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BACKGROUND: Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make realtime treatment decisions for children with relapsed/refractory solid tumors. METHODS: Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; stratum 2-relapsed/refractory CNS tumors; and stratum 3-relapsed/refractory rare solid tumors. Tumor samples were sent for tumor/normal whole-exome (WES) and tumor whole-transcriptome (WTS) sequencing, and the genomic data were used in a multi-institutional MTB to make realtime treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every two cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient clinical benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of complete response (CR), partial response (PR), stable disease (SD), no evidence of disease (NED), and progressive disease (PD) subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation. RESULTS: A total of 186 eligible patients were enrolled with 144 evaluable for safety and 124 evaluable for response. The average number of days from biopsy to initiation of the MTB-recommended combination therapy was 38 days. Patient benefit was exhibited in 65% of all subjects, 67% of neuroblastoma subjects, 73% of CNS tumor subjects, and 60% of rare tumor subjects. There was little associated toxicity above that expected for the MGT drugs used during this trial, suggestive of the safety of utilizing this method of selecting combination targeted therapy. CONCLUSIONS: This trial demonstrated the feasibility, safety, and efficacy of a comprehensive sequencing model to guide personalized therapy for patients with any relapsed/refractory solid malignancy. Personalized therapy was well tolerated, and the clinical benefit rate of 65% in these heavily pretreated populations suggests that this treatment strategy could be an effective option for relapsed and refractory pediatric cancers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02162732. Prospectively registered on June 11, 2014.
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Neuroblastoma , Niño , Humanos , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiologíaRESUMEN
AIM: In this publication, we will share our experience of AE management, provide guidance for appropriate staffing, and the discuss the importance of patient education when treating patients with R/R HR neuroblastoma using naxitamab. BACKGROUND: Approved treatments for patients with refractory and/or relapsed (R/R) high-risk (HR) neuroblastoma are limited, and there is a high unmet need for new treatment combinations. Naxitamab is a disialoganglioside 2 (GD2)-binding antibody that was approved by the United States Food and Drug Administration in 2020 for use in combination with granulocyte-macrophage colony-stimulating factor for the treatment of patients with R/R HR neuroblastoma in the bone and/or bone marrow and who have demonstrated a partial response, minor response, or stable disease with prior therapy. METHODS: The pediatric oncology team at Atrium Health Levine Children's Hospital has successfully treated several patients with naxitamab both alone and in combination with chemotherapy, with no patients requiring unplanned overnight hospitalization and few severe adverse events (AEs). To accomplish this, the team at Levine Children's Hospital established standard operating procedures for naxitamab, a therapy defined as high acuity due to the potential for acute AEs with rapid onset and that benefits from continuous monitoring by a nursing team and a dedicated provider. CONCLUSIONS: This will provide a practical guide for institutions offering naxitamab to their patients, and ensure successful administration of this high acuity treatment in the outpatient setting.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Glucolípidos , Neuroblastoma , Niño , Humanos , Pacientes Ambulatorios , Neuroblastoma/tratamiento farmacológico , HospitalesRESUMEN
PURPOSE: Long-term survival in high-risk neuroblastoma (HRNB) is approximately 50%, with mortality primarily driven by relapse. Eflornithine (DFMO) to reduce risk of relapse after completion of immunotherapy was investigated previously in a single-arm, phase II study (NMTRC003B; ClinicalTrials.gov identifier: NCT02395666) that suggested improved event-free survival (EFS) and overall survival (OS) compared with historical rates in a phase III trial (Children Oncology Group ANBL0032; ClinicalTrials.gov identifier: NCT00026312). Using patient-level data from ANBL0032 as an external control, we present new analyses to further evaluate DFMO as HRNB postimmunotherapy maintenance. PATIENTS AND METHODS: NMTRC003B (2012-2016) enrolled patients with HRNB (N = 141) after standard up-front or refractory/relapse treatment who received up to 2 years of continuous treatment with oral DFMO (750 ± 250 mg/m2 twice a day). ANBL0032 (2001-2015) enrolled patients with HRNB postconsolidation, 1,328 of whom were assigned to dinutuximab (ch.14.18) treatment. Selection rules identified 92 NMTRC003B patients who participated in (n = 87) or received up-front treatment consistent with (n = 5) ANBL0032 (the DFMO/treated group) and 852 patients from ANBL0032 who could have been eligible for NMTRC003B after immunotherapy, but did not enroll (the NO-DFMO/control group). The median follow-up time for DFMO/treated patients was 6.1 years (IQR, 5.2-7.2) versus 5.0 years (IQR, 3.5-7.0) for NO-DFMO/control patients. Kaplan-Meier and Cox regression compared EFS and OS for overall groups, 3:1 (NO-DFMO:DFMO) propensity score-matched cohorts balanced on 11 baseline demographic and disease characteristics with exact matching on MYCN, and additional sensitivity analyses. RESULTS: DFMO after completion of immunotherapy was associated with improved EFS (hazard ratio [HR], 0.50 [95% CI, 0.29 to 0.84]; P = .008) and OS (HR, 0.38 [95% CI, 0.19 to 0.76]; P = .007). The results were confirmed with propensity score-matched cohorts and sensitivity analyses. CONCLUSION: The externally controlled analyses presented show a relapse risk reduction in patients with HRNB treated with postimmunotherapy DFMO.
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Eflornitina , Neuroblastoma , Niño , Humanos , Eflornitina/efectos adversos , Puntaje de Propensión , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Recurrencia , Supervivencia sin EnfermedadRESUMEN
BACKGROUND: Survival for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapies. AIMS: To study the feasibility and safety of incorporating a genomic-based targeted agent to induction therapy for HRNB as well as the feasibility and safety of adding difluoromethylornithine (DFMO) to anti-GD2 immunotherapy. METHODS: Twenty newly diagnosed HRNB patients were treated on this multicenter pilot trial. Molecular tumor boards selected one of six targeted agents based on tumor-normal whole exome sequencing and tumor RNA-sequencing results. Treatment followed standard upfront HRNB chemotherapy with the addition of the selected targeted agent to cycles 3-6 of induction. Following consolidation, DFMO (750 mg/m2 twice daily) was added to maintenance with dinutuximab and isotretinoin, followed by continuation of DFMO alone for 2 years. DNA methylation analysis was performed retrospectively and compared to RNA expression. RESULTS: Of the 20 subjects enrolled, 19 started targeted therapy during cycle 3 and 1 started during cycle 5. Eighty-five percent of subjects met feasibility criteria (receiving 75% of targeted agent doses). Addition of targeted agents did not result in toxicities requiring dose reduction of chemotherapy or permanent discontinuation of targeted agent. Following standard consolidation, 15 subjects continued onto immunotherapy with DFMO. This combination was well-tolerated and resulted in no unexpected adverse events related to DFMO. CONCLUSION: This study demonstrates the safety and feasibility of adding targeted agents to standard induction therapy and adding DFMO to immunotherapy for HRNB. This treatment regimen has been expanded to a Phase II trial to evaluate efficacy.
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Antineoplásicos , Neuroblastoma , Humanos , Eflornitina/efectos adversos , Proyectos Piloto , Quimioterapia de Inducción , Estudios Retrospectivos , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/genética , Inmunoterapia , Antineoplásicos/uso terapéutico , Factores Inmunológicos , Genómica , ARN/uso terapéuticoRESUMEN
AIMS: Recurrent alterations in receptor tyrosine kinase (RTK) and downstream effectors are described in infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) and a subset of spindle cell sarcomas, provisionally designated 'NTRK-rearranged' spindle cell neoplasms. These two groups of tumours demonstrate overlapping morphologies and harbour alterations in NTRK1/2/3, RET, MET, ABL1, ROS1, RAF1 and BRAF, although their relationship is not fully elucidated. We describe herein a cohort of paediatric tumours with clinicopathological features not typical for inflammatory myofibroblastic tumour, but rather with similarities to cCMN/IFS harbouring ALK fusions. METHODS AND RESULTS: Clinicopathological features were assessed and partner agnostic targeted RNA sequencing on clinically validated platforms were performed. Tumours occurred in patients aged from 2 to 10 years (median age 2 years) with a 2:2 male to female ratio and an average size of 8.4 cm. Two tumours arose in soft tissues and two in the kidney. Morphological features included spindle to ovoid cells arranged in long fascicles or haphazardly within a myxoid to collagenised stroma; a subset of cases had either dilated, ectatic vessels or focal perivascular hyalinosis. By immunohistochemistry, all cases tested showed cytoplasmic expression of anaplastic lymphoma kinase (ALK) and one case demonstrated co-expression of CD34 and S100. CONCLUSIONS: This series of ALK-rearranged IFS-like tumours expands the spectrum of targetable kinases altered in these tumours and reinforces the potential overlap between IFS/cCMN-like tumours and the provisional entity of 'NTRK-rearranged' spindle cell neoplasms.
