RESUMEN
BACKGROUND: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. RESULTS: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. CONCLUSION: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.
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Adenina/análogos & derivados , Compuestos Bicíclicos Heterocíclicos con Puentes , Linfoma de Células del Manto , Sulfonamidas , Adulto , Humanos , Anciano , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Japón , Piperidinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Age and comorbidities are important factors to be considered in the selection of tyrosine kinase inhibitors (TKIs) for first-line treatment in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, it is yet unclear whether TKI selection, particularly, imatinib versus second-generation TKIs (2GTKIs), impacts treatment outcomes in the clinical practice. To address this, we compared the clinical outcomes of prospectively registered 452 patients with CML-CP treated with imatinib and 2GTKIs, taking into consideration their age and/or comorbidities. A total of 136 patients (30.1%) were classified into an older cohort (≥65 years) and 316 (69.9%) into a younger cohort (18-64 years). The TKI selection did not vary based on age (70.6% received 2GTKIs in the younger cohort and 66.2% in the older cohort). The median follow-up period was 5.4 years. Treatment responses including the cumulative incidence of deep molecular response (BCR-ABL1 international scale ≤0.0032%) at any time were similar between the two age cohorts regardless of the type of TKI. The 5-year overall survival (OS) in the older cohort was lower than that in the younger cohort (95.9% vs 83.8%; p < 0.0001), whereas the 5-year OS in patients treated with 2GTKIs was not influenced by age factors and comorbidities. Therefore, our results suggest that the selection of 2GTKIs as first-line treatment is an effective option for both younger and older CML-CP patients with or without comorbidities. This trial was registered at UMIN-CTR as 00003581.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Anciano , Humanos , Proteínas de Fusión bcr-abl , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
DSP-7888 is an immunotherapeutic cancer vaccine derived from the Wilms' tumor gene 1 (WT1) protein. This phase 1/2 open-label study evaluated the safety and efficacy of DSP-7888 dosing emulsion in patients with myelodysplastic syndromes (MDS). DSP-7888 was administered intradermally (3.5 or 10.5 mg) every 2 weeks for 6 months and then every 2-4 weeks until lack of benefit. Twelve patients were treated in phase 1 (3.5 mg, n = 6; 10.5 mg, n = 6), with no dose-limiting toxicities reported. Thus, the 10.5 mg dose was selected as the recommended phase 2 dose, and 35 patients were treated in phase 2. Forty-seven patients received ≥1 dose of the study drug and comprised the safety analysis set. The most common adverse drug reaction (ADR) was injection site reactions (ISR; 91.5%). Grade 3 ISR were common (58.8%) in phase 1 but occurred less frequently in 2 (22.9%) following implementation of risk minimization strategies. Other common ADR were pyrexia (10.6%) and febrile neutropenia (8.5%). In the efficacy analysis set, comprising patients with higher-risk MDS after azacitidine failure in phases 1 and 2 (n = 42), the disease control rate was 19.0%, and the median overall survival (OS) was 8.6 (90% confidence interval [CI], 6.8-10.3) months. Median OS was 10.0 (90% CI, 7.6-11.4) months in patients with a WT1-specific immune response (IR; n = 33) versus 4.1 (90% CI, 2.3-8.1) months in those without a WT1-specific IR (n = 9; P = .0034). The acceptable safety and clinical activity findings observed support the continued development of DSP-7888 dosing emulsion.
