RESUMO
This study aimed to investigate the usefulness of allogeneic stem cell transplantation (allo-SCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in the first complete remission (CR1) with complete molecular remission (CMR). We compared the outcomes between Ph+ALL patients who did or did not undergo allo-SCT in CR1. We included patients enrolled in the prospective clinical studies in the tyrosine kinase inhibitor era conducted by the Japan Adult Leukemia Study Group, who achieved CMR within 3 months. A total of 147 patients (allo-SCT: 101; non-SCT: 46) were eligible for this analysis. In the multivariate analyses, allo-SCT was significantly associated with both superior overall survival (OS) (adjusted hazard ratio (aHR): 0.54; 95% CI: 0.30-0.97; p = .04) and relapse-free survival (RFS) (aHR: 0.21; 95% CI: 0.12-0.38; p < .001). The 5-year adjusted OS and RFS were 73% and 70% in the allo-SCT cohort, whereas they were 50% and 20% in the non-SCT cohort. Despite the higher non-relapse mortality (aHR: 3.49; 95% CI: 1.17-10.4; p = .03), allo-SCT was significantly associated with a lower relapse rate (aHR: 0.10; 95% CI: 0.05-0.20; p < .001). In addition, allo-SCT was also associated with superior graft-versus-host disease-free, relapse-free survival (aHR: 0.43; 95% CI: 0.25-0.74; p = .002). Propensity score-matched analyses confirmed the results of the multivariate analyses. In patients who achieved CMR within 3 months, allo-SCT in CR1 had superior survival and lower relapse compared with the non-SCT cohort.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Estudos Prospectivos , Transplante Homólogo , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Resposta Patológica Completa , Estudos RetrospectivosRESUMO
OBJECTIVE: Minimal residual disease assessment of BCR-ABL messenger ribonucleic acid levels is crucial in Philadelphia chromosome-positive acute lymphoblastic leukemia for prognosis and treatment planning. However, accurately quantifying minor BCR-ABL transcripts, which comprise 70% of Philadelphia chromosome-positive acute lymphoblastic leukemia cases, lacks a national-approved method. METHODS: We developed the "Otsuka" minor BCR-ABLmessenger ribonucleic acid assay kit with exceptional precision (0.00151%). Minor BCR-ABL messenger ribonucleic acid levels were analyzed in 175 adults, 36 children with acute lymphoblastic leukemia and 25 healthy individuals to evaluate the kit's performance. RESULTS: The "Otsuka" kit showed high concordance with a commonly used chimeric gene screening method, indicating reliable detection of positive cases. Quantitative results demonstrated a robust correlation with both a laboratory-developed test and a diagnostic research product. The "Otsuka" kit performs comparably or even surpass to conventional products, providing valuable insights into Philadelphia chromosome-positive acute lymphoblastic leukemia pathology. CONCLUSIONS: The 'Otsuka" minor BCR-ABL messenger ribonucleic acid assay kit exhibits excellent performance in quantifying minor BCR-ABL transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia patients. Our results align well with established screening methods and show a strong correlation with laboratory-developed tests and diagnostic research products. The "Otsuka" kit holds great promise as a valuable tool for understanding Philadelphia chromosome-positive acute lymphoblastic leukemia pathology and guiding effective treatment strategies.
