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1.
Blood ; 142(7): 629-642, 2023 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-37172201

RESUMEN

Advancing cure rates for high-risk acute lymphoblastic leukemia (ALL) has been limited by the lack of agents that effectively kill leukemic cells, sparing normal hematopoietic tissue. Molecular glues direct the ubiquitin ligase cellular machinery to target neosubstrates for protein degradation. We developed a novel cereblon modulator, SJ6986, that exhibits potent and selective degradation of GSPT1 and GSPT2 and cytotoxic activity against childhood cancer cell lines. Here, we report in vitro and in vivo testing of the activity of this agent in a panel of ALL cell lines and xenografts. SJ6986 exhibited similar cytotoxicity to the previously described GSPT1 degrader CC-90009 in a panel of leukemia cell lines in vitro, resulting in apoptosis and perturbation of cell cycle progression. SJ6986 was more effective than CC-90009 in suppressing leukemic cell growth in vivo, partly attributable to favorable pharmacokinetic properties, and did not significantly impair differentiation of human CD34+ cells ex vivo. Genome-wide CRISPR/Cas9 screening of ALL cell lines treated with SJ6986 confirmed that components of the CRL4CRBN complex, associated adaptors, regulators, and effectors were integral in mediating the action of SJ6986. SJ6986 is a potent, selective, orally bioavailable GSPT1/2 degrader that shows broad antileukemic activity and has potential for clinical development.


Asunto(s)
Antineoplásicos , Piperidonas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Piperidonas/uso terapéutico , Isoindoles/uso terapéutico
2.
Cancer Sci ; 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38923173

RESUMEN

Our study highlights the discovery of recurrent copy number alterations in noncoding regions, specifically blood enhancer cluster (BENC-CNA), in B-precursor acute lymphoblastic leukemia (BCP-ALL) cell lines. We demonstrate that BENC-CNA acts as a super-enhancer, driving MYC expression and possibly contributing to the immortalization and proliferative advantage of BCP-ALL cells in vitro.

3.
J Pediatr Hematol Oncol ; 46(5): 233-240, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38691057

RESUMEN

Metronomic chemotherapy (MC) is based on chronic administration of chemotherapeutic agents at minimally toxic doses without prolonged drug-free breaks, that inhibits tumor angiogenesis and induces tumor dormancy. This study aimed to determine the efficacy of MC for pediatric refractory solid tumors. We retrospectively analyzed the data of pediatric patients with relapsed/refractory solid tumors who received treatment, including low-dose continuous administration of anticancer drugs, at our institute. Of the 18 patients, the disease statuses at the initiation of MC were complete remission (n=2), partial remission/stable disease (n=5), and progressive disease (n=11). The overall survival rate was 61% at 12 months and 34% at 24 months, and the progression-free survival rate was 21% at 12 and 24 months. Although only 5 of the 18 patients showed certain tumor regression or maintained remission, tumors that stabilized, maintained remission/stable disease, and showed certain advantages in terms of overall survival rate, even if limited to progressive disease. Approximately half of the patients demonstrated temporal tumor stabilization and improved survival time. Overall, previous reports and the present study support the conclusion that MC has the potential to play an important role in pediatric cancer treatment during the advanced stage.


Asunto(s)
Administración Metronómica , Neoplasias , Humanos , Estudios Retrospectivos , Niño , Femenino , Masculino , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Neoplasias/patología , Adolescente , Preescolar , Tasa de Supervivencia , Lactante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación
4.
Pediatr Hematol Oncol ; 41(1): 81-87, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-37129918

RESUMEN

Germline genetic variants influence development of pediatric B cell acute lymphoblastic leukemia (B-ALL). Genome-wide association studies (GWAS) have identified several pediatric B-ALL susceptibility loci. IKZF1 and PAX5, transcription factors involved in B cell development, have been reported as susceptibility genes for B-ALL development. Therefore, we hypothesized that rare variants of genes involved in B cell development would be candidate susceptibility loci for pediatric B-ALL. Thus, we sequenced TCF3, a key transcription factor gene involving in B cell development. Saliva DNA from 527 pediatric patients with pediatric B-ALL in remission who were registered with the Tokyo Children's Cancer Study Group (TCCSG) were examined. As a TCF3 gene-based evaluation, the numbers of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a TCF3 single-variant evaluation, the frequencies of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were also compared with those in control data. TCF3 gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, TCF3 variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, p = 0.0006) and pediatric B-ALL development. TCF3 variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.


