RESUMO
BACKGROUND: Wilms' tumor gene 1 (WT1) mRNA quantification is a useful marker of measurable residual disease in acute myeloid leukemia (AML). However, whether monitoring the WT1 mRNA levels may predict the outcome of venetoclax (VEN) combination therapy in AML is not reported. This study aims to elucidate whether WT1 mRNA dynamics could predict long-term prognosis. METHODS: 33 patients with untreated or relapsed/refractory AML evaluated for peripheral blood WT1 dynamics in VEN combination therapy were analyzed. RESULTS: The median age was 73 years (range 39-87). Azacitidine was combined with VEN in 91% of patients. Overall, the median overall survival (OS) was 334 days (95% CI 210-482), and the complete remission (CR) plus CR with incomplete hematologic recovery rate was 59%. A 1-log reduction of WT1 mRNA values by the end of cycle 2 of treatment was associated with significantly better OS and event-free survival (EFS) (median OS 482 days vs. 237 days, p = 0.049; median EFS 270 days vs. 125 days, p = 0.02). The negativity of post-treatment WT1 mRNA value during the treatment was associated with significantly better OS and EFS (median OS 482 days vs. 256 days, p = 0.02; median EFS not reached vs. 150 days, p = 0.005). Multivariate analysis confirmed the significance of these two parameters as strong EFS predictors (HR 0.26, p = 0.024 and HR 0.15, p = 0.013, respectively). The increase in WT1 mRNA values was correlated with relapse. CONCLUSION: This study demonstrates that WT1 mRNA dynamics can be a useful marker for assessing long-term prognosis of VEN combination therapy for AML.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Neoplasias Renais , Leucemia Mieloide Aguda , Sulfonamidas , Tumor de Wilms , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Prognóstico , RNA Mensageiro/genética , Proteínas WT1/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologiaRESUMO
Atraumatic splenic rupture (ASR) is a rare but fatal complication of malignant lymphoma. However, only one case of intravascular large B-cell lymphoma (IVLBCL)-related ASR (IVLBCL-ASR) has previously been reported, and the mechanism of IVLBCL-ASR is unknown. We present the case of a 78-year-old man who died unexpectedly and was diagnosed with IVLBCL-ASR pathologically by autopsy. A massive intraperitoneal hemorrhage and four lacerations on the splenic surface were discovered during the autopsy. CD20-positive lymphoma cells that infiltrated into small vessels were highly concentrated in the center of the spleen and were only slightly distributed in the lacerations on the splenic surface. Therefore, increased intrasplenic pressure due to lymphoma cell proliferation was identified as the cause of ASR. The patient had undergone 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for tongue cancer evaluation 3 months earlier, and positive uptake was found in the right adrenal gland, where lymphoma cell infiltration was confirmed by the autopsy. Our findings suggest that clinicians should be aware that the advanced stage of IVLBCL can cause fatal ASR via increased intrasplenic pressure. Therefore, early diagnosis and early treatment intervention are desirable to prevent the onset of IVLBCL-ASR, and 18F-FDG PET/CT is useful for the early diagnosis of IVLBCL.
Assuntos
Lacerações , Linfoma Difuso de Grandes Células B , Ruptura Esplênica , Idoso , Fluordesoxiglucose F18 , Humanos , Lacerações/complicações , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ruptura Esplênica/etiologiaRESUMO
Pure red cell aplasia (PRCA) is characterized by normocytic anemia with reticulocytopenia and marked reduction of the bone marrow erythroid precursors. PRCA may be congenital (Diamond-Blackfan anemia) or acquired. Acquired PRCA may present in the context of various backgrounds, the most common type in Japan being idiopathic, thymoma-associated, and large granular lymphocyte leukemia. Idiopathic and secondary PRCA that do not respond to the treatment of the underlying disease are generally treated using immunosuppressive agents. A retrospective study PRCA2004/2006 suggests that maintenance therapy and management of infectious complications is crucial for improving the prognosis in patients with PRCA. Recently, allogeneic stem cell transplantation has been considered as a potential option for the treatment of patients with PRCA who are refractory to immunosuppressive therapy. Sirolimus and roxadustat may be effective for relapsed/refractory PRCA with renal insufficiency and anti-erythropoietin antibody-mediated PRCA, respectively. Some gene mutations were detected in certain patients who had acquired PRCA, and the identification of STAT3 mutations may be useful in PRCA management. A prospective cohort study PRCA2016 has been ongoing in Japan, and novel discoveries provide hope for improving the outcome in patients with PRCA.
