Therapeutic potential of ruxolitinib and ponatinib in patients with &lt;i&gt;EPOR&lt;/i&gt;-rearranged Philadelphia chromosome-like acute lymphoblastic leukemia

Niswander, Lisa M; Loftus, Joseph P.; Lainey, Élodie; Caye-Eude, Aurélie; Pondrom, Morgane; Hottman, David A.; Iacobucci, Ilaria; Mullighan, Charles G.; Jain, Nitin; Konopleva, Marina; Cavé, Hélène; Baruchel, André; Röhrlich, Pierre; Tasian, Sarah K.

doi:10.3324/haematol.2021.278697

Cited by 15 publications

(5 citation statements)

References 14 publications

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“…However, safety data of post-transplant TKI maintenance can be extrapolated from the Ph-positive ALL, and its use could be encouraged [ 91 ]. This is in agreement with what was reported by Niswander et al, as they reported a substantial response to the addition of ruxolitinib or ponatinib to post-induction chemotherapy; one patient achieved MRD-negative remission by adding ponatinib to blinatumomab and then underwent Allo-HSCT followed by 2 years of maintenance ponatinib posttransplant [ 66 ].…”

Section: Role Of Hematopoietic Stem Cell Transplantation Based On Mrd...supporting

confidence: 92%

Philadelphia-like acute lymphoblastic leukemia: the journey from molecular background to the role of bone marrow transplant—review article

2023

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Philadelphia chromosome-like (Ph-like) ALL is a recent subtype of acute lymphoblastic leukemia. Although it does not express the BCR-ABL fusion gene, it has a behavior like true BCR/ABL1–positive cases. This subtype harbors different molecular alterations most commonly CRLF2 rearrangements. Most cases of Ph-like ALL are associated with high white blood cell count, high minimal residual disease level after induction therapy, and high relapse rate. Efforts should be encouraged for early recognition of Ph-like ALL to enhance therapeutic strategies. Recently, many trials are investigating the possibility of adding the tyrosine kinase inhibitor (TKI) to chemotherapy to improve clinical outcomes. The role and best timing of allogeneic bone marrow transplant in those cases are still unclear. Precision medicine should be implemented in the treatment of such cases. Here in this review, we summarize the available data on Ph-like ALL

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Section: Role Of Hematopoietic Stem Cell Transplantation Based On Mrd...supporting

confidence: 92%

Philadelphia-like acute lymphoblastic leukemia: the journey from molecular background to the role of bone marrow transplant—review article

2023

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“…Several recent studies have described the efficacy of ABL1 and NTRK inhibitors in the treatment of Ph-like ALL cases with rearrangement of these genes [117,118]. Combinatorial use of kinase inhibitors against multiple signaling has shown synergism in patient-derived xenograft (PDX) models of CRLF2/JAK mutant (JAK and PI3K/mTOR inhibitors), ABL/PDGFR mutant (dasatinib and PI3K/mTOR inhibitor) and EPOR-rearranged (ponatinib and ruxolitinib) [119]. Moreover, recently dual JAK/GSPT1-degrading proteolysis-targeting chimeras PROTACs have been developed and showed efficacy in Ph-like B-ALL kinase-driven PDX models which were otherwise unresponsive to type I JAK inhibitors [120].…”

Section: Subtypes That Phenocopy Established Subtypesmentioning

confidence: 99%

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

Iacobucci

Kimura

Mullighan

2021

JCM

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Acute lymphoblastic leukemia (ALL) is the most successful paradigm of how risk-adapted therapy and detailed understanding of the genetic alterations driving leukemogenesis and therapeutic response may dramatically improve treatment outcomes, with cure rates now exceeding 90% in children. However, ALL still represents a leading cause of cancer-related death in the young, and the outcome for older adolescents and young adults with ALL remains poor. In the past decade, next generation sequencing has enabled critical advances in our understanding of leukemogenesis. These include the identification of risk-associated ALL subtypes (e.g., those with rearrangements of MEF2D, DUX4, NUTM1, ZNF384 and BCL11B; the PAX5 P80R and IKZF1 N159Y mutations; and genomic phenocopies such as Ph-like ALL) and the genomic basis of disease evolution. These advances have been complemented by the development of novel therapeutic approaches, including those that are of mutation-specific, such as tyrosine kinase inhibitors, and those that are mutation-agnostic, including antibody and cellular immunotherapies, and protein degradation strategies such as proteolysis-targeting chimeras. Herein, we review the genetic taxonomy of ALL with a focus on clinical implications and the implementation of genomic diagnostic approaches.

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“…There are few patients with this gene fusion in the literature who were treated with ponatinib post‐HSCT 22 . EPOR rearrangements have one of the worst outcomes for patients with Ph‐like ALL and represent about 4% of Ph‐like B‐ALL cases 23 . These gene rearrangements lead to hypersensitivity to erythropoietin stimulation and constitutive activation of JAK–STAT signaling pathways 21 .…”

Section: Discussionmentioning

confidence: 99%

“… 22 EPOR rearrangements have one of the worst outcomes for patients with Ph‐like ALL and represent about 4% of Ph‐like B‐ALL cases. 23 These gene rearrangements lead to hypersensitivity to erythropoietin stimulation and constitutive activation of JAK–STAT signaling pathways. 21 EPOR::IGH fusion treatment regimens commonly involve the use of ruxolitinib, a JAK1 kinase inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Pre‐and post‐HSCT use of TKI therapy for fusion‐driven B‐ALL: A case series of five pediatric, adolescent and young adult patients

Shumock,

Temple,

Marinoff

et al. 2023

Cancer Reports

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BackgroundThe development of tyrosine kinase inhibitors (TKIs) has significantly improved survival rates among patients with Philadelphia chromosome (Ph+) B cell acute lymphoblastic leukemia (B‐ALL). Ph‐like B‐ALL patients lack the BCR::ABL1 translocation but share gene expression profiles with Ph+ B‐ALL. The role of TKIs for Ph‐like patients pre‐ and post‐hematopoietic stem cell transplantation (HSCT) is not yet clear.CaseHere we present five cases of pediatric, adolescent, and young adult patients who presented with Ph‐like B‐ALL or CML in B‐ALL blast phase who were treated with personalized TKI regimens pre‐ and post‐HSCT.ConclusionThis report describes several novel Ph‐like fusions as well as combinations of TKIs with chemotherapy or immunotherapy not yet reported in the pediatric population. This case series provides real‐world experience highlighting the potential application of pre‐ and post‐HSCT use of TKIs in a subset of patients with targetable fusions.

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Therapeutic potential of ruxolitinib and ponatinib in patients with <i>EPOR</i>-rearranged Philadelphia chromosome-like acute lymphoblastic leukemia

Cited by 15 publications

References 14 publications

Philadelphia-like acute lymphoblastic leukemia: the journey from molecular background to the role of bone marrow transplant—review article

Philadelphia-like acute lymphoblastic leukemia: the journey from molecular background to the role of bone marrow transplant—review article

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

Pre‐and post‐HSCT use of TKI therapy for fusion‐driven B‐ALL: A case series of five pediatric, adolescent and young adult patients

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