RESUMO
OBJECTIVE: This phase II clinical trial evaluated feasibility and tolerability of 90-minute rituximab infusion and a concentration of 4 mg/mL rituximab infusion in Japanese patients with previously untreated follicular lymphoma or diffuse large B-cell lymphoma. METHODS: Treatment was rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone. In cycle 1, rituximab at a dose of 375 mg/m2 (4 mg/mL) was administered at the standard infusion rate stipulated in the package insert. On confirmed tolerance of rituximab, patients received 90-minute infusion in second and subsequent cycles. The primary endpoint was incidence of grade 3 or higher infusion-related reactions during 90-minute rituximab infusion in cycle 2 of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone. RESULTS: All 32 patients (median age 61.5 years, 16 males, 24 with diffuse large B-cell lymphoma) completed the prescribed six or eight cycles of treatment. One patient withdrew consent after cycle 1, and another developed grade 2 erythema and continued receiving 4 mg/mL at the standard infusion rate for cycle 2. The remaining 30 patients received 90-minute rituximab infusion; 28 (93.3%) completed cycle 2 at the scheduled infusion rate and dosage. No grade 3 or higher infusion-related reactions were associated with a concentration of 4 mg/mL rituximab dose or 90-min rituximab infusion in cycle 2. The most common infusion-related reaction symptoms were pruritus, hypertension and oropharyngeal discomfort. During the study, toxicities and adverse events were as expected, with no new safety signals. CONCLUSION: High-concentration dosing (4 mg/mL) and 90-minute infusion of rituximab are feasible and tolerable in Japanese patients with previously untreated follicular lymphoma or diffuse large B-cell lymphoma. CLINICAL TRIAL NUMBER: JapicCTI-173 663.
Assuntos
Linfoma Folicular , Linfoma Difuso de Grandes Células B , Masculino , Humanos , Pessoa de Meia-Idade , Rituximab/uso terapêutico , Vincristina/efeitos adversos , Linfoma Folicular/tratamento farmacológico , Japão , Prednisona/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Doxorrubicina/uso terapêutico , Prednisolona/uso terapêuticoRESUMO
E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin-2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single-arm phase II study of E7777 in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T-cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression-free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment.
Assuntos
Interleucina-2/administração & dosagem , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Administração Intravenosa , Sítios de Ligação , Toxina Diftérica/administração & dosagem , Toxina Diftérica/efeitos adversos , Toxina Diftérica/química , Toxina Diftérica/genética , Toxina Diftérica/farmacocinética , Esquema de Medicação , Feminino , Humanos , Interleucina-2/efeitos adversos , Interleucina-2/química , Interleucina-2/genética , Interleucina-2/farmacocinética , Japão , Linfoma Cutâneo de Células T/sangue , Linfoma de Células T Periférico/sangue , Masculino , Recidiva Local de Neoplasia/sangue , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Análise de Sobrevida , Resultado do TratamentoRESUMO