Assuntos
Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Criança , Humanos , Proteínas de Fusão bcr-abl/análise , Proteínas de Fusão bcr-abl/genética , Reação em Cadeia da Polimerase em Tempo Real , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , RNARESUMO
BACKGROUND & AIMS: HBV reactivation is a risk in patients receiving anti-CD20 antibodies for the treatment of lymphoma. The purpose of this post hoc analysis was to evaluate the efficacy of an ultra-high sensitivity HBsAg assay to guide preemptive antiviral treatment in patients with lymphoma and resolved HBV infections using prospectively stored samples from an HBV DNA monitoring study. METHODS: HBV reactivation (defined as HBV DNA levels of ≥11 IU/ml) was confirmed in 22 of 252 patients. A conventional HBsAg assay (ARCHITECT, cut-off value: 0.05 IU/ml) and an ultra-high sensitivity HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA, cut-off value: 0.0005 IU/ml) were performed at baseline, at confirmed HBV reactivation and monitored after HBV reactivation. RESULTS: Baseline HBsAg was detected using ICT-CLEIA in 4 patients; in all of whom precore mutants with high replication capacity were reactivated. Of the 6 patients with HBV DNA detected below the level of quantification at baseline, 5 showed HBV reactivation and 3 of the 5 had precore mutations. Sensitivity for detection by ARCHITECT and ICT-CLEIA HBsAg assays at HBV reactivation or the next sampling after HBV reactivation was 18.2% (4 of 22) and 77.3% (17 of 22), respectively. Of the 5 patients undetectable by ICT-CLEIA, HBV reactivation resolved spontaneously in 2 patients. All 6 patients reactivated with precore mutations including preS deletion could be diagnosed by ICT-CLEIA HBsAg assay at an early stage of HBV reactivation. Multivariate analysis showed that an anti-HBs titer of less than 10 mIU/ml, HBV DNA detected but below the level of quantification, and HBsAg detected by ICT-CLEIA at baseline were independent risk factors for HBV reactivation (adjusted hazard ratios, 15.4, 31.2 and 8.7, respectively; p <0.05). CONCLUSIONS: A novel ICT-CLEIA HBsAg assay is an alternative method to diagnose HBV reactivation. CLINICAL TRIAL NUMBER: UMIN000001299. LAY SUMMARY: Hepatitis B virus can be reactivated in lymphoma patients receiving anti-CD20 antibodies such as rituximab. Currently, reactivation requires the monitoring of HBV DNA, but monitoring of the surface antigen (HBsAg) could provide a relatively inexpensive, quick and easy alternative. We assessed the performance of an ultra-high sensitivity HBsAg assay and showed that it could be effective for the diagnosis and monitoring of HBV reactivation.
Assuntos
Monitoramento de Medicamentos/métodos , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B , Hepatite B Crônica , Linfoma , Reinfecção , Rituximab , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Comorbidade , DNA Viral/isolamento & purificação , Feminino , Antígenos de Superfície da Hepatite B/análise , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/isolamento & purificação , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/sangue , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Humanos , Japão/epidemiologia , Linfoma/tratamento farmacológico , Linfoma/epidemiologia , Linfoma/virologia , Masculino , Reinfecção/etiologia , Reinfecção/prevenção & controle , Reinfecção/virologia , Reprodutibilidade dos Testes , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Testes Sorológicos/métodosRESUMO
BACKGROUND: Despite recent progress in blood systems, transfusion errors can occur at any time from the moment of collection through to the transfusion of blood and blood products. This study investigated the actual statuses of blood transfusion errors at institutions of all sizes in Aichi prefecture. MATERIALS AND METHODS: We investigated 104 institutions that perform 98 % of the blood transfusions in Aichi prefecture, and investigated the errors (incidents/accidents) that occurred at these facilities over 6 months (April to September, 2017). Incident/accident data were collected from responses to questionnaires sent to each institution; these were classified according to the categories and risk levels. RESULTS: Ninety-seven of the 104 institutions (93.3 %) responded to the questionnaire; a total of 688 incidents/accidents were reported. Most (682 cases; 99.2 %), were classified as risk level 2; however, 6 were level 3 and over, which included problems with autologous transfusion and inventory control. Approximately one-half of the incidents/accidents (394 cases; 57.3 %), were related to verification and the actual administration of blood products at the bedside; more than half of these incidents/accidents occurred at large-volume institutions. Meanwhile, a high frequency of incidents/accidents related to transfusion examination and labeling of blood products was observed at small- or medium-sized institutions. The reasons for most of these errors were simple mistakes and carelessness by the medical staff. CONCLUSIONS: Our results emphasize the importance of education, operational training, and compliance instruction for all members of the medical staff despite advances in electronic devices meant to streamline transfusion procedures.
Assuntos
Transfusão de Sangue/métodos , Erros Médicos/estatística & dados numéricos , Reação Transfusional/complicações , Humanos , Japão , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
A 56-year-old woman was referred to our hospital with symptoms of swelling, purpura, and pain in her limbs. Prior to referral, bleeding in her limbs had spontaneously appeared and disappeared several times. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged, and the factor II level was 17%. The plasma-mixing test indicated lupus anticoagulant (LA), which was confirmed using aPTT-LA and dilute Russell's viper venom time (dRVVT). Therefore, she was diagnosed with lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS). During screening for underlying disorders, chest computed tomography (CT) revealed a retrosternal mass. Biopsy was not performed because the administration of freshly frozen plasma failed to correct her coagulopathy. Prednisolone (PSL) treatment (1 mg/kg) was initiated, which normalized the coagulation tests. The retrosternal mass also disappeared. PSL was tapered without LAHPS recurrence; however, the follow-up CT revealed systemic lymphadenopathy. Follicular lymphoma was diagnosed using lymph-node biopsy. Considering the subsequent LAHPS recurrence, six cycles of bendamustine + rituximab were administered. Complete response with no LAHPS recurrence was observed at the time of drafting this report. LAHPS is rare and distinct from antiphospholipid syndrome because it can cause severe bleeding. Underlying disorders should be evaluated in cases of LAHPS.
Assuntos
Síndrome Antifosfolipídica , Hipoprotrombinemias , Linfoma Folicular , Feminino , Humanos , Inibidor de Coagulação do Lúpus , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Tempo de Tromboplastina Parcial , Tempo de ProtrombinaRESUMO
The Japan Adult Leukemia Study Group (JALSG) Ph+ALL202 study reported a high complete remission (CR) rate for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients treated with imatinib-combined chemotherapy. However, the long-term treatment efficacy remains uncertain. Here, we report a final analysis of the JALSG Ph+ALL202 study. The outcomes were compared with those of the JALSG ALL93 and ALL97 studies, which were conducted in the pre-imatinib era. Ninety-nine newly diagnosed Ph+ALL patients were enrolled in Ph+ALL202 (median age, 45 years; median follow-up, 4.5 years). CR was achieved in 96/99 (97%) patients. Fifty-nine of these 96 patients (61%) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in their first CR (CR1). The 5-year overall and disease-free survival (DFS) rates were 50 and 43%, respectively, which were significantly higher compared to those in the pre-imatinib era (15 and 19%, respectively). Multivariate analysis revealed that imatinib administration, allo-HSCT in CR1, and a white blood cell count < 30 × 109/L were favorable independent prognostic factors for long-term DFS. Improved odds of receiving allo-HSCT and a lower relapse rate leaded to good long-term outcomes. The 3-year DFS tended to be higher in PCR-negative than that in PCR-positive patients (29 vs. 14%) in the non-HSCT patients, and this tendency was also seen in the allo-HSCT patients (59 vs. 50%). The higher rate of CR upon imatinib use may have contributed to these improvements.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Adolescente , Adulto , Estudos de Coortes , Terapia Combinada , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Japão/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inibidores de Proteínas Quinases/efeitos adversos , Indução de Remissão , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