Asunto(s)
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Niño , Humanos , Estudio de Asociación del Genoma Completo , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Factores de Transcripción/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética
5.
Rinsho Ketsueki ; 65(6): 590-596, 2024.
Artículo en Japonés | MEDLINE | ID: mdl-38960661

RESUMEN

Many effective new agents for relapsed childhood acute lymphoblastic leukemia (ALL) are now becoming available, and international standard chemotherapy should be developed to optimize use of these agents. Randomized controlled trials (RCTs) are needed to establish a standard treatment, but few have been conducted for relapsed childhood ALL in Japan due to the small patient population. Participation in international RCTs is necessary to access sufficient patients for informative study results, but differences in approved drugs and healthcare systems between countries make this challenging. In 2014, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) participated in an international study on standard-risk relapsed childhood ALL (IntReALL SR 2010) involving two RCTs and multiple drugs not approved in Japan, which was addressed by replacing the unapproved drugs with alternative approved drugs with the same or similar efficacy. This article discusses the historical background of treatment development for relapsed childhood ALL, our experience in participating in the IntReALL SR 2010 trial, and prospects for treating relapsed childhood ALL.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Recurrencia , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Niño , Japón , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
6.
Blood ; 137(4): 471-484, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-32881995

RESUMEN

Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells, shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). To determine tumor-intrinsic and -extrinsic determinants of response, we studied 44 adults with relapsed or refractory B-ALL (including 2 minimal residual disease positive) treated with blinatumomab using bulk tumor and single-cell sequencing. The overall response rate in patients with hematological disease was 55%, with a high response rate in those with CRLF2-rearranged Philadelphia chromosome-like ALL (12 [75%] of 16). Pretreatment samples of responders exhibited a tumor-intrinsic transcriptomic signature of heightened immune response. Multiple mechanisms resulted in loss of CD19 expression, including CD19 mutations, CD19-mutant allele-specific expression, low CD19 RNA expression, and mutations in CD19 signaling complex member CD81. Patients with low hypodiploid ALL were prone to CD19- relapse resulting from aneuploidy-mediated loss of the nonmutated CD19 allele. Increased expression of a CD19 isoform with intraexonic splicing of exon 2, CD19 ex2part, at baseline or during therapy was associated with treatment failure. These analyses demonstrate both tumor-intrinsic and -extrinsic factors influence blinatumomab response. We show that CD19 mutations are commonly detected in CD19- relapse during blinatumomab treatment. Identification of the CD19 ex2part splice variant represents a new biomarker predictive of blinatumomab therapy failure.


Asunto(s)
Anticuerpos Biespecíficos/uso terapéutico , Antígenos CD19/genética , Antígenos de Neoplasias/genética , Antineoplásicos Inmunológicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Terapia Recuperativa , Subgrupos de Linfocitos T/efectos de los fármacos , Adolescente , Adulto , Anciano , Secuencia de Aminoácidos , Aneuploidia , Anticuerpos Biespecíficos/inmunología , Anticuerpos Biespecíficos/farmacología , Antígenos CD19/biosíntesis , Antígenos CD19/inmunología , Antígenos de Neoplasias/biosíntesis , Antígenos de Neoplasias/inmunología , Antineoplásicos Inmunológicos/inmunología , Antineoplásicos Inmunológicos/farmacología , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Citotoxicidad Inmunológica/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Recurrencia , Estudios Retrospectivos , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Análisis de la Célula Individual , Subgrupos de Linfocitos T/inmunología , Adulto Joven
7.
Blood ; 138(23): 2313-2326, 2021 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-34110416

RESUMEN

CRLF2-rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) accounts for more than half of Philadelphia chromosome-like (Ph-like) ALL and is associated with a poor outcome in children and adults. Overexpression of CRLF2 results in activation of Janus kinase (JAK)-STAT and parallel signaling pathways in experimental models, but existing small molecule inhibitors of JAKs show variable and limited efficacy. Here, we evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against JAKs. Solving the structure of type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 tyrosine kinase domain enabled the rational design and optimization of a series of cereblon (CRBN)-directed JAK PROTACs utilizing derivatives of JAK inhibitors, linkers, and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation, and activity was tested in a panel of leukemia/lymphoma cell lines and xenograft models of kinase-driven ALL. Multiple PROTACs were developed that degraded JAKs and potently killed CRLF2r cell lines, the most active of which also degraded the known CRBN neosubstrate GSPT1 and suppressed proliferation of CRLF2r ALL in vivo, e.g. compound 7 (SJ988497). Although dual JAK/GSPT1-degrading PROTACs were the most potent, the development and evaluation of multiple PROTACs in an extended panel of xenografts identified a potent JAK2-degrading, GSPT1-sparing PROTAC that demonstrated efficacy in the majority of kinase-driven xenografts that were otherwise unresponsive to type I JAK inhibitors, e.g. compound 8 (SJ1008030). Together, these data show the potential of JAK-directed protein degradation as a therapeutic approach in JAK-STAT-driven ALL and highlight the interplay of JAK and GSPT1 degradation activity in this context.


Asunto(s)
Quinasas Janus/antagonistas & inhibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteolisis/efectos de los fármacos , Receptores de Citocinas/genética , Animales , Línea Celular Tumoral , Descubrimiento de Drogas , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Quinasas Janus/metabolismo , Ratones Endogámicos NOD , Modelos Moleculares , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico
8.
Haematologica ; 108(2): 394-408, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36005560

RESUMEN

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is an intractable disease and most cases harbor genetic alterations that activate JAK or ABL signaling. The commonest subtype of Ph-like ALL exhibits a CRLF2 gene rearrangement that brings about JAK1/2-STAT5 pathway activation. However, JAK1/2 inhibition alone is insufficient as a treatment, so combinatorial therapies targeting multiple signals are needed. To better understand the mechanisms underlying the insufficient efficacy of JAK inhibition, we explored gene expression changes upon treatment with a JAK1/2 inhibitor (ruxolitinib) and found that elevated BCL6 expression was one such mechanism. Upregulated BCL6 suppressed the expression of TP53 along with its downstream cell cycle inhibitor p21 (CDKN2A) and pro-apoptotic molecules, such as FAS, TNFRSF10B, BID, BAX, BAK, PUMA, and NOXA, conferring cells some degree of resistance to therapy. BCL6 inhibition (with FX1) alone was able to upregulate TP53 and restore the TP53 expression that ruxolitinib had diminished. In addition, ruxolitinib and FX1 concertedly downregulated MYC. As a result, FX1 treatment alone had growth-inhibitory and apoptosis- sensitizing effects, but the combination of ruxolitinib and FX1 more potently inhibited leukemia cell growth, enhanced apoptosis sensitivity, and prolonged the survival of xenografted mice. These findings provide one mechanism for the insufficiency of JAK inhibition for the treatment of CRLF2-rearranged ALL and indicate BCL6 inhibition as a potentially helpful adjunctive therapy combined with JAK inhibition.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Animales , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Nitrilos , Pirimidinas , Transducción de Señal , Proteínas Proto-Oncogénicas c-bcl-6
9.
Tohoku J Exp Med ; 261(1): 51-56, 2023 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-37344418

