Page 217 - 2021_06-Haematologica-web

Letters to the Editor
low levels by allele-specific oligonucleotide polymerase chain reaction does not invariably predict relapse, or have a negative impact on cytogenetic response or event-free survival.15 Patients with subclonal T681I mutations detected by ddPCR at diagnosis had a trend towards increased risk of relapse compared to the T681I-negative subgroup; however, these analyses were hindered by small numbers of patients and should be validated in larger cohorts of uniformly treated patients. Furthermore, confirmation of the T681I mutation in relapsed samples would be essential in future studies to validate that relapse was driven by the clonal expansion of drug-resis- tant mutations under the selective pressure of TKI thera- py. However, none of our 23 patients was treated with TKI and relapse samples after TKI treatment were not available for testing.
In conclusion, KD point mutations represent a poten- tial mechanism of acquired resistance in EBF1-PDGFRB Ph-like ALL. The T681I gatekeeper KD mutation was the most common KD mutation in EBF1-PDGFRB Ph-like ALL that was resistant to both imatinib and dasatinib, and could be identified in clinical samples at diagnosis by ddPCR. Validation of our in vitro saturation mutagenesis screens would be important in future clinical trials of Ph- like ALL and concerted efforts should focus on exploring novel therapies targeting the T681I KD mutation.
Thai Hoa Tran,1,2 Jonathan V. Nguyen,2 Adrian Stecula,3 Jon Akutagawa,2 Anthony V. Moorman,4 Benjamin S. Braun,2 Andrej Sali,3 Charles G. Mullighan,5 Neil P. Shah,6
Yunfeng Dai,7 Meenakshi Devidas,8 Kathryn G. Roberts,5 Catherine C. Smith6 and Mignon L. Loh2
1Division of Pediatric Hematology-Oncology, Charles-Bruneau Cancer Center, CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada; 2Department of Pediatrics, Benioff Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; 3Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California San Francisco, San Francisco, CA, USA; 4Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; 5Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA; 6Division of Hematology-Oncology and the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; 7Department of Biostatistics, College of Medicine and Public Health & Health Professions, University of Florida, Gainesville, FL, USA and 8Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN, USA
Correspondence: THAI HOA TRAN - thai.hoa.tran@umontreal.ca doi:10.3324/haematol.2020.261354
Received: June 11, 2020.
Accepted: February 2, 2021.
Pre-published: February 25, 2021.
Disclosures: no conflicts of interest to disclose.
Contributions: THT and MLL designed the study; JN and THT performed the experiments and analyzed the data; AS performed comparative protein structure modeling of PDGFRB; JA, JN and THT performed the drug screens; AVM, YD and MD provided the clinical
data; THT and MLL wrote the manuscript. All authors reviewed the manuscript.
Acknowledgments: we thank the Children’s Oncology Group ALL Biology Committee and the UK Childhood Leukemia Cell Bank for providing the patients’ precious samples.
Funding: this work was supported by National Institutes of Health grants U10 CA98543 and U10 CA180886 (COG Chair's grants), U10 CA98413 and U10 CA180899 (COG Statistics and Data Center grants), U24 CA114766 and U24-CA196173 (COG Specimen Banking), and by the American Lebanese Syrian Associated Charities. MLL is the Benioff Chair of Children’s Health and the Deborah and Arthur Ablin Endowed Chair for Pediatric Molecular Oncology at Benioff Children’s Hospital. THT and MLL were sup- ported by the Innovation Grant of Alex’s Lemonade Stand Foundation as well as the Frank A. Campini Foundation.
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