Assuntos
Aplasia Pura de Série Vermelha , Neoplasias do Timo , Humanos , Imunossupressores , Estudos Prospectivos , Aplasia Pura de Série Vermelha/diagnóstico , Aplasia Pura de Série Vermelha/terapia , Estudos RetrospectivosRESUMO
BACKGROUND: The Japan Study Group for Cell Therapy and Transplantation (JSCT) organized a phase II study to evaluate the efficacy and safety of a treatment protocol (JSCT-MM12) for multiple myeloma (MM) patients who were previously untreated and transplantation-eligible. Since bortezomib-based therapy is known to be effective for MM, the protocol is intensified more than the previous protocol (JSCT-MM10) and comprised the subsequent treatments: bortezomib + cyclophosphamide + dexamethasone (VCD) induction; bortezomib + high-dose-melphalan (B-HDM) conditioning with autologous stem cell transplantation (ASCT); bortezomib + thalidomide + dexamethasone (VTD) consolidation; and lenalidomide (LEN) maintenance. METHODS: Sixty-four symptomatic patients aged between 20 and 65 years were enrolled for treatment and received three cycles of VCD, followed by cyclophosphamide administration for autologous stem cell harvest and B-HDM/ASCT, and subsequently two cycles of VTD, after that LEN for 1 year. RESULTS: Complete response (CR)/stringent CR (sCR) rates for induction, ASCT, consolidation, and maintenance therapies were 20, 39, 52, and 56%, respectively. The grade 3/4 toxicities (≥ 10%) with VCD treatment included neutropenia (27%), anemia (19%), and thrombocytopenia (11%). There was no treatment-related mortality. After median follow-up of 41 months, estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 64% and 88%, respectively. The high-risk group revealed lower CR/sCR, PFS, and OS than the standard-risk group. CONCLUSIONS: The study revealed that the treatment protocol consisting of VCD induction, B-HDM/ASCT followed by VTD consolidation, and LEN maintenance could produce highly beneficial responses and favorable tolerability in newly diagnosed MM. However, future study is required for improving treatment in the high-risk group.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/terapia , Terapia Neoadjuvante/métodos , Transplante de Células-Tronco/métodos , Adulto , Idoso , Bortezomib/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Humanos , Japão , Lenalidomida/administração & dosagem , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Prognóstico , Taxa de Sobrevida , Talidomida/administração & dosagem , Transplante AutólogoRESUMO
BACKGROUND: Plasma removal by washing is an effective approach to prevent transfusion reactions by platelet concentrates (PCs). Recently, washed PCs were released by the Japanese Red Cross Society (JRCS). MATERIALS AND METHODS: This retrospective multicenter study evaluated the efficacy and safety of released washed PCs (RWPCs) between September 2016 and January 2017 in Japan. The RWPCs were prepared by washing leukoreduced apheresis PCs with the platelet additive solution, BRS-A, using automated cell processors. RESULTS: Clinical data were obtained from 91 patients and 1210 RWPC transfusions at 50 institutions. The median number of RWPC transfusions per patient was 8 (range, 1-91). RWPCs were used in 94.5% of the patients with a history of recurrent or severe transfusion reactions for preventing such reactions. Responses of RWPCs were evaluated as complete response (91.6%), partial response (8.2%), no-change (0.2%), and progression (0%) and overall response was equal across subgroups divided by patients' profiles. The median corrected count increment (CCI) at 1 and 24 h post-transfusion were 13.5 (range, 1.9-35.4) × 109/L and 3.5 (range, -13 to 53.6) × 109/L, respectively, and median CCI at 24 h was 5.5 (range, -13 to 53.6) × 109/L in patients without risk factors associated with platelet transfusion refractoriness. Transfusion reactions to RWPCs were observed in only nine transfusions (0.7%), all of which were mild allergic reactions. CONCLUSION: This study demonstrated that RWPCs were effective and safe in patients with a history of transfusion reactions. Further prospective studies on efficacy together with cost-benefit analysis in RWPCs are needed.
