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1.
Blood Adv ; 4(9): 2032-2043, 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32396615

RESUMO

CWP232291 (CWP291) is a small-molecule inhibitor of Wnt signaling that causes degradation of ß-catenin via apoptosis induction through endoplasmic reticulum stress activation. This first-in-human, open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of CWP291 enrolled 69 patients with hematologic malignancies (acute myeloid leukemia [AML], n = 64; myelodysplastic syndrome, n = 5) in 15 dose-escalation cohorts of 4 to 334 mg/m2 using a modified 3+3 design and 1 dose-expansion cohort. CWP291 was administered IV daily for 7 days every 21 days. The most common treatment-emergent adverse events (TEAEs) were nausea (n = 44, 64%), vomiting (n = 32, 46%), diarrhea (n = 25, 36%), and infusion-related reactions (n = 20, 29%). Grade ≥3 TEAEs in >3 patients (5%) were pneumonia (n = 8, 12%); hypophosphatemia (n = 6, 8%); leukocytosis, nausea, cellulitis, sepsis, and hypokalemia (n = 5 each, 7% each); and hypertension (n = 4, 6%). Dose-limiting toxicities included nausea (n = 3) and abdominal pain, anaphylactic reaction, myalgia, and rash (n = 1, each); the MTD was defined at 257 mg/m2. CWP232204, the active metabolite of CWP291, showed pharmacokinetic linearity on both days 1 and 7, and a terminal half-life of ∼12 hours. Among 54 response-evaluable AML patients, there was one complete response at a dose of 153 mg/m2 and one partial response at 198 mg/m2; bone marrow blast percentage reduced from a median of 58.3% to 3.5% and 15.0% to 4.2%, respectively. Future studies will explore CWP291, with a mechanism of action aimed at eradication of earlier progenitors via Wnt pathway blockade, as combination therapy. This trial was registered at www.clinicaltrials.gov as #NCT01398462.

2.
Br J Haematol ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227648

RESUMO

Despite the availability of guidelines for the management of chronic myeloid leukaemia (CML), various issues may prevent their successful implementation. The TARGET survey examined real-world management of CML patients compared with international recommendations. This online survey was completed in 2017. Results were discussed by a Steering Committee (SC) of eight international haematologists, challenges were identified and practical solutions developed. Of the 1008 haematologists invited (33 countries), 614 completed the survey. Gaps regarding treatment efficacy and molecular monitoring were identified. Half of the physicians did not perform three-monthly testing of during the initial 12 months of treatment, citing cost as the major barrier, although they know it should be done. Treatment-free remission was not considered a primary treatment goal or as a priority factor influencing treatment decisions. European Leukemia Net guidelines interpretation was generally acceptable, but awareness regarding management of persistent adverse events was poor. Practical solutions proposed by the SC were mostly focused on enhancing physician education and awareness, or encouraging hospitals to work with the government, in order to improve the quality of BCR-ABL testing. Gaps in current CML management were identified compared with international recommendations, which the proposed practical solutions would help to address.

3.
Korean J Intern Med ; 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32279477

RESUMO

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). Conclusions: Initial hyperleukocytosis, extranodal involvement, complex karyotype, del(17) and del(11q) need to be considered in the risk stratification system for CLL.

4.
Patient Educ Couns ; 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32171555

RESUMO

OBJECTIVE: To evaluate the association of sexual knowledge with sexual desire, sexual activity, and sexual satisfaction in hematopoietic stem cell transplantation (HSCT) patients and partners, and their willingness to participate in sexual education. METHODS: This is a multi-center survey. Patients were eligible if they had received HSCT. Patients' current sexual partners were invited to the study unless they had limitations on sexual activity. Sexual desire, activity and satisfaction was assessed using the Sexual Activity Questionnaire. Sexual knowledge, experience of information seeking, sexual counseling or education, and willingness of participate in sexual education were assessed using questionnaire. RESULTS: Of 151 participants, 61.8 % had experience of receiving counseling about their sexual issues after HSCT. Compared to the lower sexual knowledge group, participants with higher sexual knowledge reported to be 1.91 times more sexually active with 3.04 times higher sexual desire. Among the participants, 79.4 % of participants had the willingness to receive sexual education after HSCT and preferred to receive sexual education from sexual education specialists CONCLUSIONS: Higher sexual knowledge was associated with higher sexual desire, sexual activity, and sexual satisfaction. PRACTICE IMPLICATIONS: Sexual education should be provided to patients and their partners after HCST by trained experts for HSCT patient's sexual life.

