The Prognostic Significance of Chromosome 17 Addition Vs. Complete and Partial Loss in Patients with Acute Myeloid Leukemia, a Single Center Experience

Background

Cytogenetic abnormalities are the most significant prognostic factor in acute myeloid leukemia (AML). Many studies in adult AML have found an association between chromosome 17 (ch17) abnormalities, poor response to therapy, and low survival rates. However, these studies primarily focused on partial deletions (del) or loss, but less is known about ch17 addition (add(17)). Therefore, we sought to investigate the impact of ch17 abnormality subtypes on the prognosis of AML.

Methods

We performed a single-center retrospective cohort study in patients with AML to investigate the impact of ch17 abnormalities on the clinical response rate to first-line therapy, overall survival (OS), and event-free survival (EFS). We identified all adult patients (≥18 years) with AML who were diagnosed and treated at Cleveland Clinic for AML between May 2015 and September 2023. Using conventional cytogenetics at the time of diagnosis, patients were divided into 3 comparison groups: 1. ch17 partial or complete loss (ch17-loss): -17, del(17), or i(17); 2. ch17 addition: add(17); and 3. normal ch17 (NL-ch17). We collected baseline variables, including age, sex, ethnicity, comorbidities, subtypes of AML, cytogenetics, BCR-ABL1 status, mutational profile based on next-generation sequencing, ECOG performance status, all treatment lines and responses, and follow-up data. Response to first-line treatment included composite complete response (CCR) (complete response (CR) + complete response with incomplete count recovery (CRi)) and responses assessed by MRD by flow cytometry (MRD-FC). OS was defined from the time of diagnosis to the date of death. EFS was defined from the time of diagnosis to the time of refractoriness, progression, or death. The Kaplan-Meier method estimated survival probabilities, and the log-rank test was used to test for differences. Multivariable analysis was used to adjust for confounding.

Results

During the study period, 730 patients were treated for AML. 678 patients had cytogenetic exams at the time of diagnosis. Among them, 609 patients (90%) were NL-ch17, 50 patients (7%) had ch17-loss, and 19 (3%) had add(17). Seven patients with concurrent loss and addition were excluded. The median age was 65, 68 and 71 for NL-ch17, ch17-loss, and add(17) groups, respectively (P=0.3). Average bone marrow blasts at diagnosis were 49, 30 and 36%, respectively (P<0.01). Average ANC at diagnosis was 1.2, 0.5, and 0.4 K/microL in NL-ch17, ch17-loss, and add(17) groups, respectively (P<0.01). The following cooccurring cytogenetic abnormalities were seen higher in the ch17-loss and add(17) groups than NL-ch17 group: -5 or del(5q), -7 or del(7q), monosomal karyotype and complex karyotype (P<0.01). Among the most observed mutations, TP53 was significantly higher in the ch17-loss (93%) and add(17) (69%) groups vs. the NL-ch17 group (10.0%) (P < 0.01). FLT3 was found in 26% of the NL-ch17, 21% in the add(17), and absent in the ch17-loss (P < 0.01). NPM1 was seen in 30% of the NL-ch17 but absent in both the ch17-loss and add(17)(P < 0.01). Both ch17-loss and add(17) had lower odds of response for first-line therapy as compared to NL-ch17 (OR=0.4; 95% CI 0.20-0.78) and (OR=0.3; 95% CI 0.08-0.95) (P<0.01). The ch17-loss group was significantly associated with decreased cytogenetic response for first-line therapy compared to NL-ch17 (OR=0.27; 95% CI 0.11-0.60). The median follow-up for OS was 34.89 months (range 0.49-108.12). During this time, 490 patients died from any cause. The median 12-month OS for ch17-loss and add(17) was 22% (95% CI 13- 37) and 21% (95% CI 8.8- 50) compared to 55% (95% CI 52-60) in the NL-ch17 group (P<0.05). On multivariable Cox proportional hazards model, both ch17-loss (hazard ratio (HR)=2.20; 95% CI 1.62-2.99) and add(17) (HR=2.28; 95% CI 1.42-3.68) had a higher mortality than NL-ch17 (P<0.01). Also, Abnormalities of ch17 were significantly associated with decreased EFS. Both ch17-loss and add(17) had worse EFS to the NL-ch17 group, respectively (HR=1.97; 95% CI 1.45-2.68) and (HR=1.78; 95% CI 1.11-2.87) (P<0.01).

Conclusions

Chromosomal abnormalities involving ch17 are associated with a poor prognosis. Both the addition and loss of ch17 were associated with a very similar impact on AML clinical response to first-line treatment and cytogenetic responses. Additionally, both have a negative impact on outcomes and significantly reduce overall survival and event-free survival.