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1.
Blood ; 142(11): 1008-1021, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37363859

RESUMO

Chronic graft-versus-host disease (cGVHD) is a multiorgan syndrome with clinical features resembling those of autoimmune diseases. Thus, understanding commonalities in the pathophysiology of cGVHD and autoimmune diseases, such as the presence of disease-risk HLA alleles, is imperative for developing novel therapies against cGVHD. Alloantibodies against H-Y antigens encoded on the Y-chromosome are well-described risk factors for cGVHD in female-to-male transplantation. However, because H-Y antigens generally localize intracellularly in the male reproductive organs, how they emerge at affected organ levels remains elusive. Here, by analyzing nationwide registry data stratified per donor-recipient sex, we identified specific HLA class II alleles that contributed to susceptibility to male cGVHD after transplantation from HLA-identical female siblings (HLA-DRB1∗15:02: hazard ratio, 1.28; 95% confidence interval, 1.03-1.58; P = .025). Coexpression of HLA-DRB1∗15:02 efficiently transported full-length H-Y antigens, especially DBY, to the surface. The presence of alloantibodies against DBY/HLA class II complexes significantly predicted the occurrence of cGVHD (68.8% vs 31.7% at 1 year; P = .002). Notably, the ability of HLA class II molecules to transport and present DBY to alloantibodies was closely associated with the susceptibility of HLA class II alleles to cGVHD. DBY specifically colocalized with HLA class II molecules on the dermal vascular endothelium in cGVHD and provoked complement-dependent cytotoxicity. Moreover, these complexes were observed in some male leukemic cells. Altogether, these findings suggest that vascular endothelial cells facilitate alloantibody-mediated cGVHD and highlight that alloantibodies against DBY/HLA class II complexes could be common targets for cGVHD and a graft-versus-leukemia effect.


Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Masculino , Humanos , Feminino , Isoanticorpos , Células Endoteliais , Cadeias HLA-DRB1/genética , Proteínas/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos
2.
Blood ; 140(6): 594-607, 2022 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-35580269

RESUMO

Triplet regimens, such as lenalidomide, bortezomib, and dexamethasone (RVd) or thalidomide, bortezomib, and dexamethasone (VTd), are standard induction therapies for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to RVd and VTd has been investigated in the GRIFFIN and CASSIOPEIA trials, respectively, resulting in improvement in the rate of minimal residual disease (MRD) negativity. In this study, we conducted a cost-effectiveness analysis with a 10-year time horizon to compare first-line and second-line use of daratumumab for transplant-eligible patients with NDMM. Because long-term follow-up data for these clinical trials are not yet available, we developed a Markov model that uses MRD status to predict progression-free survival. Daratumumab was used either in the first-line setting in combination with RVd or VTd or in the second-line setting with carfilzomib plus dexamethasone (Kd). Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios were calculated from a Japanese and US payer perspective. In the Japanese analysis, D-RVd showed higher QALYs (5.43 vs 5.18) and lower costs (¥64 479,793 vs ¥71 287 569) compared with RVd, and D-VTd showed higher QALYs (5.67 vs 5.42) and lower costs (¥43 600 310 vs ¥49 471,941) compared with VTd. Similarly, the US analysis demonstrated dominance of a strategy incorporating daratumumab in first-line treatment regimens. Given that overall costs are reduced and outcomes are improved when daratumumab is used as part of a first-line regimen, the economic analysis indicates that addition of daratumumab to first-line RVd and VTd regimens is a dominant strategy compared with reserving its use for the second-line setting.


Assuntos
Mieloma Múltiplo , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Análise Custo-Benefício , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Humanos , Mieloma Múltiplo/terapia , Talidomida/uso terapêutico
3.
Eur J Haematol ; 112(2): 248-256, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37222081