5.
Mycoses ; 63(1): 89-94, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31610064

RESUMO

BACKGROUND: Posaconazole is used to prevent invasive fungal infections (IFIs) in patients with haematologic malignancy. In this study, we compared plasma posaconazole concentrations (PPCs) and the incidence of breakthrough IFIs between patients with haematologic malignancy receiving posaconazole oral suspension vs tablet. METHODS: We retrospectively collected data on adult patients with haematologic malignancies who received posaconazole prophylaxis during chemotherapy from April 2014 through May 2018. A total of 242 cases with PPCs, 88 in the oral suspension group and 154 in the tablet group, were included in this study. RESULTS: Patients receiving tablets achieved a significantly higher mean PPC than did those on oral suspension (1.631 ± 0.878 µg/mL in the tablet group vs. 0.879 ± 0.585 µg/mL in the oral suspension group). One hundred and thirty-seven of 154 patients (89.0%) receiving tablets had PPCs of 0.7 µg/mL or more, while only 41 of 88 patients (46.6%) receiving oral suspension attained an optimal level (P < .001). The incidence of breakthrough IFIs was significantly higher in the oral suspension group compared with in the tablet group (14.8% of oral suspension vs. 4.5% of tablet; P = .005). In the analysis including patients receiving posaconazole tablets, hypoalbuminemia (< 3.5 g/dL) was found to be a risk factor associated with suboptimal levels (odds ratio: 8.872; 95% confidence interval: 3.011 - 26.141; P < .001). CONCLUSIONS: Suboptimal PPCs in the tablet group were less common than those in the oral suspension group. Therapeutic drug monitoring may be still necessary even in patients receiving posaconazole tablets, especially in those with hypoalbuminemia.

6.
Genes Chromosomes Cancer ; 59(4): 255-260, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31705772

RESUMO

Precursor B cell phenotype Burkitt lymphoma/leukemia with IGH-MYC is a rare subtype of Burkitt lymphoma (BL). BL and B lymphoblastic leukemia/lymphoma (B-ALL/LBL) differ as regards treatment and the distinction between these two entities is crucial. Patients demonstrating a terminal deoxynucleotidyl transferase (TdT)-positive precursor B cell phenotype with IGH-MYC rearrangement have been reported to be molecularly distinct from BL and closer to B-ALL/LBL. We investigated the molecular characteristics of two cases of a rare but distinct TdT-negative precursor B cell phenotype BL. Both patients showed FAB L3 morphology with IGH-MYC translocation, but had precursor B cell immunophenotypes including dim to moderate expression of CD45 and absence of BCL6, CD20, monoclonal kappa, and lambda light chain expression. To characterize the molecular features, we performed exome sequencing and analyzed the breakpoint junction of the IGH-MYC rearrangement. We detected KMT2D mutations in both cases, a rarely acquired chromatin modifying gene mutation in BL. The breakpoint analysis revealed that the IGH-MYC rearrangement occurred due to an aberrant VDJ recombination in one case. The treatment protocols differed, including high-grade lymphoma treatment and standard B-ALL treatment. Complete remission was achieved in the patient who received B-ALL treatment. The degree of resemblance of BL and B-ALL differed between two cases, but the molecular pathogenesis and manifesting features of both TdT-negative precursor B cell phenotype BL case were distinct from classic BL, which indicates the need for a better understanding of this uncommon entity that does not fit in current diagnostic and classification categories.