RESUMEN

Transient abnormal myelopoiesis (TAM) can cause early death in children with Down syndrome, and liver failure is the most common cause of death. The aim of this single-center retrospective study was to identify a quantitative index for predicting TAM-related mortality at the time of diagnosis. Of the 462 children with Down syndrome admitted to our hospital from 1992 to 2021, we studied 12 infants with TAM-related death and 31 survivors who were diagnosed with TAM. In the death and survival groups, the median gestational ages were 34.9 and 37.1 weeks, respectively (p = 0.12). At diagnosis, the white blood cell (WBC) counts were 99.2 and 36.2 × 109/L (p = 0.011), the hemoglobin concentrations were 131 and 159 g/L (p = 0.009), and the serum albumin concentrations were 23 and 31 g/L (p < 0.001), respectively. The areas under the receiver operating characteristic curve for the abilities of the WBC count, hemoglobin, and serum albumin at diagnosis to predict survival were 0.75, 0.76, and 0.85, respectively. The serum albumin concentration threshold of 28 g/L at diagnosis had sensitivity of 0.79 and specificity of 0.82. Gestational age and serum albumin concentration were entered into a logistic regression model. The serum albumin concentration was an independent indicator of TAM-related death (adjusted odds ratio, 0.78; 95% confidence interval, 0.65-0.93; p = 0.005). In conclusion, a low serum albumin concentration at diagnosis may be a good predictor of TAM-related death.


Asunto(s)
Síndrome de Down , Reacción Leucemoide , Niño , Lactante , Humanos , Síndrome de Down/diagnóstico , Síndrome de Down/metabolismo , Estudios Retrospectivos , Mielopoyesis , Reacción Leucemoide/diagnóstico , Recuento de Leucocitos , Albúmina Sérica
10.
Cancer Sci ; 113(11): 3814-3825, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35879192

RESUMEN

A lack of practical resources in Japan has limited preclinical discovery and testing of therapies for pediatric relapsed and refractory acute lymphoblastic leukemia (ALL), which has poor outcomes. Here, we established 57 patient-derived xenografts (PDXs) in NOD.Cg-Prkdcscid ll2rgtm1Sug /ShiJic (NOG) mice and created a biobank by preserving PDX cells including three extramedullary relapsed ALL PDXs. We demonstrated that our PDX mice and PDX cells mimicked the biological features of relapsed ALL and that PDX models reproduced treatment-mediated clonal selection. Our PDX biobank is a useful scientific resource for capturing drug sensitivity features of pediatric patients with ALL, providing an essential tool for the development of targeted therapies.


Asunto(s)
Bancos de Muestras Biológicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Ratones , Animales , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos NOD , Japón , Xenoinjertos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Ratones SCID , Modelos Animales de Enfermedad
11.
Br J Haematol ; 196(3): 764-768, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34816427

RESUMEN

Approximately 20% of patients with transient abnormal myelopoiesis (TAM) die due to hepatic or multiorgan failure. To identify potential new treatments for TAM, we performed in vitro drug sensitivity testing (DST) using the peripheral blood samples of eight patients with TAM. DST screened 41 agents for cytotoxic properties against TAM blasts. Compared with the reference samples of healthy subjects, TAM blasts were more sensitive to glucocorticoids, the mitogen-activated protein kinase kinase (MAP2K) inhibitor trametinib, and cytarabine. Our present results support the therapeutic potential of glucocorticoids and the role of the RAS/MAP2K signalling pathway in TAM pathogenesis.


Asunto(s)
Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Reacción Leucemoide/tratamiento farmacológico , Mielopoyesis/efectos de los fármacos , Adulto , Antineoplásicos/uso terapéutico , Biomarcadores , Técnicas de Cultivo de Célula , Células Cultivadas , Ensayos de Selección de Medicamentos Antitumorales/métodos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Secuenciación de Nucleótidos de Alto Rendimiento , Ensayos Analíticos de Alto Rendimiento , Humanos , Inmunohistoquímica , Reacción Leucemoide/etiología , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Persona de Mediana Edad
12.
Blood ; 136(20): 2319-2333, 2020 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-32573712