RESUMO

OBJECTIVES: Multiple myeloma (MM) accounts for 10% of hematologic malignancies. However, most of the patients suffered from relapsed/refractory disease. We would like to expand CAR T cell therapy to treat MM using our current platform. METHODS: BCMA CAR T lymphocytes were generated for volunteers or MM patients. The transduction efficiency was detected by the ddPCR technique. Immunophenotyping and exhaustion markers were monitored by flow cytometry. The efficacy of BCMA CAR T cells was tested using coculturing with BCMA CAR or mock, and the positive and negative targets, K562/hBCMA-ECTM and K562, respectively. RESULTS: BCMA CAR T cells were generated from consented volunteers or MM patients and could be detected CAR BCMA expression at a mean of 4.07 ± 1.95 or 4.65 ± 1.21 copies/cell, respectively. Those modified T cells were primarily effector memory T cells. Our BCMA CAR T cells could explicitly eradicate the K562/hBCMA-ECTM cell line while the K562 cell line survived. Interestingly, the BCMA CAR, mock T cells, and peripheral blood mononuclear cells from MM patients expressed similar levels of the exhaustion makers, TIM-3, LAG-3, and PD1. CONCLUSIONS: Our BCMA CAR T cells, mainly effector/effector memory, could eliminate BCMA-expressing cells in vitro and had similar levels of exhaustion markers among different populations.


Assuntos
Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Antígeno de Maturação de Linfócitos B , Linhagem Celular Tumoral , Leucócitos Mononucleares/metabolismo , Imunoterapia Adotiva/métodos , Linfócitos T
4.
Clin Transplant ; 38(4): e15313, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38581299

RESUMO

BACKGROUND: The number of CD34+ cells in the graft is generally associated with time to engraftment and survival in transplantation using cord blood or allogeneic peripheral blood stem cells. However, the significance of abundant CD34+ in bone marrow transplantation (BMT) remained unclear. METHODS: We retrospectively reviewed 207 consecutive adult patients who underwent their first BMT at Jichi Medical University between January 2009 and June 2021. RESULTS: The median nucleated cell count (NCC) and CD34+ cell dose were 2.17 × 108/kg (range .56-8.52) and 1.75 × 106/kg (.21-5.84), respectively. Compared with 104 patients in the low CD34+ group (below the median), 103 patients in the high CD34+ group (above the median) showed faster engraftment at day +28 in terms of neutrophil (84.6% vs. 94.2%; p =  .001), reticulocyte (51.5% vs. 79.6%; p < .001), and platelet (39.4% vs. 72.8%; p < .001). There were no significant differences in overall survival, relapse, nonrelapse mortality, acute or chronic graft-versus-host disease, or infectious complications between the two groups in univariate and multivariate analyses. Low or high NCC had no significant effect on overall survival, nonrelapse mortality, cumulative incidence of relapse and graft-versus-host disease, either. While a positive correlation was observed between NCC and the CD34+ cell dose, a high CD34+ cell dose was associated with rapid hematopoietic recovery, even in patients with NCC below the median. CONCLUSION: Measurement of CD34+ cell dose in addition to NCC was useful for predicting hematopoietic recovery, but seemed to have little influence on the long-term outcome in BMT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Transplante de Medula Óssea/efeitos adversos , Estudos Retrospectivos , Antígenos CD34 , Recidiva , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos
5.
Br J Haematol ; 200(6): 694-703, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36661264

RESUMO

The prognosis of multiple myeloma (MM) has dramatically improved with the development of new drugs, and it has become important to determine the appropriate combinations of these novel agents. This study was a systematic review and network meta-analysis (NMA) of randomized trials in patients with relapsed and/or refractory (RR) MM. The PubMed, Cochrane, and Embase databases were searched for randomized trials from 1 January 2002 to 28 February 2022 of patients treated for MM. The primary end-point was progression-free survival (PFS), evaluated as a hazard ratio (HR) with a 95% confidence interval (95% CI) compared to dexamethasone (DEX). The p-score was used to rank treatments. Of a total of 1136 abstracts screened, 37 studies were selected, including 34 treatment options for RRMM. Daratumumab, lenalidomide and DEX was found to be the best treatment for RRMM, with the best HR compared to DEX (HR, 0.13; 95% CI, 0.08-0.20; p-score 0.9796). There was no evidence of significant heterogeneity (I2 , 41.3%; p = 0.146). The current NMA confirmed the excellent efficacy of three-drug regimens including anti-CD38 antibodies to treat RRMM and provides background data to evaluate the efficacy of chimeric antigen receptor T-cell treatments and bispecific T-cell engager therapies.


Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Metanálise em Rede , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Lenalidomida/uso terapêutico , Intervalo Livre de Progressão , Dexametasona/uso terapêutico
6.
Clin Transplant ; 37(12): e15116, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37641561

RESUMO

BACKGROUND: The early recovery of lymphocyte and monocyte cells is associated with a favorable prognosis after allogeneic stem cell transplantation (allo-HSCT); however, it is not clear whether the balance of lymphocyte and monocyte recovery affects the post-transplant prognosis. METHODS: We examined whether the time-point at which the number of lymphocytes exceeded the number of monocytes, which we termed lymphocyte-to-monocyte ratio reversal (LMRR), affected the prognosis after allo-HSCT. We retrospectively evaluated 235 patients who underwent their first allo-HSCT at our institution. RESULTS: The median number of days from HSCT to LMRR was 46 (range, 0-214), and the patients were divided into two groups according to the occurrence of LMRR by day 45 (LMRR45). In a multivariate analysis, early LMRR contributed favorably to overall survival (hazard ratio [HR] .519; 95% confidence interval [CI] .332-.812; p = .004) with fewer post-transplant relapses (HR .462; 95% CI, .274-.777; p = .004). Differences in the timing of LMRR did not affect non-relapse mortality (HR 1.477; 95% CI .779-2.80; p = .23) or the incidence of grade II-IV acute GVHD (LMRR45(+): 25.0% vs. LMRR45(-) 35.2%. p = .111). In subgroup analyses, LMRR45(+) was found to be a favorable factor for survival with less relapse, regardless of the disease risk, stem cell source, or the recovery of either lymphocyte or monocyte counts. CONCLUSIONS: An early LMRR may be a novel factor that is associated with reduced relapse and improved survival after allo-HSCT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Monócitos , Estudos Retrospectivos , Linfócitos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Prognóstico , Doença Crônica , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Recidiva
7.
Ann Hematol ; 101(6): 1211-1216, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35403851

RESUMO

Aprepitant (Apr) is an effective antiemetic agent for chemotherapy-induced nausea and vomiting (CINV). Current CINV guidelines recommend the antiemetic combination of a 5-HT3 receptor antagonist, Apr, and dexamethasone (Dex) for highly emetogenic chemotherapies. Apr inhibits CYP3A4 dose-dependently. Since Dex is metabolized by CYP3A4, the combined use of Apr and Dex inhibits Dex metabolism. CINV guidelines therefore recommend dose-reduction of Dex when Apr and Dex are used together. However, there is some controversy over whether or not Dex should be reduced when administered as an antitumor agent for lymphoid malignancies. We retrospectively compared the antitumor effect of Dex-containing chemotherapy in which Dex is administered at the usual dose without Apr (group A) or administered at a half-dose in combination with Apr (group B). We analyzed 62 consecutive patients with refractory or relapsed CD20 + B cell lymphoma who received R-DHAP therapy in our hospital, including 29 and 33 cases in groups A and B, respectively. The response rate at the end of the first course of R-DHAP was 62.1% and 54.5%, respectively (P = 0.61). As another endpoint to evaluate the effect of Dex, group B tended to show greater suppression of the lymphocyte count (P = 0.05). Therefore, decreasing the dose of Dex by half appeared to be reasonable when combined with Apr.


Assuntos
Antieméticos , Antineoplásicos , Linfoma , Antieméticos/uso terapêutico , Antineoplásicos/uso terapêutico , Aprepitanto/efeitos adversos , Citocromo P-450 CYP3A , Dexametasona/efeitos adversos , Humanos , Linfoma/tratamento farmacológico , Náusea/induzido quimicamente , Náusea/prevenção & controle , Estudos Retrospectivos , Vômito/induzido quimicamente , Vômito/prevenção & controle
8.
Cancer Sci ; 112(7): 2845-2854, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33942442

RESUMO

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m2 , rituximab 375 mg/m2 (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography-computed tomography (PET-CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty-five patients (median age 71 [range 46-86] years) were enrolled. Twenty-three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow-up of 5.4 (0.7-11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1-52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression-free survival was 5.2 months (95% CI 3.6-not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3-4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1-2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI-184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/farmacocinética , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/farmacocinética , Japão , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Intervalo Livre de Progressão , Rituximab/administração & dosagem , Rituximab/farmacocinética
9.
Ann Hematol ; 100(2): 345-352, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33165625