Assuntos
Plaquetas/metabolismo , Transfusão de Sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Hypoplastic myelodysplastic syndrome (hMDS) is a distinct entity with bone marrow (BM) hypocellularity and the risk of death from BM failure (BMF). To elucidate the characteristics of hMDS, the data of 129 patients diagnosed between April 2003 and March 2012 were collected from 20 institutions and the central review team of the National Research Group on Idiopathic Bone Marrow Failure Syndromes, and compared with 115 non-hMDS patients. More RA and fewer CMMoL and RAEB-t in French-American-British (FAB) and more RCUD and MDS-U and fewer RCMD in World Health Organization (WHO) classifications were found in hMDS than non-hMDS with significant differences. The overall survival (OS) and AML progression-free survival (AML-PFS) of hMDS were higher than those of non-hMDS, especially in patients at age ≥50 and of lower risk in Revised International Prognostic Scoring System (IPSS-R). In competing risks analysis, hMDS exhibited decreased risk of AML-progression in lower IPSS or IPSS-R risk patients, and higher risk of death from BMF in patients at age ≥50. Poor performance status (PS ≥2) and high karyotype risks in IPSS-R (high and very high) were significant risk factors of death and AML-progression in Cox proportional hazards analysis.
Assuntos
Síndromes Mielodisplásicas/patologia , Prognóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/patologia , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/etiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Estudos Retrospectivos , Inquéritos e Questionários , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Although voriconazole (VRCZ) is metabolized to VRCZ N-oxide principally by CYP2C19, VRCZ clearance is affected by multiple factors. In this study, we investigated the relationship between the CYP2C19 phenotype using the VRCZ-to-VRCZ N-oxide plasma concentration ratio (VRCZ/N-oxide) and demographic and clinical characteristics of Japanese patients taking VRCZ. METHODS: A total of 65 Japanese patients taking VRCZ for prophylaxis or treatment of fungal infection were enrolled in this study. Stepwise selection multiple linear regression analysis was performed to investigate the effect of factors on the VRCZ/N-oxide ratio. RESULTS: In patients not undergoing concurrent treatment with a drug influencing CYP2C19 activity (n = 54), the VRCZ/N-oxide ratio with definite thresholds for CYP2C19 genotypes, CYP2C19*1/*1, *1/*2 + *1/*3 + *2/*17, and *2/*2 + *2/*3, was specifically identified in patients taking VRCZ (<0.48, ≥0.48 < and <0.82 and ≥0.82). However, the VRCZ/N-oxide ratio could not be predicted based solely on the CYP2C19 genotype (R = 0.053). The route of VRCZ administration, C-reactive protein concentration determined on the same day as VRCZ plasma concentration measurement, CYP2C19 extensive metabolizer, and patient age were independent factors influencing the VRCZ/N-oxide ratio (R = 0.489, standardized regression coefficient = 0.385, 0.380, -0.231, and 0.231; P = 0.001, 0.001, 0.032, and 0.036, respectively). CONCLUSIONS: It is possible to comprehensively evaluate CYP2C19 activity using the actual measured value of the VRCZ/N-oxide ratio in patients taking VRCZ. The predictive performance of the VRCZ/N-oxide ratio was improved by including the route of administration, C-reactive protein level, and patient age in addition to the CYP2C19 genotype as predictive factors.