RESUMEN

Karyotype is an important prognostic factor in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but the underlying pharmacogenomics remain unknown. Asparaginase is an integral component in current chemotherapy for childhood BCP-ALL. Asparaginase therapy depletes serum asparagine. Normal hematopoietic cells can produce asparagine by asparagine synthetase (ASNS) activity, but ALL cells are unable to synthesize adequate amounts of asparagine. The ASNS gene has a typical CpG island in its promoter. Thus, methylation of the ASNS CpG island could be one of the epigenetic mechanisms for ASNS gene silencing in BCP-ALL. To gain deep insights into the pharmacogenomics of asparaginase therapy, we investigated the association of ASNS methylation status with asparaginase sensitivity. The ASNS CpG island is largely unmethylated in normal hematopoietic cells, but it is allele-specifically methylated in BCP-ALL cells. The ASNS gene is located at 7q21, an evolutionally conserved imprinted gene cluster. ASNS methylation in childhood BCP-ALL is associated with an aberrant methylation of the imprinted gene cluster at 7q21. Aberrant methylation of mouse Asns and a syntenic imprinted gene cluster is also confirmed in leukemic spleen samples from ETV6-RUNX1 knockin mice. In 3 childhood BCP-ALL cohorts, ASNS is highly methylated in BCP-ALL patients with favorable karyotypes but is mostly unmethylated in BCP-ALL patients with poor prognostic karyotypes. Higher ASNS methylation is associated with higher L-asparaginase sensitivity in BCP-ALL through lower ASNS gene and protein expression levels. These observations demonstrate that silencing of the ASNS gene as a result of aberrant imprinting is a pharmacogenetic mechanism for the leukemia-specific activity of asparaginase therapy in BCP-ALL.


Asunto(s)
Asparaginasa/uso terapéutico , Aspartatoamoníaco Ligasa/genética , Variantes Farmacogenómicas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Animales , Niño , Aberraciones Cromosómicas , Metilación de ADN/genética , Impresión Genómica/genética , Humanos , Ratones
13.
Pediatr Blood Cancer ; 69(7): e29488, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-34889497

RESUMEN

BACKGROUND: The prognosis of metastatic hepatoblastoma remains poor; to improve it, pulmonary metastasis must be controlled. Indocyanine green (ICG) fluorescent imaging has been used recently for lung metastasectomy. The objective of our study was to clarify the usefulness of ICG imaging for lung metastasectomy of hepatoblastoma using detailed clinicopathological analysis. PROCEDURE: Patients with hepatoblastoma who underwent resection of pulmonary metastases with ICG fluorescent imaging were studied using a retrospective analysis of clinical information, a review of their surgical records, and a histological analysis of their metastatic nodules. RESULTS: Sixteen patients were enrolled. In total, 61 ICG imaging-guided pulmonary metastasectomies were performed, and 350 ICG-positive and 23 ICG-negative specimens were identified. Tumors were confirmed in 250 of the ICG-positive specimens, including eight nonpalpable nodules, on microscopic examination. ICG-positive and tumor-negative specimens showed histological changes suggesting the regression of a tumor or bloodstream disturbance. CONCLUSIONS: Surgical resection is one of the few treatment strategies available to patients with hepatoblastoma with multiple relapses of pulmonary metastasis resistant to chemotherapy. This study demonstrates the high sensitivity of ICG imaging and that thorough metastasectomy can be achieved with ICG imaging. Because a number of false-positive specimens were detected, further optimization of the dose of ICG and the timing of its administration, and establishment of detection of ICG-positive, tumor-negative nodules during surgery are important issues. Several false-negative specimens were also detected, suggesting the presence of ICG-negative metastatic tumors. Palpation during surgery and imaging studies remain essential for detecting metastatic lesions, even in the era of ICG imaging.


