Contributions
Abstract: EP662
Type: E-Poster Presentation
Session title: Chronic myeloid leukemia - Biology & Translational Research
Background
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the BCR-ABL1 fusion gene and is treated using tyrosine kinase inhibitors (TKI). The development of new technologies such as next-generation sequencing (NGS) has led to major advances in the understanding of CML pathogenesis. Molecular studies are beginning to reveal genetic profiles associated with adverse events among patients with CML, including thrombotic events, resistance and/or intolerance to TKI and risk of progression. Moreover, the majority of studies on TKI discontinuation show that approximately half of patients maintain treatment-free remission (TFR), but the factors that determine this are yet to be elucidated.
Aims
Study the mutational profile of CML patients and its association with the development of adverse events and maintenance of TFR after TKI discontinuation.
Methods
We retrospectively analyzed 200 ng genomic DNA extracted from peripheral blood at diagnosis of 63 CML patients subsequently treated with TKI with a minimum follow-up of 3 years. NGS was performed with the MiSeq (Illumina) platform using the targeted panel Myeloid Solution™ (SOPHiA GENETICS). Only variants with VAF≥2%, MAF<1% and described as having a pathogenic or probably pathogenic effect were considered. Adverse events considered include thromboembolic or chronic ischemic events, progression to accelerated or blastic phase, and TKI resistance. With respect to TKI discontinuation, we considered relapse vs. no relapse, and late relapse (TFR maintained>6 months) vs early relapse (<6 months).
Results
Of the 63 patients, 32 (50.8%) were male; average age at diagnosis was 54 years. In 48 patients (76.2%) no mutation was detected; 15 (23.8%) presented ≥1 mutation, with an average allelic frequency (VAF) of 25.7%. The most frequently mutated genes were ASXL1 (n=9) and TET2 (n=3) (Figure 1). No association was found between the presence of mutation in the CHIP genes (TET2, ASXL1, DNMT3A or JAK2) and age.
Sixteen patients had a thrombotic event during follow-up (25.4%). No differences were found in the presence of CHIP mutations between patients with and without a thrombotic event (no event: 7/47, 14.9%; event: 4/16, 25%) or presence of any pathogenic mutation (no event: 10/47, 21.3%; event: 5/16, 31.3%).
Three patients (4.7%) developed TKI resistance; two of them carried pathogenic mutations. One patient presented two mutations in ASXL1 (VAF 8-9%); the other in WT1 (VAF 22%) and KRAS (VAF 24%), the latter patient was the only one in our series that advanced to blastic phase. Of the 24 patients who attempted TKI discontinuation, 17 (70.8%) maintained TFR for >6 months while 7 (29.2%) had early relapse. There was no difference between the patients who relapsed vs those who maintained TFR, or between early and late relapse in terms of myeloid mutations.
Conclusion
Less than a quarter of the CML patients analyzed presented pathogenic mutations. These results contrast with those observed in the BCR-ABL1-negative myeloproliferative neoplasms, of whom approximately 50% present mutations (besides the driver genes) and with a higher average VAF. Although patients with thrombotic events presented a higher incidence of myeloid mutations, these differences were not significant. Our results suggest that myeloid mutations are not predictive of TFR or relapse following TKI discontinuation. Larger series are needed to determine whether these mutations are associated with TKI resistance or blastic phase evolution.
Keyword(s):
Abstract: EP662
Type: E-Poster Presentation
Session title: Chronic myeloid leukemia - Biology & Translational Research
Background
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the BCR-ABL1 fusion gene and is treated using tyrosine kinase inhibitors (TKI). The development of new technologies such as next-generation sequencing (NGS) has led to major advances in the understanding of CML pathogenesis. Molecular studies are beginning to reveal genetic profiles associated with adverse events among patients with CML, including thrombotic events, resistance and/or intolerance to TKI and risk of progression. Moreover, the majority of studies on TKI discontinuation show that approximately half of patients maintain treatment-free remission (TFR), but the factors that determine this are yet to be elucidated.
Aims
Study the mutational profile of CML patients and its association with the development of adverse events and maintenance of TFR after TKI discontinuation.
Methods
We retrospectively analyzed 200 ng genomic DNA extracted from peripheral blood at diagnosis of 63 CML patients subsequently treated with TKI with a minimum follow-up of 3 years. NGS was performed with the MiSeq (Illumina) platform using the targeted panel Myeloid Solution™ (SOPHiA GENETICS). Only variants with VAF≥2%, MAF<1% and described as having a pathogenic or probably pathogenic effect were considered. Adverse events considered include thromboembolic or chronic ischemic events, progression to accelerated or blastic phase, and TKI resistance. With respect to TKI discontinuation, we considered relapse vs. no relapse, and late relapse (TFR maintained>6 months) vs early relapse (<6 months).
Results
Of the 63 patients, 32 (50.8%) were male; average age at diagnosis was 54 years. In 48 patients (76.2%) no mutation was detected; 15 (23.8%) presented ≥1 mutation, with an average allelic frequency (VAF) of 25.7%. The most frequently mutated genes were ASXL1 (n=9) and TET2 (n=3) (Figure 1). No association was found between the presence of mutation in the CHIP genes (TET2, ASXL1, DNMT3A or JAK2) and age.
Sixteen patients had a thrombotic event during follow-up (25.4%). No differences were found in the presence of CHIP mutations between patients with and without a thrombotic event (no event: 7/47, 14.9%; event: 4/16, 25%) or presence of any pathogenic mutation (no event: 10/47, 21.3%; event: 5/16, 31.3%).
Three patients (4.7%) developed TKI resistance; two of them carried pathogenic mutations. One patient presented two mutations in ASXL1 (VAF 8-9%); the other in WT1 (VAF 22%) and KRAS (VAF 24%), the latter patient was the only one in our series that advanced to blastic phase. Of the 24 patients who attempted TKI discontinuation, 17 (70.8%) maintained TFR for >6 months while 7 (29.2%) had early relapse. There was no difference between the patients who relapsed vs those who maintained TFR, or between early and late relapse in terms of myeloid mutations.
Conclusion
Less than a quarter of the CML patients analyzed presented pathogenic mutations. These results contrast with those observed in the BCR-ABL1-negative myeloproliferative neoplasms, of whom approximately 50% present mutations (besides the driver genes) and with a higher average VAF. Although patients with thrombotic events presented a higher incidence of myeloid mutations, these differences were not significant. Our results suggest that myeloid mutations are not predictive of TFR or relapse following TKI discontinuation. Larger series are needed to determine whether these mutations are associated with TKI resistance or blastic phase evolution.
Keyword(s):