Assuntos
Antifúngicos/sangue , Citocromo P-450 CYP2C19/genética , Óxidos/sangue , Voriconazol/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Proteína C-Reativa/metabolismo , Demografia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético/genética , Adulto JovemRESUMO
A 64-year-old woman was admitted to our hospital to undergo allogeneic stem cell transplantation. She was diagnosed with polycythemia vera with a JAK2 V617F mutation 7 years ago. She was administered ruxolitinib for splenomegaly two years prior to admission but this was discontinued because of progressive pancytopenia. One months after cessation of ruxolitinib, she developed acute myeloid leukemia transformed from post-polycythemia vera myelofibrosis. Although she achieved complete remission after induction therapy, 8-finger-breadth splenomegaly remained below the left costal margin. Ruxolitinib was re-administered following two courses of consolidation therapy. She underwent unrelated peripheral blood stem cell transplantation. Ruxolitinib was administered until the day before transplantation, and the spleen was palpated in 4-finger breadth below costal arc. Neutrophil engraftment was achieved 13 days after transplantation. In allogeneic stem cell transplantation, splenomegaly is one of the risk factors for engraftment failure and/or therapy-related mortality. Hence, a smaller spleen size can theoretically improve the outcome after transplantation. The administration of ruxolitinib prior to transplantation may have contributed to engraftment with a non-invasive reduction in the size of the spleen.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Mielofibrose Primária/complicações , Pirazóis/uso terapêutico , Esplenomegalia/tratamento farmacológico , Feminino , Humanos , Leucemia Mieloide Aguda/etiologia , Pessoa de Meia-Idade , Nitrilas , Pirimidinas , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
Immunosuppressive therapy has been employed as the initial treatment for acquired chronic pure red cell aplasia (PRCA), such as idiopathic, thymoma-associated, or large granular lymphocyte (LGL) leukaemia-associated PRCA, which is thought to be immune-mediated. To explore the overall long-term outcome following immunosuppression and to identify the risk factors for death in these disorders, we conducted nationwide surveys in Japan 2004 and 2006, and identified a total of 185 patients with acquired chronic PRCA, including 72 idiopathic, 41 thymoma-associated and 14 LGL leukaemia-associated cases of PRCA for whom data was available. The present study evaluated 127 patients with these three subsets of PRCA. The median overall survival has not yet been reached in idiopathic PRCA. The estimated median overall survival times in patients with thymoma-associated and LGL leukaemia-associated PRCA were 142·1 and 147·8 months, respectively. Twenty-two deaths were reported, and the response to induction therapy and relapse of anaemia were found to be associated with death. The major causes of death were infection in seven patients and organ failure in another seven patients. The results suggest that maintenance therapy and the management of infectious complications are crucial for improving the prognosis of chronic PRCA.
Assuntos
Imunossupressores/uso terapêutico , Aplasia Pura de Série Vermelha/tratamento farmacológico , Aplasia Pura de Série Vermelha/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Doença Crônica , Estudos de Coortes , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Aplasia Pura de Série Vermelha/epidemiologia , Aplasia Pura de Série Vermelha/mortalidade , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The aim of this study was to develop a model able to predict the area under the lenalidomide plasma concentration-time curve (AUC) in multiple myeloma (MM) patients using a limited sampling strategy. METHODS: Forty-six hospitalized Japanese MM patients (25 men and 21 women) participated in this study. On days 3-10 of lenalidomide therapy, whole-blood samples were collected just before oral lenalidomide administration, and 1, 2, 4, 8, 12, and 24 hours thereafter. Plasma concentrations of lenalidomide were analyzed using liquid chromatography-tandem mass spectrometry. RESULTS: The AUC0-24 predicted from a single lenalidomide plasma concentration measured 8 hours after the administration (C8h) showed the highest correlation with the measured AUC0-24 of lenalidomide (AUC0-24 = 13.0 × C8h + 1305.0; r = 0.832). To enhance the correlation between the predicted and the actual AUC0-24 of lenalidomide, we included information regarding lenalidomide elimination by entering creatinine clearance (CCr) data in the predictive formula of lenalidomide AUC0-24. Predicting the AUC0-24 of lenalidomide using data from 2 time points, C0h and C4h, along with CCr data further strengthened the correlation with the measured AUC0-24 of lenalidomide [AUC0-24 = 37.1 × C0h + 6.4 × C4h - 32.1 × CCr + 3265.6; r = 0.842]. CONCLUSIONS: The AUC0-24 of lenalidomide can be predicted using plasma concentrations measured at only 2 time points, C0h and C4h, in combination with CCr. Our study also suggests that the limited sampling strategy approach might help to identify patients with renal function impairment and who, despite dose adjustments, accumulate the drug, leading to a high AUC.
Assuntos
Inibidores da Angiogênese/sangue , Inibidores da Angiogênese/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Inibidores da Angiogênese/farmacocinética , Área Sob a Curva , Povo Asiático , Feminino , Humanos , Lenalidomida , Masculino , Talidomida/sangue , Talidomida/farmacocinética , Talidomida/uso terapêuticoRESUMO
PURPOSE: An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy. METHODS: The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML. RESULTS: Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (P = 0.01). Median duration of grade 3 neutropenia was 28 days (range 8-46 days). Area under the concentration-time curve (AUC0-24) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration (< 28 days) (P = 0.03); multivariate analysis revealed that a higher AUC0-24 was a significant predictor of a longer duration of neutropenia (odds ratio 54.3, P = 0.007). CONCLUSION: Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy.
