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Additional chromosomal abnormalities at chronic myeloid leukemia diagnosis predict an increased risk of progression.

ABSTRACT: At diagnosis of chronic-phase chronic myeloid leukemia (CML), there are conflicting data as to whether additional cytogenetic abnormalities (ACAs) beyond a standard Philadelphia (Ph) translocation confer a higher risk of subsequent disease progression. In the United Kingdom SPIRIT2 trial comparing imatinib 400 mg daily with dasatinib 100 mg daily, diagnostic karyotypes were available in 763 of the 814 patients recruited. Of these, 27 had ACAs in either/both the original 4 major route group (trisomy 8 or 19, iso17q or a second Ph) or the 5 additional lesions recently described (trisomy 21, 3q26.2, monosomy 7/7q-, 11q23, and complex karyotypes), and their progression rate was significantly higher (22.2%) than in patients without one of these ACAs (2.2%; P < .001). Patients with ACAs had worse progression-free survival (PFS; hazard ratio [HR], 5.21; 95% confidence interval [CI], 2.59-10.50; P < .001) and freedom from progression (FFP; HR, 12.66; 95% CI, 4.95-32.37; P < .001) compared with patients without ACAs. No association was seen between the Sokal or European Treatment and Outcome Study long-term survival (ELTS) scores and the presence of ACAs. Univariate analysis showed that higher Sokal and ELTS scores and the presence of ACAs were associated with poorer PFS, though only ACAs and high-risk ELTS scores were associated with poorer FFP. Multivariable models identified both the Sokal/ELTS score and ACAs as significant independent factors for PFS but only ELTS score and ACAs as significant independent factors for FFP. The data support the view that certain ACAs are predictive of disease progression independently of Sokal or ELTS scores.

SUBMITTER: Clark RE

PROVIDER: S-EPMC7903225 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAdditional chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia are non-random and strongly associated with disease progression, but their prognostic impact and effect on treatment response is not clear. Point mutations in the BCR-ABL kinase domain are probably the most common mechanisms of imatinib resistance.Design and methodsWe assessed the influence of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to the second-generation tyrosine kinase inhibitor nilotinib after imatinib-failure. Standard cytogenetic analysis of metaphases was performed to detect additional chromosomal aberrations and the BCR-ABL kinase domain was sequenced to detect point mutations.ResultsAmong 53 patients with a median follow-up of 16 months, of whom 38, 5 and 10 were in chronic phase, accelerated phase and blast crisis, respectively, 19 (36%) had additional chromosomal aberrations and 20 (38%) had BCR-ABL kinase domain mutations. The 2-year overall survival rate of all patients with-out additional chromosomal aberrations (89%) was higher than that of patients with such aberrations (54%) (P=0.0025). Among patients with chronic phase disease, overall survival at 2 years was 100% and 62% for patients without or with additional chromosomal aberrations, respectively (P=0.0024). BCR-ABL kinase domain mutations were associated with lower remission rates in response to nilotinib, with 9 of 20 (45%) of these patients achieving a major cytogenetic remission as compared to 26 of 33 (79%) patients without mutations (P<0.05). However, overall survival was not affected by BCR-ABL kinase domain mutations.ConclusionsWhereas BCR-ABL kinase domain mutations may confer more specific resistance to nilotinib, which will predominantly affect response rates, the presence of additional chromosomal aberrations may reflect genetic instability and, therefore, intrinsic aggressiveness of the disease which will be less amenable to subsequent alternative treatments and thus negatively affect overall survival. Conventional cytogenetic analyses remain mandatory during follow-up of patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy.

Project description:BackgroundAberrant DNA methylation plays a crucial role in the progression of myeloid neoplasms. Previously, our literature reported that slit guidance ligand 2 (SLIT2) promoter methylation was associated with disease progression and indicated a poor prognosis in patients with myelodysplastic syndrome. Herein, we further investigated the clinical implications and role of SLIT2 promoter methylation in patients with chronic myeloid leukemia (CML).MethodsThe level of SLIT2 promoter methylation was determined in 104 CML patients, and its clinical significance was analyzed. Moreover, demethylation studies were performed in K562 cells to determine the epigenetic mechanism by which SLIT2 promoter methylation is regulated in CML.ResultsThe level of SLIT2 promoter methylation was similar between CML patients and controls. However, deeper analysis revealed that the SLIT2 promoter methylation level in the accelerated phase (AP) and blast crisis (BC) was markedly higher than that in the chronic phase (CP) and controls. Additionally, a marked difference was identified between the SLIT2 promoter hypermethylated and non-hypermethylated groups among CML patients grouped by clinical stage. The frequency of SLIT2 hypermethylation was markedly increased with the progression of clinical stage, that is, it was the lowest in CP samples (12/80, 15%), higher in AP samples (4/8, 50%) and the highest in BC samples (11/16, 69%). Importantly, the level/density of SLIT2 promoter methylation was significantly higher in the advanced stage than in the early stage among the 6 tested paired CML patients. Epigenetically, the expression of the SLIT2-embedded non-coding genes SLIT2-IT1 and miR-218 expression was decreased in patients with CML. SLIT2 promoter hypermethylated cases had a markedly lower SLIT2-IT1 expression level than SLIT2 promoter non-hypermethylated cases. Moreover, SLIT2-IT1 and miR-218 expression was remarkably upregulated in a dose-dependent manner after demethylation treatment of K562 cells.ConclusionsHypermethylation of the SLIT2 promoter is correlated with disease progression in CML. Furthermore, SLIT2 promoter methylation may function by regulating the expression of the SLIT2-embedded non-coding genes SLIT2-IT1 and miR-218 during CML progression.

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Additional chromosomal abnormalities at chronic myeloid leukemia diagnosis predict an increased risk of progression.

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