RESUMO

Immune thrombocytopenia (ITP) can coexist with autoimmune thyroid disease. However, the detailed clinical features remain unknown. We retrospectively reviewed 248 patients with newly diagnosed ITP in our institute for whom we had thyroid function data at diagnosis between 2000 and 2019. Of the 248 patients with ITP, 74 patients also had thyroid disease, including 36 with overt thyroid disease (13 Graves' disease and 23 Hashimoto's thyroiditis) and 38 with subclinical thyroid disease (3 hyperthyroidism and 35 hypothyroidism). ITP and thyroid disease were concurrently diagnosed in 54 patients. Female sex and positivity for antinuclear antibodies (ANA) were significantly associated with thyroid diseases. Platelet-associated immunoglobulin G (PAIgG) levels in patients with Graves' disease were higher than those in patients with Hashimoto's thyroiditis. Platelet counts were similar among euthyroid patients and patients with thyroid disease. Thrombopoietin-receptor agonist was administered more frequently in patients with thyroid disease. The cumulative incidences of thrombosis and bleeding and overall survival did not differ between patients with and without thyroid disease. Treatment for thyroid disease in 22 patients improved thrombocytopenia in 21 patients, especially in 4 patients who were not treated for ITP. This study demonstrated that thyroid diseases were commonly found in patients with ITP. Treatment of the underlying thyroid disease may improve thrombocytopenia.


Assuntos
Púrpura Trombocitopênica Idiopática , Doenças da Glândula Tireoide , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Plaquetas/imunologia , Plaquetas/metabolismo , Plaquetas/patologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/imunologia , Receptores de Trombopoetina/agonistas , Receptores de Trombopoetina/sangue , Receptores de Trombopoetina/imunologia , Estudos Retrospectivos , Doenças da Glândula Tireoide/sangue , Doenças da Glândula Tireoide/tratamento farmacológico , Doenças da Glândula Tireoide/imunologia
10.
Ann Hematol ; 99(12): 2893-2901, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32572522

RESUMO

The amount of infused CD34+ cells has been reported to be the strongest predictor of platelet recovery after autologous stem cell transplantation (ASCT). However, the timing of platelet recovery varies widely among patients even after the infusion of similar amounts of CD34+ cells. Therefore, we retrospectively assessed 99 patients who underwent their first ASCT for lymphoma or myeloma at our center. Thirteen patients (13%) did not achieve platelet engraftment, defined as a platelet count of at least 2.0 × 104/µL without transfusion, at day 28 after transplantation, whereas 58 of 60 patients (97%) who received at least 2.0 × 106/kg CD34+ cells achieved platelet engraftment within 28 days. Multivariate analysis identified the following significant risk factors for delayed platelet recovery: hemoglobin level and platelet count before stem cell harvest, body temperature of > 39 °C within 5 days after ASCT, and infusion of a small amount (< 2.0 × 106/kg) of CD34+ cells. In a subgroup analysis of 39 patients infused with < 2.0 × 106/kg CD34+ cells, a need for repeated apheresis for stem cell harvest and a body temperature of > 39 °C within 5 days after ASCT were identified as independent factors for delayed platelet recovery. In summary, platelet recovery following ASCT was affected by insufficient hematopoietic recovery at stem cell harvest, a need for repeated apheresis, and high fever early after ASCT, particularly when the amount of infused stem cells was insufficient.


Assuntos
Plaquetas/fisiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma/sangue , Linfoma/terapia , Mieloma Múltiplo/sangue , Mieloma Múltiplo/terapia , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recuperação de Função Fisiológica/fisiologia , Estudos Retrospectivos , Transplante Autólogo/métodos , Transplante Autólogo/tendências , Adulto Jovem
11.
Ann Hematol ; 99(1): 49-55, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31853702