This is the first study in which the carfilzomib, lenalidomide and dexamethasone (KRd) regimen was evaluated in heavily pretreated multiple myeloma. This study is a multicenter, open-label phase 1 study of KRd in Japanese patients with relapsed or refractory multiple myeloma (RRMM) patients. The objectives were to evaluate the safety, tolerability, efficacy and pharmacokinetics of the regimen. Carfilzomib was administrated intravenously over 10 min on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. In cycle 1, the dosage for days 1 and 2 was 20 mg/m2 , followed by 27 mg/m2 . Lenalidomide and dexamethasone were administered at 25 mg (days 1-21) and 40 mg (days 1, 8, 15 and 22), respectively. Twenty-six patients were enrolled. Patients had received a median of four prior regimens and 88.5% and 61.5% received previous bortezomib and lenalidomide, respectively. High-risk cytogenetics were seen in 53.8% of patients. The overall response rate was 88.5%. A higher rate of hyperglycemia was observed than in a previous carfilzomib monotherapy study, but this was attributed to dexamethasone. Carfilzomib pharmacokinetics were not affected by lenalidomide and dexamethasone. The KRd regimen was well tolerated and showed efficacy in Japanese RRMM patients.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Japão , Lenalidomida , Masculino , Pessoa de Meia-Idade , Talidomida/uso terapêuticoRESUMO
This study investigated the efficacy of imatinib based therapy with intensified consolidation therapy in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) to prevent early relapse. We conducted a phase II trial of imatinib-combined chemotherapy for newly diagnosed BCR-ABL-positive ALL in adults. Sixty-eight patients were included in the trial between October 2008 and December 2010. The median age was 49 years, with 28 patients >55 years of age. Sixty-five patients achieved CR (95.6%). The estimated 2-year event-free survival (EFS) and overall survival (OS) were 62.3% and 67.4%, respectively. Allogeneic stem cell transplantation (allo-SCT) at initial CR was performed in 43 patients. Thirty-five of 39 patients <55 years and 8 of 26 patients >55 years underwent allo-SCT at first CR. The 3-year OS in patients <55 years receiving allo-SCT at first CR, patients >55 years receiving allo-SCT at first CR, patients <55 years not receiving allo-SCT at first CR, and patients >55 years not receiving allo-SCT at first CR were 80.4%, 41.1%, 32.5%, and 52.0%, respectively (P = 0.058). The three-year EFS in each group was 76.7%, 53.6%, not reached, and 26.4%, respectively (P = 0.150). A high CR rate was observed with imatinib-based chemotherapy allowing allo-SCT in a high proportion of patients, particularly those <55 years. Moreover, intensified consolidation therapy reduced early relapse rates following induction therapy and resulted in improved OS and EFS rates following allo-SCT. This trial was registered with the UMIN (000001226).
Assuntos
Mesilato de Imatinib/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Quimioterapia de Consolidação/métodos , Feminino , Proteínas de Fusão bcr-abl , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão/métodos , Análise de Sobrevida , Taxa de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Objective: Autologous stem cell transplantation is an important strategy for patients with relapsed or refractory lymphoma. Although various regimens for peripheral blood stem cell collection have been used, the optimal regimen has not yet been established. We aimed to evaluate the mobilization efficacy and safety of the regimen consisted of etoposide and cytarabine (EC regimen). Methods: We retrospectively analyzed the clinical data of 46 lymphoma patients who received peripheral blood stem cell mobilization with the EC regimen [etoposide (100 mg/m2/day, days 1-4) and cytarabine (100 mg/m2/day, days 1-4)] at Toyohashi municipal hospital from 2004 to 2013. Results: The median age of the patients was 55 years. The most common underlying diseases were diffuse large B-cell lymphoma (46%) and follicular lymphoma (26%). Three-quarters of patients were in their second complete or partial remission. The median total number of collected CD34+ cells was 10.6 × 106 kg-1. Forty-two patients (91%) yielded at least 2 × 106 kg-1 CD34+ cells within a median of 2 apheresis days, and 33 patients (72%) achieved it with only one apheresis. Successful mobilization was observed in five of six patients who failed to mobilize previously. Although febrile neutropenia occurred in 22 patients (48%), no fatal infection was observed. Conclusion: The EC regimen was highly effective in lymphoma patients, including patients who mobilized poorly with other regimens.