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Quinasa de Linfoma Anaplásico/genética , Fibrosarcoma/genética , Reordenamiento Génico , Neoplasias Renales/genética , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Niño , Preescolar , Femenino , Humanos , MasculinoRESUMEN
Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment. SIGNIFICANCE: Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos , Evasión Inmune , Mutación , Recurrencia Local de Neoplasia/patología , Neoplasias/patología , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Lactante , Estudios Longitudinales , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/inmunología , Pronóstico , Tasa de Supervivencia , Transcriptoma , Adulto JovenAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Adolescente , Adulto , Antraciclinas/administración & dosificación , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B/patología , Masculino , Pronóstico , Rituximab/administración & dosificación , Tasa de Supervivencia , Adulto JovenRESUMEN
Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6 years of age. The long-term prognosis for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB. Event-free survival (EFS) and overall survival (OS) of 81 subjects with HRNB treated with standard COG induction, consolidation and immunotherapy followed by 2 years of DFMO on the NMTRC003/003b Phase II trial were compared to a historical cohort of 76 HRNB patients treated at Beat Childhood Cancer Research Consortium (BCC) hospitals who were disease-free after completion of standard upfront therapy and did not receive DFMO. The 2- and 5-year EFS were 86.4% [95% confidence interval (CI) 79.3%-94.2%] and 85.2% [77.8%-93.3%] for the NMTRC003/003b subset vs 78.3% [69.5%-88.3%] and 65.6% [55.5%-77.5%] for the historical control group. The 2- and 5-year OS were 98.8% [96.4-100%] and 95.1% [90.5%-99.9%] vs 94.4% [89.3%-99.9%] and 81.6% [73.0%-91.2%], respectively. DFMO maintenance for HRNB after completion of standard of care therapy was associated with improved EFS and OS relative to historical controls treated at the same institutions. These results support additional investigations into the potential role of DFMO in preventing relapse in HRNB.
