Publications by authors named "Chang-Ki Min"

279 Publications

IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

Department of Biomedical Sciences, Seoul National University College of Medicine, Chongno-gu, 03080 Seoul, Korea;

Tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) also has an immunological function to suppress T cell activation in inflammatory circumstances, including graft-versus-host disease (GVHD), a fatal complication after allogeneic bone marrow transplantation (allo-BMT). Although the mononuclear cell expression of IDO1 has been associated with improved outcomes in GVHD, the underlying mechanisms remain unclear. Herein, we used IDO-deficient () BMT to understand why myeloid IDO limits the severity of GVHD. Hosts with BM exhibited increased lethality, with enhanced proinflammatory and reduced regulatory T cell responses compared with wild type (WT) allo-BMT controls. Despite the comparable expression of the myeloid-derived suppressor cell (MDSC) mediators, arginase-1, inducible nitric oxide synthase, and interleukin 10, Gr-1CD11b cells from allo-BMT or in vitro BM culture showed compromised immune-suppressive functions and were skewed toward the Ly6CLy6G subset, compared with the WT counterparts. Importantly, Gr-1CD11b cells exhibited elevated levels of reactive oxygen species (ROS) and neutrophil numbers. These characteristics were rescued by human IDO1 with intact heme-binding and catalytic activities and were recapitulated by the treatment of WT cells with the IDO1 inhibitor L1-methyl tryptophan. ROS scavenging by -acetylcysteine reverted the Gr-1CD11b composition and function to an MDSC state, as well as improved the survival of GVHD hosts with BM. In summary, myeloid-derived IDO1 enhances GVHD survival by regulating ROS levels and limiting the ability of Gr-1CD11b MDSCs to differentiate into proinflammatory neutrophils. Our findings provide a mechanistic insight into the immune-regulatory roles of the metabolic enzyme IDO1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2011170118DOI Listing
March 2021

Subcutaneous daratumumab in Asian patients with heavily pretreated multiple myeloma: subgroup analyses of the noninferiority, phase 3 COLUMBA study.

Ann Hematol 2021 Feb 18. Epub 2021 Feb 18.

Division of Hematology and Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate, Japan.

The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (C). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of C was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the C concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03-185.00%) and 148.02% (90% CI, 113.32-193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-021-04405-2DOI Listing
February 2021

Impact of depression on adherence to lenalidomide plus low-dose dexamethasone in patients with relapsed or refractory myeloma.

Support Care Cancer 2021 Feb 11. Epub 2021 Feb 11.

Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, South Korea.

Purpose: While continued lenalidomide and low-dose dexamethasone (Rd) treatment could improve survival outcomes for multiple myeloma (MM), the association of depression on the adherence to Rd regimen in myeloma patients has never been studied even though depression is a common symptom among MM patients. This study aims to evaluate the impact of depression prior to Rd treatment on adherence to the treatment among patients with MM.

Methods: This multicenter cohort study was conducted from January 2015 to October 2018 at five tertiary hospitals in Korea. Patients who completed fewer than 4 cycles, 4-11 cycles, and more than 12 cycles were categorized as the poor adherence group (PAG), moderate adherence group (MAG), and good adherence group (GAG), respectively.

Results: Among141 patients, 41.8% of them had depression before beginning Rd treatment and 46% of participants were in the GAG. Compared with patients in the GAG (30.3%), patients in the PAG were more likely to have depression at baseline (90.0%) and had the higher distress scores (6.35 vs. 4.28, P < 0.01). Presence of depression prior to Rd treatment was significantly associated with poor adherence (IRR = 6.67, 95% CI = 1.45, 30.61) after adjusting for age, sex, education, ECOG, ISS stage, number of previous treatments, and disease status prior to Rd treatment.

Conclusions: Patients with depression had a substantially high risk of poor adherence compared to patients without depression. Given that Rd treatment is mainly offered by outpatient clinics, active interventions to reduce depression should be considered for MM patients prior to Rd treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00520-021-06017-yDOI Listing
February 2021

Incidence and risk factors of hepatic veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation in adults with prophylactic ursodiol and intravenous heparin or prostaglandin E1.

Bone Marrow Transplant 2021 Feb 1. Epub 2021 Feb 1.

Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

We attempted to identify the incidence and survival outcome of hepatic sinusoidal obstruction syndrome/veno-occlusive disease (VOD/SOS) after hematopoietic cell transplantation (HCT) under strategy of prophylactic ursodiol and intravenous heparin or prostaglandin E1 (PGE1). From 2009 to 2018, 2572 consecutive allogeneic-HCT cases were reviewed. We used oral ursodiol for all transplants, and most were administered low-dose heparin, while PGE1 in selected cases with low platelet count at the time of preconditioning. Diagnosis and severity grades were reassessed by revised EBMT criteria. The overall incidence of hepatic VOD/SOS was 3.4% (Mild 0.9%, Moderate 0.6%, Severe 0.7%, Very severe 1.2%) after allogeneic-HCT under strategy of intravenous prophylaxis. The 1-year overall survival of VOD/SOS was 41.4% which was divided into 73.9% for mild, 66.7% for moderate, 38.9% for severe, and 6.5% for very severe grade. Very high disease risk index, male gender, donor other than matched sibling donor, and busulfex > 9 mg/kg were affecting factors for development of VOD/SOS. For severe to very severe VOD/SOS, history of pre-HCT liver dysfunction was an additionally affecting factor. Allogeneic-HCT using ursodiol and intravenous prophylaxis was considered safe without significant bleeding complications and should be evaluated in future clinical trials. For those with high-risk of VOD/SOS, early intervention and management is important.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-021-01215-yDOI Listing
February 2021

Prognostic Impacts of D816V Mutation and Peri-Transplant MRD Monitoring on Acute Myeloid Leukemia with .

Cancers (Basel) 2021 Jan 18;13(2). Epub 2021 Jan 18.

Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.

The prognostic significance of mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, = 112) or autologous HSCT (Auto-HSCT, = 54). D816V mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V mutation and pre-transplant MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V mutation and MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13020336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831332PMC
January 2021

Carfilzomib in addition to lenalidomide and dexamethasone in Asian patients with RRMM outside of a clinical trial.

