Mutation T315I -   Chronic Myeloid Leukemia-      CML

"Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of resistance continues to challenge the treatment of this disease. Mutations within the kinase domain of BCR-ABL1 constitute the most frequent mechanism of resistance in patients with chronic myelogenous leukemia treated with imatinib or the second generation tyrosine kinase inhibitors nilotinib and dasatinib. Of particular concern is the substitution of the threonine residue at the highly conserved gatekeeper residue 315 with a bulkier hydrophobic isoleucine amino acid. This mutation causes steric hindrance precluding the access ATP-competitive inhibitors to the ATP-binding pocket. To expedite the identification of strategies to override the resistance imposed by the T315I mutation, several strategies have been pursued, including the exploitation of BCR-ABL1 kinase sites distant from the ATP-binding pocket to cripple the kinase activity of the enzyme and inhibiting signaling pathways downstream from BCR-ABL1."
Extract of Therapeutic Options Against BCR-ABL1 T315I-Positive Chronic Myelogenous Leukemia
DRUGS FOR THE T315I MUTATION

Iclusig (Ponatinib)
Scemblix (Asciminib) 
HQP1351 ( Olverembatinib ) 
Synribo (Omacetaxine)
PF-114
DCC-2036 (Rebastinib)
BGB324
​S116836
​MK0457
KW-2449
ELVN-001
                                                 Attention​ 
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CLINICAL TRIALS 

KW-2449 by Kyowa Hakko Kirin Pharma, Inc

A Phase II Study of MK0457 in Patients  With T315I Mutant CML and Ph+All  (0457-008)

Axitinib and Bosutinib for Patients With Chronic Myeloid Leukemia in Chronic, Accelerated or Blastic Phases

Study to Evaluate Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy of PF-114 for Oral Administration in Adults With Ph+ Chronic Myeloid Leukemia, Which is Resistant to the 2-nd Generation Bcr-Abl Inhibitors or Has T315I Mutation in the BCR-ABL Gene

A Pivotal Study of HQP1351 in Patients of Chronic Myeloid Leukemia in Accelerated Phase With T315I Mutation

ARTICLES

Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results
May 16, 2024, Leukemia

Activity of First-in-Class STAMP Inhibitor in T315I-Mutated CML
February 1, 2021, JNCCN360

Mutations in the BCR‑ABL1 kinase domain in patients with chronic myeloid leukaemia treated with TKIs or at diagnosis
May 20, 2020, Spadidos Publications

Preclinical development of a novel BCR-ABL T315I inhibitor against chronic myeloid leukemia
December 11, 2019, PubMed

Durable Molecular Remission in a Lymphoid BP-CML Patient Harboring T315I Mutation Treated with Anti-CD19 CAR-T Therapy
December 13, 2019, Dovepress

Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure 
December 12, 2019, The New England Journal of Medicine

Ascentage Pharma Releases Updated Data of its Novel BCR-ABL Inhibitor, HQP1351, in an Oral Presentation Nominated for "Best of ASH" 
December 10, 2019, Biospace

Ascentage Pharma to Release Updated Data of its Novel, Third-Generation BCR-ABL Inhibitor, HQP1351, in Chinese Chronic Myeloid Leukemia Patients in an Oral Presentation at the 61st American Society of Hematology Annual Meeting
November 14, 2019, PrNewswire

Ascentage Pharma to Initiate Phase Ib Study of HQP1351 in Tyrosine Kinase Inhibitors -resistant Chronic Myeloid Leukemia Patients in the US
July 22, 2019, Biospace

Safety and Efficacy of HQP1351, a 3rd Generation Oral BCR-ABL Inhibitor in Patients with Tyrosine Kinase Inhibitor—Resistant Chronic Myelogenous Leukemia: Preliminary Results of Phase I Study
2018, Blood Journal

Phase-1 Study of PF-114 Mesylate in CML Failing Prior Tyrosine Kinase-Inhibitor Therapy
December 3, 2018, ASH 2018

Association of T315I mutation with resistance to tyrosine kinase inhibitor therapy in patients with CML attended the Oncology-Hematology center in Al-Najaf city of Iraq
December 2017, Karbala International Journal of Modern Science