We conducted a nationwide retrospective analysis of 116 hepatitis B virus (HBV) surface antigen (HBsAg)-positive patients with diffuse large B-cell lymphoma (DLBCL) and 278 HBsAg-negative patients with DLBCL, as a control cohort, who received rituximab-containing regimens as an induction chemotherapy at 30 Japanese medical centers between January 2004 and December 2014. Hepatitis was defined as an absolute serum alanine aminotransferase (ALT) level of ≥100 U/L. HBV reactivation-related hepatitis was defined as hepatitis with an absolute serum HBV DNA level of ≥3.3 log IU/mL or an absolute increase of ≥2 log compared with the baseline value. HBsAg-positive patients were divided into three groups based on anti-HBV prophylactic therapy: no nucleos(t)ide analogue (non-NA, n = 9), lamivudine (LAM, n = 20), and entecavir (ETV, n = 87). The 4-year cumulative incidence (CI) of hepatitis in HBsAg-positive and HBsAg-negative patients was 21.1% and 14.6% (P = .081), respectively. The 4-year CI of HBV reactivation-related hepatitis was higher in HBsAg-positive patients than in HBsAg-negative patients (8.0% vs 0.4%; P < .001). Among HBsAg-positive patients, the 4-year CI of HBV reactivation-related hepatitis was the highest in the non-NA group (33.3%), followed by the LAM (15.0%) and ETV (3.8%) groups (P < .001). Of note, 3 non-NA patients (33%) and 1 LAM patient (5%) (but no ETV patients) died due to HBV hepatitis. Based on Cox multivariate analysis, HBsAg positivity was not associated with poor overall survival. Prophylactic use of ETV would reduce the occurrence of HBV reactivation-related hepatitis and mortality in HBsAg-positive DLBCL patients receiving rituximab-containing chemotherapy.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antivirais/uso terapêutico , Antígenos de Superfície da Hepatite B/sangue , Hepatite B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Ciclofosfamida/administração & dosagem , DNA Viral/sangue , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Hepatite B/sangue , Hepatite B/epidemiologia , Vírus da Hepatite B/genética , Humanos , Incidência , Quimioterapia de Indução/métodos , Japão/epidemiologia , Testes de Função Hepática , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Estudos Retrospectivos , Rituximab/administração & dosagem , Análise de Sobrevida , Vincristina/administração & dosagem , Ativação ViralRESUMO
CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.).
Assuntos
Linfoma Difuso de Grandes Células B , Metotrexato , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Etoposídeo/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Metotrexato/uso terapêutico , Recidiva Local de Neoplasia , Prednisona/efeitos adversos , Rituximab/uso terapêutico , Vincristina/efeitos adversosRESUMO
To investigate the factors that affect molecular responses on dasatinib treatment in patients with chronic-phase chronic myeloid leukemia (CML-CP), we performed a clinical trial named the "D-First study." Fifty-two patients with newly diagnosed CML-CP were enrolled in this study and received 100 mg dasatinib once daily. A deep molecular response (DMR) was defined as <50 copies/µg RNA of BCR-ABL1 transcript value corrected by GAPDH, which ensures <0.01% of BCR-ABL1 transcript value according to International Scale (BCR-ABL1(IS)). The halving time for BCR-ABL1 transcripts was calculated using transcript levels before dasatinib treatment, transcript levels after 3 months of treatment, and the treatment time between these two points. In terms of molecular response, 38 of 51 (75%) patients reached major molecular response (MMR) by 12 months, and the rate of DMR by 18 months was 59% (30/51). While both BCR-ABL1 transcript levels before treatment and a shorter halving time of BCR-ABL1 transcripts (≤14 days) were significant factors affecting achievement of MMR by 12 months, the Sokal score at diagnosis was not associated with MMR. Importantly, the halving time was the only factor that predicted achievement of DMR by 18 months. We showed that patients with CML-CP treated with dasatinib can be stratified according to the early treatment response as determined by the halving time of BCR-ABL1 transcripts. These data emphasize the significance of the early response from dasatinib treatment in achieving a DMR. (ClinicalTrials.gov; NCT01464411).
Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Terapia de Alvo Molecular , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Transcrição Gênica , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Dasatinibe , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/biossíntese , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Curva ROC , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Fatores de Tempo , Adulto JovemRESUMO
Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mg day(-1) ) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/µL for NK cells and 347/µL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Antígenos CD/genética , Antígenos CD/imunologia , Dasatinibe , Proteínas de Fusão bcr-abl/imunologia , Expressão Gênica , Humanos , Imunofenotipagem , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Leucemia Mieloide de Fase Crônica/genética , Leucemia Mieloide de Fase Crônica/imunologia , Leucemia Mieloide de Fase Crônica/patologia , Contagem de Linfócitos , Linfocitose/induzido quimicamente , Linfocitose/genética , Linfocitose/imunologia , Linfocitose/patologia , Estudos Prospectivos , Curva ROC , Indução de Remissão , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologiaRESUMO
Testicular lymphoma is a rare disease, accounting for 1-2% of non-Hodgkin lymphoma and 5-9% of all testicular tumors, and has a high relapse rate with a poor prognosis. We report a patient with testicular diffuse large B-cell lymphoma (DLBCL) who relapsed after being in remission for 16 years. He had undergone orchiectomy of the right testis and was diagnosed as having DLBCL (stage IAE) at 49 years of age. After 3 cycles of CHOP, he achieved a complete remission. Orchiectomy was performed because of a left testicular tumor, and he was again diagnosed with DLBCL at the age of 65. VH3-21 was detected in lymphoma cells at the times of both the first diagnosis and the relapse based on analysis of the variable region of the immunoglobulin heavy chain. Accordingly, the lymphoma cells at relapse were confirmed to be the same clone as that which had been documented at the first diagnosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/terapia , Neoplasias Testiculares/tratamento farmacológico , Idoso , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Masculino , Recidiva , Indução de Remissão , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/patologia , Fatores de TempoRESUMO
The prognosis of patients with primary mediastinal large B-cell lymphoma has improved over recent years. However, the optimal treatment strategy including the role of radiotherapy remains unknown. We retrospectively analyzed the clinical outcomes of 345 patients with newly diagnosed primary mediastinal large B-cell lymphoma in Japan. With a median follow up of 48 months, the overall survival at four years for patients treated with R-CHOP (n=187), CHOP (n=44), DA-EPOCH-R (n=9), 2(nd)- or 3(rd)-generation regimens, and chemotherapy followed by autologous stem cell transplantation were 90%, 67%, 100%, 91% and 92%, respectively. Focusing on patients treated with R-CHOP, a higher International Prognostic Index score and the presence of pleural or pericardial effusion were identified as adverse prognostic factors for overall survival in patients treated with R-CHOP without consolidative radiotherapy (IPI: hazard ratio 4.23, 95% confidence interval 1.48-12.13, P=0.007; effusion: hazard ratio 4.93, 95% confidence interval 1.37-17.69, P=0.015). Combined with the International Prognostic Index score and the presence of pleural or pericardial effusion for the stratification of patients treated with R-CHOP without radiotherapy, patients with lower International Prognostic Index score and the absence of effusion comprised approximately one-half of these patients and could be identified as curable patients (95% overall survival at 4 years). The DA-EPOCH-R regimen might overcome the effect of these adverse prognostic factors. Our simple indicators of International Prognostic Index score and the presence of pleural or pericardial effusion could stratify patients with primary mediastinal large B-cell lymphoma and help guide selection of treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/terapia , Neoplasias do Mediastino/terapia , Derrame Pericárdico/diagnóstico , Derrame Pleural/diagnóstico , Transplante de Células-Tronco , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Japão , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Neoplasias do Mediastino/complicações , Neoplasias do Mediastino/mortalidade , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Derrame Pericárdico/etiologia , Derrame Pleural/etiologia , Prednisona/administração & dosagem , Prognóstico , Estudos Retrospectivos , Rituximab , Taxa de Sobrevida , Transplante Autólogo , Vincristina/administração & dosagem , Adulto JovemRESUMO
Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase. Although ABL1-specific tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML, the TKI efficacy depends on the individual patient. In this work, we found that the patients with different nilotinib responses can be classified by using the estimated parameters of our simple dynamical model with two common laboratory findings. Furthermore, our proposed method identified patients who failed to achieve a treatment goal with high fidelity according to the data collected only at three initial time points during nilotinib therapy. Since our model relies on the general properties of TKI response, our framework would be applicable to CML patients who receive frontline nilotinib or other TKIs.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêuticoRESUMO