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Eflornitina/administración & dosificación , Neuroblastoma/tratamiento farmacológico , Preescolar , Supervivencia sin Enfermedad , Eflornitina/uso terapéutico , Femenino , Humanos , Quimioterapia de Mantención , Masculino , Pronóstico , Nivel de Atención , Resultado del TratamientoRESUMEN
BACKGROUND: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent sarcoma. Nab-paclitaxel is a taxane modified to improve drug exposure and increase intratumoral accumulation and, in combination with gemcitabine, is standard therapy for pancreatic cancer. Applying the dosages and schedule used for pancreatic cancer, we performed a phase II trial to assess the response rate of gemcitabine and nab-paclitaxel in patients with relapsed Ewing sarcoma. PROCEDURE: Using a Simon's two-stage design to identify a response rate of ≥ 35%, patients received nab-paclitaxel 125 mg/m2 followed by gemcitabine 1000 mg/m2 i.v. on days 1, 8, and 15 of four-week cycles. Immunohistochemical analysis of archival tissue was performed to identify possible biomarkers of response. RESULTS: Eleven patients from four institutions enrolled, with a median age of 22 years (range, 14-27). Patients were heavily pretreated (median 3 prior regimens, range, 1-7). Thirty-five cycles were administered (median 2, range, 1-8). Accrual was stopped after 11 patients, due to only one confirmed partial response. Two other patients had partial responses after two cycles, but withdrew because of adverse effects or progression before confirmation of continued response. The predominant toxicity was myelosuppression, and four (36%) patients were removed due to hematologic toxicity despite pegfilgrastim and dose reductions. Expression of secreted protein, acidic and rich in cysteine (SPARC) and CAV-1 in archival tumors was not predictive of clinical benefit in this small cohort of patients. CONCLUSIONS: In patients with heavily pretreated Ewing sarcoma, the confirmed response rate of 9% was similar to multi-institutional studies of gemcitabine and docetaxel.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológico , Adolescente , Adulto , Albúminas/administración & dosificación , Neoplasias Óseas/patología , Niño , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Estudios de Seguimiento , Humanos , Masculino , Recurrencia Local de Neoplasia/patología , Paclitaxel/administración & dosificación , Pronóstico , Sarcoma de Ewing/patología , Adulto Joven , GemcitabinaRESUMEN
PURPOSE: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution. PATIENTS AND METHODS: We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial. RESULTS: The most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (n = 1); seizure, somnolence, and delirium (n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia (n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects. CONCLUSIONS: Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Adulto , Asparaginasa/administración & dosificación , Bortezomib/administración & dosificación , Niño , Preescolar , Decitabina/administración & dosificación , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Mitoxantrona/administración & dosificación , Recurrencia Local de Neoplasia/patología , Proyectos Piloto , Polietilenglicoles/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Terapia Recuperativa/métodos , Tasa de Supervivencia , Vincristina/administración & dosificación , Vorinostat/administración & dosificación , Adulto JovenRESUMEN
High risk neuroblastoma (HRNB) accounts for 15% of all pediatric cancer deaths. Despite aggressive therapy approximately half of patients will relapse, typically with only transient responses to second-line therapy. This study evaluated the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) as maintenance therapy to prevent relapse following completion of standard therapy (Stratum 1) or after salvage therapy for relapsed/refractory disease (Stratum 2). This Phase II single agent, single arm multicenter study enrolled from June 2012 to February 2016. Subjects received 2 years of oral DFMO (750 ± 250 mg/m2 twice daily). Event free survival (EFS) and overall survival (OS) were determined on an intention-to-treat (ITT) basis. 101 subjects enrolled on Stratum 1 and 100 were eligible for ITT analysis; two-year EFS was 84% (±4%) and OS 97% (±2%). 39 subjects enrolled on Stratum 2, with a two-year EFS of 54% (±8%) and OS 84% (±6%). DFMO was well tolerated. The median survival time is not yet defined for either stratum. DFMO maintenance therapy for HRNB in remission is safe and associated with high EFS and OS. Targeting ODC represents a novel therapeutic mechanism that may provide a new strategy for preventing relapse in children with HRNB.
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Eflornitina/administración & dosificación , Quimioterapia de Mantención , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/mortalidad , Preescolar , Supervivencia sin Enfermedad , Eflornitina/efectos adversos , Femenino , Humanos , Masculino , Tasa de SupervivenciaRESUMEN
The survival of pediatric patients with multiply relapsed and/or refractory (R/R) B-cell acute lymphoblastic leukemia has historically been very poor; however, data are limited in the current era. We conducted a retrospective study to determine the outcome of multiply R/R childhood B-ALL treated at 24 TACL institutions between 2005 and 2013. Patient information, treatment, and response were collected. Prognostic factors influencing the complete remission (CR) rate and event-free survival (EFS) were analyzed. The analytic set included 578 salvage treatment attempts among 325 patients. CR rates (mean ± SE) were 51 ± 4% for patients with bone marrow R/R B-ALL who underwent a second salvage attempt, 37 ± 6% for a third attempt, and 31 ± 6% for the fourth through eighth attempts combined. For patients achieving a CR after their second, third, and fourth through eighth attempts, the 2 year EFS was 41 ± 6%, 13 ± 7%, and 27 ± 13% respectively. Our results showed slight improvement when compared to previous studies. This is the largest and most recent study to date that evaluates the outcome of this patient population. Our data will provide detailed reference for the evaluation of new agents being developed for childhood B-ALL.
