Assessment of Additional Chromosomal Abnormalities at Diagnosis in a Cohort of Patients with Chronic Myeloid Leukemia Treated with Generic Imatinib
Authors: Santos Gustavo Emmanuel Alves Abrantes , Emiliano Estela Gasparotto , Miranda Eliana , Duarte Gislaine Oliveira , Duffles Guilherme , Gonçalves Natalia Nunes , Magalhães Gustavo HR , Clementino Nelma , Seguro Fernanda Salles , Bendit Israel , Toni Isabella Macedo , Furlin Graziele CP , Zocca Maristela , Oliveira Rosemary de , Melo Campos Paula , De Souza Carmino , Conchon Monika , Pagnano Katia B 
Published: December 2024

Introduction

Additional chromosomal abnormalities (ACAs) beyond the standard Philadelphia (Ph) translocation at diagnosis may confer worse outcomes for chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI).

Aims

This retrospective observational study aimed to evaluate the frequency and type of additional chromosomal abnormalities (ACAs) at diagnosis in a Brazilian cohort of patients with CML treated with generic imatinib as first-line therapy and to evaluate its influence on CML outcomes.

Methods

We evaluated clinical and laboratory data from patients with newly diagnosed CML between January 2015 and June 2024. Inclusion criteria: Adult CML patients treated with generic imatinib as the first-line therapy, any phase. Major route ACAs (+8, +Ph, i[17q], +19, and +17) and +21, complex karyotypes, -7/7q-, 3q26.2, and 11q23 abnormalities were classified as high-risk ACAs, and other ACAs were classified as minor route or low-risk. All patient data were managed and stored in the REDCap platform. Survival curves were calculated using Kaplan-Meier and the differences by log-rank test. Overall survival (OS) was calculated from the start of imatinib until death from any cause or last follow-up. Progression-free survival (PFS) was calculated from starting imatinib until progression to AP, BC, or death. Cox regression was used in multivariate analysis to identify factors impacting OS and PFS. The cut-off date of this analysis was July 2024.

Results

A total of 242 patients were analyzed; 54.5% were male. The median age at diagnosis was 51 (range 17-89) years. According to the Sokal score, 31% were low risk, 33.5% intermediate risk, 21.9% high risk, and 13.6% had missing data. Hasford score: 44.6% had low risk, 29.8% intermediate risk, 10.3% high risk, and 15.3% had missing data. According to the Eutos score, 71.5% had low risk, 12% high risk, and 16.5% had missing data. Regarding the BCR::ABL transcript type, 49.6% had b3a2, 31.8% b2a2, 7% had both b3a2 and b2a2, 1.7% had others, and 9.9% were missing. At diagnosis, the median WBC was 104000/mm3 (range 5.47-757), hemoglobin 11.3 g/dL (5.4-12.2), hematocrit 35% (18.8-49.4), eosinophils 2% (0-21), basophils 3% (0-19), platelets 375000/mm3 (71-2625), blasts 2% (0-50), bone marrow blasts 1% (0-63), and bone marrow basophils 1.4% (0-124). Cytogenetic findings: 77.3% had standard Ph1 chromosomes, 9.5% had no metaphases available, 7% variant Ph1, 6.2% minor route ACAs (low risk), 2.9% high-risk ACAs, and 1.2% had missing data. The OS for those without and with ACAs was 89% and 77%, respectively, at 60 months (p=0.17), and the PFS was 89% and 74% at 60 months (P=0.08), respectively. OS for Ph1, variant Ph1, low-risk cytogenetics, and high-risk cytogenetics was 90%, 68%, 86%, and 71%, respectively (P=0.36), and PFS was 89%, 68%, 79%, and 71%, respectively (P=0.33). OS for the Sokal score low, intermediate, and high-risk groups was 95%, 93%, and 67%, respectively, at 60 months (P&lt;0.0001), and the PFS was 97%, 91%, and 65%, respectively, at 60 months (P&lt;0.0001). The OS for the Hasford score low, intermediate, and high-risk groups was 97%, 87%, and 49%, respectively, at 60 months (P&lt;0.0001)., and the PFS was 96%, 86%, and 49%, respectively, at 60 months (P&lt;0.0001). The OS for the Eutos score for low and high-risk groups was 93% and 53%, respectively, at 60 months ((P&lt;0.0001), and the PFS was 92% and 50%, respectively, at 60 months (P&lt;0.0001). In the multivariate analysis, older age and a high Hasford score were independent factors for survival. Fourteen of 242 patients progressed to advanced phases, 5 to accelerated phase, and 9 to blast crisis. At the last follow-up, 36.8% continued with imatinib therapy.

Conclusions: Patients with high-risk ACA had lower rates of OS and PFS, but this was not statistically significant in our cohort, probably due to the number of cases. Patients with high-risk Sokal, Hasford, and EUTOS scores had inferior outcomes.