Abstract
Introduction The Venetoclax Real-World Observational study on effectiveness and treatment management in patients with Newly-Diagnosed (ND) Acute Myeloid Leukemia (AML) who are ineligible for intensive chemotherapy in Italy (VERO, NCT06058741) collects prospective real-world data on the effectiveness and safety of the combination Venetoclax+Azacitidine (Ven/Aza) in Italy, with the additional aim to evaluate patients' quality of life (QoL).
Methods This multi-center observational study is ongoing in 25 clinical sites and was designed to enroll 150 pts. Key inclusion criteria: Adults with ND AML ineligible for IC; independent investigator's decision on Ven/Aza first-line treatment; therapy prescribed in accordance with the approved label/local regulatory/reimbursement policies. This descriptive interim analysis was planned once 50% of the enrolled pts reached at least 3 months follow-up and focused on patient and diseases characteristics and QoL data at baseline. The questionnaires used were EORTC QLQ C-30 and EQ-5D-5L: a high score for a functional scale represents a high / healthy level of functioning,a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
Results Seventy-five pts enrolled (Mar-Oct2024) were analyzed. Mean age was 76.2 (±6) years, with 24% of pts > 80 years and 48% between 75-80 years. All pts were white and 37.3%/62.7% were female/male); 88% of pts were retired at AML diagnosis. Mean BMI was 25.3±4.4 kg/m2. AML was categorized as de novo in 70.7% of the pts, and as secondary AML in 29.3%, half of which occurred after a myelodysplastic syndrome. Mean time from diagnosis to treatment initiation was 3.4±6.3 weeks.
Molecular analyses showed the presence of an NPM1 mutation in 15.9% of 69 pts tested, TP53 in 13.9% of 43 pts, IDH1/2 in 23% of 61 pts and FLT3 in 20.6% of 68 pts.
The ELN2022 risk classification was performed for 66 pts and the main results are reported below:
Mutated NPM1 w/o FLT3-ITD: positive in 7/56 (12.5%)
Mutated NPM1 with FLT3-ITD: positive in 6/54(12.7%)
Wild-type NPM1 with FLT3-ITD: positive in 5/53 (9.4%)
Mutated TP53: positive in 6/38 (15.8%)
The assigned risk was intermediate for 16 pts (21.3%), adverse for 41 (55%), while missing for 18 pts.
According to the 2022 WHO classification, 44 pts had AML with defining genetic abnormalities, most of them (25, 38%) with myelodysplasia related, 22 pts were not evaluated/evaluable (NE); 32 pts had AML defined by differentiation (34 pts NE). The main cytogenetic and molecular abnormality defining Myelodysplasia-Related AML was a complex karyotype (>=3 abnormalities) for 14 pts (21.2%) (45pts NE), while 25 pts had various defining somatic mutations (41 pts NE).
The main reason for ineligibility to IC was an age ≥75 years (39pts, 59%), followed by any other comorbidity that the physician judges to be incompatible (23pts)), and pulmonary disease with DLCO or FEV≤65% (6pts).
Main mean results from EORTC QLQ-C30 at baseline were: Global health status 50.8±23.7; Functional scales: Physical / Cognitive functioning: 67.5±25.9 / 80.5±22.8; Symptoms scales: Fatigue 43.1±27.8, Dyspnea 25.5±27.1, Insomnia 26.4±27.3, Appetite loss 27.8±27.4.
The EQ-5D-5L results at baseline show that the majority of pts had no or little problems in Mobility (72%), Self-care (77.3%), Usual Activities (65.3%), Pain/discomfort (77.3%), Anxiety/depression (73.4%); the mean VAS result was 55.8±19.9.
Conclusions The interim analysis of the VERO study focuses on an elderly cohort, predominantly >80 years, with most having de novo AML, and secondary cases from myelodysplastic syndromes. Molecular testing showed mutations in NPM1, TP53, IDH1/2, and FLT3. Patients largely fell into the adverse category per ELN risk classification, with many having AML with defining genetic abnormalities per 2022 WHO standards. Treatment ineligibility was often due to age and poor ECOG performance status. These data are descriptive, and no final conclusions can be drawn. VERO participants reported moderate global health, with higher cognitive scores and lower physical functioning scores, highlighting the genetic complexity and treatment challenges of AML in the elderly.