7.
J Clin Lab Anal ; 34(2): e23064, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31692115

RESUMO

BACKGROUND: Atypical chronic myeloid leukemia (aCML) is a hematologic disorder characterized by leukocytosis with increased dysplastic neutrophils and their precursors. In CSF3R gene, the activation mutation including T618I is frequently reported in aCML but is rarely accompanied by truncation mutations. Herein, we report a unique aCML patient with two CSF3R mutations (T618I and Y779*) in the same DNA strand. METHODS: High-coverage next-generation sequencing for 40 genes related with myeloid leukemia was performed. Sanger sequencing was performed to confirm CSF3R mutations. To confirm whether two CSF3R mutations are in cis or not, TA cloning was used. Clinical information and bone marrow pathology were reviewed by two hematopathologists. RESULTS: In the patient diagnosed with aCML in bone marrow study, two CSF3R mutations, (T618I and Y779*) a SETBP1 mutation (G870S) and an U2AF1 mutation (Q157P), were identified by high-coverage next-generation sequencing. The two CSF3R mutations were confirmed to be located in the same DNA strand by TA cloning, indicating that the two mutations are harbored in one malignant clone. The SETBP1 mutation is known to be related with poor prognosis in aCML. Likewise, the patient was refractory to hydroxyurea and showed disease progression. Additionally, we discussed the potential therapeutic targets by reviewing the molecular profile of the patient. CONCLUSION: We believe that the accurate diagnosis and maximum therapeutic chance could be achieved by profiling the mutations and their characteristics.

9.
Transplantation ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31634324

RESUMO

BACKGROUND: Tolerance induction is an important goal in the field of organ transplantation. We have sequentially modified our conditioning regimen for induction of donor-specific tolerance in recipients of major histocompatibility complex (MHC)-mismatched combined kidney and bone marrow transplantation (CKBMT). METHODS: From December 2011 to May 2017, eight MHC-mismatched patients received CKBMT. The initial conditioning regimen (Protocol 1) consisted of cyclophosphamide (CP), rituximab, antithymocyte globulin (rATG), and thymic irradiation. Tacrolimus and steroids were used for the maintenance of immunosuppression (IS). RESULTS: This regimen was complicated by transient acute kidney injury which has been the major clinical feature of engraftment syndrome and side effects of CP, although one of two subjects successfully discontinued his IS for 14 months. The conditioning regimen was modified by reducing the CP dose and adding fludarabine (Protocol 2). The final modification was reducing the fludarabine and rATG doses (Protocol 3). Mixed chimerism, detected by the short-tandem repeat method, was achieved transiently in all subjects for 3-20 weeks. Among the three subjects treated with Protocol 2, IS was successfully discontinued for >35 months in one subject, but the other two subjects suffered from severe BK virus associated nephritis (BKVAN). All three subjects treated with Protocol 3 tolerated the protocol well and have successfully discontinued IS for >4-41 months. Interestingly, de novo DSA was not detected in any subject during all the follow-up periods. CONCLUSIONS: Our clinical trial has shown that long-term renal allograft survival without maintenance IS can be achieved by induction of mixed chimerism following CKBMT.

10.
Int J Hematol ; 110(6): 709-722, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31655984

RESUMO

Inotuzumab ozogamicin (InO) is a targeted treatment for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). InO was previously studied in INO-VATE, an international, open-label, randomized phase 3 trial comparing InO against standard of care (SoC). In the present subgroup analysis, we evaluated outcomes in the 55 Asian patients who were randomized in INO-VATE (31 InO and 24 SoC). Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 22/31 patients treated with InO versus 5/24 treated with SoC. In the InO arm, more of the patients achieving CR/CRi were minimal residual disease (MRD)-negative (17/22 versus 1/5), and more patients proceeded directly to hematopoietic stem cell transplantation (15/31 versus 3/24). Median overall survival for the respective arms was 5.8 versus 3.9 months (hazard ratio 0.67; 97.5% CI 0.28, 1.62). In the safety analysis (n = 51), the most common adverse events were hematologic. Sinusoidal obstruction syndrome was reported in five InO patients and one SoC patient. In conclusion, Asian patients with relapsed or refractory B-cell ALL experienced improved efficacy with InO versus SoC, with an efficacy and safety profile consistent with results of the overall INO-VATE population.Clinical trial registration: ClinicalTrials.gov identifier: NCT01564784.

