Poor prognosis of chromosome 7 clonal aberrations in Philadelphia-negative metaphases and relevance of potential underlying myelodysplastic features in chronic myeloid leukemia

Abstract

Clonal chromosome abnormalities in Philadelphia-negative cells could concern chronic myeloid leukemia patients treated by tyrosine kinase inhibitors. The European LeukemiaNet distinguishes -7/del(7q) abnormalities as a "warning". However, the impact of clonal chromosome abnormalities, and specifically those of -7/del(7q), in Philadelphia-negative cells on clinical outcomes is unclear and based on case-reports showing morphological dysplasia and increased risk of acute myeloid leukemia, suggesting the coexistence of chronic myeloid leukemia and high-risk myelodysplastic syndrome. The aim of this study was to determine whether the impact of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells on the clinical outcome is different from that of other types of abnormalities, and we argue for an underlying associated high-risk myelodysplastic syndrome. Among 102 chronic myeloid leukemia patients with clonal chromosome abnormalities in Philadelphia-negative cells with more than a median of 6 years of follow up, patients with -7/del(7q) more frequently had signs of dysplasia, a lower cumulative incidence of deep molecular response and often needed further treatment lines, with the consequent impact on event-free and progression-free survival. Morphological features of dysplasia are associated with myelodysplastic syndrome/acute myeloid leukemia mutations and compromise the optimal response to tyrosine kinase inhibitors, irrespectively of the type of clonal chromosome abnormalities in Philadelphia-negative cells. However, mutation patterns determined by next-generation sequencing could not clearly explain the underlying high-risk disease. We hereby confirm the pejorative prognostic value of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells and suggest that myelodysplastic features constitute a warning signal that response to tyrosine kinase inhibitors may be less than optimal.

Figure 1.

Landscape of mutations detected by next-generation sequencing in patients with chronic myeloid leukemia and myelodysplastic syndromes. Columns (patients) are first sorted by the type of clonal chromosome abnormalities in Philadelphia chromosome-negative cells (CCA/Ph⁻), then by disease [chronic myeloid leukemia in green, myelodysplastic syndrome (MDS) in yellow, advanced disease in orange) and by the presence of morphological features of MDS (in blue characters) from the youngest to the oldest. Pink cells indicate somatic mutations that were detected.

Figure 2.

Cumulative incidence of deep molecular response following the first line of tyrosine kinase inhibitor therapy. (A) Cumulative incidence of deep molecular response (MR4.5) following initiation of the first line of tyrosine kinase inhibitor (TKI) therapy according to the type of clonal chromosome abnormalities in Philadelphia chromosome-negative cells (CCA/Ph⁻). (B) Cumulative incidence of MR4.5 according to the type of CCA/Ph⁻ by landmark analysis 36 months after initiation of the first line of TKI therapy.

Figure 3.

Landmark survival analyses according to the type of clonal chromosome abnormalities in Philadelphia chromosome-negative cells 36 months after initiation of the first line of tyrosine kinase inhibitor therapy. (A) Event-free survival. (B) Progression-free survival. TKI: tyrosine kinase inhibitor.