International Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory HEMatological Malignancies in Children, Subprotocol C Ruxolitinib + Venetoclax + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients With Relapsed or Refractory Hematological Malignancies

HEM-iSMART is a master protocol which investigates multiple investigational medicinal products in children, adolescents and young adults (AYA) with relapsed/refractory (R/R) ALL and LBL. Sub-protocol C is a phase I/II trial evaluating the safety and efficacy of ruxolitinib and venetoclax in combination with dexamethasone, cyclophosphamide and cytarabine in children and AYA with R/R ped ALL/LBL whose tumor present with alterations in the IL7R/JAK-STAT pathway.

开始日期2024-10-01

申办/合作机构

Princess Maxima Centre For Pediatric Oncology

NCT05751044

/ Not yet recruiting临床1/2期IIT

International Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory HEMatological Malignancies in Children, Sub-protocol B Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients With Relapsed or Refractory Hematological Malignancies

HEM-iSMART is a master protocol which investigates multiple investigational medicinal products in children, adolescents and young adults (AYA) with relapsed/refractory (R/R) ALL and LBL. Sub-protocol B is a phase I/II trial evaluating the safety and efficacy of dasatinib + venetocolax in combination with dexamethasone + Cyclophosphamide and cytarabine in children and AYA with R/R ped ALL/LBL whose tumor present with alterations in the MAPK/SRC pathway.

开始日期2024-10-01

申办/合作机构

Princess Maxima Centre For Pediatric Oncology

NCT05658640

/ Recruiting临床1/2期IIT

International Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory HEMatological Malignancies in Children, Subprotocol D: Trametinib + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients with Relapsed or Refractory Hematological Malignancies

HEM-iSMART is a master protocol which investigates multiple investigational medicinal products in children, adolescents and young adults (AYA) with relapsed/refractory (R/R) ALL and LBL. Sub-protocol D is a phase I/II trial evaluating the safety and efficacy of trametinib in combination with dexamethasone, cyclophosphamide and cytarabine in children and AYA with R/R ped ALL/LBL whose tumor present with alterations in the RAS-RAF-MAPK pathway.

开始日期2023-11-14

申办/合作机构

Princess Maxima Centre For Pediatric Oncology

100 项与难治性T淋巴细胞淋巴瘤相关的临床结果

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100 项与难治性T淋巴细胞淋巴瘤相关的转化医学

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0 项与难治性T淋巴细胞淋巴瘤相关的专利（医药）

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项与难治性T淋巴细胞淋巴瘤相关的文献（医药）

2024-09-14·Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi

[Ruxolitinib combined with venetoclax and azacitidine in the treatment of refractory T-ALL patients with JAK1, JAK3, and STAT5B gene mutations: a case report and literature review].

Review

作者: Chen, B ; Xie, T ; Zhou, T ; Yang, Y G ; Ouyang, J ; Peng, M X ; Xu, P P ; Xu, Y Y ; Du, Y

难治性急性T淋巴细胞白血病（T-ALL）在常规诱导缓解过程中对药物敏感性低、整体预后差。南京大学附属鼓楼医院报道了1例伴JAK1、JAK3、STAT5B基因突变的难治性T-ALL患者。标准VDLP（长春地辛、柔红霉素、培门冬酶、地塞米松）方案诱导化疗1个疗程后患者疾病未缓解，调整治疗方案为芦可替尼联合维奈克拉及阿扎胞苷。经治疗后，患者骨髓微小残留病（MRD）转阴，同阶段予以地塞米松联合依托泊苷胸腔灌注治疗后，患者胸腔积液及纵隔肿块较前明显好转。该患者骨髓缓解后行异基因造血干细胞移植，随访至移植后17个月，病情持续缓解。芦可替尼联合维奈克拉及阿扎胞苷治疗伴有JAK1、JAK3、STAT5B突变的难治性T-ALL疗效及安全性良好，为此类患者的治疗提供了新思路。.

2023-11-14·Clinical Cancer Research

Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Article

作者: Sulis, Maria Luisa ; Shukla, Neerav N ; Li, Yen Der ; Tsai, Jonathan ; Kim, Annette S ; Ocasio-Martinez, Nicole ; Bledsoe, Jacob ; Jacobson, Matthew P ; Gotti, Giacomo ; Harris, Marian H ; Magee, Jeffrey A ; Ebert, Benjamin L ; Kavanagh, Julia ; Sandoval-Perez, Angelica ; Dilig, Anthony ; Rangarajan, Amith Vikram ; Hatton, Charlie ; Tsai, Harrison K ; Cooper, Stacy L ; Khalid, Delan ; Robichaud, Amanda L ; Polonen, Petri ; Gillani, Riaz ; Dimitrov, Boris ; Mar, Brenton G ; Apsel Winger, Beth ; Li, Yuting ; Van Allen, Eliezer M ; Pikman, Yana ; Mullighan, Charles G ; Adhav, Asmani A ; Stegmaier, Kimberly ; Place, Andrew E ; Luskin, Marlise R ; Burke, Michael J ; Hijiya, Nobuko ; Gow, Sean ; Cooper, Todd M ; Paolino, Jonathan ; Tasian, Sarah K

AbstractPurpose:Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy.Experimental Design:We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia.Results:Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL.Conclusions:Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.

2023-06-22·Blood

How I treat newly diagnosed and refractory T-cell acute lymphoblastic lymphoma in children and young adults.

Article

作者: Ford, James B ; Si Lim, Stephanie J ; Hermiston, Michelle L

T-cell lymphoblastic lymphoma (T-LLy) and T-cell acute lymphoblastic leukemia (T-ALL) have historically been considered a spectrum of the same disease. However, recent evidence demonstrating differential responses to chemotherapy raise the possibility that T-LLy and T-ALL are distinct clinical and biologic entities. Here, we examine differences between the 2 diseases and use illustrative cases to highlight key recommendations on how to best treat patients with newly diagnosed and relapsed/refractory T-LLy. We discuss results of recent clinical trials incorporating use of nelarabine and bortezomib, choice of induction steroid, role of cranial radiotherapy, and risk stratification markers to identify patients at highest risk of relapse and to further refine current treatment strategies. Because prognosis for relapsed or refractory T-LLy patients is poor, we discuss ongoing investigations incorporating novel therapies, including immunotherapeutics, into upfront and salvage regimens and the role of hematopoietic stem cell transplantation.

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