Introduction:

Recently, the presence of a variety of AGA to the BCR-ABL1 oncogene in CP-CML has been described to impair the prognosis of this disease and response to TKIs. We have taken the opportunity of the Trial of Imatinib After Ponatinib Induction (TIPI) to explore such consequences by NGS targeting the most frequently mutated lympho-myeloid genes in AL, in newly diagnosed CP-CML patients (pts) undergoing this sequential therapy. .

Methods

TIPI is an open-label phase II national academic trial (Clinical Trial: NCT04070443) for newly diagnosed adult CP-CML pts ≤65 years, harbouring major BCR::ABL1 transcripts. The primary endpoint is the rate of pts reaching TFR criteria at M36. Pts were treated with ponatinib 30 mg QD for 6 months, followed by a de-escalation with imatinib 400 mg QD until TFR criteria (MR4.5 ≥2 years) are reached, before M60. Molecular assessments were centralised and BCR::ABL1/ABL1 transcripts expressed in % on the international scale. BCR::ABL1 TKD mutations were screened by NGS. AGA were assessed by NGS (30-genes panel). Only VAF>5% were retained as pathological. The MMEJ signature was inferred from the BCR::ABL1 breakpoint sequences determined by an asymmetric capture sequencing strategy, as described by H. Guerineau et al (AJH 2025; 100: 507–510).

Results

One hundred and sixty nine pts were enrolled between November 2019 and October 2022, median age was 48 (18-65) years, 113 pts were males (67%) and 15 (9%) pts harboured additional chromosomal abnormalities (ACA). Eighty-four (51.5%) pts had b2a2 and 99 (61%) b3a2 transcripts and could eventually harbour both. ELTS were low for 67 (40%), intermediate for 73 (44%) and high for 27 (16%) pts, data unavailable for 2. The median follow-up was 18 (2.8-46.1) months. The CI of MR4 and MR4.5 were respectively 33 (26-40)% and 10 (5-14)% at M12; 40 (33-48)% and 13 (8-18)% at M18. One possible toxic death and 2 progressions (1 MBC, 1 LBC) occurred, resulting into death after allo-SCT. Only 3ABL1 mutations (2%) were observed, [1 on ponatinib, E255K at M6 (MBC pt), and 2 M244V on imatinib]. Full clinical results have already been presented (Nicolini FE et al. ASH 2024). At the time of writing, 148 patients were sequenced on diagnosis samples and mutated clones are followed-up and presented, on ponatinib and further on imatinib. We compared pts with AGA (n=30, 20%) with pts with no AGA (n=118). Thirty patients (20%) were harbouring AGA consisting in ASXL1 (n=18, 60%), KDM6A (n=3, 10%), DNMT3A (n=2, 7%) IKZF1, RUNX1, SETD1B, BCORL1, BCOR, TET2 and WT1 (n=1 each, 3.3%) and 24/133 (18%, 15 MD) patients showed a MMEJ signature. There was no difference between the 2 groups in age and sex. ACA were present in 4/30 patients with AGA (13%) and in 5/117 (1 MD, 4%) patients without AGA. Sokal score was low in 45%, intermediate in 36% and high in 19% of pts with AGA versus low in 17%, intermediate in 33% and high in 50% of pts without AGA (p<0.001). ELTS score was low in 40.5%, intermediate in 47.5% and high in 12.5% of patients with AGA versus low in 30%, intermediate in 37% and high in 33% of pts without AGA (p=0.02). While the 18-month cumulative incidence (CI) of MMR and MR4 were not different between the 2 groups, the CI of MR4.5 was significantly higher in the AGA group 24% (8.2-40.2) vs without AGA 10.25% (4.73-15.78) with HR=2.62 (95% CI: 1.03-6.64), p=0.043 in univariate analysis. Moreover, the presence of MMEJ had a strong negative impact on the 18-month CI of MR4.5: 0% with MMEJ vs 16.5% (9.5-23.5) without MMEJ p<0.001. The MMEJ+ versus MMEJ- groups show no difference except the ELTS intermediate + high scores were higher in the MMEJ+ group (p=0.016). Neither the presence of AGA nor the presence of MMEJ had an impact on 18-month EFS (p=0.38 and p=0.166 respectively). Interestingly, one of the 2 BC that occurred harboured AGA at diagnosis (WT1, VAF=6%) but no MMEJ signature. Multivariate analysis adjusted on MR4.5 at M18 identified the presence of AGA as beneficial [HR=3.46 (1.29-9.26), p=0.014].The kinetics of AGA on sequential treatment by ponatinib followed by imatinib will be presented.

Conclusions

Twenty percent of newly diagnosed CP-CML harbour AGA at diagnosis that significantly impact on molecular response at 18 months on sequential therapy by ponatinib followed by imatinib. Additionally, the role of MMEJ seems to have a strong negative impact on obtaining deep molecular response.

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2025
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