Asunto(s)
Hepatoblastoma , Neoplasias Hepáticas , Neoplasias Pulmonares , Colorantes , Hepatoblastoma/diagnóstico por imagen , Hepatoblastoma/cirugía , Humanos , Verde de Indocianina , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Recurrencia Local de Neoplasia , Estudios Retrospectivos
14.
Acta Haematol ; 145(6): 592-602, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35790143

RESUMEN

INTRODUCTION: The safety and efficacy of blinatumomab, a CD19/CD3 bispecific T-cell engager (BiTE®) molecule, was evaluated in an expansion cohort of the phase 1b/2 study (NCT02412306) in Japanese adult (n = 14) and pediatric (n = 17) patients with relapsed/refractory Philadelphia-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Globally recommended blinatumomab doses were administered to adult (9-28 µg/day) and pediatric (5-15 µg/m2/day) patients. Primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and treatment-related AEs. RESULTS: All adult and pediatric patients experienced ≥1 TEAE. Grade ≥3 TEAEs were observed in 11 (79%) adult and 15 (88%) pediatric patients. Blinatumomab was discontinued in 1 (6%) pediatric patient due to treatment-related grade 4 cytokine release syndrome. Fatal AEs such as disease progression and multiple-organ dysfunction syndrome, which were not treatment-related, were reported in 2 (12%) pediatric patients. Eleven (79%) adults achieved complete remission (CR)/CR with partial hematological recovery (CRh) within the first two blinatumomab cycles. Nine of 10 adult patients with CR/CRh and evaluable minimal residual disease (MRD) achieved MRD response. CR/CRh was achieved by 5 (29%) pediatric patients, of which two had MRD response. CONCLUSION: In conclusion, blinatumomab was safe and efficacious in Japanese patients with relapsed/refractory BCP ALL.


Asunto(s)
Antineoplásicos , Linfoma de Células B , Recurrencia Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Adulto , Niño , Humanos , Enfermedad Aguda , Antineoplásicos/efectos adversos , Japón , Linfoma de Células B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico
15.
Pediatr Int ; 64(1): e15106, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35396889

RESUMEN

BACKGROUND: Plerixafor is approved in Japan for hematopoietic stem cell mobilization prior to autologous transplant, but limited data are available on the use in children. This study evaluates the safety and effectiveness of plerixafor in Japanese children aged <15 years. METHODS: A multicenter, post-marketing surveillance study was conducted in Japan to evaluate the safety and effectiveness of plerixafor in routine clinical practice. This subgroup analysis examined the safety and effectiveness of plerixafor administered as a once-daily, subcutaneous injection in children aged <15 years. The primary effectiveness outcome was the proportion of patients with 2 × 106 cells CD34+ cells/kg collected via apheresis within 4 days. RESULTS: Eighteen patients with solid tumors were included in this analysis; (median age 6.0 years, range, 1-13 years). In addition to granulocyte colony-stimulating factor, all patients had received chemotherapy immediately prior to plerixafor administration. The mean (SD) daily dose of plerixafor was 0.24 (0.01) mg/kg. Seven of the 18 patients (38.9%) developed adverse drug reactions (ADRs), all occurring in patients aged ≥6 years and weighing ≥16 kg. The most common ADRs were pyrexia (n = 4), vomiting (n = 3), nausea (n = 2), and abdominal pain (n = 2). Twelve patients (66.7%) achieved a CD34+ cell count ≥2 × 106 cells/kg within 4 days after the start of plerixafor administration. CONCLUSIONS: The results provide an encouraging sign that plerixafor 0.24 mg/kg may be safe and effective in pediatric patients in routine clinical practice in Japan, but further research in larger studies is needed.