11.
Lancet Haematol ; 6(11): e562-e572, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31474546

RESUMO

BACKGROUND: Aplastic anaemia is a rare, life-threatening condition, characterised by pancytopenia with hypocellular bone marrow. Haematopoietic stem cells and most progenitor cells express thrombopoietin receptor (c-MPL). Romiplostim is a peptibody with c-MPL agonist activity that stimulates endogenous thrombopoietin production and leads to promoting the proliferation and differentiation of megakaryocytes in the bone marrow. In this phase 2 trial we aimed to assess the activity and safety of romiplostim in patients with aplastic anaemia who were previously treated with immunosuppressive therapy. METHODS: We did an open-label, phase 2 study including a randomised, parallel, dose-finding part followed by an extension part to evaluate long-term treatment at two clinical centres in Seoul, South Korea. Eligible patients were aged 19 years or older, and had aplastic anaemia confirmed by bone marrow and cytogenetic studies and thrombocytopenia (platelet count ≤30 × 109/L), an Eastern Cooperative Oncology Group performance status score of 2 or lower, and were previously treated with immunosuppressive therapy, including at least one course of antithymocyte globulin plus cyclosporin. In the dose-finding part, patients were randomly assigned to fixed dose cohorts (1, 3, 6, or 10 µg/kg) of subcutaneous romiplostim once weekly for 8 weeks, according to a static allocation procedure after stratification by platelet count. In the extension part of the study, patients continued romiplostim titrated every 4 weeks in single steps (1, 3, 6, 10, 13, 16, and 20 µg/kg once weekly), depending on platelet response and safety up to 1 year (weeks 9-52). Patients who had a platelet response during weeks 46-53 continued dose titration in single steps (3, 6, 10, 13, 16, and 20 µg/kg once weekly) for an additional 2 years (weeks 53-156). The primary endpoint was the proportion of patients achieving a platelet response at week 9 (after completion of the dose-finding part). Activity was assessed per-protocol in all patients evaluable for response at week 9 and safety was assessed in all patients who received at least one dose of romiplostim. This trial is registered with ClinicalTrials.gov, NCT02094417. FINDINGS: Between April 14 and Nov 24, 2014, 35 patients were enrolled and randomly assigned to one of four dose cohorts: romiplostim 1 µg/kg (n=7), 3 µg/kg (n=9), 6 µg/kg (n=9), and 10 µg/kg (n=10). Data cutoff for this final analysis was on April 14, 2018. The median duration of treatment for all patients was 53 weeks (IQR 35-155). Ten (30%) of 33 evaluable patients achieved a platelet response at week 9, including seven (70%) of ten patients in the 10 µg/kg cohort, three (33%) of nine patients in the 6 µg/kg cohort, and no patients in both the 3 µg/kg and 1 µg/kg cohorts. During the extension study, 18 (55%) of 33 evaluable patients had a platelet response during weeks 46-53 and were eligible for continued treatment. Ten (30%) patients maintained a platelet response at 2 and 3 years, of whom nine had an erythroid response and five a neutrophil response, and completed protocol treatment. Treatment-related adverse events occurred in three (9%) of 35 patients, including grade 1 or 2 myalgia, fatigue, and dizziness. 17 (49%) of 35 patients had adverse events of grade 3 or higher; seven (20%) had serious adverse events (one event of febrile neutropenia, cataract, retinal detachment, macular fibrosis, inguinal hernia, appendicitis, cellulitis, tendon injury, and transfusion reaction); and one patient died from sepsis during treatment; none of these events were related to treatment. No patients developed clonal evolution. INTERPRETATION: Romiplostim seems to be active and has a favourable safety profile in patients with refractory aplastic anaemia. 10 µg/kg once weekly might be used as a recommended starting dose in future studies. These findings warrant further investigation. FUNDING: Kyowa Hakko Kirin Korea.