Information regarding rituximab monotherapy with eight weekly infusions for relapsed or refractory indolent B cell non-Hodgkin lymphoma (B-NHL), in particular for patients pretreated with rituximab, is limited. To evaluate the efficacy and safety of eight doses of rituximab monotherapy, 52 patients with relapsed or refractory indolent B-NHL were enrolled in the present study. Forty of 45 eligible patients (89%) had follicular lymphoma and 24 (53%) were at intermediate or high risk group according to the Follicular Lymphoma International Prognostic Index. The median number of prior chemotherapy regimens was 1 (range 1-7). At the median follow-up of 12.2 months, the overall response rate (ORR), complete response rate (%CR), and median progression-free survival (PFS) were 69% (95% confidence interval [CI] 53%-82%), 47% (95% CI 32%-62%), and 15.6 months (95% CI 10.6- months), respectively. In the 33 patients pretreated with rituximab, the ORR, %CR, and median PFS were inferior compared with values for the 12 patients who had not received rituximab previously (64%vs 83% for ORR; 39%vs 67% for %CR; and 13.8 vs 17.5 months for median PFS, respectively). All mild-to-moderate infusion-related toxicities were reversible. Grade 3/4 non-hematologic adverse events occurred in six of the 52 patients. Two patients developed Grade 4 late-onset neutropenia and a decrease (>50%) in serum immunoglobulin was observed in six patients. In conclusion, rituximab monotherapy with eight weekly infusions is effective in relapsed patients with indolent B-NHL, with acceptable toxicities, including in patients pretreated with rituximab; however, careful monitoring is recommended for infections associated with late-onset neutropenia and hypogammaglobulinemia. (University Hospital Medical Information Network no. UMIN000002974.)
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Murinos/efeitos adversos , Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva , Retratamento , RituximabRESUMO
Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) is one of the most frequently applied initial treatments for indolent B-cell non-Hodgkin lymphoma (B-NHL); however, information on its long-term outcome is limited. Untreated patients in the concurrent arm (Arm C) received six R (375 mg/m(2) ) treatments, 2 days prior to each cycle of CHOP, and patients in the sequential arm (Arm S) received 6 weekly R (375 mg/m(2) ) treatments following six cycles of CHOP. Sixty-nine patients were randomized but two patients were withdrawn before receiving the protocol treatment. Sixty-five patients (94%) had follicular lymphoma, and 37 (55%) were at low risk, 23 (34%) at intermediate risk and seven (10%) at high risk according to the Follicular Lymphoma International Prognostic Index. We previously reported that the overall response rate (ORR) in Arm C and in Arm S was 94% and 97%, respectively. The median progression-free survival (PFS)/7-year PFS rate in Arm C, Arm S and all 67 assessable patients was 2.4 years/23% (95% confidence interval [CI], 9-40%), 3.8 years/41% (95% CI, 23-57%) and 2.8 years/32% (95% CI, 20-45%), respectively. There was no significant difference between the two arms (P = 0.107). The overall survival (OS) of the 67 patients was 95% at 7 years. In conclusion, R-CHOP is a highly effective initial treatment for untreated indolent B-NHL in terms of ORR and OS; however, its long-term PFS is not good enough either in concurrent or sequential combination, warranting further investigations on post-remission therapy.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Rituximab , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêuticoRESUMO
AIMS AND BACKGROUND: To further clarify the clinicopathological, molecular genetic and karyotypic findings of reactive lymph node hyperplasia with giant follicles (RLHGF) associated with a posttherapeutic state of hematological malignancies, we studied eight such cases. METHODS: Using formalin-fixed, paraffin-embedded sections, histological, immunohistochemical, in situ hybridization (ISH), and polymerase chain reaction (PCR) were performed. RESULTS: Six patients had a history of malignant lymphoma (diffuse large B-cell lymphoma [DLBCL] = 4, marginal zone B-cell lymphoma = 2), and two had acute myeloid leukemia (AML). Six patients initially presented with lymphadenopathy of the head and neck area and the remaining one presented with swelling of the tonsil. All seven cases demonstrating analyzable metaphases showed a normal karyotype. Histologically, all eight lesions were characterized by numerous enlarged, bizarre-shaped coalescing lymphoid follicles with follicular lysis. Immunohistochemical and flow cytometry study demonstrated the reactive nature of the B cells in all eight lesions. However, three of our eight cases demonstrated immunoglobulin heavy-chain (IgH) gene rearrangement on PCR study. Different clonal bands were detected in the initial lymphomatous tissue and RLHGF in one of the studied cases. There was no development of B-cell lymphoma or recurrence of B-cell lymphoma in any of the three lesions demonstrating IgH rearrangement. There were no human herpes virus type-8+ or human immunodeficiency virus type-1+ cells in any of the eight lesions. ISH demonstrated Epstein-Barr virus (EBV)-encoded small RNA (EBER)+ cells in only two lesions. PCR analyses demonstrated that there was no Toxoplasma gondii DNA in any of the eight lesions. CONCLUSIONS: As suggested in RLHGF posttransplant, RLHGF arising after therapy for hematological malignancies is also a consequence of chronic stimulation in the setting of immune deregulation rather than various infectious agents. It is important for pathologists and clinicians to be aware of this type of lesion in diagnostic practice.
