Mixed phenotype acute leukemia

BOSTON--( BUSINESS WIRE )-- Foundation Medicine, Inc. today announced a collaboration with Syndax Pharmaceuticals (Nasdaq: SNDX) to develop a companion diagnostic for the identification of acute myeloid leukemia (AML) patients harboring an NPM1 mutation. As part of the collaboration, Syndax will also support Foundation Medicine’s efforts to pursue regulatory approval of an assay based on the FoundationOne ® Heme platform. NPM1 mutations are unique to AML patients and are the most frequently found genetic alteration at approximately 30% of newly diagnosed AML. 1 There are currently no targeted treatments approved for patients with NPM1- mutated AML, 2 and the 5-year overall survival for patients with NPM1 -mutated AML is approximately 50%. 3 Menin inhibitors such as revumenib, currently under development by Syndax, are emerging as a promising targeted therapy option for NPM1 -mutated AML. 1 To date, only six biomarkers associated with hematologic malignancies have approved targeted therapies, 4 but more than 40 additional biomarkers are being studied in hematology clinical trials. 5 “Blood cancers have a devastating impact on the lives of so many patients and their families,” said Ashley Yocum, PhD, Executive Research Lead at The Leukemia & Lymphoma Society. “Thanks to advancements in comprehensive genomic profiling, and decades of scientific research for new treatments, we are seeing a paradigm shift in how many types of blood cancer are diagnosed and treated, allowing more patients to benefit from the promise of precision medicine with access to more personalized treatment options.” If approved, the assay could be the first next-generation sequencing companion diagnostic to detect genomic alterations in hematologic neoplasms, including enhancing the identification of patients with NPM1 mutations who may be eligible for revumenib. “As the number of biomarkers with targeted therapies in hematologic malignancies reaches a critical inflection point, it is essential for physicians to have access to high-quality tests to make informed treatment decisions for their patients,” said Troy Schurr, Chief Biopharma Officer at Foundation Medicine. “We are incredibly excited to work with Syndax to advance the FoundationOne Heme platform as a companion diagnostic, a potential first for the FoundationOne Heme platform, and if approved, help patients with AML access this potential therapy.” Foundation Medicine’s portfolio of FDA-approved diagnostic tests offer physicians both blood- and tissue-based testing options for detecting genomic alterations that help guide personalized treatment decisions. Foundation Medicine is the global leader in companion diagnostic approvals, with approximately 60% of all U.S. companion diagnostic approvals for next-generation sequencing (NGS) testing. Foundation Medicine ® and FoundationOne ® are registered trademarks of Foundation Medicine, Inc. About Foundation Medicine: Your Essential Partner in Cancer Care Foundation Medicine is a pioneer in molecular profiling for cancer, working to shape the future of clinical care and research. We collaborate with a broad range of partners across the cancer community and strive to set the standard for quality, scientific excellence, and regulatory leadership. Our deep understanding of cancer biology helps physicians make informed treatment decisions for their patients and empowers researchers to develop new medicines. Every day, we are driven to help our partners find answers and take action, enabling more people around the world to benefit from precision cancer care. For more information, please visit us on www.FoundationMedicine.com and follow us on LinkedIn and X . About FoundationOne ® Heme FoundationOne ® Heme is a laboratory developed test that was developed and its performance characteristics determined by Foundation Medicine. FoundationOne Heme has not been cleared or approved by the U.S. Food and Drug Administration. For more information on FoundationOne Heme, please see its Technical Specifications at foundationmedicine.com/heme . The test employs RNA sequencing in addition to DNA sequencing to simultaneously detect all classes of genomic alterations, including base pair substitutions, insertions and deletions, copy number alterations and rearrangements, and gene fusions. About Revumenib Revumenib is a potent, selective, small molecule inhibitor of the menin-KMT2A binding interaction that is being developed by Syndax Pharmaceuticals for the treatment of KMT2A-rearranged (KMT2Ar), also known as mixed lineage leukemia rearranged or MLLr, acute leukemias including ALL and AML, and mutant nucleophosmin (mNPM1) AML. Revumenib was granted Orphan Drug Designation for the treatment of AML, ALL and MPAL by the FDA and for the treatment of AML by the European Commission, and Fast Track designation by the FDA and is currently under review for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation. A New Drug Application (NDA) for revumenib for the treatment of adult and pediatric R/R KMT2Ar acute leukemia is currently under review by the U.S. FDA with a PDUFA action date of December 26, 2024. 