RESUMO

Immune thrombocytopenia (ITP) has been reported to be associated with thrombotic events. The incidence of thrombosis in 303 newly diagnosed ITP patients in our institute between 2000 and 2016 was retrospectively reviewed. During a median follow-up of 3.6 years, 16 thrombotic events (12 arterial and four venous) occurred. The median platelet count at thrombotic events was 102 × 109/l. At 10 years, the cumulative thrombosis incidence was 10%. A univariate analysis showed that smoking, hypertension, male gender, a history of thrombosis, and atrial fibrillation (Af) were significantly associated with the occurrence of thrombosis, and a multivariate analysis identified smoking and Af as independent risk factors. The thrombotic risk was not increased by lupus anticoagulant positivity or ITP treatment. At 5 years, the cumulative incidence of bleeding and overall survival probability was 5.6% and 92%, respectively. This study demonstrates that smoking and Af were associated with an increased risk of thrombosis. Previously identified risk factors were not confirmed in these Japanese ITP patients.


Assuntos
Púrpura Trombocitopênica Idiopática , Trombose , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Trombose/etiologia , Trombose/mortalidade
12.
Transpl Int ; 33(12): 1723-1731, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32939883

RESUMO

The speed of neutrophil recovery following allogeneic hematopoietic cell transplantation (allo-HCT) varies widely among patients. We retrospectively evaluated the slope of neutrophil recovery (N slope) in 120 patients who underwent a first unrelated bone marrow transplantation with granulocyte-colony-stimulating factor support between 2009 and 2018. The median N slope was 205.5/µl/day. We classified patients into low (n = 59) and high (n = 61) N slope groups with a cutoff value of 200/µl/day. The high N slope group correlated with older patients, RIC regimen, high CD34+ cells, and recent transplantation. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was significantly higher in the high N slope group than in the low N slope group (44.3% vs. 16.9%, P < 0.001). In multivariate analysis, high N slope was identified as a significant independent risk factor for grade II-IV aGVHD, irrespective of the involved organs. There were no differences in relapse, nonrelapse mortality, or overall survival between the two groups. In conclusion, the difference in N slope after allo-HCT may predict the risk of aGVHD. Prevention and treatment of GVHD according to the changes in the neutrophil count may improve post-transplant complications.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Neutrófilos , Estudos Retrospectivos , Fatores de Risco
13.
Acta Haematol ; 143(3): 250-259, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31461700

RESUMO

BACKGROUND: Danaparoid sodium and synthetic protease inhibitors (SPIs) have been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan. OBJECTIVES: To compare the clinical results of the treatment of DIC with danaparoid or SPIs. METHODS: We retrospectively examined 188 patients with hematological malignancy-related DIC. RESULTS: DIC resolution rate in the danaparoid group was higher than that in the SPIs group (61.5 vs. 42.6%; p = 0.031) on day 7. Multivariate analysis identified the response to chemotherapy as independent predictive factor for DIC resolution on day 7 (odds ratio, OR, 2.28; 95% confidence interval, CI, 1.21-4.31; p = 0.011). While there was no significant difference in the DIC resolution rate on day 14 (75.0 vs. 62.4%; p = 0.117), in a subgroup analysis of patients who did not show an improvement in the underlying disease, the danaparoid group showed a significantly better DIC resolution rate (OR 3.89; 95% CI 1.15-13.2; p = 0.030). There was no difference in the rate of cumulative mortality from bleeding within 28 days between the 2 groups (6.6 vs. 3.3%; p = 0.278). CONCLUSIONS: Danaparoid may be associated with more frequent resolution of DIC in patients with refractory underlying disease.


Assuntos
Sulfatos de Condroitina/uso terapêutico , Dermatan Sulfato/uso terapêutico , Neoplasias Hematológicas/sangue , Heparitina Sulfato/uso terapêutico , Inibidores de Proteases/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transfusão de Componentes Sanguíneos , Sulfatos de Condroitina/efeitos adversos , Dermatan Sulfato/efeitos adversos , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/terapia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Neoplasias Hematológicas/tratamento farmacológico , Hemorragia/etiologia , Hemorragia/mortalidade , Heparitina Sulfato/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Plasma , Inibidores de Proteases/efeitos adversos , Tempo de Protrombina , Estudos Retrospectivos , Resultado do Tratamento
14.
Ann Hematol ; 98(9): 2121-2129, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31240469