Assuntos
Anemia Aplástica/tratamento farmacológico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Adulto , Plaquetas/citologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mialgia/etiologia , Neutrófilos/citologia , Proteínas Recombinantes de Fusão/efeitos adversos , Trombopoetina/efeitos adversos , Resultado do Tratamento
12.
Mol Biol Rep ; 46(6): 5859-5866, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31452046

RESUMO

The statins are a group of therapeutic drugs widely used for lowering plasma cholesterol level, while it has also been reported to induce cell death in human acute myeloid leukemia (AML) cells. To determine antitumor activity triggered by simvastatin, four AML cell lines-U937, KG1, THP1 (NRASG12D mutant) and HL60 (NRASQ61L mutant)-were cultured with simvastatin and cell viability was assessed using the CellTiter-Glo reagent. For understanding mechanism of antitumor activity, immunoblot analysis for pAkt (Ser473), Akt, pMEK, MEK, pERK (Thr202/Tyr204) and ERK (Thr202/Tyr204) was performed. Apoptotic cell population was calculated using the Annexin V-FITC assay, and cell cycle state was assessed by flow cytometry. Simvastatin showed different cytotoxic effect among AML cells, of which NRASG12D mutant THP1 was the most statin sensitive cell line (IC50 values: 1.96 uM in HL60, 7.87 uM in KG1, 0.83 uM in THP1 and 1.37 uM in U937). Western blot analysis revealed that Ras downstream signaling molecules including Akt, MEK, and ERK1/2 were markedly inhibited in THP1 cells compared to other AML cells when exposed to simvastatin. In addition, only in THP1 cells, increased apoptosis and cell cycle arrest by simvastatin was observed. The combination of simvastatin and MEK inhibitor AZD6244 synergistically reduced THP1 cell proliferation compared to simvastatin alone and AZD6244 alone (IC50 values: 0.88 uM in simvastatin, 0.32 uM in AZD6244, and 0.23 uM in combination of simvastatin and AZD6244). Simvastatin exhibited anti-leukemic effect in human AML cells in vitro, especially at NRASG12D mutant AML cell line.

13.
J Clin Lab Anal ; 33(7): e22951, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31187545

RESUMO

Del(20q) is the most frequently detected large structural genetic mosaicism alteration in the healthy aging population, occurring in approximately 0.1% of older persons. Age-related clonal hematopoiesis of copy number variations (CNVs) is linked to an increased risk of hematologic malignancies, but the clinical impact of hematopoietic stem cells (HSCs) harboring such CNVs, such as del(20q), is not clearly understood. Here, we report an acute myeloid leukemia (AML) patient with known del(20q) who acquired donor-derived del(20q) after allogeneic hematopoietic stem cell transplantation (HSCT). The HSCs with del(20q) engrafted and expanded over time, but the patient did not clinically progress to myeloid neoplasm. Although donor-derived del(20q) from a healthy donor has been reported previously, our case is the first to review the clonal dynamics of a del(20q) clone and its post-transplantation impact. Since recurrent hematology neoplasm-associated CNVs, including del(20q), may not be rare among aged HSCT donors, identifying the origin of such a CNV is necessary for clinical decisions when clonal abnormality appears after HSCT, even in recipients who previously had the same abnormality.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 20/genética , Células Clonais/patologia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/genética , Doadores de Tecidos , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Transplante Homólogo
15.
Ann Hematol ; 98(5): 1135-1147, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30758645

RESUMO

Core-binding factor acute myeloid leukemia (CBF-AML) data in Asian countries has been rarely reported. We analyzed 392 patients with CBF-AML [281 with t(8;21), 111 with inv.(16)/t(16;16)] among data from 3041 patients with AML from the Korean AML Registry. Interestingly, del(9q) was less frequently detected in Korean than in German patients with t(8;21) (7.5% vs. 17%), and del(7q) was more frequently detected in Korean patients with inv(16). Overall survival (OS) was similar between patients in the first complete remission (CR) who received allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) for CBF-AML. OS of t(8;21) patients was poor when undergoing alloSCT in second/third CR, while OS of inv(16) patients in second/third CR was similar to that in first CR. Patients with > 3-log reduction of RUNX1/RUNX1T1 qPCR had improved 3-year event-free survival (EFS) than those without (73.2% vs. 50.3%). Patients with t(8;21) AML with D816 mutation of the c-Kit gene showed inferior EFS and OS. These poor outcomes might be overcome by alloSCT. Multivariate analysis for OS in patients with t(8;21) revealed older age, > 1 course of induction chemotherapy to achieve CR, loss of sex chromosome, del(7q), and second/third CR or not in CR before SCT as independent prognostic variables. Especially, del(7q) is the most powerful prediction factor of poor outcomes, especially in patients with t(8;21) (hazard ratio, 27.23; P < 0.001). Further study is needed to clarify the clinical effect of cytogenetics and gene mutation in patients with CBF-AML, between Asian and Western countries.