Ann Hematol 2021 Jan 15. Epub 2021 Jan 15.

Department of Hematology, Seoul St. Mary's Hematology Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.

Carfilzomib, lenalidomide, and dexamethasone (KRd) effectively improve survival in patients with relapsed and refractory multiple myeloma (RRMM). However, the outcome of KRd treatment in Asian patients reflecting a general RRMM population outside of a clinical trial has not been reported. Fifty-five RRMM patients who were treated with carfilzomib in combination with Rd from the time of the first approval of KRd in the Republic of Korea were analyzed. The median age was 61 years. The percentage of patients with an ECOG performance status ≥ 3, creatinine clearance < 50 mL/min, high-risk cytogenetics, and ≥ 4 lines of prior treatment were 9%, 22%, 31%, and 27%, respectively. Forty-one patients started treatment with KRd, whereas the remaining 14 patients (25%) were added carfilzomib during the Rd treatment. In the whole cohort, the overall response rate was 73% and progression-free survival was 8.8 months. The addition of carfilzomib in patients who were refractory or had disease progression during Rd treatment reattained a response in half of the patients. The advantage of carfilzomib with Rd was significant in patients in the first relapse. Toxicity profile was acceptable, excluding severe infections. Carfilzomib in combination with Rd is effective and has a reasonable adverse event rate in Asian patients with RRMM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-021-04407-0DOI Listing
January 2021

The therapeutic efficacy of mesenchymal stromal cells on experimental colitis was improved by the IFN-γ and poly(I:C) priming through promoting the expression of indoleamine 2,3-dioxygenase.

Stem Cell Res Ther 2021 Jan 7;12(1):37. Epub 2021 Jan 7.

Department of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Background: Inflammatory bowel disease is a chronic and excessive inflammation of the colon and small intestine. We previously reported that priming of mesenchymal stromal cells (MSCs) with poly(I:C) induced them to express indoleamine 2,3-dioxygenase (IDO). We tried to find out whether the IFN-γ and poly(I:C)-primed MSCs have better therapeutic efficacy on the experimental colitis in the IDO1-dependent manner.

Methods: To compare the therapeutic effects between the unstimulated MSCs and primed MSCs on murine colitis, mice (C57BL6) were administered with 2.5% dextran sodium sulfate (DSS) in drinking water for 5 days and injected with MSCs intraperitoneally on days 1 and 3 following DSS ingestion. The disease activity index score and body weight loss were assessed daily until day 9.

Results: Mice receiving the IFN-γ and poly(I:C)-primed MSCs showed a reduced disease activity index and less weight loss. Colon tissue from the same mice presented attenuated pathological damage, increased Paneth cells, increased IDO1-expressing cells, and better proliferation of enterocytes. The primed MSC treatment upregulated the mRNA expression of intestinal stem cell markers (Lgr5, Olfm4, and Bmi1), enterocyte differentiation markers (Muc2, Alpi, Chga, and occludin), and regulatory T (Treg) cells (Foxp3). The same treatment decreased inflammatory cell infiltration to lymphoid organs and the level of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, and MCP-1) in colon tissue. Notably, in vivo pharmacologic inhibition of the IDO1 activity blocked the Foxp3 upregulation in colon tissue and diminished the protective effects of the primed MSC.

Conclusions: The priming of MSCs with the IFN-γ and poly(I:C) is a promising new strategy to improve the therapeutic efficacy of MSC and is worth further research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13287-020-02087-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791665PMC
January 2021

Daratumumab monotherapy for relapsed/refractory multiple myeloma, focussed on clinical trial-unfit patients and subsequent therapy.

Br J Haematol 2020 Dec 27. Epub 2020 Dec 27.

Department of Hematology, Seoul St. Mary's Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Real-world outcomes of daratumumab monotherapy (DM) for relapsed/refractory multiple myeloma (RRMM) have remained unclear. We conducted a multicentre retrospective study of 107 patients receiving DM for RRMM. The cohort included 64 trial-unfit patients whose characteristics could not meet inclusion criteria in two previous clinical trials (GEN501 and SIRIUS). The overall response rate (ORR), and median first and second progression-free survival (PFS1 and PFS2) and overall survival were 42·1%, and 3·6, 8·1 and 11·9 months, respectively. Refractoriness to carfilzomib and/or lenalidomide, and neutropenia (<1.0 × 10 /l) resulted in poorer ORRs. An Eastern Cooperative Oncology Group Performance Status of ≥3, neutropenia (<1.0 × 10 /l), thrombocytopenia (<75 × 10 /l), and renal failure (glomerular filtration rate of <20 ml/min/1·73 m ) were associated with poor PFS1 and PFS2 in respective univariate analysis. The modified trial-unfit group, based on the above factors, showed significantly negative impacts on PFS1 and PFS2 (hazard ratio 2·823 and 3·677, all P < 0·001) in multivariate analysis despite having a 34% ORR. Fatal infections occurred more often in the modified trial-unfit group than in the others (16·1% vs. 4·3%; P = 0·099). Despite failure of DM, subsequent therapy with pomalidomide-based therapy or carfilzomib-dexamethasone provided a 66·6% ORR. Real-world DM showed favourable efficacies for RRMM and, potentially, additional benefits with subsequent therapies. However, characteristics corresponding with trial-unfitness might offset the efficacy of DM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17071DOI Listing
December 2020

Impact of donor type on long-term graft-versus-host disease-free/relapse-free survival for adult acute lymphoblastic leukemia in first remission.

Bone Marrow Transplant 2020 Oct 30. Epub 2020 Oct 30.

Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary's Hospital, Leukemia Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

We assessed the impact of donor type on long-term outcomes of allogeneic hematopoietic cell transplantation (HCT) in 440 consecutive adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1), particularly focusing on the donor type-specific difference in graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS). Donor sources were matched sibling donor (MSD; n = 199), matched unrelated donor (MUD; n = 110), 1-allele-mismatched unrelated donor (1-MMUD; n = 83), and cord blood (CB; n = 48). Cumulative incidence of severe chronic GVHD was 14.8% for MSD-HCT, 30.1% for MUD-HCT, 9.6% for 1-MMUD-HCT, and 4.2% for CBT, respectively (P < 0.001), while no difference was observed in grade III-IV acute GVHD. After a median follow-up of 58.1 months, cumulative incidence of relapse was 26.1% for MSD-HCT, 27.2% for MUD-HCT, 31.2% for 1-MMUD-HCT, and 7.2% for CBT, respectively (P = 0.042). Disease-free survival and overall survival were comparable among all donor sources. However, GRFS for MSD-HCT, MUD-HCT, 1-MMUD-HCT, and CBT was 33.1%, 14.5%, 42.1%, and 50.3%, respectively (P = 0.001). In multivariate analysis, CBT showed a comparable GRFS to MSD-HCT (HR, 0.78; P = 0.290), while MUD-HCT was associated with a poorer GRFS (HR, 1.53; P = 0.002). Given the encouraging GRFS of CBT, our data suggest that CBT remains a valid option for adult ALL in CR1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01097-6DOI Listing
October 2020

International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM).

Blood Cancer J 2020 10 16;10(10):102. Epub 2020 Oct 16.

Clinica Universidad de Navarra, CIMA, CIBERONC, IDISNA, Pamplona, Spain.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2-3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41408-020-00366-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567803PMC
October 2020

Quantitative analysis of metal artefacts of dental implant in CBCT image by correlation analysis to micro-CT: A microstructural study.

Dentomaxillofac Radiol 2021 Mar 8;50(3):20200365. Epub 2020 Oct 8.

Research Institute of Clinical Medicine of Jeonbuk National University, Jeonju, South Korea.

Objectives: Quantification of dental implant metal artefacts in CBCT images using correlation analysis of trabecular microstructural parameters from CBCT and micro-CT, and analysis of the effect of varying the angular position of the subject.

Methods: Polyurethane synthetic bone blocks were first scanned without implants by micro-CT and CBCT. Two dental implants were then placed parallel in the bone blocks and these specimens were scanned by CBCT with different alpha angles. Three volumes of interest (VOI) were set for further analysis. Six microstructural parameters were measured: trabecular thickness (Tb), trabecular spacing (Th), bone volume per total volume (BV/TV), bone surface per total volume (BS/TV), connectivity density (CD) andfractal dimension (FD). Micro-CT measurements were used as a gold standard for CBCT. Spearman correlation coefficients for each microstructural parameter from CBCT and micro-CT were calculated and compared using Steiger's Z test.

Results: Without the implants, in VOI, the Spearman correlation coefficients of Tb, Tb, BV/TV, BS/TV, CD and FD were 0.599, 0.76, 0.552, 0.566, 0.664 and 0.607, respectively. With the implants, the correlation coefficients decreased sharply in VOI. As the alpha angle increased from zero to 90°, the correlation coefficients increased and became significant. Similar results appeared in VOI. In contrast, in VOI, the correlation coefficient decreased as the alpha angle increased.

Conclusions: Metal artefacts were successfully quantified using microstructural parameters in terms of the image quality of the CBCT. Changes in alpha angle affected the quality of the CBCT image.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1259/dmfr.20200365DOI Listing
March 2021

HLA-mismatched donor and high ferritin level showed poor clinical outcomes after allogeneic hematopoietic cell transplantation in patients with advanced myelofibrosis.

Ther Adv Hematol 2020 18;11:2040620720936935. Epub 2020 Sep 18.

Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea.

Background: Preconditioning intensity, donor choice and graft--host disease (GVHD) prophylaxis of allogeneic hematopoietic cell transplantation (allo-HCT) for advanced myelofibrosis (MF) have not been fully elucidated.

Methods: Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling donors first, followed by matched or mismatched unrelated donors and familial mismatched donors. Preconditioning regimen consisted of fludarabine (total 150 mg/m) and busulfan (total 6.4 mg/kg) with total body irradiation ⩽400cGy.

Results: All showed engraftments, but four showed either leukemic relapse or delayed graft failure. Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD (eight grade III and four grade IV) was higher in human leukocyte antigen (HLA)-mismatched donor HCT compared with HLA-matched HCT (70% 20%). Chronic GVHD was observed in 16 patients, and a cumulative incidence of severe chronic GVHD was 33% in HLA-mismatched donor HCT and 7.7% in HLA-matched HCT. Significant hepatic GVHD was observed in nine patients (five acute, four chronic) and six of them died. Multivariate analysis revealed inferior OS in HLA-mismatched donor HCT (hazard ratio (HR) = 6.40, 95% confidence interval (CI) 1.6-25.7,  = 0.009) and in patients with high ferritin level at the time of pre-conditioning period (HR = 7.22, 95% CI 1.9-27.5,  = 0.004), which were related to higher incidence of hepatic GVHD with high NRM rate.

Conclusion: RIC allo-HCT can be a valid choice providing graft--fibrosis effect for advanced MF patients. However, HLA-mismatched donor and high pre-HCT ferritin level related to fatal hepatic GVHD should be regarded as poor-risk parameters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2040620720936935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502801PMC
September 2020

, , and mutations in plasma cell myeloma at a single Korean institute.

Blood Res 2020 Sep;55(3):159-168

Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: Plasma cell myeloma (PCM) is a genetically heterogeneous disease. The genetic spectrum of PCM has been expanded to mutations such as , , and genes in the RAS-RAF-MAPK pathway. In this study, we have evaluated the frequency of these mutations and their significance, including baseline characteristics and clinical outcomes.

Methods: We explored 50 patients who were newly diagnosed with PCM between 2009 and 2012 at a single Korean institute. Clinical and laboratory parameters were gathered through careful review of medical records. Mutation analysis was carried out using DNA from the bone marrow at the time of diagnosis. Pyrosequencing was performed to detect G12V, G13D, and G61R. V600E was analyzed by allele-specific real- time PCR. Comparison of clinical and laboratory parameters was carried out according to those mutations.

Results: We identified 14 patients (28%) with activating mutations in the RAS-RAF-MAPK pathway (RAS/RAF mutations): (N=3), (N=4), (N=7), and both and (N=1). RAS/RAF mutations were more frequently observed in patients with complex karyotypes and showed poorer progression free survival (PFS). Specifically, the V600E mutation had a significantly negative impact on median PFS.

