Impact of additional genetic abnormalities at diagnosis of chronic myeloid leukemia for first-line imatinib-treated patients receiving proactive treatment intervention

Abstract

The BCR::ABL1 gene fusion initiates chronic myeloid leukemia (CML); however, evidence has accumulated from studies of highly selected cohorts that variants in other cancer-related genes are associated with treatment failure. Nevertheless, the true incidence and impact of additional genetic abnormalities (AGA) at diagnosis of chronic phase (CP)-CML is unknown. We sought to determine whether AGA at diagnosis in a consecutive imatinib-treated cohort of 210 patients enrolled in the TIDEL-II trial influenced outcome despite a highly proactive treatment intervention strategy. Survival outcomes including overall survival, progression-free survival, failure-free survival, and BCR::ABL1 kinase domain mutation acquisition were evaluated. Molecular outcomes were measured at a central laboratory and included major molecular response (MMR, BCR::ABL1 ≤0.1%IS), MR4 (BCR::ABL1 ≤0.01%IS), and MR4.5 (BCR::ABL1 ≤0.0032%IS). AGA included variants in known cancer genes and novel rearrangements involving the formation of the Philadelphia chromosome. Clinical outcomes and molecular response were assessed based on the patient's genetic profile and other baseline factors. AGA were identified in 31% of patients. Potentially pathogenic variants in cancer-related genes were detected in 16% of patients at diagnosis (including gene fusions and deletions) and structural rearrangements involving the Philadelphia chromosome (Ph-associated rearrangements) were detected in 18%. Multivariable analysis demonstrated that the combined genetic abnormalities plus the EUTOS long-term survival clinical risk score were independent predictors of lower molecular response rates and higher treatment failure. Despite a highly proactive treatment intervention strategy, first-line imatinib-treated patients with AGA had poorer response rates. These data provide evidence for the incorporation of genomically-based risk assessment for CML.

Figure 1.

The genomic findings of the TIDEL-II cohort at diagnosis. (A) Oncoplot of additional genetic abnormalities identified at diagnosis. (B) The predominant Philadelphia chromosome (Ph)-associated rearrangements for individual patients based on the fusion read counts are shown. The diversity of the partner genes (outer circle) involved in the Ph-associated rearrangements is illustrated. Color of the inner circle corresponds to the chromosome location of the involved gene. Width of the ribbon correlates with the frequency of co-occurrence of the fusion partner. All events were in addition to the primary BCR::ABL1 transcript. The complete list of Ph-associated rearrangements is documented in Online Supplementary Table S2. Fusions between BCR and ABL1 in the Circos plot represent inversions.

Figure 2.

The clonal dynamics of two patients with ASXL1 variants at diagnosis illustrated by fishplots. (A) Patient 430 had a Philadelphia chromosome (Ph)-associated rearrangement in addition to the BCR::ABL1 clone (dark blue) at diagnosis. The Ph-associated rearrangement involved an inversion between ABL1 exon 1 and an intergenic region on chromosome 17q12. In addition, two mutant subclones were detected at diagnosis. One clone contained an ASXL1 frameshift variant (light blue) and the second subclone harbored a BCORL1 frameshift variant, a 34 Kb RUNX1 deletion, and an IKZF1::IGKV3-7 fusion (represented in pink). With the decline of BCR::ABL1 in response to imatinib, the subclones were reduced and the ASXL1 clone became undetectable. However, the second clone expanded and evolved to lymphoid blast phase at 4 months of imatinib. Several independent subclones arose from the original BCORL1/RUNX1/IKZF1 subclone, including an SMC3 nonsense variant, an EZH2 missense variant, and six ABL1 kinase domain mutations. The second patient (384) harbored a single ASXL1 nonsense variant at diagnosis. A rapid deep molecular response was achieved and the ASXL1 subclone became undetectable. The optimal response was maintained. (B) Integrative Genomics Viewer (IGV) screenshot of amino acids 252-255 of ABL1 of patient 430, demonstrating that the Q252H, Y253H, E255K and E255V kinase domain mutations were on separate reads, which indicates that these mutations were in separate clones and were not compound mutations. Only a proportion of each of the mutant reads is shown. TKI: tyrosine kinase inhibitor.

Figure 3.

Additional genetic abnormalities at diagnosis were an independent predictor of specific outcomes and molecular responses. The graphs show the outcomes and responses according to additional genetic abnormalities (AGA) status at diagnosis. (A) Kaplan-Meier estimates of failure-free survival. (B) Cumulative incidence of the acquisition of BCR::ABL1 kinase domain mutations. (C) Cumulative incidence of major molecular response. (D) Cumulative incidence of MR4. (E) Cumulative incidence of MR4.5. The number at risk table is included below the relevant graphs. TKI: tyrosine kinase inhibitor.

Figure 4.

Failure-free survival and molecular response among the EUTOS long-term survival score risk groups according to additional genetic abnormalities at diagnosis. Failure-free survival (FFS) according to (A) low and (B) intermediate-/high-risk EUTOS long-term survival score (ELTS). The 48-month cumulative incidence of major molecular response (MMR) according to (C) low and (D) intermediate-/high-risk ELTS; 12-month values indicated. The 4-year cumulative incidence of MR4 according to (E) low and (F) intermediate/high-risk ELTS, and the 4-year cumulative incidence of MR4.5 according to (G) low and (H) intermediate-/high-risk ELTS. TKI: tyrosine kinase inhibitor.

Figure 5.

Impact of additional genetic abnormalities on molecular response for patients who switched to nilotinib for trial-defined failure criteria. Outcomes and responses according to additional genetic abnormalities (AGA) status at diagnosis in patients who switched to nilotinib for trial-defined nilotinib switch criteria, excluding imatinib intolerance. (A) Cumulative incidence of major molecular response (MMR). (B) Cumulative incidence of MR4 by 4 years. (C) Cumulative incidence of MR4.5 by 4 years. TKI: tyrosine kinase inhibitor.

Figure 6.

ASXL1 variants were associated with treatment failure, including the acquisition of BCR::ABL1 kinase domain mutations. ASXL1 variants predicted for (A) inferior failure-free survival (FFS) and (B) the acquisition of BCR::ABL1 mutations compared with other additional genetic abnormalities (AGA) or no AGA at diagnosis.