Assuntos
Linfócitos B/imunologia , Hiperplasia do Linfonodo Gigante/etiologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Pseudolinfoma/etiologia , Adolescente , Adulto , Idoso , Hiperplasia do Linfonodo Gigante/genética , Hiperplasia do Linfonodo Gigante/imunologia , Hiperplasia do Linfonodo Gigante/patologia , Feminino , Citometria de Fluxo , Neoplasias Hematológicas/imunologia , Humanos , Cadeias Pesadas de Imunoglobulinas/análise , Imuno-Histoquímica , Hibridização In Situ , Cariotipagem , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/terapia , Linfoma de Zona Marginal Tipo Células B/complicações , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Pseudolinfoma/genética , Pseudolinfoma/imunologia , Pseudolinfoma/patologiaRESUMO
Treatment outcomes for chronic myeloid leukemia (CML) have dramatically improved with the development of tyrosine kinase inhibitors (TKI). However, due to the improved prognosis for CML, problems have arisen from long-term administration of TKI. The present study sought to verify whether more patients could achieve treatment-free remission (TFR) after stopping the administration of dasatinib using dasatinib as frontline treatment. Treatment-naïve chronic phase CML cases were treated with dasatinib as frontline treatment. Dasatinib treatment was stopped for 26 patients who achieved deep molecular response (DMR) within 24 months and were able to maintain DMR for an additional 2 years. Ten patients (38.5%) achieved DMR maintenance after 12 months. Recurrence was confirmed in 16 patients, and the median recurrence-free survival time was 5.1 months. The cumulative DMR rates at six and 12 months after restarting treatment were 84.6% and 100%, respectively. The results of this study demonstrated that the DMR maintenance rate after 12 months was 38.5%, which was not significantly different from previous TKI stop trials. The 2-year dasatinib administration period after reaching DMR did not contribute to improve TFR rates. These results suggest that the type of TKI is not associated with better TFR rates.
Assuntos
Dasatinibe/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Indução de Remissão , Dasatinibe/administração & dosagem , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases , Taxa de Sobrevida , Fatores de TempoRESUMO
For patients who have chronic myeloid leukemia (CML), one of the primary treatment options is administration of nilotinib 300 mg twice daily (BID). In previous studies which compared outcomes associated with nilotinib or imatinib treatment, nilotinib achieved a higher rate of deep molecular response (MR). We conducted a phase II, open-label, multicenter study to investigate an intrapatient nilotinib dose-escalation strategy for patients with newly diagnosed chronic-phase (CP) CML based on early MR4.5 achievement. The primary study endpoint was achievement of MR4.5 by 24 months following the initiation of nilotinib 300 mg BID. Fifty-three patients were enrolled, 51 received nilotinib, and 37 completed the treatment. An increase in the nilotinib dose (to 400 mg BID) was allowed when patients satisfied our criteria for no optimal response at any time point. The median (range) dose intensity was 600 (207-736) mg/day. Of 46 evaluable patients, 18 achieved an optimal response and 28 did not. Of the latter, nine patients underwent dose escalation to 400 mg BID, and none achieved MR4.5 . The remaining 19 patients could not undergo dose escalation, 12 (63%) because of adverse events (AEs), and 7 (37%) for non-AE related reasons. Four of these patients achieved MR4.5 . The MR4.5 rate by 24 months was 45.7%. The progression-free, overall and event-free survival were each 97.6%. No new safety concerns were observed. Our findings support the use of continuous nilotinib at a dose of 300 mg BID for newly diagnosed patients with CML-CP.
