-day cycles). Patients achieving disease control entered a 2-year maintenance period. CT-P10 or rituximab were administered every 8 weeks (6 cycles) in year 1; all patients could receive CT-P10 (every 8 weeks; 6 cycles) in year 2. Secondary endpoints (reported here) were overall response rate (ORR) during the study period, progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Safety and immunogenicity were evaluated. Results: Between November 9, 2015 and January 4, 2018, 258 patients were randomized (130 for CT-P10; 128 for rituximab). ORR was similar between groups over the study period (CT-P10: 88%; rituximab: 87%). After 29.2 months' median follow-up, median PFS, TTP, and OS were not estimable; 24-month Kaplan-Meier estimates suggested similarity between groups. Overall, 114 (CT-P10: 88%), and 104 (rituximab: 81%) patients experienced treatment-emergent adverse events. The single switch was well tolerated. Conclusion: These updated data support therapeutic similarity of CT-P10 and rituximab and support the use of CT-P10 monotherapy for previously untreated LTBFL.ope

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.ope