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.

Start Date01 Oct 2024

Sponsor / Collaborator

Princess Maxima Centre For Pediatric Oncology

NCT05751044 / Not yet recruitingPhase 1/2IIT

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.

Start Date01 Oct 2024

Sponsor / Collaborator

Princess Maxima Centre For Pediatric Oncology

NCT05658640 / RecruitingPhase 1/2IIT

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.

Start Date14 Nov 2023

Sponsor / Collaborator

Princess Maxima Centre For Pediatric Oncology

100 Clinical Results associated with Precursor B-lymphoblastic lymphoma/leukemia refractory

100 Translational Medicine associated with Precursor B-lymphoblastic lymphoma/leukemia refractory

0 Patents (Medical) associated with Precursor B-lymphoblastic lymphoma/leukemia refractory

Literatures (Medical) associated with Precursor B-lymphoblastic lymphoma/leukemia refractory

01 Dec 2020·Journal of Hematology & Oncology

Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia

Article

Author: Tong, Chuan ; Jia, Hejin ; Wang, Yao ; Chen, Meixia ; Wang, Chunmeng ; Zhang, Yajing ; Han, Weidong ; Dai, Hanren ; Yang, Qingming ; Zhang, Wenying ; Han, Xiao ; Wu, Zhiqiang ; Liu, Yang ; Guo, Yelei ; Ti, Dongdong

AbstractBackgroundDespite the impressive complete remission (CR) induced by CD19 CAR-T cell therapy in B-ALL, the high rate of complete responses is sometimes limited by the emergence of CD19-negative leukemia. Bispecific CAR-modified T cells targeting both CD19 and CD22 may overcome the limitation of CD19-negative relapse.MethodsWe here report the design of a bispecific CAR simultaneous targeting of CD19 and CD22. We performed a phase 1 trial of bispecific CAR T cell therapy in patients with relapsed/refractory precursor B-ALL at a dose that ranged from 1.7 × 106 to 3 × 106 CAR T cells per kilogram of body weight.ResultsWe demonstrate bispecific CD19/CD22 CAR T cells could trigger robust cytolytic activity against target cells. MRD-negative CR was achieved in 6 out of 6 enrolled patients. Autologous CD19/CD22 CAR T cells proliferated in vivo and were detected in the blood, bone marrow, and cerebrospinal fluid. No neurotoxicity occurred in any of the 6 patients treated. Of note, one patient had a relapse with blast cells that no longer expressed CD19 and exhibited diminished CD22 site density approximately 5 months after treatment.ConclusionIn brief, autologous CD19/CD22 CAR T cell therapy is feasible and safe and mediates potent anti-leukemic activity in patients with relapsed/refractory B-ALL. Furthermore, the emergence of target antigen loss and expression downregulation highlights the critical need to anticipate antigen escape. Our study demonstrates the reliability of bispecific CD19/CD22 CAR T cell therapy in inducing remission in adult patients with relapsed/refractory B-ALL.Trial registrationClinicalTrials.gov identifier: NCT03185494.

01 Nov 2020·British Journal of Haematology

Impact of number of cycles on outcomes of patients with relapsed or refractory acute lymphoblastic leukaemia treated with inotuzumab ozogamicin

Letter

Author: Marks, David I. ; DeAngelo, Daniel J. ; Cassaday, Ryan D. ; Kantarjian, Hagop M. ; Stelljes, Matthias ; Stock, Wendy ; O’Brien, Susan ; Vandendries, Erik ; Jabbour, Elias J. ; Wang, Tao ; Advani, Anjali S. ; Neuhof, Alexander

Inotuzumab ozogamicin an anti-CD22 antibody-calicheamicin conjugate is approved for adults with relapsed/refractory B-cell precursor acute lymphoblastic leukaeamia.Two cycles[maximum three cycles without minimal residual disease(MRD)-neg. remission after two cycles] were recommended for patients proceeding to haematopoietic stem cell transplant (HSCT) and maximum six cycles if not proceeding to HSCT.Since higher treatment cycle number was associated with increased risk of veno-occlusive disease/sinusoidal obstruction syndrome post-HSCT efficacy and safety were assessed according to the number of InO cycles received.Here, patients achieving complete remission or complete remission with incomplete haematol. response (CR/CRi) to reduce potential bias since patients might discontinue treatment earlier than the six-cycle limit due to suboptimal responses were included.These results agree with current treatment recommendations that patients proceeding to HSCT should receive ≤2 InO cycles,whereas those not proceeding to HSCT may benefit from receiving up to six cycles of InO therapy depending on individual response and tolerability.

01 Jul 2020·Seminars in HematologyQ2 · MEDICINE

Optimal approach to the treatment of young adults with acute lymphoblastic leukemia in 2020

Q2 · MEDICINE

Article

Author: Schmiegelow, Kjeld ; Rank, Cecilie Utke

Akin to the introduction of tyrosine kinase inhibitors to Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), pediatric-based asparaginase-heavy approaches have revolutionized the treatment of young adults with the Philadelphia chromosome-negative subset the past decades. Once again, we are approaching a new era. An era of precision medicine with immunotherapy and other molecularly targeted treatments that offers unique opportunities to customize treatment intensity with or without hematopoietic stem cell transplantation, reduce the burden of toxicities, and combat persistent residual disease. Recently approved agents for refractory/relapsed B-cell precursor ALL include the chimeric antigen receptor-modified T-cells, the anti-CD22 monoclonal antibody-drug conjugate, inotuzumab ozogamicin, and the bispecific anti-CD19 T-cell engager, blinatumomab. These agents are expected to move widely into the frontline setting along with the proteasome inhibitors, bortezomib and carfilzomib, as well as tyrosine kinase inhibitors for Philadelphia-like rearrangements that are especially frequent among young adults. To this add the BH3 mimetics, venetoclax and navitoclax, which are being widely explored in refractory/relapsed as well as frontline settings for B- and T-cell ALL. The promising anti-CD38 monoclonal antibody, daratumumab, is entering the scene of refractory/relapsed T-ALL, whereas the old purine analogue, nelarabine, is being evaluated in a new upfront setting. This review focuses on 2 main questions: How do we optimize frontline as well as salvage ALL treatment of young adults in the 2020s? Not least, how do we address the current burden of serious toxicities unique to young adults?

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