Assuntos
Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Pirimidinas/normas , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Leucemia Mieloide de Fase Crônica/patologia , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
To investigate the relationship between the degree of liver dysfunction and the pharmacokinetics of docetaxel, a population pharmacokinetic model was developed in an oncology practice without excluding patients with moderate to severe liver dysfunction. Two hundred patients were treated with docetaxel as a single agent or in combination chemotherapy. The plasma concentration-time course data were analyzed using a three-compartment open model with zero-order administration and first-order elimination on the NONMEM program. Sixty-one had elevated transaminase levels, and alkaline phosphatase was elevated in 40. Body surface area, albumin, alpha1-acid glycoprotein, and liver function were found to be significant covariates for the systemic clearance of docetaxel. Compared to patients with normal or minimal impairment of liver function, patients with grade 2 and 3 elevations of transaminases at baseline in conjunction with elevation of alkaline phosphatase had 22 and 38% lower clearances, respectively. Goodness-of-fit plots indicated that the model was fitted well with the observed data, and the bootstrap method guaranteed robustness of the model. We developed a population pharmacokinetic model for docetaxel, which can be used in the setting of an oncology practice. Based on the model, dose reduction by approximately 20 and 40% should be considered for patients with grade 2 and 3 elevations of transaminases at baseline in conjunction with elevation of alkaline phosphatase, respectively.
Assuntos
Antineoplásicos/farmacocinética , Hepatopatias/metabolismo , Neoplasias/tratamento farmacológico , Taxoides/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Docetaxel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismoRESUMO
BACKGROUND/AIM: Although neurokinin-1 receptor antagonists are approved chemotherapy drugs in Japan, no nationwide surveys have been performed to validate chemotherapy-induced nausea and vomiting (CINV) guidelines in clinical practice. This study evaluated CINV in patients with haematological malignancies starting first-time chemotherapy. PATIENTS AND METHODS: A nationwide CINV survey on patients with haematological malignancies was conducted at 118 institutions. Patients undergoing moderately emetic chemotherapy (n=17) and highly emetic chemotherapy (HEC; n=180) were compared. RESULTS: Forty-one patients undergoing HEC received triple antiemetics. Female gender and young age were risk factors for early-phase nausea, while female gender remained a risk factor for late-phase nausea and vomiting. Among 125 patients receiving CHOP (doxorubicin, cyclophosphamide, vincristine, prednisone)-like regimens, complete response and complete control were increased in patients receiving triple antiemetics, compared to those with double antiemetics. CONCLUSION: Guideline compliance was very low. Although not statistically significant, there was a trend for reduced CINV and improved disease control for triple versus double antiemetics, suggesting that triple antiemetics should be considered for HEC, especially in young female patients with non-Hodgkin lymphoma receiving CHOP-like regimens.