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Vacunas contra el Cáncer , Síndromes Mielodisplásicos , Azacitidina/uso terapéutico , Vacunas contra el Cáncer/efectos adversos , Emulsiones/uso terapéutico , Humanos , Síndromes Mielodisplásicos/tratamiento farmacológico , Resultado del Tratamiento , Vacunas de Subunidad/efectos adversos , Proteínas WT1RESUMEN
Therapeutic improvements are needed for patients with acute myeloid leukemia (AML), particularly those who have relapsed or who have treatment-refractory (R/R) AML or newly diagnosed patients with poor prognostic factors. Alvocidib (DSP-2033), a potent cyclin-dependent kinase 9 inhibitor, has previously demonstrated promising clinical activity for the treatment of AML. In this multicenter, open-label, uncontrolled, 3 + 3 phase I study, we investigated the safety and tolerability of alvocidib administered in combination with either cytarabine and mitoxantrone (ACM) for R/R AML or cytarabine/daunorubicin (A + 7 + 3) for newly diagnosed AML. Alvocidib was administered to all patients as a 30-min intravenous (i.v.) bolus (30 mg/m2 /d), followed by a continuous i.v. infusion over 4 h on days 1-3 (60 mg/m2 /d). A total of 10 patients were enrolled: six received ACM (at two dose levels of cytarabine and mitoxantrone) and four received A + 7 + 3. Alvocidib was tolerated and no dose-limiting toxicities were observed. All patients experienced adverse events, of which diarrhea was the most frequent (100%); hematologic events were also common. Alvocidib concentration peaked at the end of dosing (4.5 h after start of administration), plasma accumulation after repeated dosing was minimal and urinary excretion was negligible. The rate of complete remission/complete remission with incomplete hematologic recovery was 66.7% with the ACM regimen in R/R AML, including four complete remission (median duration 13.6 months), and 75% (three complete remission) with the A + 7 + 3 regimen. Further development of alvocidib in hematologic malignancies is warranted. The trial is registered with Clinicaltrials.gov, NCT03563560.
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Citarabina , Leucemia Mieloide Aguda , Humanos , Citarabina/efectos adversos , Leucemia Mieloide Aguda/patología , Daunorrubicina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inducción de Remisión , JapónRESUMEN
The immunomodulatory drug (IMiD) thalidomide and its derivatives lenalidomide and pomalidomide are therapeutic agents used in the treatment of multiple myeloma. Although pomalidomide offers considerable clinical benefits to patients with lenalidomide-resistant multiple myeloma, the molecular mechanisms underlying its superior efficacy remain unclear. Here we show that ARID2, a component of the polybromo-associated BAF (PBAF) chromatin-remodeling complex, is a pomalidomide-induced neosubstrate of CRL4CRBN. BRD7, another subunit of PBAF, is critical for pomalidomide-induced ARID2 degradation. ARID2 is involved in transcriptional regulation of pomalidomide target genes including MYC. Pomalidomide is more effective than lenalidomide in degrading ARID2 and is capable of inhibiting MYC expression and proliferation in lenalidomide-resistant cell lines. Notably, ARID2 expression is associated with a poor prognosis and is higher in chemoresistant minimal residual disease (MRD) populations, and in patients with relapsed/refractory multiple myeloma. These findings suggest that ARID2 is a promising target for overcoming lenalidomide resistance in patients with multiple myeloma.
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Antineoplásicos/farmacología , Mieloma Múltiple/metabolismo , Talidomida/análogos & derivados , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Antineoplásicos/metabolismo , Línea Celular Tumoral , Proteínas Cromosómicas no Histona/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Lenalidomida/farmacología , Mieloma Múltiple/tratamiento farmacológico , Mutación , Unión Proteica , Proteolisis/efectos de los fármacos , ARN Mensajero , ARN Interferente Pequeño , Talidomida/metabolismo , Talidomida/farmacología , Factores de Tiempo , Factores de Transcripción/genética , UbiquitinaciónRESUMEN
Aim: To evaluate the safety and effectiveness of carfilzomib in a real-world setting. Methods: A post-marketing surveillance of Japanese patients with relapsed or refractory multiple myeloma who received carfilzomib treatment was performed. Results: Overall incidences of adverse events of any grade, ≥grade 3 treatment-related adverse events and serious adverse events were 63.5, 44.6 and 37.7% of patients, respectively. No new safety findings were observed. Treatment-related adverse events of special interest (≥5%) were hematological toxicities, infectious disease, cardiac disorders (including cardiac failure, myocardial infarction and QT prolongation), renal disorders, liver failure or liver dysfunction, and hypertension or hypertensive crisis. The overall response rate was 46.5%. Conclusion: Carfilzomib was found to be a safe and effective treatment for relapsed or refractory multiple myeloma in Japanese patients.