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Etoposídeo/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/métodos , Adolescente , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacologia , Citarabina/administração & dosagem , Citarabina/farmacologia , Etoposídeo/administração & dosagem , Etoposídeo/farmacologia , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The phase I/II study of melphalan-prednisolone-bortezomib (MPB) therapy in Japanese patients with previously untreated multiple myeloma (MM) who are ineligible for hematopoietic stem cell transplantation (JPN-102 trial) (registered between July 2008 and March 2011) showed an overall response rate in the MPB arm equivalent to that of the VISTA trial. In this study, we followed up the clinical data of 92 of the 101 patients registered in the JPN-102 trial to clarify the long-term outcomes of MPB therapy. The median follow-up period was 50.8 (0.9-66.1) months. The median age of this cohort was 72 (48-84) years. The median progression-free survival was 25.7 (95%CI: 21.3-33.9) months and the overall survival rates at 1, 3 and 5 years were 98, 86 and 76%, respectively. There was no significant difference in either progression-free survival or overall survival when comparing a total bortezomib amount of 39 mg/m2 or more being administered versus less than 39 mg/m2. The outcomes of the JPN-102 cohort appeared, at a minimum, to not be inferior to those of the MPB cohort in the VISTA trial. A prospective trial is needed to establish the MPB regimen as being suitable for Japanese patients with multiple myeloma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Bortezomib , Feminino , Seguimentos , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs). METHODS: We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of ≥ 11 IU/mL. RESULTS: With a median HBV DNA follow-up of 562 days, HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5-12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of <10 mIU/mL and detectable HBV DNA remaining below the level of quantification at baseline were independent risk factors for HBV reactivation (hazard ratio, 20.6 and 56.2, respectively; P < .001). Even in 6 patients with a rapid increase of HBV due to mutations, the monthly HBV DNA monitoring was effective at preventing HBV-related hepatitis. CONCLUSIONS: Monthly monitoring of HBV DNA is useful for preventing HBV reactivation-related hepatitis among B-NHL patients with resolved HBV infection following R-steroid-chemo (UMIN000001299).
Assuntos
DNA Viral/sangue , Vírus da Hepatite B/genética , Hepatite B/tratamento farmacológico , Hepatite B/virologia , Linfoma de Células B/complicações , Idoso , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Feminino , Hepatite B/complicações , Hepatite B/epidemiologia , Humanos , Linfoma de Células B/epidemiologia , Linfoma de Células B/virologia , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Peripheral blood stem cell apheresis from a healthy donor is indispensable for allogeneic peripheral blood stem cell transplantation. Here, we report a rare adverse event following peripheral blood stem cell apheresis. A female sibling donor, aged 61 years with an unremarkable medical history, complained of pain in the left neck and shoulder and numbness in the left upper limb 1 h after the end of peripheral blood stem cell apheresis. Paralysis of the left upper and lower limbs appeared consecutively. Computed tomography and magnetic resonance imaging of the head showed no abnormalities. Anticoagulant therapy was initiated according to the standard treatment of atherothrombotic brain infarction. Magnetic resonance imaging of the cervical cord on the following day revealed a cervical epidural hematoma. An emergency C4-C5 laminectomy was performed, and the paralysis was improved immediately after surgery. This report is the first case of cervical epidural hematoma in a healthy donor who underwent peripheral blood stem cell apheresis and presented symptoms confusingly similar to those of brain infarction.