RESUMO

We retrospectively analyzed 70 patients with classical Hodgkin lymphoma (cHL) who were treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiotherapy to assess the influence of the soluble interleukin-2 receptor (sIL-2R) level at diagnosis on the clinical outcome. Receiver operating characteristic analyses determined that the optimal cutoff value of the sIL-2R level for progression-free survival (PFS) was 2490 U/mL. Using this cutoff value, patients were classified into low (n = 46) and high (n = 24) sIL-2R groups. The patients in the high sIL-2R group exhibited a significantly inferior PFS (44.1% vs. 90.4% at 5 years, P < 0.001) and overall survival (OS) (67.6% vs. 94.7% at 5 years, P = 0.001) compared with those in the low sIL-2R group. Multivariate analysis showed that a high sIL-2R level was an independent prognostic factor for PFS after adjusting for stage, white blood cell, hemoglobin, and B symptoms, and also OS after adjusting for age and stage (hazard ratio (HR) 6.49, P < 0.001 and HR 5.98, P = 0.009, respectively). In patients with advanced-stage cHL, a high sIL-2R level predicted 5-year PFS even after adjustment for international prognostic score > 4 (HR 6.00, P = 0.007). These results demonstrate that the sIL-2R level can be a useful prognostic factor in patients with cHL treated with ABVD with or without radiotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimiorradioterapia , Doença de Hodgkin , Proteínas de Neoplasias/sangue , Receptores de Interleucina-2/sangue , Adolescente , Adulto , Idoso , Bleomicina/administração & dosagem , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Doença de Hodgkin/sangue , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Vimblastina/administração & dosagem
15.
Ann Hematol ; 98(5): 1127-1133, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30474718

RESUMO

It is controversial whether blast percentage based on all nucleated cells (ANC) or non-erythroid cells (NEC) more accurately reflects the prognosis of patients with myelodysplastic syndromes (MDS). We considered that the impact of blast percentage on survival should be similar in MDS with erythroid hyperplasia (MDS-E) and MDS with no erythroid hyperplasia (MDS-NE), and from this perspective, we retrospectively analyzed 322 patients, including 44 with MDS-E and 278 with MDS-NE. Overall survival was similar between the MDS-E and MDS-NE groups (P = 0.94). In a subgroup of patients with bone marrow (BM) blasts of < 5%, no difference in survival was found between MDS-E and MDS-NE by either calculation method. However, in patients with a blast percentage between 5 and 10%, a significant difference in survival was observed only when the blast percentage in MDS-E was calculated from ANC (P < 0.001 by ANC and P = 0.66 by NEC). A similar result was observed when we analyzed the remaining patients with higher blasts together with those with blasts between 5 and 10%. These results suggest that the calculation of the BM blast percentage based on NEC in MDS-E provides a blast percentage value with a clinical impact consistent with that in MDS-NE.


Assuntos
Crise Blástica , Células da Medula Óssea , Leucócitos Mononucleares , Síndromes Mielodisplásicas , Adulto , Idoso , Idoso de 80 Anos ou mais , Crise Blástica/classificação , Crise Blástica/metabolismo , Crise Blástica/mortalidade , Crise Blástica/patologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Intervalo Livre de Doença , Feminino , Humanos , Hiperplasia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Estudos Retrospectivos , Taxa de Sobrevida
16.
Acta Haematol ; 141(3): 158-163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799408

RESUMO

TAFRO syndrome, a rare systemic inflammatory disease, can lead to multiorgan failure without appropriate treatment. Although thrombocytopenia is frequently seen in patients with TAFRO syndrome, little is known about its pathogenesis. Moreover, while recent studies have reported the presence of an anterior mediastinal mass in some patients, the pathological status of this remains unclear. Here, we report a case of fatal bleeding in a patient with TAFRO syndrome accompanied by an anterior mediastinal mass. A 55-year-old female was transferred to our hospital with a 2-week history of fever, epistaxis, and dyspnea. Laboratory tests revealed severe thrombocytopenia, computed tomography (CT) showed pleural effusions, and bone marrow biopsy revealed reticulin myelofibrosis. We suspected TAFRO syndrome, but the CT scan showed an anterior mediastinal mass that required a biopsy to exclude malignancy. She soon developed severe hemorrhagic diathesis and died of intracranial hemorrhage despite intensive treatment. She had multiple autoantibodies against platelets, which caused platelet destruction. An autopsy of the mediastinal mass revealed fibrous thymus tissues with infiltration by plasma cells. Our case suggests that thrombocytopenia could be attributed to antibody-mediated destruction and could be lethal. Hence, immediate treatment is imperative in cases of severe thrombocytopenia, even when accompanied by an anterior mediastinal mass.