Conclusion: We first showed the frequency of RAS/RAF mutations in Korean patients with PCM. Screening of these mutations could be considered as a routine clinical test at the time of diagnosis and follow-up due to their influence on clinical outcome, as well as its potential as a therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5045/br.2020.2020137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536562PMC
September 2020

Effects of decitabine on allogeneic immune reactions of donor lymphocyte infusion via activation of dendritic cells.

Exp Hematol Oncol 2020 3;9:22. Epub 2020 Sep 3.

Laboratory of Hematological Disease and Immunology, Seoul, Republic of Korea.

Background: Successful prevention of post-transplantation relapse after donor lymphocyte infusion (DLI) depends on its capability to mediate an effective graft-versus-leukemia (GVL) response while minimizing DLI-related toxicity, including graft-versus-host disease (GVHD).

Methods: We assessed the effects of decitabine (DEC), a hypomethylating agent, upon allogeneic immune reaction in a murine model of DLI.

Results: Significantly greater tumor growth retardation and survival prolongation occurred in mice administered with 1.0 mg/kg DEC for 5 days (DEC-1.0) than in control or DEC-0.1 mice. Upon prompt DEC and DLI co-administration, dendritic cells (DCs) were activated; DEC-1.0/DLI induced severe GVHD, and survival was significantly lower than with DLI alone or DEC-0.1/DLI treatments. IFN-γ and CD28 levels were higher in splenic DCs of DEC-1.0 mice than in those of control mice. Assessment of delayed DLI co-administration with DEC, when IFN-γ levels were normalized to control levels, revealed that DEC-1.0/DLI successfully facilitated tumor management without causing severe GVHD.

Conclusions: Our results suggest that DEC primes allogeneic immune reactions of DLI via DC activation, and GVHD and GVL effects are separable through optimal DLI timing based on DEC-induced increase in IFN-γ expression levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40164-020-00178-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470611PMC
September 2020

Haploidentical vs matched unrelated donor transplantation for acute myeloid leukemia in remission: A prospective comparative study.

Am J Hematol 2021 01 24;96(1):98-109. Epub 2020 Nov 24.

Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Despite comparable outcomes of haploidentical transplants (Haplo-HSCT) with HLA-matched unrelated transplants (MUD-HSCT) in retrospective comparisons, few studies have prospectively compared Haplo-HSCT with MUD-HSCT in AML. Here, we prospectively compared the outcomes of Haplo-HSCT with MUD-HSCT for AML in remission (n = 110) to prove non-inferiority of overall survival in Haplo-HSCT. Both groups were well balanced in factors related to biological features of AML and measurable residual disease (MRD) status by Wilms' tumor gene 1 (WT1) assay. A unique, reduced-toxicity preparative regimen was used for Haplo-HSCT, whereas mostly-myeloablative regimen was for MUD-HSCT. Both groups showed similar patterns of neutrophil and platelet recovery, whereas delayed T-cell reconstitution in Haplo-HSCT was found compared with MUD-HSCT. No significant differences were found in acute or chronic graft-vs-host-disease (GVHD) and post-transplant infectious events with an exception of EBV or CMV infection, which occurred more frequently in Haplo-HSCT. After a median follow-up of 47 months, no significant differences in overall survival (65% vs 54%, P = .146), disease-free survival (67% vs 53%, P = .142), relapse (20% vs 21%, P = .858), non-relapse mortality (14% vs 26%, P = .103), or GVHD-free/relapse-free survival (54% vs 41%, P = .138) were observed for Haplo-HSCT vs MUD-HSCT. In multivariate analysis, WT1 expression before transplantation independently predicted relapse, resulting in inferior survival. Separate analysis of unenrolled patients (n = 110) who were excluded or refused to participate in this study showed consistent results with enrolled patients. This prospective study demonstrated the non-inferiority of Haplo-HSCT to MUD-HSCT for AML in remission, and validated the role of WT1 quantification as an MRD marker (ClinicalTrial.gov identifier: NCT01751997).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.25993DOI Listing
January 2021

Clinical impact of frailty on treatment outcomes of elderly patients with relapsed and/or refractory multiple myeloma treated with lenalidomide plus dexamethasone.

Int J Hematol 2021 Jan 5;113(1):81-91. Epub 2020 Sep 5.

Department of Internal Medicine, Seoul St. Mary's Hospital, Catholic University of Korea, 505, Banpo-dong, Seocho-gu, Seoul, 137-701, South Korea.

We compared efficacy and safety, according to frailty, of elderly patients with relapsed and refractory multiple myeloma (RRMM) treated with lenalidomide and dexamethasone (Rd), for whom bortezomib treatment had failed. Patients, 164 (52.9%) and 146 (47.1%), were classified as non-frail and frail using a simplified frailty scale. The overall response rates (ORR) and survival outcomes were lower in frail than in non-frail patients (ORR: 56.2% vs. 67.7%, P = 0.069; median progression free survival: 13.17 vs. 17.80 months, P = 0.033; median overall survival: 23.00 vs. 36.27 months, P = 0.002, respectively). The number of treatment emergent adverse events in grade 3 or worse was higher in frail than in non-frail patients (41.8% vs. 24.4%, P = 0.002, respectively). In frail patients, independent poor prognostic factors for survival were two or more Charlson comorbidity index (CCI) score, prior to exposure to both bortezomib and thalidomide, and achieved less than partial response In conclusion, frailty could predict clinical outcomes of Rd treatment in elderly patients with RRMM who had failed prior bortezomib. In frail patients, lower CCI in addition to less previous treatment exposure and deep response were associated with better survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-02988-6DOI Listing
January 2021

Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk.

J Hematol Oncol 2020 08 20;13(1):115. Epub 2020 Aug 20.

University Hospital of Salamanca/IBSAL/Cancer Research Center-IBMCC (USAL-CSIC), Salamanca, Spain.

Background: Multiple myeloma (MM) patients with high cytogenetic risk have poor outcomes. In CASTOR, daratumumab plus bortezomib/dexamethasone (D-Vd) prolonged progression-free survival (PFS) versus bortezomib/dexamethasone (Vd) alone and exhibited tolerability in patients with relapsed or refractory MM (RRMM).

