-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.

4543 Final Report: Somatic Mutations and HMGCLL1 Haplotype Are Not Associated with Molecular Relapse-Free Survival in Patients with Chronic Myeloid Leukemia Who Attempt Treatment-Free Remission

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical Research, CML, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Maria Agustina Perusini, MD1, Katia Pagnano, MD, PhD2*, Carolina Pavlovsky, MD3*, Beatriz Moiraghi, MD4*, Ana Varela, MD4*, Michele Bianchini5*, Carmen Fava, MD, PhD6*, Jiří Mayer, MD7, Daniela Žáčková, MD8*, Anežka Kvetková, MD8*, Tomáš Jurček, PhD8*, Ivana Ježíšková, PhD8*, Ana Beatriz Pascoal Lopes2*, Gislaine Borba Oliveira, MD, Msc2*, Carmino De Souza, MD, PhD2*, Amirthagowri Ambalavanan9*, Anthea Travas9*, Jaeyoon John Kim10*, Danielle Pyne9*, Jessie Medeiros9, Sagi Abelson11* and Dennis Dong Hwan Kim, MD, PhD12

1Princess Margaret Cancer Centre / University Health Network, Toronto, ON, Canada
2Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil
3FUNDALEU, Buenos Aires, Argentina
4Hospital Jose Maria Ramos Mejia, Buenos Aires, Argentina
5CIO-FUCA, Instituto Alexander Fleming, Buenos Aires, Argentina
6Department of Clinical and Biological Sciences, University of Turin, Torino, Italy, Orbassano, To, Italy
7University Hospital Brno and Masaryk University, Brno, Czech Republic
8Dpt. of Internal Medicine Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic
9University Health Network, Toronto, Canada
10Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
11University Health Network, Princess Margaret Cancer Centre, Toronto, Canada
12Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada


Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder resulting from the BCR::ABL1 rearrangement. Patients with CML have a comparable life expectancy to that of age-matched individuals in the general population when they achieve an optimal response with tyrosine kinase inhibitor (TKI) therapy. With the aim of improving the quality of life of patients who are significantly affected by drug-related adverse events and financial burden, the practical goal of CML treatment has shifted to treatment-free remission (TFR), defined as the successful discontinuation (DISC) of TKI therapy without losing leukemia control. TKI treatment DISC is a safe procedure but requires appropriate candidate selection and frequent molecular monitoring. Several biomarkers were investigated, but no definite biomarker has yet been successfully identified and validated. We have investigated somatic mutations before TKI discontinuation and HMGCLL1 haplotype as a potential biomarker for TFR, given that they were previously described as predictors of CML outcomes.

Patients and methods

A total of 155 patients who attempted TKI discontinuation for TFR from 5 countries were included: Canada (n=71), Brazil (n=30), Argentina (n=28), Italy (n=23), and the Czech Republic (n=3). We applied our in-house single molecule-molecular inversion probe (smMIP) panel which is a barcoded error-corrected DNA-based sequencing with a limit of detection up to 0.2%. The panel encompasses 40 genes with 332 amplicon probes: epigenetic modifiers (n=7), activation signaling (n=12), myeloid transcription factor (TF; n=5), spliceosome (n=3), tumor suppressor (n=3), cohesion (n=4), miscellaneous (n=3) and 8 HMGCLL1 single nucleotide polymorphisms (SNPs). Two groups were constructed based on these eight SNPs: group 1: CTCAGGCA (C- haplotype) or group 2: ACGTAATG (A-haplotype). Samples were collected prior to TKI DISC when patients met the criteria for TFR attempt. Molecular relapse-free survival (mRFS) was calculated from the date of TKI DISC to the date of confirmed loss of deep molecular response (DMR). Loss of DMR includes single-time loss of major molecular response (MMR) or two consecutive episodes of loss of molecular response 4 log or deeper response (MR4). Kaplan-Meier survival estimate was used to evaluate mRFS and Cox’s proportional hazard regression model was applied.


The median MR4 duration prior to TKI DISC was 7.2 years (range 4.7-9.3), while overall TKI treatment duration was 8.5 years (range 6.0-11.6). With a median follow-up of 831 days (range: 460-1,415), out of the 155 patients, 68 (43.9%) lost response, among whom 6 lost MMR only, 12 lost MR4 only, and 50 lost MMR and MR4, both. Median time to MMR loss was 95 days (range 83.5-137). A total of 71 mutations were detected in 51 patients (32.9%). TET2 mutation was the most frequent mutation, detected in 17 cases (24%) followed by ASXL1 (n=14; 20%) and DNMT3A (n=12; 17%). When grouped by relevant biological pathways involved, mutations in epigenetic genes (n=42, 61%) were the most frequently involved. mRFS rate was 64% (95% CI [55.8-71.1%]) and 56% [48.2-64.0%] at 6 and 12 months, respectively. During the univariate analysis, no significant difference was observed in mRFS according to the presence, number, or type of somatic mutations, or the HMGCLL1 haplotype. Additionally, there were no significant differences in mRFS based on age, sex, Sokal risk group, line of TKI therapy, or TKI drug type prior to TKI DISC. However, MR4 duration prior to TKI DISC was associated with mRFS rate: patients with≥7.3 years (n=71) showed higher mRFS: 74.09% [62.05-82.82%] compared to those <7.3 years (n=74) with mRFS rate of 44.36% [32.54 -55.51] (p <0.01, HR 0.36 [0.21-0.63]). In addition, a longer duration of TKI treatment before TKI DISC was associated with higher mRFS: patients with ≥ 8.3 years of treatment (n=85) showed 71.8% mRFS [60.4-80.4], compared to 42.5% mRFS [30.5-54.0%] in those with <8.3 years (n=71) (p<0.01, HR 0.48 [0.31-0.74]). Multivariate analyses for mRFS confirmed that MR4 duration and the total duration of TKI treatment before TKI DISC were associated with TFR outcomes, but not the presence of epigenetic mutations, any mutation, or HMGCLL1 haplotype (Table1).


In CML, somatic mutations before attempting TFR are frequently observed. However, our current study does not support their prognostic significance as TFR-predictive biomarkers.

Disclosures: Pagnano: Novartis, Pfizer, EMS, Pintpharma: Speakers Bureau; Novartis, Pfizer: Honoraria. Pavlovsky: Pfizer: Speakers Bureau; Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Moiraghi: Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Takeda: Speakers Bureau. Mayer: BeiGene: Research Funding; MSD: Research Funding. Žáčková: Astra Zeneca: Other: travel grant; Pfizer: Honoraria, Other: travel grant, Speakers Bureau; Angelini Pharma: Consultancy, Honoraria, Other: travel grant, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Speakers Bureau. Oliveira: Janssen: Speakers Bureau. Kim: Pfizer: Consultancy, Honoraria, Research Funding; Paladin: Consultancy, Research Funding; BMS: Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

*signifies non-member of ASH