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Antineoplásicos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Linfocitos B/efectos de los fármacos , Linfocitos B/patología , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Inducción de Remisión/métodos , Estudios Retrospectivos , Terapia Recuperativa/métodosRESUMEN
Relapsed/refractory acute myeloid leukemia (AML) has an extremely poor prognosis. We describe 17 children and adolescents with relapsed/refractory AML who received clofarabine, cyclophosphamide, and etoposide. Seven patients (41%) responded: 4 with a complete response (CR); 1 with CR with incomplete platelet recovery; and 2 with a partial response. Additionally, 4 developed hypocellular marrow without evidence of leukemia; 5 patients had resistant disease; and 1 suffered early toxic death. After further therapy including transplantation, 4 patients (24%) are alive without evidence of disease at a median of 60 months. This anthracycline-free regimen may be studied for relapsed or refractory AML, but due to the high risk of marrow aplasia reduced doses of clofarabine and cyclophosphamide should be used.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Nucleótidos de Adenina/administración & dosificación , Nucleótidos de Adenina/efectos adversos , Adolescente , Adulto , Aloinjertos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Arabinonucleósidos/administración & dosificación , Arabinonucleósidos/efectos adversos , Niño , Preescolar , Clofarabina , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Masculino , Tasa de SupervivenciaRESUMEN
PURPOSE: To determine a safe and biologically active dose of quizartinib (AC220), a potent and selective class III receptor tyrosine kinase (RTK) FLT3 inhibitor, in combination with salvage chemotherapy in children with relapsed acute leukemia. EXPERIMENTAL DESIGN: Quizartinib was administered orally to children with relapsed AML or MLL-rearranged ALL following 5 days of high-dose cytarabine and etoposide (AE). A 3+3 dose escalation design was used to identify a safe and biologically active dose. Plasma inhibitory assay (PIA) testing was performed weekly to determine biologic activity. RESULTS: Toxicities were consistent with intensive relapsed leukemia regimens. One of 6 patients experienced a dose-limiting toxicity (DLT) at 40 mg/m(2)/day (elevated lipase) and 1 of 9 had a DLT (hyperbilirubinemia) at the highest tested dose of 60 mg/m(2)/day. Of 17 response evaluable patients, 2 had complete response (CR), 1 complete response without platelet recovery (CRp), 1 complete response with incomplete neutrophil and platelet recovery (CRi), 10 stable disease (SD), and 3 progressive disease (PD). Of 7 FLT3-ITD patients, 1 achieved CR, 1 CRp, 1 Cri, and 4 SD. FLT3-ITD patients, but not FLT3 wild-type (WT) patients, had significantly lower blast counts post-quizartinib. FLT3 phosphorylation was completely inhibited in all patients. CONCLUSIONS: Quizartinib plus intensive chemotherapy is well tolerated at 60 mg/m(2)/day with near complete inhibition of FLT3 phosphorylation in all patients. The favorable toxicity profile, pharmacodynamic activity, and encouraging response rates warrant further testing of quizartinib in children with FLT3-ITD AML. Clin Cancer Res; 22(16); 4014-22. ©2016 AACR.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia/tratamiento farmacológico , Leucemia/patología , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzotiazoles/administración & dosificación , Médula Ósea/patología , Niño , Preescolar , Resistencia a Antineoplásicos , Femenino , Expresión Génica , Genotipo , Humanos , Lactante , Leucemia/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Mutación , Compuestos de Fenilurea/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Recurrencia , Resultado del Tratamiento , Adulto Joven , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mg/kg orally three times daily) with a target serum level of 75-100 mcg/ml. Tem was started at an initial dose of 60 mg/m/week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mg/m/week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug-drug interactions will be important in future multiagent trials including Tem.