Assuntos
Cromossomos Humanos , Fatores de Ligação ao Core , Leucemia Mieloide Aguda , Sistema de Registros , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos/genética , Cromossomos Humanos/metabolismo , Fatores de Ligação ao Core/genética , Fatores de Ligação ao Core/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias , República da Coreia/epidemiologia , Taxa de Sobrevida
16.
Bone Marrow Transplant ; 54(8): 1361-1368, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30809031

RESUMO

Traditional severity criteria of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) were determined retrospectively but found inappropriate for therapeutic decisions. Data of 203 patients with SOS/VOD were collected according to the modified Seattle diagnostic criteria and were analyzed for validation of the revised severity criteria recently proposed from European Society for Blood and Marrow Transplantation (EBMT). According to the traditional severity criteria, none of the patients were mild grade, while 63.1% were moderate and 36.9% were severe grade. However, according to the revised EBMT criteria, the majority of patients (63.1%) were very severe, 18.2% were severe, 12.8% were moderate, and 5.9% were mild grade. The 100-day overall survival (OS) of mild, moderate, severe and very severe groups was 83.3, 84.3, 94.6, and 58.6%, respectively. Very severe SOS/VOD showed a significantly lower OS than the others (58.6 vs. 89.3%, p < 0.0001). The 100-day transplantation-related mortality was 25.2% in the entire cohort; 8.3% in mild, 8.0% in moderate, 2.7% in severe, and 36.7% in very severe SOS/VOD (p < 0.0001). The very severe grade newly classified by the revised EBMT criteria accounted for the majority of SOS/VOD associated with worse 100-day OS. Therefore, intervention should be applied at the latest for moderate to severe SOS/VOD before deterioration.

17.
Leukemia ; 33(6): 1439-1450, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30555164

RESUMO

Achieving a deep molecular response (DMR) to tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) remains challenging and at present, there is no biomarker to predict DMR in this setting. Herein, we report that an HMGCLL1 genetic variant located in 6p12.1 can be used as a predictive genetic biomarker for intrinsic sensitivity to imatinib (IM) therapy. We measured DMR rate according to HMGCLL1 variant in a discovery set of CML patients (n = 201) and successfully replicated it in a validation set (n = 270). We also investigated the functional relevance of HMGCLL1 blockade with respect to response to TKI therapy and showed that small interfering RNA mediated blockade of HMGCLL1 isoform 3 results in significant decrease in viability of BCR-ABL1-positive cells including K562, CML-T1 or BaF3 cell lines with or without ABL1 kinase domain mutations such as T315I mutation. Decreased cell viability was also demonstrated in murine CML stem cells and human hematopoietic progenitor cells. RNA sequencing showed that blockade of HMGCLL1 was associated with G0/G1 arrest and the cell cycle. In summary, the HMGCLL1 gene polymorphism is a novel genetic biomarker for intrinsic sensitivity to IM therapy in CML patients that predicts DMR in this setting.


Assuntos
Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Mutação , Oxo-Ácido-Liases/genética , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Estudos de Casos e Controles , Sobrevivência Celular , Estudos de Coortes , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Adulto Jovem
18.
J Clin Microbiol ; 56(11)2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30135226