RESUMO
Quizartinib is a potent, oral, second-generation, selective type II FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase 3 (QuANTUM-First) study in patients with FLT3-internal tandem duplication (ITD)-positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose-escalation method in each study, including 3 patients who were FLT3-ITD positive. No dose-limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib-related, treatment-emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM-First study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Benzotiazóis , Quimioterapia de Consolidação , Leucemia Mieloide Aguda , Compostos de Fenilureia , Tirosina Quinase 3 Semelhante a fms , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Feminino , China , Benzotiazóis/efeitos adversos , Benzotiazóis/farmacocinética , Benzotiazóis/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Adulto , Japão , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Quimioterapia de Consolidação/efeitos adversos , Quimioterapia de Consolidação/métodos , Idoso , Quimioterapia de Indução/métodos , Relação Dose-Resposta a DrogaRESUMO
The aim of this study was to evaluate the clinical factors, drug-related genetic polymorphisms, and human leukocyte antigen (HLA) types to determine the association with sorafenib-induced high-grade skin rash (HGSR) in Japanese patients with advanced renal cell carcinoma (RCC). A total of 55 patients with advanced RCC treated with sorafenib were analyzed retrospectively. Of these, 33 patients were subjected to HLA typing and polymorphism analyses of CYP3A5, ABCB1, ABCC2, and UGT1A1, which are involved in the metabolism and membrane transport of sorafenib. Grade 3 or higher SR developed in 12 (22%), and a higher incidence was observed in female patients than in male patients (40 vs. 15%, P=0.046). The initial dose, initial dose per body weight, and initial dose per body surface area in patients with HGSR were significantly higher than those in patients without HGSR. Patients with the ABCC2 -24CC genotype were at a significantly higher risk of SR than those with the CT genotype (35 vs. 0%, P=0.032). HLA-A*24 was significantly associated with the occurrence of HGSR (P=0.049). Our finding suggested that women, higher initial dose per body weight or body surface area, the ABCC2 -24CC genotype, and HLA-A*24 are associated with the risk of sorafenib-induced HGSR in Japanese RCC patients.
Assuntos
Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Exantema/induzido quimicamente , Antígeno HLA-A24/genética , Neoplasias Renais/tratamento farmacológico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Idoso , Antineoplásicos/uso terapêutico , Povo Asiático , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Citocromo P-450 CYP3A/genética , Relação Dose-Resposta a Droga , Feminino , Glucuronosiltransferase/genética , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/uso terapêutico , Estudos Retrospectivos , SorafenibeRESUMO
PURPOSE: The purpose of this study was to investigate the interactions of itraconazole (ITCZ) with orally administered calcineurin inhibitors (CNIs) in Japanese allogeneic hematopoietic stem cell transplant (HSCT) recipients. METHODS: Sixteen HSCT patients (8 patients each receiving tacrolimus or cyclosporine) were enrolled. An ITCZ oral solution was administered from day 30 after the initiation of ITCZ administration as a loading dose. Before the co-administration of ITCZ and CNI and 1 week daily thereafter, whole blood ITCZ and CNI (tacrolimus or cyclosporine) concentrations were measured in samples taken just before (C0h) and 2 h (C2h) after CNI administration. RESULTS: The median dose-adjusted C0h values of tacrolimus and cyclosporine on day 7 after the start of ITCZ co-administration were 5.6- and 2.7-fold higher, respectively, than the corresponding values obtained before the initiation of ITCZ treatment. On day 7 after ITCZ treatment, the mean single dosages of tacrolimus and cyclosporine were reduced to 33.7 and 66.5 % of the dosages before ITCZ co-administration, respectively, to adjust the CNI target concentration. Although ITCZ co-administration did not alter the dose-adjusted C0h values of tacrolimus in a patient with a CYP3A5 1/ 1 allele, it did change this value of tacrolimus in patients with CYP3A5 3 alleles. However, in patients receiving cyclosporine, no such tendency was observed. CONCLUSION: The magnitude of the interaction between orally administered tacrolimus and ITCZ was significantly greater than that between cyclosporine and ITCZ. Prospective analysis of the CYP3A5 polymorphism may be important to ensure safe and reliable immunosuppressive therapy with tacrolimus in patients treated with ITCZ.
