Standard Non-Intensive Chemotherapy Vs Venetoclax-Azacytidine (Ven-AZA) for Unfit AML Patients with Therapy-Related Acute Myeloid Leukaemia (t-AML) - a Retrospective Study of Polish Adult Leukemia Group (PALG)
Authors: Bolkun Lukasz , Strzala Judyta , Czemerska Magdalena , Budziszewska Bozena Katarzyna , Golos Aleksandra , Holownia Anna , Knopinska-Posluszny Wanda , Marańda Ewa Lech , Piszcz Jaroslaw , Halka Janusz , Wierzbowska Agnieszka 
Published: December 2024

Introduction
Therapy-related acute myeloid leukaemia (t-AML), defined as AML arising from prior cytotoxic, radiation, or immunosuppressive therapy for an unrelated disease, accounts for 7 %-10% of AML cases. The treatment for solid cancer increases the risk of AML up to 10-fold with chemotherapy (patients who receive alkylating agents as part of their therapy) and 2.5-fold after treatment with radiotherapy. While solid and hematologic tumors dominate as the primary disease, t-AML may also occur after the treatment of non-malignant diseases, especially inflammatory disorders. The most frequent primary malignancy preceding t-AML is breast cancer, followed by non-Hodgkin lymphoma (NHL).
The mechanism behind the increased risk of AML after chemo- and/or radiation therapy are not fully understood. More importantly, t-AML is associated with an increased probability of adverse cytogenetics and shortened survival compared with de novo AML. Thus, a clear understanding of t-AML and its optimal treatment options is important to help improve outcomes for this challenging population, especially for patients who are not candidates for intensive therapy such as CPX-351 (liposomal daunorubicin and cytarabine) or conventional chemotherapy.
Patients
Between 2014 and 2024, we identified 107 unfit patients diagnosed with t-AML who were not eligible for intensive therapy due to their age or comorbidities. None of these patients had active primary cancer at the time of their AML diagnosis. The median interval between the treatment of the initial neoplasm and the development of t-AML was 7 years (1 to 12 years). Of these patients, 60% were female. The most frequent primary malignancies preceding t-AML were breast cancer (45%), colon cancer (20%), and non-Hodgkin lymphoma (NHL) (12%).
Patients deemed unfit for intensive treatment before 2021 received either azacitidine (AZA, n=20) or a low-dose of cytarabine (AraC) (n=27). In contrast, from 2021 onward, 50 patients were treated with the Venetoclax-Azacitidine (VenAza) regimen.
The Kaplan-Meier analysis and log-rank test were used for overall survival (OS) in months (m). To evaluate significant differences between categorical data Fisher's exact test was used.
Results
Of the 107 patients identified, the median age was 72. The majority of patients had adverse (n=59) or intermediate-risk (n=45) genetics as defined by the 2017 ELN genetic risk classification. The composite complete remission (cCR=CR+CRi) rate significantly differed among the groups: for low-dose AraC, it was 3%, for Aza alone, it was 20%, and for AzaVen, it was 52% (p=0.01). The median overall survival (OS) for low-dose AraC (4 months) and Aza alone (6.5 months) were poor and showed no significant difference. Conversely, the median OS for VenAza was 10 months, which was significantly different from the median OS for low-dose AraC (p=0.003) and approached significance compared to Aza alone (p=0.07). Within the AzaVen group, patients with p53 mutations had the lowest OS of 3.5 months (12 patients). Conversely, IDH1/2 mutations were associated with a significantly improved OS (median 15 months) compared to unmutated cases; however, both analyses did not achieve statistical significance probably due to the small sample size.
Conclusions
Furthermore, we demonstrated that VenAza significantly improves the cCR rate and overall survival in patients with t-AML who were not eligible for intensive therapy. Nevertheless, the reported higher prevalence of p53 mutations and complex karyotypes in t-AML leads to poorer OS compared to de novo AML patients treated with Ven-Aza.