Clinical features and outcomes in chronic myeloid leukemia with T315I mutation
July 31, 2017, Cellular Therapy and Transplantation

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia
December 7, 2016, PubMed

Anti-Leukemic Effects of Venetoclax on Philadelphia Chromosome Positive Leukemia Cells
2016, Journal Blood
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Ponatinib Ups Overall Survival in Patients with CP-CML and T315I Mutation
December 7, 2015, OncologyNurseAdvisor

Detection of BCR-ABL T315I mutation by peptide nucleic acid directed PCR clamping and by peptide nucleic acid FISH
July 3, 2015, BMC

Evolution of BCR/ABL Gene Mutation in CML Is Time Dependent and Dependent on the Pressure Exerted by Tyrosine Kinase Inhibitor
January 28, 2015,  NCBI

BCR-ABL Point Mutations and  TKI Treatment in CML Patients
July 8, 2014, SciMedCentral

Novel Therapies for T315I-Mutant Chronic Myeloid Leukemia
January 10, 2014, OncLive

The BCR-ABL T315I mutation compromises  survival in chronic phase chronic myelogenous leukemia patients resistant to  tyrosine kinase inhibitors, in a matched pair analysis
May 28, 2013,  Haematologica

Ponatinib thwarts T315I gene mutation in  chronic myeloid leukemia
November 29, 2012, News Medical
         
Analysis of Mutations in the BCR-ABL1 Kinase Domain, Using Direct Sequencing: Detection of the T315I Mutation in Bone Marrow CD34+ Cells of a Patient with Chronic Myelogenous Leukemia 6 Months Prior to its Emergence in Peripheral Blood
June 1, 2012, PubLMed
Novel potent inhibitor (P2745) of Bcr-Abl mutated imatinib resistant chronic myeloid leukemia cell lines (included T315I)
April 2, 2012, AACR Annual Meeting 2012
Successful treatment of a chronic-phase T-315I-mutated chronic myelogenous leukemia patient with a combination of imatinib and interferon-alfa
January 20, 2012, PubMed

Treatment of chronic phase (CP) chronic myeloid leukemia (CML) patients who harbour the BCR-ABL T315I mutation with subcutaneous omacetaxine results in improved survival compared to historical data
June 12 2011, EHA 2011

A pyrosequencing-based test for detection and relative quantification of the BCR-ABL1 T315I point mutation
April 12, 2011,  Journal of clinical pathology

Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036
April 12, 2011, Cancer cell

Ariad, MolecularMD Partner on Companion Dx for T315I Mutation
March 28, 2011,  genomeweb

HDAC Inhibitors Potentiate the Activity of the BCR/ABL Kinase Inhibitor KW-2449 in Imatinib-Sensitive or -Resistant BCR/ABL+ Leukemia Cells In  Vitro and In Vivo
March 24, 2011, Clinical Cancer  Research

Phase I Trial Shows Ponatinib May Thwart Most Resistant CML
December 16, 2010,  MD Anderson Cancer Center - Department of Leukemia

Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia
November 17, 2010, Clinical Cancer Research

The ABL Switch Control Inhibitor DCC-2036 Is Active against the Chronic Myeloid Leukemia Mutant BCR-ABLT315I and Exhibits a Narrow Resistance Profile
November 15, 2010,  Cancer Research

The Durable Clearance of the T315I BCR-ABL Mutated Clone in Chronic Phase Chronic Myelogenous Leukemia Patients on Omacetaxine Allows Tyrosine Kinase Inhibitor Rechallenge
March 3, 2010, Clinical Lymphoma,  myeloma & Leukemia

KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutatedBCR/ABL translocation
May 28, 2009, Journal Blood

ChemGenex's Omacetaxine Demonstrates 80% Complete Hematological Response Rate In Drug-Resistant CML Patients With The T315I Mutation
December 10, 2008,  Medical News Today

Complete Suppression of in Vitro Resistance by AP24534, a Pan-BCR-ABL Inhibitor
December 8, 2008, ASH2008

Therapeutic Options Against BCR-ABL1 T315I-Positive Chronic Myelogenous Leukemia
March 6, 2008, Clinical Cancer Research