Carfilzomib is a medicine that was recently approved for the treatment of cancer of bone marrow (multiple myeloma) that comes back or does not respond to previous treatment (relapsed or refractory). Data gathered from the hospitals, where the medicine is commonly used, was used to generate evidence. We looked at how well carfilzomib works in Japanese participants and if it is safe. Overall, 63.5% of participants treated with carfilzomib had side effects and 37.7% had serious side effects. Death occurred in 3.1% of participants during the study. Decrease in bone marrow and blood cells, infections, heart and kidney disorder, liver failure or dysfunction, and high blood pressure occurred in 5% or more participants. In 46.5% of participants the tumors had disappeared or shrank. In Japanese participants, carfilzomib was found to be safe and effective treatment for cancer of bone marrow that comes back or does not respond to previous treatment.
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Mieloma Múltiple , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/uso terapéutico , Humanos , Japón/epidemiología , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/epidemiología , Oligopéptidos/efectos adversos , Vigilancia de Productos ComercializadosRESUMEN
A 76-year-old woman with leukocytosis and thrombocytopenia was admitted to our hospital. A bone marrow examination showed a composition of 82.0% blasts, i.e., positive for TdT, CD10, CD19, CD34, and HLA-DR and negative for cyCD3, CD13, CD33, MPO, and cyµ. The reverse transcription-polymerase chain reaction analysis revealed a minor BCR-ABL1 fusion gene, leading to a diagnosis of acute lymphocytic leukemia (ALL) with a BCR-ABL1 fusion gene. G-band assay was negative for Philadelphia (Ph) chromosome and also revealed add (21) (q22. 1) and del (20) (q11. 2q13.3). Fluorescence in situ hybridization (FISH) assaying revealed a positive BCR-ABL1 fusion signal. Thus, this patient was diagnosed as Ph chromosome-negative and BCR-ABL1-positive fusion gene ALL, which suggested the presence of ALL with the "masked" Ph chromosome found in approximately 1% of chronic myeloid leukemia. Therefore, the FISH analysis may complement cytogenetic analysis when cytogenetic and molecular genetic findings are contradictory in ALL.
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Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Hibridación Fluorescente in Situ , Citogenética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
A 62-year-old woman was presented at our hospital with visual disturbance. An ocular examination revealed bilateral Roth spots. Laboratory data revealed leukocytosis (236,200 µl) with an excess blast (11%). Physical examination and computed tomography (CT) showed systemic lymphadenopathy. A bone marrow examination revealed a composition of 9.2% blast. Chromosomal analysis on bone marrow cells revealed 46,XX,t (3;12)(q26.2;p13),t (9;22)(q34.1;q11.2) in 80% of metaphases (16/20). Inguinal lymph node biopsy revealed diffuse proliferation of myeloperoxidase (MPO)-positive abnormal cells. Fluorescence in situ hybridization analysis was used to detect the BCR-ABL1 fusion gene and split the signals of MECOM and ETV6. She was diagnosed with de-novo chronic myeloid leukemia (CML) extramedullary blast crisis. She received tyrosine kinase inhibitor (TKI) combination chemotherapy and allogeneic hematopoietic stem cell transplantation and achieved a major molecular response. In this study, we reported a case of CML in blast-phase initially presenting as extramedullary, in which cytogenetic and molecular analyses were useful in the staging method.