1 Swaminathan M, Bourgeois W, Armstrong SA, Wang ES. Menin inhibitors in acute myeloid leukemia—What does the future hold?. The Cancer J. 2022;28(1):62-66. https://doi.org/10.1097/PPO.0000000000000571 2 Ranieri R, Pianigiani G, Sciabolacci S, et al. Current status and future perspectives in targeted therapy of NPM1-mutated AML. Leukemia. 2022;36(10):2351-2367. https://doi.org/10.1038/s41375-022-01666-2 3 Angenendt L, Röllig C, Montesinos P, et al. Chromosomal abnormalities and prognosis in NPM1-mutated acute myeloid leukemia: A pooled analysis of individual patient data from nine international cohorts. J Clin Oncol. 2019;37(29):2632-2642. https://doi.org/10.1200/JCO.19.00416 4 List of Cleared or Approved Companion Diagnostic Devices. https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools . 5 Multiple secondary sources used to cross validate information, including Trialtrove, clinicatrials.gov, EudraCT, ChiCTR; FDA approval timeline estimation based on Ph3 PCD + 8 months review; analysis based on current Phase 1/2, Phase 2 and Phase 3 trials with inclusion criteria requiring patient selection based on alterations to specific biomarkers.

June 06, 2024 -- HUTCHMED (China) Limited (“HUTCHMED”) (Nasdaq/AIM:HCM; HKEX:13) today announces that it has initiated Phase I clinical trial of its menin inhibitor HMPL-506 in patients with hematological malignancies in China. The first patient received their first dose on May 31, 2024. This is a Phase I, multicenter, open-label clinical study to evaluate the safety, pharmacokinetics and efficacy of HMPL-506 in patients with hematological malignancies. The study is divided into two phases, a dose escalation phase and a dose expansion phase. The study is expected to enroll at least 60 patients. The lead principal investigators are Dr. Jianxiang Wang and Dr. Hui Wei of Chinese Academy of Medical Sciences Blood Diseases Hospital. Additional details may be found at clinicaltrials.gov, using identifier NCT06387082. HMPL-506 is a novel, investigational, selective small molecule inhibitor for oral administration targeting the menin protein. The menin protein is a scaffold protein that controls gene expression and cell signaling. Mixed-lineage leukemia (“MLL”, also known as KMT2A) rearrangement and nucleophosmin 1 (“NPM1”) mutation play key roles in acute myeloid leukemia (“AML”). MLL-rearranged AML accounts for approximately 5% of adult AML and NPM1-mutant AML accounts for approximately 30% of AML.1,2,3 Current research has demonstrated that the inhibition of menin-MLL interaction is a feasible therapeutic strategy in MLL-rearranged and/or NPM1-mutant AML.4,5,6,7 Currently there is no menin inhibitor approved worldwide. HUTCHMED currently retains all rights to HMPL-506 worldwide. According to the National Cancer Institute (NCІ), there will be approximately 20,380 new cases of AML in the U.S. in 2023 and the five-year relative survival rate is 31.7%.8 There were an estimated 19,700 new cases of AML in China in 2018 and is estimated to reach 24,200 in China in 2030.9 HUTCHMED (Nasdaq/AIM:HCM; HKEX:13) is an innovative, commercial-stage, biopharmaceutical company. It is committed to the discovery and global development and commercialization of targeted therapies and immunotherapies for the treatment of cancer and immunological diseases. It has approximately 5,000 personnel across all its companies, at the center of which is a team of about 1,800 in oncology/immunology. Since inception it has focused on bringing cancer drug candidates from in-house discovery to patients around the world, with its first three oncology drugs marketed in China, the first of which is also marketed in the U.S. For more information, please visit: www.hutch-med.com or follow us on LinkedIn. 1Ibrahim S, Estey EH, Pierce S, et al. 11q23 abnormalities in patients with acute myelogenous leukemia and myelodysplastic syndrome as detected by molecular and cytogenetic analyses. Am J Clin Pathol, 2000, 114(5):793-7. 2Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood, 2010,116(3):354-65. 3Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254-66. 4Krivtsov AV, Evans K, Gadrey JY, et al. A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia. Cancer Cell 2019;36:660–73 e11. 5Uckelmann HJ, Kim SM, Wong EM, et al. Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia. Science 2020;367:586–90. 6Borkin D, He S, Miao H, et al. Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell 2015;27:589–602. 7Klossowski S, Miao H, Kempinska K, et al. Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia. J Clin Invest 2020;130:981–97. 8National Cancer Institute – seer.cancer.gov/statfacts/html/amyl.html. 9Lin J, Yao D, Qian J, et al. ІDH1 and ІDH2 mutation analysis in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome. Ann Hematol. 2012;91(4):519-525. doi:10.1007/s00277-011-1352-7. The content above comes from the network. if any infringement, please contact us to modify.

Researchers used various sequencing technologies to explore the molecular characteristics of myeloid/natural killer cell precursor acute leukemia (MNKPL). They observed activation of the NOTCH1 and RUNX3 genes, with lower expression of the BCL11B gene. MNKPL cells were also highly sensitive to a drug called L-asparaginase. Collectively, these qualities make MNKPL distinct from other leukemia types. These insights will assist with more accurate clinical diagnoses and therapeutic development for MNKPL. Leukemia is a common term used to refer to a form of blood cancer. However, there are different types of leukemia depending on the cell type involved. One unique form is myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL). Because of its rarity, there is no consensus on the specific characteristics needed to clinically identify this disease. In a recent article published in Science Advances, a team led by researchers at Tokyo Medical and Dental University (TMDU) used various approaches to better assess the molecular pro drug sensitivity characteristics of MNKPL. MNKPL was only first proposed as a leukemia subtype in 1997. Extramedullary involvement is one of the hallmarks of MNKPL. It is prevalent in East Asian countries. Although the immunological phenotype of MNKPL was explored previously, a full genetic characterization of this cancer type had not been performed. These details would help support more accurate diagnoses for patients, which would lead to more appropriate therapeutic decisions. Therefore, the TMDU group aimed to investigate MNKPL on a single-cell level. "A single-cell exploration of MNKPL would not only help us better understand its clinical and genomic features, but also clarify the specific cellular origin of this disease," says Dr. Akira Nishimura, lead author of the study. The team first used what is known as a multiomics approach to investigate MNKPL patient samples. They used various sequencing technologies to determine if there were any relevant mutations in specific genes, look for expression differences in certain signaling pathways at the RNA level, and examine any unique DNA methylation patterns. "Our results demonstrate that MNKPL has molecular qualities that are distinct from other similar cancers, such as acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia," explains Dr. Masatoshi Takagi, senior author. "Specific hallmarks of MNKPL include activation of the NOTCH1 and RUNX3, as well as lower expression of the BCL11B." Further work at the single-cell level in MNKPL cells showed that NK cells and myeloid cells come from a common progenitor cell type. The researchers also conducted in vitro drug sensitivity assays where they measured MNKPL cell responses to 79 individual anti-cancer drugs. "We observed that MNKPL cells were highly sensitive to a drug called L-asparaginase, which has already shown clinical effectiveness for this disease," says Dr. Nishimura. "Mechanistically, we found that this was from low expression of asparagine synthetase, a quality that was distinct from other similar types of leukemia." Overall, the robust and comprehensive analysis performed in this study provides crucial molecular details for characterizing MNKPL. This work will undoubtedly help clinicians more effectively diagnose MNKPL and choice of therapeutic option. Additionally, this work provides data that will assist with novel therapeutic target identification and drug development in this leukemia.