Assuntos
Antifúngicos/administração & dosagem , Ciclosporina/farmacocinética , Imunossupressores/farmacocinética , Itraconazol/administração & dosagem , Transplante de Células-Tronco , Tacrolimo/farmacocinética , Administração Oral , Adulto , Povo Asiático , Distribuição de Qui-Quadrado , Ciclosporina/administração & dosagem , Ciclosporina/sangue , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Japão , Masculino , Pessoa de Meia-Idade , Farmacogenética , Fenótipo , Projetos Piloto , Polimorfismo Genético , Estudos Prospectivos , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/etnologia , Tacrolimo/administração & dosagem , Tacrolimo/sangue , Transplante HomólogoRESUMO
BACKGROUND: Liposomal amphotericin B (L-AmB) is recommended as an empirical antifungal treatment for patients at increased risk of fungal infections although renal toxicity remains a clinical problem. We therefore conducted a pilot study to evaluate the safety and efficacy of low-dose L-AmB as an empirical antifungal therapy for patients with prolonged neutropenia. METHODS: High-risk patients with hematological malignancies were eligible to enroll in this study provided they had: exhibited neutropenia for at least 1 week; suffered from high-grade fever for 4 days despite treatment with a broad-spectrum antibacterial; and no identified fever-causing pathogen. Low-dose L-AmB (1 mg/kg) was administrated as empirical antifungal therapy. RESULTS: Sixteen patients were registered and, of these, data from the13 patients who did not receive allogeneic stem cell transplantation were analyzed. The median duration of low-dose L-AmB treatment was 8 days. Hypokalemia was seen in one patient: administration of potassium supplements for 10 days restored potassium levels to the normal range. A two-fold increase in creatinine levels was not found in any patients even those taking concomitant nephrotoxic drugs (e.g., amynoglycoside) during the study. One patient stopped receiving the drug due to an infusion-related adverse event. No patients showed breakthrough fungal infections or died during therapy or within 7 days after the end of the study. Increase in the L-AmB dose was necessary due to persistent fever in three patients who withdrew from the study. The satisfactory response rate for low-dose L-AmB was 69 %. CONCLUSION: This study suggests that low-dose L-AmB may be an effective option as empirical antifungal therapy for high-risk patients with febrile neutropenia.
Assuntos
Anfotericina B/administração & dosagem , Neoplasias Hematológicas/tratamento farmacológico , Neutropenia/tratamento farmacológico , Adulto , Idoso , Antifúngicos/administração & dosagem , Feminino , Febre/complicações , Febre/tratamento farmacológico , Febre/patologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/patologia , Humanos , Lipossomos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Micoses/complicações , Micoses/tratamento farmacológico , Micoses/patologia , Neutropenia/induzido quimicamente , Neutropenia/patologiaRESUMO
A 63-year-old woman was admitted to our hospital with high-grade fever, liver dysfunction, and pancytopenia. Computed tomography of the whole body revealed hepatosplenomegaly but no lymphoadenopaties. Bone marrow aspiration showed infiltrations of CD20-positive large atypical B-lymphocytes with severe hemophagocytosis. Although she was a human T-cell leukemia virus type 1 carrier, the atypical lymphocyte in bone marrow had IgH rearrangement but not TCR rearrangement. From these clinical and laboratory data, the patient was diagnosed as having B-cell lymphoma-associated hemophagocytic syndrome (B-LAHS) and treated with R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). After 4 cycles of R-CHOP, she had achieved complete remission. However, increased numbers of CD4+CD25+ flower cells were observed in peripheral blood and HTLV-1 provirus DNA was detected after 5 cycle of R-CHOP. The patient was diagnosed as adult T-cell leukemia-lymphoma (ATL) complicated by B-LAHS. Our observations suggest that continuous immunosuppressive statement for B-cell lymphoma or the chemotherapy against B-LAHS may induce the development of ATL in an HTLV-1 carrier.