Methods: This subgroup analysis evaluated D-Vd versus Vd in CASTOR based on cytogenetic risk, determined using fluorescence in situ hybridization and/or karyotype testing performed locally. High-risk patients had t(4;14), t(14;16), and/or del17p abnormalities. Minimal residual disease (MRD; 10 sensitivity threshold) was assessed via the clonoSEQ® assay V2.0. Of the 498 patients randomized, 40 (16%) in the D-Vd group and 35 (14%) in the Vd group were categorized as high risk.

Results: After a median follow-up of 40.0 months, D-Vd prolonged median PFS versus Vd in patients with standard (16.6 vs 6.6 months; HR, 0.26; 95% CI, 0.19-0.37; P < 0.0001) and high (12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21-0.83; P = 0.0106) cytogenetic risk. D-Vd achieved deep responses, including higher rates of MRD negativity and sustained MRD negativity versus Vd, regardless of cytogenetic risk. The safety profile was consistent with the overall population of CASTOR.

Conclusion: These updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status.

Trial Registration: ClinicalTrials.gov, NCT02136134 . Registered 12 May 2014.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13045-020-00948-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439722PMC
August 2020

Prognosis Prediction in Initially Diagnosed Multiple Myeloma Patients Using Intravoxel Incoherent Motion-Diffusion Weighted Imaging and Multiecho Dixon Imaging.

J Magn Reson Imaging 2021 Feb 19;53(2):491-501. Epub 2020 Aug 19.

Department of Hematology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Background: Multiparametric MRI provides complementary information for the diagnosis and management of multiple myeloma (MM).

Purpose: To evaluate the association of prognostic factors of MM and parameters derived from intravoxel-incoherent motion diffusion-weighted imaging (IVIM-DWI) and multiecho (ME) Dixon.

Study Type: Retrospective.

Population: In all, 78 MM patients.

Field Strength/sequences: T -weighted turbo spin-echo sequences (TSE), IVIM-DWI, ME 3D gradient echo sequence with multistep adaptive fitting at 3T.

Assessment: The region of interest (ROI) on the vertebral body was independently measured on four parametric maps (D , D and perfusion fraction [f], and proton-density fat-fraction [Ff] maps) by two readers. All patients were categorized into three groups based on the International Staging System (ISS).

Statistical Tests: Three groups were compared using analysis of variance (ANOVA) and post-hoc tests with Bonferroni correction. Logistic regression analysis was performed to predict the advancement of disease (early vs. advanced). Principal component analysis (PCA) was used to find the deterministic parameters.

Results: D and Ff were significantly different among ISS-1 (n = 38), ISS-2 (n = 22), and ISS-3 (n = 18) groups in both readers: 0.36, 0.41, and 0.58 × 10 mm /s for D (P < 0.05), and 46%, 30%, and 15% for Ff (P < 0.05) in reader 1; 0.34, 0.41, and 0.58 × 10 mm /s for D (P < 0.05), 43%, 27%, and 13.2% for Ff (P < 0.05) in reader 2, respectively. D between ISS-3 and the other groups was significantly different in one reader only: 2.03, 2.29, and 2.85 × 10 mm /s (P < 0.05). There was no significant difference in f among the groups in both readers. Logistic regression by stepwise selection indicated Ff as the single most significant factor for differentiating early and advanced stages of MM with an accuracy of 76% and area under the curve (AUC) of 0.83 (P < 0.05). PCA revealed Ff, and D as the deterministic parameters, with a cumulative proportion of 0.84.

Data Conclusion: D and Ff are associated with the prognostic factor of MM. Level of Evidence 3 Technical Efficacy Stage 5. J. MAGN. RESON. IMAGING 2021;53:491-501.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmri.27321DOI Listing
February 2021

Comparison of Myeloablative (CyTBI, BuCy) versus Reduced-Intensity (FluBu2TBI400) Peripheral Blood Stem Cell Transplantation in Acute Myeloid Leukemia Patients with Pretransplant Low WT1 Expression.

Biol Blood Marrow Transplant 2020 11 11;26(11):2018-2026. Epub 2020 Jul 11.

Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea; Leukemia Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea. Electronic address:

Relapse is a major concern with reduced-intensity conditioning. We analyzed 257 patients with acute myeloid leukemia (AML) who received allogeneic stem cell transplantation (SCT) and fulfilled the following criteria: intermediate- or poor-risk disease by National Comprehensive Cancer Network guidelines (2017, version 3), in first complete remission (CR1) at SCT, received either myeloablative conditioning (MAC; busulfan plus cyclophosphamide or cyclophosphamide plus total body irradiation) or reduced-intensity conditioning (RIC; FluBu2TBI400) peripheral blood SCT from 8/8 matched sibling or unrelated donor, and having bone marrow Wilms tumor gene 1 (WT1) expression results before transplant. We and other groups serially published a predictive value for pretransplant WT1 expression in patients with AML to identify patients at higher risk of relapse. Among the total 257 patients, 191 (74.3%) and 66 (25.7%) patients received MAC and RIC transplants, respectively. WT1 ≥250 copies/10ABL was defined as WT1. WT1 before SCT was found to be an independent prognostic factor for inferior overall survival (OS), disease-free survival (DFS), and higher cumulative incidence of relapse (CIR). There were 201 patients with WT1 low expression based upon pretransplant analysis. There was no significant difference in OS, DFS, CIR, and nonrelapse mortality between MAC and RIC patients. To conclude, post-transplant survival or relapse was not different by conditioning intensity in AML CR1 patients whose WT1 level was below 250 copies per 10ABL at transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2020.07.006DOI Listing
November 2020

Experiences of allogeneic hematopoietic cell transplantation following non-myeloablative conditioning regimen in severely comorbid patients with myelofibrosis: case series with a patient presenting with extensive extramedullary hematopoiesis.

Ther Adv Hematol 2020 30;11:2040620720932038. Epub 2020 Jun 30.

Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea.