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Crisis Blástica , Leucemia Mielógena Crónica BCR-ABL Positiva , Femenino , Humanos , Persona de Mediana Edad , Crisis Blástica/genética , Crisis Blástica/patología , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Análisis Citogenético , Ganglios Linfáticos/patologíaRESUMEN
A previous dose-finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as a starting dose. In this Phase II/III, multicentre, open-label study, romiplostim was administered subcutaneously at a fixed dose of 10 µg/kg once weekly for 4 weeks (weeks 1-4) followed by weekly doses (5, 10, 15 and 20 µg/kg) titrated by platelet response for up to 52 weeks (weeks 5-52). A total of 31 patients with AA who were refractory to immunosuppressive therapy (IST) and thrombocytopenia (platelet count of ≤30 × 109 /l) were enrolled. The primary efficacy endpoint of the proportion of patients achieving any haematological (platelet, neutrophil and erythrocyte) response at week 27 was 84% [95% confidence interval (CI) 66-95%]. Trilineage response was 39% (95% CI 22-58%) at week 53. The most common treatment-related adverse events (AEs) were headache and muscle spasms (each 13%). All AEs were mild or moderate except for three patients with Grade 3 hepatic AEs; no AEs necessitated romiplostim discontinuation. Two patients developed cytogenetic abnormalities, of whom one returned to normal karyotype at last follow-up. High-dose romiplostim is effective and well tolerated in the treatment of patients with AA refractory to IST.
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Anemia Aplásica/tratamiento farmacológico , Anemia Refractaria/tratamiento farmacológico , Receptores Fc/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Trombopoyetina/uso terapéutico , Adulto , Anciano , Anemia Aplásica/sangre , Anemia Refractaria/sangre , Recuento de Células Sanguíneas , Femenino , Cefalea/inducido químicamente , Hematopoyesis/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Receptores Fc/administración & dosificación , Receptores Fc/sangre , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/sangre , Espasmo/inducido químicamente , Trombopoyetina/administración & dosificación , Trombopoyetina/efectos adversos , Trombopoyetina/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The International Myeloma Working Group response criteria require two consecutive assessments of paraprotein levels. We conducted an exploratory analysis to evaluate whether a single response assessment could be a substitute for the International Myeloma Working Group criteria using data from JCOG1105, a randomized phase II study on melphalan, prednisolone and bortezomib. METHODS: Of 91 patients with transplant-ineligible newly diagnosed multiple myeloma, 79 patients were included. We calculated the kappa coefficient to evaluate the degree of agreement between the International Myeloma Working Group criteria and the single response assessment. RESULTS: Based on the International Myeloma Working Group criteria, 11 (13.9%), 20 (25.3%), 36 (45.6%) and 12 (15.2%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. Based on the single response assessment, 17 (21.5%), 19 (24.1%), 35 (44.3%) and 8 (10.1%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. The kappa coefficient was 0.76 (95% confidence interval, 0.65-0.88), demonstrating good agreement. The single response assessment was not inferior to the International Myeloma Working Group criteria in the median progression-free survival (3.8 and 2.9 years) in stringent complete response/complete response patients, suggesting that the single response assessment was not an overestimation. CONCLUSIONS: The single response assessment could be a substitute for the current International Myeloma Working Group criteria for transplant-ineligible newly diagnosed multiple myeloma.
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Bortezomib/uso terapéutico , Melfalán/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Prednisolona/uso terapéutico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Femenino , Humanos , Masculino , Supervivencia sin ProgresiónRESUMEN
The current World Health Organization (WHO) classification defines a new disease entity of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, making fluorescence in situ hybridization (FISH) screening for these genes mandatory. In addition, the prognostic significance of MYC expression was reported, with a cut-off value of 40%. However, interobserver discrepancies arise due to the heterogeneous intensity of MYC expression by immunohistochemistry. Moreover, a cut-off value of positivity for MYC protein in diffuse large B-cell lymphoma (DLBCL) varies among studies at present. Here, we applied a high-sensitivity semiquantitative immunohistochemical technique using fluorescent nanoparticles called phosphor-integrated dots (PID) to evaluate the MYC expression in 50 de novo DLBCL cases, and compared it with the conventional diaminobenzidine (DAB)-developing system. The high MYC expression detected by the PID-mediated system predicted poor overall survival in DLBCL patients. However, we found no prognostic value of MYC protein expression for any cut-off value by the DAB-developing system, even if the intensity was considered. These results indicate that the precise evaluation of MYC protein expression can clarify the prognostic values in DLBCL, irrespective of MYC rearrangement.