Assuntos
Remoção de Componentes Sanguíneos/efeitos adversos , Hematoma Epidural Espinal/complicações , Hematoma Epidural Espinal/diagnóstico , Doadores Vivos , Células-Tronco , Vértebras Cervicais , Diagnóstico Diferencial , Feminino , Hematoma Epidural Espinal/etiologia , Humanos , Laminectomia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Cervicalgia/etiologia , Dor de Ombro/etiologia , Acidente Vascular Cerebral/diagnóstico , Tomografia Computadorizada por Raios XAssuntos
Colite , Colonoscopia , Dasatinibe/efeitos adversos , Hemorragia Gastrointestinal , Leucemia Mielogênica Crônica BCR-ABL Positiva , Sangue Oculto , Adulto , Colite/induzido quimicamente , Colite/diagnóstico por imagem , Colite/patologia , Dasatinibe/administração & dosagem , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/diagnóstico por imagem , Hemorragia Gastrointestinal/patologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , MasculinoRESUMO
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
Background: Patients with hematological malignancies (HMs) are reported to receive more aggressive care at the end of life (EOL) than patients with solid tumors. However, the reasons behind this occurrence are not fully understood. Objectives: To examine whether the care at EOL for HMs is mainly because of the disease characteristics or hematologists' attitudes and systems of care, we compared the EOL care of patients with acute myeloid leukemia (AML) and diffuse large B cell lymphoma (DLBCL). Design: We retrospectively analyzed the EOL care of patients with AML and DLBCL younger than 80 years who were receiving combination chemotherapy at a city hospital in Japan. Results: Fifty-nine patients with AML and 65 with DLBCL were included. Those with AML received chemotherapy more often within their last 30 days (48% vs. 19%, p < 0.001) and 14 days (37% vs. 1.5%, p < 0.001) of life, and consulted the palliative team less frequently (5.3% vs. 29%, p < 0.001). In the last 3 years, the mortality rate in hematological wards decreased from 74% to 29% in the DLBCL group, but only from 95% to 90% in the AML group. In multivariate analysis, AML (odds ratio [OR] 0.065) and death before 2018 (OR, 0.077) were significant factors associated with reduced referrals to specialized palliative teams. Conclusion: Patients with AML tend to have lesser access to specialized palliative care and fewer options for their place of death than those with DLBCL. Detailed EOL care plans are needed for these patients, considering the characteristics of the disease.
RESUMO
Autologous hematopoietic stem cell transplantation (SCT) is not a standard treatment option for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL); however, its position has been reassessed since the introduction of tyrosine kinase inhibitors (TKIs). We prospectively analyzed the efficacy and safety of autologous peripheral blood SCT (auto-PBSCT) for Ph+ALL patients aged between 55 and 70 years who had achieved complete molecular remission. Melphalan, cyclophosphamide, etoposide, and dexamethasone were used for conditioning. A total of 12 courses of maintenance therapy, including dasatinib, were performed. The required number of CD34+ cells was harvested in all five patients. No patient died within 100 days after auto-PBSCT, and no unexpected serious adverse events were observed. Although 1-year event-free survival was 100%, hematological relapse was observed in three patients at a median of 801 days (range, 389-1088 days) after auto-PBSCT. Molecular progressive disease was observed in the other two patients, although they maintained their first hematological remission at the last visit. Auto-PBSCT can be safely performed for Ph+ALL with TKIs. A limitation of auto-PBSCT was suggested, despite the increase in the intensity of a single treatment. The development of long-term therapeutic strategies by including new molecular targeted drugs is warranted to maintain long-term molecular remission.
RESUMO
Primary gastric diffuse large B cell lymphoma (PG-DLBCL) is common subtype of extranodal non-Hodgkin lymphoma. The optimal treatment strategy for PG-DLBCL in the rituximab era still remains unknown. To evaluate clinical outcomes of PG-DLBCL in the rituximab era, we conducted a retrospective, multicenter analysis of 95 patients with PG-DLBCL. In 58 patients with localized disease, 3-year progression-free survival (PFS) and overall survival (OS) were 91% and 91% for patients with six cycles of rituximab plus CHOP (R-CHOP) and 92% and 95% for patients with three to four cycles of R-CHOP plus radiotherapy (Log-rank test, P = 0.595 and P = 0.278, respectively). In 37 patients with advanced disease, 3-year PFS and 3-year OS were 43% and 64% for patients with R-CHOP chemotherapy with or without radiotherapy. On multivariate analysis, advanced stage and elevated serum LDH levels were independent predictors of survival in patients with PG-DLBCL. One patient with localized disease relapsed in lymph node, and eight patients with advanced disease relapsed in lymph node (n = 3), stomach (n = 2), central nervous system (CNS; n = 2), and duodenum (n = 1). Intriguingly, CNS relapse developed within 6 months after initial series of treatment (4.9 and 5.8 months, respectively), and stomach relapse developed in later phase (27.2 and 32.9 months, respectively). Clinical outcomes of PG-DLBCL were extremely favorable for localized-stage patients in the rituximab era, although these might be poor for advanced-stage patients even in the rituximab era. Further prospective analyses are warranted.