Assuntos
Autoanticorpos , Hiperplasia do Linfonodo Gigante , Doenças do Mediastino , Púrpura Trombocitopênica Idiopática , Tomografia Computadorizada por Raios X , Autopsia , Hiperplasia do Linfonodo Gigante/sangue , Hiperplasia do Linfonodo Gigante/diagnóstico por imagem , Hiperplasia do Linfonodo Gigante/patologia , Hiperplasia do Linfonodo Gigante/terapia , Evolução Fatal , Feminino , Humanos , Hemorragias Intracranianas/sangue , Hemorragias Intracranianas/diagnóstico por imagem , Hemorragias Intracranianas/patologia , Hemorragias Intracranianas/terapia , Doenças do Mediastino/sangue , Doenças do Mediastino/diagnóstico por imagem , Doenças do Mediastino/patologia , Doenças do Mediastino/terapia , Pessoa de Meia-Idade , Derrame Pleural/sangue , Derrame Pleural/diagnóstico , Derrame Pleural/patologia , Derrame Pleural/terapia , Mielofibrose Primária/sangue , Mielofibrose Primária/diagnóstico por imagem , Mielofibrose Primária/patologia , Mielofibrose Primária/terapia , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/diagnóstico por imagem , Púrpura Trombocitopênica Idiopática/patologia , Púrpura Trombocitopênica Idiopática/terapia
17.
Biol Blood Marrow Transplant ; 24(8): 1563-1574, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29678638

RESUMO

Xenogeneic graft-versus-host disease (GVHD) models in highly immunodeficient mice are currently being used worldwide to investigate human immune responses against foreign antigens in vivo. However, the individual roles of CD4+ and CD8+ T cells, and donor/host hematopoietic and nonhematopoietic antigen-presenting cells (APCs) in the induction and development of GVHD have not been fully investigated. In the present study, we comprehensively investigated the immune responses of human T cells and the antigen presentation capacity of donor/host hematopoietic and nonhematopoietic APCs in xenogeneic GVHD models using nonobese diabetic/Shi-scid-IL2rgnull mice. CD4+ T cells and, to a lesser extent, CD8+ T cells individually mediated potentially lethal GVHD. In addition to inflammatory cytokine production, CD4+ T cells also supported the activation and proliferation of CD8+ T cells. Using bone marrow chimeras, we demonstrated that host hematopoietic, but not nonhematopoietic, APCs play a critical role in the development of CD4+ T cell-mediated GVHD. During early GVHD, we detected 2 distinct populations in memory CD4+ T cells. One population was highly activated and proliferated in major histocompatibility complex antigen (MHC)+/+ mice but not in MHC-/- mice, indicating alloreactive T cells. The other population showed a less activated and slowly proliferative status regardless of host MHC expression, and was associated with higher susceptibility to apoptosis, indicating nonalloreactive T cells in homeostasis-driven proliferation. These observations are clinically relevant to donor T cell response after allogeneic hematopoietic stem cell transplantation. Our findings provide a better understanding of the immunobiology of humanized mice and support the development of novel options for the prevention and treatment for GVHD.


Assuntos
Apresentação de Antígeno , Células Apresentadoras de Antígenos , Doença Enxerto-Hospedeiro/imunologia , Xenoenxertos/imunologia , Linfócitos T/citologia , Animais , Proliferação de Células , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Cinética , Ativação Linfocitária , Camundongos SCID , Linfócitos T/imunologia , Transplante Homólogo/efeitos adversos
18.
J Infect Chemother ; 24(10): 812-814, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30006248

