Prognostic Impact of Complex Karyotype in Acute Promyelocytic Leukemia
Authors: Ribes-Amoros Julia , Pomares Helena , Vives Susana , Brey Nuria , Verge Jordi , Coll Rosa , Cervera Marta , Bechtold Javier Elena , Quiñones Shiomara , Sotelo Maria Isabel , Galiano Mercedes , Alonso Esther , Sureda Balari Anna , Zamora Lurdes , Granada Isabel , Arnan Montserrat 
Published: December 2024

INTRODUCTION
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia defined by a reciprocal translocation t(15;17)(q24.1;q21.2), giving rise to a PML::RARA fusion gene product (Arber et al.,2016). Arsenic trioxide (ATO) or chemotherapy plus all-trans retinoic acid (ATRA) frontline treatment regimens are the current standard of care (SOC) for patients with newly diagnosed APL (Sanz et al., 2019). Additional cytogenetic abnormalities (ACA) are frequently found in APL and more rarely complex karyotype (CK) (Arber et al.,2016). Different groups have tried to establish the prognostic impact of CK, but their low prevalence and the variability within the alterations do not make it an easy task (Epstein-Peterson et al., 2022). This study aims to analyze our cohort's overall survival (OS), event free survival (EFS) and to determine the prognostic impact of complex karyotype in this setting of patients.
METHODS
We included all APL patients diagnosed at 4 oncology centers associated with the Catalan Institute of Oncology (ICO-Institut Català d'Oncologia“) between 2005 and 2024 analyzing those with the presence of t(15;17) demonstrated by karyotype.CK was defined as the presence of ≥ 2 cytogenetic alterations in addition to the t(15;17). OS and EFS were determined by Kaplan-Meyer method. A multivariable Cox proportional hazards model was used to correlate OS and EFS with clinical and biological characteristics.
RESULTS
One hundred eighty-six patients were included and a total of 148 were analyzed. Thirteen patients were excluded due to lack of karyotype growth, 12 patients for presenting a normal karyotype which made impossible to distinguish between the normal clone selection or a cryptic karyotype, 11 patients for not being treated with SOC and received ATRA alone and 2 patients due to loss to follow-up.
Median age at diagnosis was 51 years (range:16-85 years). Sixty-nine (46.6%) were male. At diagnosis: median hemoglobin 89 g/L (range:4.4-161g/L), platelets 28 x109/L (range: 3-256 x109/L), total leucocytes count 3.4 x109/L (range: 0.3-169.87 x109/L) and 103 patients (69.6%) presented with associated coagulopathy. One hundred and twenty-two (82.4%) patients had a karyotype with 46 chromosomes and the t(15;17) (n=122, 82.4%) as unique alteration. Four (2.7%) presented with ACA and 22 (14.9%) with CK. All patients received treatment, 93 (62.8%) with chemotherapy (idarubicin 12mg/m 2) plus ATRA and 55 (37.2%) with ATO plus ATRA. Median follow-up among surviving patients was 52 months (range: 0- 297 months) Thirty-five patients (23.6%) died (32 died from disease related complications and 3 non-disease related) and 15 (10%) relapsed during follow-up. OS was significantly worse in the CK-group as compared with non-CK (71.6 months vs not reached (NR); p=0.002). Moreover, CK patients had a significantly lower median EFS compared to non-CK patients (46.8 months vs NR; p&lt;0.001). We also observed worse OS and EFS in the CK group regardless of the treatment received (ATRA plus chemotherapy vs ATRA plus ATO, p=0.012). Multivariate analysis performed including gender, age, total leucocyte count, karyotype at diagnosis and treatment received, showed that older age (&gt;60years) was associated to a worse OS, independently of treatment, total leukocyte count karyotype and gender (p &lt;0.001; HR 9.4). Regarding EFS, multivariate analysis showed that CK was associated with poor EFS, independently of treatment, leukocyte counts at diagnosis, age and gender (p=0.015; HR 4.1).
CONCLUSIONS
Our cohort results confirm the negative impact on OS and EFS of CK. As therapeutical decisions are based on the initial prognostic risk assessment, the inclusion of CK as a variable in this assessment may provide more precise prognostic information and may indicate a need for better treatment strategies to overcome this adverse effect and improve outcomes in this subgroup of patients. Larger prospective analyses are required to confirm our data.