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Linfoma de Células B Grandes Difuso/patología , Nanopartículas/química , Proteínas Proto-Oncogénicas c-myc/metabolismo , 3,3'-Diaminobencidina/química , Adulto , Anciano , Femenino , Reordenamiento Génico , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Sustancias Luminiscentes/química , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética , Adulto JovenRESUMEN
BACKGROUND: Multiple myeloma (MM) is an incurable hematological malignancy. Despite the introduction of several novel drugs, most patients relapse. Biomarkers to identify the early signs of relapse will make it possible to adjust the therapeutic strategy before the disease worsens. Although understanding genetic changes is important for the treatment of MM, currently known biomarkers of relapse, including serum free-light chains and monoclonal paraproteins, are not associated with genetic changes. METHODS: We therefore performed a multicenter study to examine the usefulness of circulating cell-free DNA (cfDNA) present in the peripheral blood (PB) plasma of patients as a biomarker for MM relapse. RESULTS: We identified several driver mutations by combined analysis of next-generation sequencing and existing databases of candidate oncogenes. Furthermore, relapse was detected more sensitively by monitoring the circulating cfDNA with these driver mutations than by conventional serum free-light chain examination. CONCLUSION: These results suggest the potential utility of cfDNA in the PB plasma of patients as a relevant early biomarker for MM relapse.
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Ácidos Nucleicos Libres de Células , Mieloma Múltiple , Biomarcadores , Ácidos Nucleicos Libres de Células/genética , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/genética , Mutación , Recurrencia Local de Neoplasia/genética , PlasmaRESUMEN
BACKGROUND: Until recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P < 0.001). METHODS: We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC. RESULTS: Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%). CONCLUSION: Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.
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Leucemia Mieloide Aguda , Pirazinas , Compuestos de Anilina , Humanos , Japón , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Comorbidities at diagnosis among patients with chronic myeloid leukemia in chronic phase (CML-CP) may affect their overall survival (OS) rate even in the tyrosine kinase inhibitor (TKI) era. However, the prognostic impact of comorbidities in patients with CML-CP treated with a second-generation TKI (2GTKI) has not been elucidated. We evaluated the effect of comorbidities on survival using the Charlson Comorbidity Index (CCI) in patients with CML-CP treated with imatinib or a 2GTKI (nilotinib and dasatinib). From April 2010 to March 2013, 506 patients with CML-CP were registered for the population-based cohort study, and 452 with a median age of 56 y were assessable. Treatment groups included 139 patients receiving imatinib, 169 receiving nilotinib, and 144 receiving dasatinib. Comorbidities were diagnosed in 99 patients. CCI scores were stratified as follows: 2, 353 patients; 3, 72 patients; and ≥4, 27 patients. Treatment response did not vary relative to CCI scores. However, across the entire cohort, the OS rate was significantly lower among patients with higher CCI scores than in those with a CCI score of 2 (94.4% in score 2, 89.0% in score 3, and 72.8% in score ≥4; P < .001). Multivariate analysis identified a CCI score of ≥4 as a strong adverse prognostic factor for OS rather than the disease-specific risk factor, older age, performance status, or selection of TKI (Wald test, P < .01). Our results demonstrated that comorbidities at diagnosis were the most important predictive factor for successful treatment, regardless of the TKI type used in CML-CP. This trial was registered at UMIN-CTR as 00003581.