Asunto(s)
Ciclamas , Compuestos Heterocíclicos , Bencilaminas , Niño , Movilización de Célula Madre Hematopoyética/métodos , Compuestos Heterocíclicos/efectos adversos , Humanos , Japón , Mercadotecnía
16.
J Cell Mol Med ; 25(22): 10521-10533, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34636169

RESUMEN

In chemotherapy for childhood acute lymphoblastic leukaemia (ALL), maintenance therapy consisting of oral daily mercaptopurine and weekly methotrexate is important. NUDT15 variant genotype is reportedly highly associated with severe myelosuppression during maintenance therapy, particularly in Asian and Hispanic populations. It has also been demonstrated that acquired somatic mutations of the NT5C2 and PRPS1 genes, which are involved in thiopurine metabolism, are detectable in a portion of relapsed childhood ALL. To directly confirm the significance of the NUDT15 variant genotype and NT5C2 and PRPS1 mutations in thiopurine sensitivity of leukaemia cells in the intrinsic genes, we investigated 84 B-cell precursor-ALL (BCP-ALL) cell lines. Three and 14 cell lines had homozygous and heterozygous variant diplotypes of the NUDT15 gene, respectively, while 4 and 2 cell lines that were exclusively established from the samples at relapse had the NT5C2 and PRPS1 mutations, respectively. Both NUDT15 variant genotype and NT5C2 and PRPS1 mutations were significantly associated with DNA-incorporated thioguanine levels after exposure to thioguanine at therapeutic concentration. Considering the continuous exposure during the maintenance therapy, we evaluated in vitro mercaptopurine sensitivity after 7-day exposure. Mercaptopurine concentrations lethal to 50% of the leukaemia cells were comparable to therapeutic serum concentration of mercaptopurine. Both NUDT15 variant genotype and NT5C2 and PRPS1 mutations were significantly associated with mercaptopurine sensitivity in 83 BCP-ALL and 23 T-ALL cell lines. The present study provides direct evidence to support the general principle showing that both inherited genotype and somatically acquired mutation are crucially implicated in the drug sensitivity of leukaemia cells.


Asunto(s)
5'-Nucleotidasa/genética , Resistencia a Antineoplásicos/genética , Mercaptopurina/farmacología , Mutación , Polimorfismo Genético , Pirofosfatasas/genética , Ribosa-Fosfato Pirofosfoquinasa/genética , Alelos , Antimetabolitos Antineoplásicos/farmacología , Apoptosis/genética , Línea Celular Tumoral , Supervivencia Celular/genética , Relación Dosis-Respuesta a Droga , Genotipo , Humanos
17.
Br J Haematol ; 193(1): 176-180, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-32337716

RESUMEN

The variability in myelosuppression after chemotherapy for acute myeloid leukaemia (AML) can affect its prognosis; however, the underlying mechanism remains controversial. In the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study, we showed that prolonged neutropenia was associated with high overall survival (P = 0·011) and low frequency of relapse (P = 0·042) in patients without granulocyte-colony stimulating factor (G-CSF) who completed the indicated treatment protocol. Our data indicate that predisposition to prolonged neutropenia after chemotherapy is correlated with a better outcome of AML treatment. Our results promote the usage of individualised drug dosing strategies to improve the therapeutic outcome in AML patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Factor Estimulante de Colonias de Granulocitos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/inmunología , Neutropenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trastornos de Fallo de la Médula Ósea/inducido químicamente , Niño , Susceptibilidad a Enfermedades , Femenino , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Japón/epidemiología , Leucemia Mieloide Aguda/mortalidad , Masculino , Neutropenia/epidemiología , Pronóstico , Análisis de Supervivencia
18.
Blood ; 134(23): 2036-2045, 2019 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-31511239

RESUMEN

Chronic myeloid leukemia (CML) is rare in children and accounts for ≤15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph+ CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph+ CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph+ CML-CP were enrolled, and 58 were treated (R/I, n = 33; newly diagnosed, n = 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Cromosoma Filadelfia , Pirimidinas/administración & dosificación , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Masculino , Pirimidinas/efectos adversos
19.
Pediatr Blood Cancer ; 68(1): e28736, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32991072

RESUMEN

BACKGROUND: The prognosis of children with acute myeloid leukemia (AML) has improved with the efficacy of hematopoietic cell transplantation (HCT) as a second-line therapy and improvements in supportive care following anthracycline- and cytarabine-based chemotherapy; however, the outcomes of children with relapsed AML still remain unsatisfactory. PROCEDURE: In order to identify prognostic factors and improve their prognosis, we analyzed 111 patients who relapsed after treatment with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol and who were registered in the retrospective JPLSG AML-05R study. RESULTS: The 5-year overall survival rate was 36.1%. The major determinant of survival was duration from the diagnosis to relapse. The mean duration in the nonsurviving group (10.1 ± 4.1 months) was shorter than that in the surviving group (16.3 ± 8.3 months) (P < .01). Moreover, achieving a second complete remission (CR2) prior to HCT was associated with a good prognosis (P < .01). Etoposide, cytarabine, and mitoxantrone (ECM)- or fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG)-based regimens were therefore recommended for reinduction therapy (P < .01). A genetic analysis also revealed the prognostic significance of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication as a poor prognostic marker (P = .04) and core binding factor-AML, t(8;21), and inv(16) as good prognostic markers (P < .01). CONCLUSIONS: Achieving a CR2 prior to HCT is important in order to improve the prognosis of relapsed pediatric AML. Recent molecular targeted therapies, such as FLT3 inhibitors, may contribute to overcome their prognoses. Larger prospective investigations are necessary to establish individualized treatment strategies for patients with relapsed childhood AML.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/mortalidad , Leucemia Mieloide Aguda/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Adolescente , Antraciclinas/administración & dosificación , Biomarcadores de Tumor/genética , Niño , Preescolar , Terapia Combinada , Citarabina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lactante , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados
20.
Jpn J Clin Oncol ; 51(8): 1204-1211, 2021 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-34021341

RESUMEN

BACKGROUND: Palonosetron has demonstrated non-inferiority to ondansetron for prevention of chemotherapy-induced nausea and vomiting in pediatric patients in the United States and Europe. We conducted a single-arm registration study to evaluate the efficacy, safety and pharmacokinetics of palonosetron in pediatric patients in Japan. METHODS: Key inclusion criteria were age of 28 days to 18 years and malignant disease for which initial highly emetogenic chemotherapy or moderately emetogenic chemotherapy was planned. Patients received palonosetron at 20 µg/kg over at least 30 s intravenously before the start of highly emetogenic chemotherapy or moderately emetogenic chemotherapy and received dexamethasone on Days 1-3. The primary endpoint was the proportion of patients achieving a complete response in the overall phase (0-120 h) in Course 1, and its threshold was set at 30%. RESULTS: From December 2016 to June 2019, 60 patients were enrolled, and 58 received at least one dose of palonosetron. The proportion of patients achieving a complete response during the overall phase was 58.6% (95% confidence interval, 44.9%-71.4%), showing the primary endpoint was met (P < 0.0001). Treatment-related adverse events occurred in two patients (3.4%). Regarding the pharmacokinetics of palonosetron, neither the plasma concentration immediately after administration nor the area under the plasma concentration-time curve from time 0 to infinity differed significantly among the age groups. CONCLUSION: We demonstrated the efficacy of palonosetron in pediatric patients receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy and confirmed the appropriateness of the 20 µg/kg dose, regardless of age, considering the safety and pharmacokinetic profiles. TRIAL REGISTRATION: JapicCTI-163305, registered 6 June 2016.


Asunto(s)
Antieméticos , Antineoplásicos , Náusea , Neoplasias , Palonosetrón , Vómitos , Antieméticos/uso terapéutico , Antineoplásicos/efectos adversos , Niño , Dexametasona/uso terapéutico , Método Doble Ciego , Humanos , Recién Nacido , Isoquinolinas/uso terapéutico , Náusea/inducido químicamente , Náusea/tratamiento farmacológico , Náusea/prevención & control , Neoplasias/tratamiento farmacológico , Palonosetrón/uso terapéutico , Quinuclidinas/uso terapéutico , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológico , Vómitos/prevención & control
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