We have performed allogeneic hematopoietic cell transplantation (allo-HCT) using a reduced intensity conditioning regimen for curative management of advanced myelofibrosis (MF). However, allo-HCT is rarely considered for elderly or patients with severe comorbidities due to high transplantation-related mortality. In those patients, an alemtuzumab-based non-myeloablative (NMA) conditioning regimen followed by stem cell transplantation could be a possible treatment that has been tried in sickle cell anemia showing stable mixed chimerism and improvement of the disease. However, it is uncertain whether this regimen can provide durable donor-dominant chimerism also in patients with MF. We planned a two-stage allo-HCT in four patients - initially aimed at mixed chimerism with NMA conditioning and then reinforced with additional stem cell infusion if graft failure occurred. In one case with extensive extramedullary hematopoiesis, causing blindness and paraplegia, we achieved stable complete donor-chimerism and complete molecular response with disappearance of bone marrow fibrosis after allo-HCT. Although this NMA regimen failed to achieve durable donor-chimerism, additional stem cell infusion showed a possible role for stable long-term chimerism with good clinical outcomes. Although it leaves room for further improvement, allo-HCT using an NMA conditioning regimen may be worth consideration for advanced MF patients with severe comorbidity, otherwise no appropriate treatment option is available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2040620720932038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328483PMC
June 2020

Comparable Outcomes Between Unrelated and Haploidentical Stem Cell Transplantation in Adult Patients With Severe Aplastic Anemia.

Transplantation 2020 Jun 29. Epub 2020 Jun 29.

Department of Hematology, Seoul St. Mary''s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Backgrounds: Regarding patients with severe aplastic anemia (SAA) who fail immunosuppressive therapy and lack an HLA-matched sibling donor (MSD), the best alternative donor including unrelated (URD) and haploidentical (HAPLO) donors for allogeneic stem cell transplantation (SCT) remains to be established.

Methods: We analyzed the comprehensive outcomes of 153 consecutive adult SAA patients treated with SCT from alternative donors: 73 HLA-well matched (8/8) URDs (WM-URDs), 34 mismatched (6-7/8) URDs (MM-URDs), and 46 HAPLOs.

Results: Neutrophil/platelet engraftments were achieved at a median of 11/15 days for WM-URDs, 13/16.5 days for MM-URDs, and 12/14 days for HAPLOs, respectively. The 3-year overall survival (OS), failure-free survival, cumulative incidence of graft-failure, and transplant-related mortality were statistically not different among the 3 groups: 90.3%, 87.5%, 2.7%, and 9.8% for WM-URDs; 85.3%, 81.7%, 0%, and 14.7% for MM-URDs, and 84.4%, 82.3%, 6.5%, and 11.2% for HAPLOs, respectively. The rates of other complications, including graft-versus-host disease, cytomegalovirus DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancies, and sinusoidal obstruction syndrome, were also statistically not different. Subgroup analysis of the MM-URD group showed that the 3-year OS of patients receiving SCTs from 6/8-URDs were worse than those receiving SCTs from 7/8-URDs (75.0% vs. 94.4%, p=0.26).

Conclusion: There was no significant difference in the SCT outcomes with WM-URDs, MM-URDs, or HAPLO donors. The clinician can make the best choice among these alternative donor sources based on the host/donor features and the urgency of the need for SCT. However, the selection of 6/8-URDs should be avoided due to inferior survival outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000003342DOI Listing
June 2020

Reducing metal artifacts between implants in cone-beam CT by adjusting angular position of the subject.

Oral Radiol 2020 Jul 7. Epub 2020 Jul 7.

Department of Oral and Maxillofacial Radiology, School of Dentistry, Jeonbuk National University, Gunjiro-20, Jeonju, South Korea.

Objectives: To reduce inter-implant metal artifacts in cone-beam CT (CBCT) imaging by adjusting angular position of the subject relative to the source-detector plane.

Materials And Methods: Two dental implants were placed in a block made of homogeneous dental impression material. Using a custom-made apparatus, the specimen was scanned with a CBCT machine at seven different angles (0°, 15°, 30°, 45°, 60°, 75°, and 90°) along three different spatial axes, yielding 21 experimental groups. Thirteen volumes of interest (VOI) including inter- and peri-implant areas were selected from each axial reconstruction perpendicular to the implants. Gray values (GVs) of each pixel within these VOIs were measured. Mean differences in GV (ΔGV) between the VOIs and control area were calculated and expressed as a percentage. These ΔGVs from different spatial angle were compared and analyzed by Welch's analysis of variance (ANOVA) and linear regression using SPSS 25.0 software.

Results: As alpha angle increased, the ΔGV of the inter-implant area increased from - 62.02% to near-zero while the standard deviation decreased. Welch's ANOVA and linear regression analysis revealed ΔGV increased significantly with alpha angle (p < 0.001, R = 0.406). VOIs on the extension line of two implants showed similar results. After adjusting the beta and gamma angles, there was no significant change in ΔGV.

Conclusions: Increasing the alpha angle can reduce metal artifacts in the inter-implant area in CBCT images.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11282-020-00458-7DOI Listing
July 2020

Outcomes of Haploidentical Stem Cell Transplantation using Total Body Irradiation (600 cGy) and Fludarabine with Antithymocyte Globulin in Adult Patients with Severe Aplastic Anemia: A Prospective Phase II Study.

Biol Blood Marrow Transplant 2020 10 5;26(10):1906-1914. Epub 2020 Jul 5.