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Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Comorbilidad , Dasatinib/uso terapéutico , Femenino , Humanos , Mesilato de Imatinib/uso terapéutico , Masculino , Persona de Mediana Edad , Pronóstico , Pirimidinas/uso terapéutico , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
The revised WHO classification newly defined the entities "High-grade B-cell lymphoma with MYC and BCL2, and/or BCL6 rearrangements (HGBL-DH/TH)" and "HGBL, NOS." Standard immunochemotherapy for diffuse large B-cell lymphoma (DLBCL), R-CHOP, is insufficient for HGBL patients, and there are currently no optimized therapeutic regimens for HGBL. We previously reported that CCND3, which encodes cyclin D3, harbored high mutation rates in Burkitt lymphoma (BL), HGBL and a subset of DLBCL. Furthermore, the knockdown of cyclin D3 expression was toxic to germinal center (GC)-derived B-cell lymphomas. Thus, the fundamental function of cyclin D3 is important for the pathogenesis of GC-derived B-cell lymphoma. We herein used two structurally different CDK4/6 inhibitors, palbociclib and abemaciclib, and examined their suppressive effects on cell proliferation and their ability to induce apoptosis in various aggressive B-cell lymphoma cell lines. The results obtained demonstrated that abemaciclib more strongly suppressed cell proliferation and induced apoptosis in GC-derived B-cell lymphoma cell lines than the control, but only slightly inhibited those features in activated B-cell (ABC)-like DLBCL cell lines. Palbociclib exerted partial or incomplete effects compared with the control and the effect was intermediate between abemaciclib and the control. Moreover, the effects of abemaciclib appeared to depend on cyclin D3 expression levels based on the results of the expression analysis of primary aggressive B-cell lymphoma samples. Therefore, abemaciclib has potential as a therapeutic agent for aggressive GC-derived B-cell lymphomas.
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Aminopiridinas/farmacología , Bencimidazoles/farmacología , Ciclina D3/genética , Linfoma de Células B/genética , Inhibidores de Proteínas Quinasas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Ensayos de Selección de Medicamentos Antitumorales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma de Células B/tratamiento farmacológico , Mutación , Piperazinas/farmacología , Piridinas/farmacologíaRESUMEN
Anaplastic large cell lymphoma (ALCL) with TP63 rearrangement is a new entity and has the most dismal prognosis in all types of ALCL. This might be due to the resulting fusion protein having N-terminal truncated p63 with high oncogenic ability. Since this N-terminal domain has the function of tumor suppressor activity, the mechanism for high oncogenic capacity is thought to be the dominant negative function. Here, we report two ALCL cases with TP63 rearrangement that was each given too short a prognosis (Case 1 and 2: four and six months) in spite of intensive treatment. Immunohistochemically, p63 was highly expressed, and a sprit signal was detected using a TP63 break apart fluorescence in situ hybridization (FISH) in each case. Additionally, a poor prognostic marker of ALCL, all cytotoxic molecules (TIA-1, Granzyme B, and Perforin) were also expressed in almost all ALCL cells. Taken together, we suggest that not only the dominant negative function of N-truncated p63 but also the effect of cytotoxic molecules may influence the dismal prognosis of ALCL with TP63 rearrangement.
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Enfermedad de Hodgkin/patología , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patología , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Anciano , Femenino , Granzimas , Enfermedad de Hodgkin/diagnóstico , Humanos , Hibridación Fluorescente in Situ/métodos , Linfoma Anaplásico de Células Grandes/diagnóstico , Masculino , Pronóstico , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Antígeno Intracelular 1 de las Células T/metabolismoRESUMEN
Methotrexate-associated lymphoproliferative disorders (MTX-LPD) is categorized into other iatrogenic immunodeficiency-associated lymphoproliferative disorders, developing LPD in patients with autoimmune diseases (AIDs) under low dose MTX administration. Two-thirds of MTX-LPDs regresses after MTX withdrawal with the higher incidence in Japanese patients, MTX-LPDs consist of various subtypes of LPDs, the feature of each LPD such as the regressive rate, relapse/regrowth rate, and prognosis, widely varies. The absolute lymphocyte count (ALC) in peripheral blood is suggested to influence LPD development, regression, and relapse/regrowth events. Because various factors might effect the pathogenesis and clinical features of MTX-LPD, careful attention should be paid to assess MTX-LPD.
