Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy

Abstract

Key Points Mutation clearance in CML does not directly result in successful treatment in CML. Clinical implications of patterns of mutation acquisition, persistence, and clearance in CML should be interpreted with caution.

Antecedent CHIP in CML?

“…1 These results are consistent with prior smaller studies and indicate that CML can sometimes arise from a preexisting Ph-negative (Ph 2 ) hematopoietic clone already harboring additional gene mutations. This work also adds to the growing body of evidence suggesting that BCR/ABL expression alone may not be sufficient to induce CML.…”

“…The authors show that, under conditions of replicative stress, conditional deletion of Sin3B leads to an accumulation of LT-HSCs and a concomitant loss of differentiated blood cell types. 1 T he capacity of LT-HSCs to undergo selfrenewal upon cell division is a key trait that ensures a continuous output of various differentiated hematopoietic cell types in the blood system over the life span of each individual. 2 Sudden changes in blood cell homeostasis (ie, as a consequence of inflammation, blood loss, or treatment with chemotherapeutics) require an immediate response from the LT-HSC compartment by…”

Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients

“…Whether this transition depends on exposure to a TKI or is secondary to an inherent mutation profile of various subclones that evolve over time is unclear. 19 The existence of these subclones, which could predispose to an overt BP, is supported by one study that demonstrated that the presence of cells with aberrant immunophenotype (myeloid or lymphoid) in patients with CML-CP can predispose them to CML-BP. 20 To our knowledge, the question of whether the subclones give rise to a more resistant disease is not known, but because we have demonstrated that patients with de novo CML-BP had better outcomes compared with patients whose CML transformed from CP/AP (see Supporting Information Fig.…”

“…The data from the current study could be viewed as supportive of this hypothesis because we have demonstrated that prior TKI therapy was a poor prognostic factor in patients with CML‐BP. Whether this transition depends on exposure to a TKI or is secondary to an inherent mutation profile of various subclones that evolve over time is unclear . The existence of these subclones, which could predispose to an overt BP, is supported by one study that demonstrated that the presence of cells with aberrant immunophenotype (myeloid or lymphoid) in patients with CML‐CP can predispose them to CML‐BP .…”

A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation

“…ASXL1 mutations are commonly associated with clonal hematopoiesis in healthy individuals [9][10][11], indicating that ASXL1 mutation may be a pre-leukemic event in hematopoiesis. Accumulating evidence points to a role for ASXL1 mutations in leukemogenesis during early hematopoietic events in many hematological malignancies, as described in AML [18] and CML [19,20]. In the latter case, mutations in ASXL1 occur early in CML stem cells, prior to bcr-abl translocation stage [19], as these cells clonally evolve [20].…”