RESUMO

The 1,3-beta-D-Glucan (BDG) assay is widely used for the diagnosis of fungal infections, especially in patients with hematologic malignancies. Some antimicrobials have been reported to cause false-positive results for BDG, but there has been no report on the effect of penicillin G (PCG) on BDG levels. We experienced a patient who developed false-positive BDG elevation during the administration of PCG for osteomyelitis due to Streptococcus pneumoniae infection. The serum BDG level increased up to 81.0 pg/ml during the continuous administration of PCG at 24 million units per day. However, chest and paranasal CT scan showed no evidence of fungal infection. The BDG level decreased to 38.0 pg/ml at 14 hours after the discontinuation of PCG. The amount of BDG in one vial of PCG inferred from these serum BDG levels is very similar to the actual BDG concentration in a vial of PCG. Therefore, during the administration of PCG, elevated BDG levels should be interpreted with caution, as they may be false-positive results.


Assuntos
Antibacterianos/administração & dosagem , Osteomielite/tratamento farmacológico , Penicilina G/administração & dosagem , Infecções Pneumocócicas/tratamento farmacológico , Streptococcus pneumoniae/efeitos dos fármacos , beta-Glucanas/sangue , Antibacterianos/farmacologia , Reações Falso-Positivas , Humanos , Masculino , Pessoa de Meia-Idade , Osteomielite/sangue , Osteomielite/etiologia , Penicilina G/farmacologia , Infecções Pneumocócicas/sangue , Infecções Pneumocócicas/complicações
19.
Rinsho Ketsueki ; 59(8): 1058-1065, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30185706

RESUMO

A chimeric antigen receptor (CAR) comprises an extracellular ligand recognition domain linked to CD3ζ and induces T-cell activation upon antigen binding. Recently, the potential of CD19-targeted CAR T-cells (CAR-T) to treat multiple myeloma has been explored. A group in the University of Pennsylvania reported that 4 out of 10 patients with refractory myeloma achieved an objective response (sCR: 1, VGPR: 1, and PR: 2). Although the resultant cancer ablation was an arresting sight, it remains unclear whether CD19 is a suitable target for myeloma. Therefore, CAR-T therapy employing alternative target antigens is being attempted. Some current clinical trials are utilizing CAR against differentiation antigens, including CD138, CD38, and kappa light chain. B-cell maturation antigen (BCMA) is also a potential candidate. A group in the NCI described 12 patients with refractory myeloma enrolled in a BCMA-CAR phase 1 clinical trial. Two patients receiving the highest dosage attained an objective response. Nevertheless, considerable research is required for CAR immunotherapy to become universally available to patients with myeloma. The current enthusiasm for the development of this cutting-edge technology is justified because extraordinary evidence indicates that it is effective, although this may not apply to every case. CAR-T therapy for myeloma is currently undergoing rapid, wide-scale growth both in academia and in industry-sponsored clinical development.


Assuntos
Imunoterapia Adotiva , Mieloma Múltiplo/terapia , Antígenos CD , Antígeno de Maturação de Linfócitos B , Humanos , Receptores de Antígenos de Linfócitos T , Linfócitos T
20.
Hematol Oncol ; 35(3): 357-364, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26639319

RESUMO

The early clearance of blast cells in peripheral blood (PB) during induction chemotherapy can predict the clinical outcome in acute leukemia. We retrospectively analyzed the kinetics of white blood cell (WBC) count, blast cell percentage (BCP), and blast cell count (BCC) in PB in 78 patients with de novo acute myeloid leukemia who underwent a uniform induction chemotherapy between December 2001 and December 2015 at Jichi Medical University. By a repeated-measures analysis of variance, the interaction of the decline in BCP with the achievement of complete remission (CR) was stronger than those of the decline in WBC or BCC. A receiver operating characteristic curve analysis for the achievement of CR showed that the areas under the curve for the decline in WBC, BCP, and BCC were 0.592, 0.703, and 0.634, respectively, and a decline in BCP of 9.25%/day within 4 or 5 days from induction chemotherapy was the optimal cutoff value. A multivariate analysis showed that a rapid decline in BCP (≥9.25%/day) was a significant predictive factor for CR, independent of the cytogenetic risk (p = 0.0096). A rapid decline in BCP during the first 5 days of induction chemotherapy may be a good predictor of CR. Copyright © 2015 John Wiley & Sons, Ltd.


Assuntos
Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Células Mieloides/patologia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Terapia Combinada , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Curva ROC , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
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