Department of Hematology, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address:

The aim of this study was to verify the feasibility of rabbit antithymocyte globulin (ATG; 5 mg/kg) in combination with 600 cGy of fractionated total body irradiation (fTBI; 3 doses of 200 cGy) and fludarabine (Flu; 150 mg/m) as a conditioning regimen for haploidentical stem cell transplantation from a related mismatched donor (haplo-SCT) in adult patients with severe aplastic anemia (SAA). We analyzed 47 consecutive patients who underwent haplo-SCT, including 24 patients from our previous pilot report. The median age was 36.0 years (range, 17 to 61 years), and 25 patients (53%) were very severe aplastic anemia (VSAA) at transplantation. All patients achieved primary engraftment. The cumulative incidence of grade ≥II acute graft-versus-host disease (GVHD) and chronic moderate or greater GVHD was 27.7% at 100 days and 13.5% at 3 years, respectively. With a median follow-up of 32.3 months, the 3-year probability of overall survival and failure-free survival was 91.0% and 88.6%, respectively. The 3-year GVHD- and failure-free survival (GFFS) was 71.6%. Offspring donor and lower comorbidity index were independent factors correlated with higher GFFS in multivariate analysis. In conclusion, the outcomes of haplo-SCT with fTBI 600 cGy/Flu/ATG-5 indicate that haplo-SCT can be an effective alternative option when a fully matched donor is not available or a patient with VSAA needs an urgent transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2020.06.024DOI Listing
October 2020

CCL1 blockade alleviates human mesenchymal stem cell (hMSC)-induced pulmonary fibrosis in a murine sclerodermatous graft-versus-host disease (Scl-GVHD) model.

Stem Cell Res Ther 2020 06 26;11(1):254. Epub 2020 Jun 26.

Hematology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpodae-ro, Seocho-gu, Seoul, 06591, South Korea.

Background: Human chronic graft-versus-host disease (CGVHD) shares clinical characteristics with a murine sclerodermatous GVHD (Scl-GVHD, B10.D2 → BALB/c) model that is characterized by skin and lung fibrosis. In this study, bone marrow- or adipose tissue-derived human mesenchymal stem cells (hMSCs) were injected into the Scl-GVHD mice to address their therapeutic effect on CGVHD.

Methods: Lethally irradiated BALB/c mice were transplanted with B10.D2 T cell-depleted bone marrow with or without spleen cells to generate Scl-GVHD. hMSCs were intravenously treated on days 3, 5, and 7 post-transplantation, and the control antibody or CCL1 blocking antibody was subcutaneously injected according to the same schedule as the hMSCs. Fourteen days after transplantation, the recipient mice were sacrificed, and their skin and lungs were analyzed.

Results: After the early injection of hMSCs after transplantation, the clinical and pathological severity of Scl-GVHD in the skin was significantly attenuated, whereas the pathological score was exacerbated in the lungs. hMSCs had migrated into the lungs, but not into the skin. CD11b monocyte/macrophages and CD4 T cells were markedly decreased in skin tissues, whereas there was an early recruitment of CD11b cells, and subsequently increased infiltration of CD4 T cells, in the lungs. Importantly, hMSCs persistently upregulated the expression of CCL1 in the lungs, but not in the skin. Concurrent treatment of hMSCs with a CCL1-blocking antibody alleviated the severity of the lung histopathology score and fibrosis with the preservation of the cutaneous protective effect against CGVHD. Infiltration of CD3 T cells and CD68 macrophages and upregulation of chemokines were also decreased in lung tissues, along with the recruitment of eosinophils and tissue IgE expression. In the skin, chemokine expression was further reduced after CCL1 blockade.

Conclusions: These data demonstrate that despite a protective effect against Scl-GVHD in the skin, administration of hMSCs exacerbated lung fibrosis associated with eosinophilia and airway inflammation through persistent CCL1 upregulation. CCL1 blockade offers a potential treatment of pulmonary complications induced after treatment with hMSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13287-020-01768-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318460PMC
June 2020

Intravenous busulfan and melphalan versus high-dose melphalan as a conditioning regimen for early autologous stem cell transplantation in patients with multiple myeloma: a propensity score-matched analysis.

Leuk Lymphoma 2020 11 25;61(11):2714-2721. Epub 2020 Jun 25.

Seoul National University Hospital, Seoul, Republic of Korea.

We compared the efficacy and toxicity of busulfan and melphalan (BUMEL) and those of high-dose melphalan (HDMEL) as conditioning regimens for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) through a propensity score-matched analysis. No significant difference in the complete response and overall response rate after ASCT was observed between BUMEL and HDMEL. After a median follow-up of 37.3 months in the BUMEL group and 50.8 months in the HDMEL group, the median progression-free survival was calculated to be 32.9 months and 25.2 months ( = 0.995). With respect to non-hematologic toxicities, infections were more frequently reported in the BUMEL group ( < 0.001). Three patients who received BUMEL developed veno-occlusive disease (VOD), and all of them recovered without administration of defibrotide. In conclusion, BUMEL is an effective alternative conditioning regimen in terms of efficacy, but attention should be paid to toxicities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1783448DOI Listing
November 2020

Denosumab Versus Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Randomized Controlled Phase 3 Study-Asian Subgroup Analysis.

Adv Ther 2020 07 10;37(7):3404-3416. Epub 2020 Jun 10.

Department of Hematology, Seoul St. Mary's Hospital, Seoul, Republic of Korea.

Introduction: The primary analysis of a global phase 3 study that evaluated the efficacy and safety of denosumab versus zoledronic acid for preventing skeletal-related events (SREs) in adults with newly diagnosed multiple myeloma (MM) indicated that denosumab was noninferior to zoledronic acid for time to first on-study SREs. Here we present a subgroup analysis to evaluate efficacy and safety in Asian patients.

Methods: Patients were randomized 1:1 to receive denosumab 120 mg subcutaneously or zoledronic acid intravenously 4 mg every 4 weeks in a double-blind, double-dummy fashion. All patients received standard-of-care first-line antimyeloma treatment. Each patient received either study drug until an estimated 676 patients experienced at least one on-study SRE and the primary efficacy and safety analyses were completed.

Results: Of 1718 total enrolled patients, 196 Asian patients (denosumab, n = 103; zoledronic acid, n = 93) were included in this subgroup analysis. Fewer patients in the denosumab group developed first on-study SRE compared with the zoledronic acid group; the crude incidence of SREs at the primary analysis cutoff was 38.8% and 50.5%, respectively (HR [95% CI], 0.77 [0.48-1.26]). All 194 patients receiving at least one dose of study drug experienced at least one treatment-emergent AE. The most common AEs reported in either group (denosumab, zoledronic acid) were diarrhea (51.0%, 51.1%), nausea (42.2%, 46.7%), and pyrexia (38.2%, 41.3%). Treatment-emergent renal toxicity occurred in 9/102 (8.8%) and 20/92 (21.7%) patients, respectively. Similar rates of positively adjudicated osteonecrosis of the jaw (7 [6.9%] vs 5 [5.4%]) and treatment-emergent hypocalcemia (19 [18.6%] vs 17 [18.5%]) were reported in the denosumab and zoledronic acid groups, respectively.