Asunto(s)
Artritis Reumatoide , Trastornos Linfoproliferativos , Metotrexato/efectos adversos , Antirreumáticos , Humanos , Incidencia , Trastornos Linfoproliferativos/inducido químicamente , PronósticoRESUMEN
This study investigated the incidence rate and features of vascular adverse events (VAEs) in Japanese patients with chronic myeloid leukemia (CML) who were treated with tyrosine kinase inhibitors (TKIs). The analysis included 369 CML patients in the chronic or accelerated phases, selected from the CML Cooperative Study Group database; 25 events in 23 (6.2%) of these patients were VAEs. At the time of VAE incidence, nine patients were on treatment with imatinib, 12 with nilotinib, three with dasatinib, and one with bosutinib. VAE incidence comprised 13 cases of ischemic heart disease (IHD), eight of cerebral infarction (CI), and four of peripheral arterial occlusive disease (PAOD). IHD incidence rate in the study population was higher than that in the age-matched general population, particularly in nilotinib-treated patients, while CI incidence rate was almost equivalent. Compared with the Suita score, the SCORE chart and the Framingham score risk assessment tools detected more patients with high or very high risk of VAEs. In conclusion, incidence of IHD requires closer monitoring in nilotinib-treated patients. More detailed investigations for determining the most useful tool to predict VAE incidence and long-term analysis of therapy-related VAE cases are needed for improving safety during TKI therapy.
Asunto(s)
Infarto Cerebral , Leucemia Mielógena Crónica BCR-ABL Positiva , Isquemia Miocárdica , Enfermedad Arterial Periférica , Inhibidores de Proteínas Quinasas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Infarto Cerebral/inducido químicamente , Infarto Cerebral/epidemiología , Femenino , Humanos , Japón/epidemiología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/inducido químicamente , Isquemia Miocárdica/epidemiología , Enfermedad Arterial Periférica/inducido químicamente , Enfermedad Arterial Periférica/epidemiología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The JAK2V617F mutation is the commonest major genetic mutation of myeloproliferative neoplasms (MPNs) and has been defined in the WHO diagnostic criteria for MPNs. However, there is still no approved in vitro diagnostic test kit available in Japan. We evaluated a JAK2V617F allele quantification kit (test method) in a prospective, multicenter clinical performance study involving patients with MPNs who were diagnosed with polycythemia vera, essential thrombocythemia, and primary myelofibrosis; healthy volunteers were also included in the analysis. Good correlation was observed between the allele burden determined using the test method vs. that determined using next-generation sequencing (NGS) in the patient group (r=0.998, y=1.071x-0.069; n=156). Furthermore, all allele burdens in the healthy group (n=54) were below the lower limit of the measurement range of the test method (0.042%). Our results confirmed that the test method could quantitatively measure the JAK2V617F allele burden in patients with MPN. Thus, the novel JAK2V617F allele quantification kit can be considered useful for the diagnosis of MPNs.
Asunto(s)
Pruebas Genéticas/instrumentación , Janus Quinasa 2/genética , Trastornos Mieloproliferativos/genética , Policitemia Vera/genética , Estudios de Casos y Controles , Humanos , Japón , Mutación , Estudios ProspectivosRESUMEN
Human parvovirus B19 (HPV-B19) causes hemophagocytic lymphohistiocytosis (HLH). Here we describe a 35-year-old female with hereditary spherocytosis (HS) who developed HLH due to HPV-B19 infection. Upon admission, she had high fever and diarrhea. Laboratory findings included severe pancytopenia and elevated serum triglyceride and ferritin levels. Moreover, high HPV-B19 levels in the peripheral blood and increased reactive lymphocytosis in the bone marrow led to a diagnosis of HLH due to HPV-B19 infection. With supportive therapy and a blood transfusion, HLH symptoms, including fever and myelosuppression, improved in 1 week. However, symptoms of heart failure (HF) suddenly developed, and an echocardiography revealed diffuse systolic dysfunction, suggesting viral myocarditis due to HPV-B19 infection. Conservative management with diuretics gradually improved HF symptoms over a period of 2 weeks. HPV-B19 infection in adult patients with HS rarely results in severe HLH, but conservative therapy may improve the symptoms. Nonetheless, a careful follow-up is required after HLH improves because viral myocarditis can develop, as was seen in our patient.