RESUMO

QuantiFERON-TB Gold Plus (QFT-Plus) is a new-generation QuantiFERON-TB Gold In-Tube (QFT-GIT) assay which has two antigen-coated tubes called TB1, which contains long peptides derived from ESAT-6 and CFP-10, and TB2, which contains the same components as TB1 and additional short peptides which potentially stimulate CD8+ T cells through the presentation of major histocompatibility complex class I. This is the first study to compare QFT-Plus and QFT-GIT for use in the diagnosis of latent tuberculosis infection (LTBI) among immunocompromised patients in the Republic of Korea. Among 317 consecutive patients who underwent screening for LTBI before solid organ or hematopoietic stem cell transplantation and tumor necrosis factor alpha inhibitor treatment, LTBI was identified in 92 (29.0%) and 88 (27.8%) patients by QFT-GIT and QFT-Plus, respectively. The rate of concordance between QFT-GIT and QFT-Plus was 93.7% (κ value, 0.860), and the indeterminate rate (3.2%) was similar between QFT-GIT and QFT-Plus. Of 20 (6.3%) samples with discordant results, 11 (55.0%) and 7 (35.0%) were positive by QFT-GIT alone and QFT-Plus alone, respectively, and 2 (15.0%) were indeterminate by each assay. The interferon gamma level in samples with discordant results ranged from 0.39 to 1.10 IU/ml, except for one sample, in which the gamma interferon level was 2.97 IU/ml only in TB2. Conclusively, there was a high degree of agreement between the results of QFT-GIT and QFT-Plus for the screening of immunocompromised patients for LTBI. The reactivity in TB2 contributed substantially to the difference between QFT-GIT and QFT-Plus, particularly in solid organ transplant candidates. The significance of the discrete responses in TB1 and TB2 of QFT-Plus needs to be explored further by means of an immunological and clinical approach in different patient groups and clinical settings.


Assuntos
Hospedeiro Imunocomprometido , Testes de Liberação de Interferon-gama , Tuberculose Latente/diagnóstico , Programas de Rastreamento/métodos , Adolescente , Adulto , Idoso , Feminino , Humanos , Testes de Liberação de Interferon-gama/normas , Tuberculose Latente/epidemiologia , Masculino , Programas de Rastreamento/normas , Pessoa de Meia-Idade , Kit de Reagentes para Diagnóstico , República da Coreia/epidemiologia , Adulto Jovem
19.
Ann Lab Med ; 38(6): 495-502, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30027691

RESUMO

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.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Leucemia Mielomonocítica Crônica/patologia , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA/química , DNA/isolamento & purificação , DNA/metabolismo , Análise Mutacional de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Cariótipo , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , República da Coreia , Estatísticas não Paramétricas
20.
Ann Hematol ; 97(6): 955-965, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29500710

RESUMO

The present study attempted to build a single nucleotide polymorphism (SNP)-based risk model for predicting overall survival (OS) and event-free survival (EFS) in patients with core binding factor acute myeloid leukemia (CBF-AML). Adopting genome-wide SNP array using Affymetrix SNP array 6.0, we analyzed 868,157 SNPs with respect to OS and EFS in 104 patients with CBF-AML. Significant SNPs were identified from single SNP analysis. The risk model was constructed with incorporation of six SNPs and three clinical factors (age, c-kit exon 17 mutation, and LDH) for OS and six SNPs and three clinical factors (age, WBC, and LDH) for EFS. The model was further defined into low- and high-risk groups based on risk scores. The median age was 39 years, and the subgroup of t(8;21) and inv(16) or t(16;16) was assessed in 68 (65.4%) and 36 patients (34.6%). Finally, six SNPs per each OS (rs4353685, rs4908185, rs7709207, rs12034, rs1554844, and rs17241868) and EFS (rs13385610, rs11210617, rs11169282, rs7709207, rs4438401, and rs16894846) were incorporated into the risk model. OS was significantly different in favor of the low risk group (80.4 ± 8.4%) compared to the high-risk group (22.0 ± 7.3% at 3 years; p = 8.75 × 10- 13; HR 8.67). For EFS, there was also a significant difference between the low- (75.0 ± 5.8%) versus high-risk group (17.1 ± 6.3% at 3 years; p = 5.95 × 10- 13; HR 7.67). A genome-wide SNP-based risk model can stratify CBF-AML patients according to their OS and EFS in 104 patients.


Assuntos
Leucemia Mieloide Aguda/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Alelos , Terapia Combinada , Quimioterapia de Consolidação , Feminino , Seguimentos , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Transplante de Células-Tronco/efeitos adversos , Análise de Sobrevida , Adulto Jovem
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