Conclusion: Efficacy and safety outcomes from this Asian subgroup were comparable to those of the full study population. Overall, this analysis supports denosumab as an additional treatment option for standard of care for Asian patients with newly diagnosed MM with lytic bone lesions.

Clinical Trial Registration: ClinicalTrials.gov NCT01345019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12325-020-01395-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467415PMC
July 2020

Incorporating hematopoietic stem-cell transplantation after second-line carfilzomib-lenalidomide-dexamethasone (KRd).

Ther Adv Hematol 2020 12;11:2040620720921046. Epub 2020 May 12.

Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.

Background: Traditionally believed to be an integral part of multiple myeloma (MM) treatment, the role of hematopoietic stem-cell transplantation (HSCT) is being challenged. As such, we sought to evaluate the impact of HSCT in the era of novel agents.

Methods: A multicenter, retrospective, longitudinal cohort study was carried out between January 2016 and December 2018. A total of 55 patients who received VTD (bortezomib-thalidomide-dexamethasone) as first-line treatment and KRd (carfilzomib-lenalidomide-dexamethasone) as second-line treatment were analyzed for outcomes.

Results: The enrolled patients were divided into Group 1, defined as those who continued KRd treatment until progression ( = 41), Group 2, defined as those who underwent HSCT after a certain number of cycles of KRd ( = 14). Both groups showed a generally favorable response to KRd, with overall response rate (ORR) of 87.9% and clinical benefit rate of 92.8% after a median of seven cycles in Group 1, and ORR 92.8% and clinical benefit rate 100% after median of five cycles in Group 2. However, significantly poorer progression-free survival (PFS) ( = 0.004) was observed in Group 1 (median 12 months) compared with Group 2 (median not reached). Multivariate analyses identified HSCT after KRd as potential risk factors associated with PFS. Also, in Group 1, bortezomib refractoriness was associated with significantly shorter PFS compared with those who were responsive (median 12 months 14 months, respectively,  = 0.039).

Conclusions: In conclusion, even with the advent of novel agents, HSCT still remains a valuable treatment modality with additive efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2040620720921046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236395PMC
May 2020

Specific donor HLA allotypes as predictors of cytomegalovirus disease risk in acute myeloid leukemia.

HLA 2020 Oct 4;96(4):445-455. Epub 2020 Aug 4.

Department of Internal Medicine, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Some HLA alleles have been shown to be associated with susceptibility to cytomegalovirus (CMV) disease incidence in vitro. The objective of this study was to identify correlations between donor HLA allotypes and CMV disease incidence in patients with acute myeloid leukemia who had undergone allogeneic hematopoietic stem cell transplantation (HSCT). Methods and materials we retrospectively analyzed the medical records of 613 donors and recipients with acute myeloid leukemia who had received an allogeneic HSCT from matched sibling (n = 260), unrelated (n = 168), or haploidentical (n = 186) donors, from 2012 to 2017. The HLA-A, -B, -C, and -DRB1 allotypes in the donors were determined using sequence-based typing. Overall, CMV disease incidence was significantly associated with three genotype alleles, HLA-A*30:04:01G, -B*51:01:01G, and -DRB1*09:01:02G. In the donor CMV IgG seropositive subgroup, CMV disease incidence was significantly associated with HLA-B*51:01:01G and -DRB1*09:01:02G. In the IgG seropositive donors in the unrelated allo-HSCT subgroup CMV disease incidence was also significantly associated with HLA-B*51:01:01G. In the CMV seropositive donors in the haploidentical allo-HSCT subgroup, the incidence of CMV disease was significantly associated with HLA-A*24:02:01G and -DRB1*09:01:02G. HLA-DRB1*13:02:01G was a protective marker among IgG seropositive donors in the unrelated allo-HSCT recipient category. Discussion and conclusions The incidence of CMV disease among HSCT recipients varies according to donor HLA alleles and the donor CMV IgG serostatus. Certain donor HLA alleles can be considered to be risk or protective markers. Donors' HLA types and CMV IgG serostatus should be considered in donor selection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tan.13966DOI Listing
October 2020

Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Patients With Previously Treated Multiple Myeloma: Three-year Follow-up of CASTOR.

Clin Lymphoma Myeloma Leuk 2020 08 9;20(8):509-518. Epub 2019 Oct 9.

Malignant Haematology and Stem Cell Transplantation Service, Alfred Health-Monash University, Melbourne, Australia. Electronic address:

Background: In the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone. Outcomes after 40.0 months of median follow-up are discussed.

Patients And Methods: Eligible patients had received ≥ 1 line of treatment and were administered bortezomib (1.3 mg/m) and dexamethasone (20 mg) for 8 cycles with or without daratumumab (16 mg/kg) until disease progression.

Results: Of 498 patients in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247), 47% had 1 prior line of treatment (1PL; D-Vd, n = 122; Vd, n = 113). Median progression-free survival (PFS) was significantly prolonged with D-Vd versus Vd in the ITT population (16.7 vs. 7.1 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.25-0.40; P < .0001) and the 1PL subgroup (27.0 vs. 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P < .0001). In lenalidomide-refractory patients, the median PFS was 7.8 versus 4.9 months (HR, 0.44; 95% CI, 0.28-0.68; P = .0002) for D-Vd (n = 60) versus Vd (n = 81). Minimal residual disease (MRD)-negativity rates (10) were greater with D-Vd versus Vd (ITT: 14% vs. 2%; 1PL: 20% vs. 3%; both P < .0001). PFS2 was significantly prolonged with D-Vd versus Vd (ITT: HR, 0.48; 95% CI, 0.38-0.61; 1PL: HR, 0.35; 95% CI, 0.24-0.51; P < .0001). No new safety concerns were observed.

Conclusion: After 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D-Vd provided the greatest benefit at first relapse and increased MRD-negativity rates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2019.09.623DOI Listing
August 2020