Assuntos
Antieméticos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Hematológicas/complicações , Náusea/etiologia , Náusea/prevenção & controle , Vômito/etiologia , Vômito/prevenção & controle , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Pesquisas sobre Atenção à Saúde , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/epidemiologia , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Náusea/diagnóstico , Náusea/epidemiologia , Pré-Medicação , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do Tratamento , Vômito/diagnóstico , Vômito/epidemiologiaRESUMO
A randomized controlled trial was conducted to evaluate the efficacy of high-dose chemotherapy (HDC) as consolidation of the treatment of high-risk postoperative breast cancer. Patients under 56 years of age with stage I to IIIB breast cancer involving 10 or more axillary lymph nodes were eligible. The primary endpoint was relapse-free survival (RFS). Between May 1993 and March 1999, 97 patients were enrolled, and two patients became ineligible. The median age of the 97 patients was 46 years (range 27-55 years), and 72 (74%) were premenopausal. The median number of involved axillary nodes was 16 (range 10-49). All patients had undergone a radical mastectomy. Major characteristics were well balanced between the treatment arms. Forty-eight patients in the standard-dose (STD) arm received six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen. Forty-nine patients were assigned to undergo HDC with cyclophosphamide and thiotepa after six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen; however, 15 of these patients (31%) did not undergo HDC. HDC was well tolerated without any treatment-related mortality. At a median follow-up of 63 months, the 5-year RFS of 47 eligible patients in the STD arm and 48 eligible patients in the HDC arm was 37% and 52% on an intent-to-treat basis, respectively (P = 0.17). Five-year overall survival of all randomized patients was 62% for the STD arm and 63% for the HDC arm (P = 0.78). Although the prespecified values of the two arms were not so accurate as to allow detection of the observed difference, no advantage of HDC was observed in terms of RFS or overall survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tiotepa/administração & dosagemRESUMO
Regional lymph nodes of Küttner's tumor from 3 patients showed reactive follicular hyperplasia and prominent interfollicular plasmacytosis. The patients were 71-, 57-, and 73-year-old Japanese men. The polytypic nature of plasma cells was demonstrated by immunohistochemistry. There were numerous IgG-positive plasma cells with scattered IgA-positive or IgM-positive plasma cells. IgG4-positive cells comprised 25% to 40% of IgG-positive plasma cells. Prominent polyclonal hyperimmunoglobulinemia was demonstrated on laboratory test in 2 cases examined. An elevated serum IgG4 level (16%) was also demonstrated in 1 patient. The present 3 cases indicated that regional lymph node of Küttner's tumor may show reactive follicular hyperplasia and prominent interfollicular plasmacytosis and should be differentiated from various benign and malignant lymphoproliferative disorders including systemic rheumatic disease, plasma cell type of Castleman disease, and lymph node involvement of marginal B-cell lymphoma of the mucosa-associated lymphoid tissue type showing prominent plasma cell differentiation.
Assuntos
Hiperplasia do Linfonodo Gigante/patologia , Linfonodos/patologia , Plasmócitos/patologia , Sialadenite/patologia , Glândula Submandibular/patologia , Idoso , Biomarcadores/metabolismo , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/imunologia , Diagnóstico Diferencial , Humanos , Hipergamaglobulinemia/imunologia , Hipergamaglobulinemia/metabolismo , Hipergamaglobulinemia/patologia , Imunoglobulina G/metabolismo , Linfonodos/imunologia , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Plasmócitos/metabolismo , Doenças Reumáticas/diagnóstico , Esclerose , Sialadenite/imunologia , Sialadenite/metabolismo , Glândula Submandibular/imunologiaRESUMO
The aim of this randomized phase II study was to improve the treatment delays and discontinuations associated with bendamustine use by comparing the effect of Benda-14 (intravenous bendamustine, 120 mg/m2 on days 1 and 15, repeated every 4 weeks for a total of 6 cycles) with those of the standard treatment in relapsed indolent lymphoma and/or mantle cell lymphoma. Forty-six patients were randomly assigned to the treatments from September 2012 to February 2016. Treatment accomplishment rate and median relative dose intensity were similar in both arms: 38 and 63.4% in the Benda-14 arm and 41 and 66.3% in the standard treatment arm, respectively. The overall response rate and median progression-free survival, respectively, were 83% and 21.0 months for Benda-14, and 77% and 15.5 months for the standard treatment. Benda-14 induced favorable responses with less frequent hematological toxicities.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Cloridrato de Bendamustina/administração & dosagem , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Cloridrato de Bendamustina/efeitos adversos , Biomarcadores , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma de Célula do Manto/mortalidade , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Recidiva , Retratamento , Resultado do Tratamento , Adulto JovemRESUMO
The affiliation of the last author, Kenshi Suzuki has been incorrectly published in the original publication of the article. The correct affiliation is provided in this correction.