Association of Glasdegib + Low-Dose Cytarabine (AraC)) in the Real-Life Treatment of Very Frail Elderly Acute Myeloid Leukemias (AML) Patients

Background Survival of very frail/elderly patients (pts) with Acute Myeloid Leukemia (AML) not eligible for standard induction chemotherpy is very poor. Recently, the association of glasdegib + low-dose cytarabine (AraC) was registered for these pts, but limited data are still available in current clinical practice.

Methods In the present real-life analysis, data from 29 pts with AML treated frontline with glasdegib + AraC in 9 hematologic Centres in Italy outside clinical trials from 6/2022 to 3/2024 were retrospectively collected and analysed. Composite overall response rate [ORR; complete remission (CR) + CR with incomplete hematologic recovery (iCR) + partial remission (PR)], duration of response, overall survival (OS) and safety were assessed.

Results: Patient characteristics at AML diagnosis were as follows: M/F 16/13 (55.2/44.8), median age 77.4 [interquartile range (IQR) 74.8 - 81.1; 12/29 pts (41.4%) aged > 80 years], median WBC count 3.5 x 10⁹/l (IQR 1.4 - 5.8), median marrow blasts 30% (IQR 25 - 45). Twenty-three out of 29 pts (79.3%) had a previous myelodysplastic neoplasia (MDS) and 19 of them have been treated with azacytidine (AZA) during the MDS phase. The median interval from initial MDS diagnosis to AML evolution was 28.1 months (IQR 16.3-34.3). Frailty was evaluated by single responsible physician based on age > 80 years and/or previous MDS phase treated with AZA and/or Performance Status ≥ 2 and/or severe concomitant diseases. AraC was administered subcutaneously for 10 days/month [20 mg twice a day in 15 pts (51.7%) and 40 mg once a day in 14 pts (48.3%)] while glasdegib was given orally 100 mg/day. Pts were treated for a median of 2 courses (IQR 1 - 3). As to toxicity, 21 pts (72.4%) had at least one hematologic toxicity of grade 3-4: in particular, severe neutropenia (PMN < 0.5 x 10⁹/l) was reported in 15 pts (51.7%). Fifteen pts (51.7%) had at least one infective episode during the treatment: pulmonary infections were reported in 6 pts (20.7%). Three pts are still too early to evaluate response: among the remaining 26 pts, 2 achieved CR/iCR and 4 PR, with an ORR of 23.1% and a median response duration of 2.0 months (95%CI 0.9-4.1). At the last observation, 20 pts (69.0%) had died, 7 (24.1%) were alive and 2 (6.9%) were lost to follow-up. Median OS from AML evolution of the whole cohort was 3.3 months (95%CI 1.7-4.8). Pts with any type of response had a significantly longer OS compared to pts with progressive/stable disease [median not reached after 12.5 months versus 2.5 (95%CI 1.1-3.9) months, respectively (p=0.026)].

Conclusions: Our real-life data suggest that glasdegib + AraC combination could be useful only in a small fraction of very frail/elderly AML pts, with an ORR of about 20% in subjects otherwise unfit for any available curative approach: despite the poor outcomes, the potential OS benefit observed in pts who achieved any type of response points to a better selection of pts candidates to this association. Moreover, the addition of other targeted therapies driven by NGS should be explored in the next future in this subset.

Palumbo:GSK: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; AOP: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Incyte,: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Bonifacio:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Latagliata:BMS: Honoraria; Abbvie: Honoraria; Novartis: Consultancy, Honoraria.