Assuntos
Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto/terapia , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfoma de Células B/terapia , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Feminino , Humanos , Leucemia-Linfoma de Células T do Adulto/virologia , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfoma de Células B/complicações , Pessoa de Meia-Idade , Prednisona , Rituximab , Resultado do Tratamento , VincristinaRESUMO
Acquired pure red cell aplasia (PRCA) is a rare syndrome characterized by anemia with reticulocytopenia and a marked reduction in erythroid precursors. Given its rarity, the true incidence is largely unknown, and epidemiological data representing the general population, with a description of the full spectrum of etiologies, are scarce. An epidemiological study on PRCA in Japan conducted 30 years ago estimated the annual incidence as 0.3 per million. To update the data and investigate the incidence and demographics of PRCA, we conducted a nationwide epidemiological study using the Japanese Society of Hematology (JSH) Hematologic Disease Registry, a hematologic disease registration database managed by the JSH and the Diagnosis Procedure Combination (DPC) study data available at a website of the Ministry of Health, Labor, and Welfare (MHLW) of Japan. A total of 1055 patients with newly diagnosed acquired PRCA were identified between 2012 and 2019, and the average annual incidence was calculated at 1.06 (95% confidence interval [CI], 0.83-1.28) per million. The median age was 73 (range, 18-99) years. The female-to-male ratio was 1.5:1, and the female predominance was most prominent in the child-bearing age group. Sixty-nine percent of acquired PRCA was idiopathic. The incidence of PRCA was approximately 20% of that of aplastic anemia (AA) during the same period. Approximately 0.98 patients per million per year (95% CI, 0.89-1.07) required hospitalization for the treatment of PRCA. These results are expected to contribute to the discussion of resource allocation for PRCA in the aging population in many countries, including Japan.
Assuntos
Anemia Aplástica , Aplasia Pura de Série Vermelha , Humanos , Masculino , Feminino , Idoso , Japão/epidemiologia , Incidência , Aplasia Pura de Série Vermelha/epidemiologia , Aplasia Pura de Série Vermelha/etiologia , Anemia Aplástica/epidemiologia , Anemia Aplástica/terapia , Sistema de RegistrosRESUMO
A 22-year-old woman, who often carried heavy books, was admitted for evaluation of hyperreninemic hypertension. Two months prior to admission, she noted leg edema. Radiological examinations revealed bilateral renal infarction with no other abnormal findings. An echocardiography showed a patent foramen ovale (PFO). Hypertension was considered secondary to renal infarction caused by paradoxical embolism through PFO. Antihypertensive and anticoagulant therapy led to improvement of hypertension. In previously reported cases of renal paradoxical embolism, multiorgan involvement was usually observed. Our case is unique in that embolism was confirmed only in the kidneys, and that clinical characteristics of renal embolism were not observed.
Assuntos
Embolia Paradoxal/complicações , Forame Oval Patente/complicações , Hipertensão/etiologia , Infarto/etiologia , Rim/irrigação sanguínea , Anticoagulantes/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Feminino , Humanos , Hipertensão/tratamento farmacológico , Infarto/complicações , Renina/sangue , Adulto JovemRESUMO
Stenotrophomonas maltophilia is increasingly emerging as a multiresistant pathogen in the hospital environment. In immunosuppressed patients, this bacterium may cause severe infections associated with sepsis and multiple organ dysfunction. We report on a 57-year-old woman treated with intensive chemotherapy for non-Hodgkin lymphoma who developed severe neutropenia, hemorrhagic pneumonia, and acute respiratory failure, which led to her death within 36 h of onset of pneumonia. Postmortem examination revealed bilateral extensive intraalveolar hemorrhage associated with severe infection by the gram-negative bacterium Stenotrophomonas maltophilia. In vitro susceptibility testing showed resistance to carbapenem, cephalosporines and aminoglycosides, but sensitivity to minocycline, ciprofloxacin, levofloxacin, and trimethoprim/sulfamethoxazole (cotrimoxazole). Early diagnosis and adequate antibiotic treatment were difficult, as the clinical course was rapid and fulminant, and this bacterium is resistant to multiple antibiotics. To improve prognosis in such cases, it will be necessary to develop an effective prophylactic strategy for high-risk patients.