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Japão , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Rituximab , Neoplasias Gástricas/patologia , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
In cohort C of the phase 2 MM-014 trial, the efficacy and safety of pomalidomide, dexamethasone, and daratumumab therapy were investigated in 18 Japanese patients with relapsed/refractory multiple myeloma (RRMM) after their most recent regimen of lenalidomide-based therapy (NCT01946477). Patients received oral pomalidomide (4 mg daily), oral dexamethasone (20-40 mg weekly), and intravenously infused daratumumab (16 mg/kg). Median age was 67.5 years. All patients received prior lenalidomide per protocol; 89% received prior bortezomib. Twelve patients (67%) had lenalidomide-refractory disease, and 6 (33%) had lenalidomide-relapsed disease. Ten patients (56%) had only 1 prior treatment line. As of August 3, 2020, 15 patients (83%) were still on treatment; median follow-up was 8.1 months. Three patients (17%) discontinued treatment (2 for adverse events; 1 for major protocol deviation). Overall response rate (primary endpoint) was 83% (very good partial response or better, 61%). All patients had ≥ 1 grade 3/4 treatment-emergent adverse events, most commonly neutropenia (78%; febrile, 6%), leukopenia (28%), and lymphopenia (22%). Grade 3/4 infections occurred in 17%; 11% had pneumonia. In Japanese patients with RRMM, a triplet regimen of pomalidomide, dexamethasone, and daratumumab after early-line lenalidomide treatment failure showed high efficacy and safety consistent with the known safety profile.
Assuntos
Mieloma Múltiplo , Idoso , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona , Humanos , Japão , Lenalidomida , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/etiologia , Recidiva Local de Neoplasia/tratamento farmacológico , Talidomida/análogos & derivados , Resultado do TratamentoRESUMO
Objective Few reports have described the real-world outcomes of rituximab, methotrexate (MTX), procarbazine, and vincristine (R-MPV) plus response-adapted whole-brain radiotherapy (WBRT) for elderly patients with primary central nervous system lymphoma (PCNSL). We evaluated the outcome of this regimen. Methods We evaluated >60-year-old patients with newly diagnosed PCNSL who received R-MPV plus WBRT from January 2010 to December 2019 at Toyohashi Municipal Hospital. The patients' characteristics, regimen enforcement, response rate, survival, and toxicity were analyzed. Patients Ten patients were consecutively enrolled. Their median age was 69 years old, and 60% had a performance status of 3 or 4 before induction therapy. Results Seven patients achieved a complete response after induction, and all 10 patients achieved a complete response after consolidation. Seven received reduced-dose WBRT at 23.4 Gy, and 2 received WBRT at 45 Gy. The median follow-up was 44.4 months; the 3-year progression-free survival and overall survival rates were 60% and 80%, respectively; and the cumulative incidence of relapse was 40%. The incidence of symptomatic delayed neurotoxicity was 70%. Of the 7 patients who received reduced-dose WBRT, 4 (57%) developed delayed neurotoxicity, including 1 severely affected patient. Only one patient survived without relapse and delayed neurotoxicity. The ratio of patients who developed relapse or delayed neurotoxicity that impaired daily life was 33% and 100% in the MTX high- and low-intensity groups, respectively. Conclusion This regimen in elderly patients is unsatisfactory because of delayed neurotoxicity. We should consider maintaining an adequate MTX intensity, postponing or minimizing WBRT, and choosing high-dose consolidation therapy for select patients.
Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Encéfalo/patologia , Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/radioterapia , Terapia Combinada , Humanos , Linfoma/tratamento farmacológico , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The standard treatment for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, â¼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.