-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

308 Correlations between Mutations in Cancer-Related Genes, Therapy Responses and Outcomes of the 3rd Generation Tyrosine Kinase-Inhibitor (TKI) in Persons with Chronic Myeloid Leukemia Failing Prior TKI-TherapyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Mechanisms of resistance and expanded therapies
Hematology Disease Topics & Pathways:
Genomics, Epidemiology, Clinical Research, Diseases, Myeloid Malignancies, Biological Processes
Saturday, December 11, 2021: 4:15 PM

Xiaoshuai Zhang1*, Zongru Li2*, Yazhen Qin3*, Robert Peter Gale4,5, Xiaojun Huang6 and Qian Jiang, MD7

1Peking University People's Hospital, Beijing, China
2Peking University Institute of Hematology, Peking University People’s Hospital, Beijing, China
3Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematology Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
4Haematology Research Center, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, UK, London, United Kingdom
5Centre for Haematology Research, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
6Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
7Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, People’s Republic of China, Beijing, China

Background Most, but not everyone with chronic myeloid leukaemia (CML) responds to imatinib or 2nd-generation tyrosine kinase-inhibitors (TKIs). Mutations in cancer-related genes and in other than ABL1 may explain variable responses and outcomes to the 3rd-generation TKIs including ponatinib and olverembatinib.

Aim Interrogate correlations between mutations in cancer-related genes and therapy responses and outcomes to 3rd-generation TKIs.

Methods We used deep targeted sequencing for cancer-related mutations and Sanger sequencing for BCR::ABL1 on DNA samples from 167 subjects with CML failing to the prior imatinib and/or 2nd-generation TKI-therapy and just before receiving a 3rd-generation TKI. Gene ontology (GO) analysis was used to evaluate functional enrichment in GO terms among mutated genes. Optimal cut-offs for variant allele frequencies (VAFs) of the common mutations were determined by analyzing receiver-operator characteristic (ROC) curves. A Cox multi-variable regression model was used to identify correlations between mutations in cancer-related genes and therapy responses and outcomes of 3rd-generation TKI-therapy.

Results 167 subjects in chronic phase (n = 125) and accelerated phase (n = 42) received ponatinib (n = 28) or olverembatinib (n = 139) therapy. 27 subjects were exposed to imatinib; 79, a 2nd-generation TKI; 61, imatinib and a 2nd generation TKI. 142 (85%) subjects had ABL1 mutations including ABL1T315I (n = 116) or others (n = 26). 163 subjects had other cancer-related mutations which were evaluated in epigenetic regulators (n = 150), transcription factors (n = 84), cell signaling (n = 42), tumor suppressors (n = 39), protein kinases (n = 27), chromatin modification (n = 9) and DNA damage repair (n = 3) related-genes according to functional enrichment. The top 10 mutations were ASXL1 (n = 115), RUNX1 (n = 12), KMT2D (n = 12), PHF6 (n = 8), KMT2C (n = 8), IKZF1 (n = 8), STAT5A (n = 8), DNMT3A (n = 7), TET2 (n = 6) and BCOR (n = 6). 20 subjects had high-risk additional chromosomal abnormalities (ACAs). Frequency of BCR::ABL1 mutations was inversely- (p < 0.001) and of cancer-related mutations directly-related (p = 0.009) to increasing exposure to prior TKI therapies. These relationships were especially so for mutations in KMT2C (p = 0.06), DNMT3A (p = 0.09), KDM6A (p = 0.06) and TNFAIP3 (p = 0.08). BCR::ABL1 (82% vs. 95%, p = 0.03), RUNX1 (5% vs. 14%, p = 0.04), KMT2C (3% vs. 10%, p = 0.08) and IKZF1 (3% vs. 10%, p = 0.10) were more common in accelerated phase. With a median follow-up of 34 months (interquartile range [IQR], 12-40 months), 95 and 71 subjects achieved a complete cytogenetic response (CCyR) and major molecular response (MMR). 18 subjects transformed to accelerated (n = 8) or blast (n = 10) phases, 16 died of disease progression (n = 12) or other causes (n = 4). 3-year cumulative incidences of CCyR and MMR were 65% (95% Confidence Interval [CI], 58, 71%) and 52% (43, 61%). 3-year probabilities of progression-free survival (PFS) and survival were 88% (81, 92%) and 91% (85, 95%). Mutations in tumor suppressor genes were more common in subjects not achieving a CCyR (27% vs. 19%, p = 0.01). In multi-variable analyses ASXL1 mutation with a VAF ≥ 17% and a PHF6 mutation were significantly associated with lower cumulative incidences of CCyR (p < 0.001 and p = 0.032) and MMR (p < 0.001 and p = 0.04). Moreover, subjects with BCR-ABL1T315I mutation had significantly higher cumulative incidences of CCyR (p = 0.07) and MMR (p = 0.04) than those with no BCR-ABL1 mutation and other BCR-ABL1 non-T315I mutation. Increasing age, more Ph1-chromosome-positive cells, the best prior therapy-response < partial cytogenetic response (PCyR) and more TKI-therapies were associated with poor responses. STAT5A mutation was significantly associated with worse PFS (p = 0.002) and survival (p < 0.001), RUNX1 mutation (p = 0.006), high-risk ACAs (p = 0.07) and accelerated phase (p = 0.002) with worse PFS and increasing age (p = 0.05) and comorbidity(ies) (p = 0.05) with wosre survival.

Conclusions ASXL1 mutations with a VAF ≥ 17% and PHF6 mutations were associated with poor responses of the 3rd-generation TKI-therapy. STAT5A and RUNX1 mutations and high-risk ACAs were also associated with worse outcomes in persons receiving a 3rd-generation TKI. These data should help physicians select people to receive 3rd-generation TKIs.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH