Pb1886: real world experience of venetoclax-azacytidine combination in frail elderly patients unfit for intensive chemotherapy

Topic: 4. Acute myeloid leukemia - Clinical Background: The prognosis of older patients with AML unfit for intensive chemotherapy is poor, particularly in those with secondary/therapy related AML or those with adverse genetics. Although CPX-351 has been approved for this subset of patients, (ORR-59%), a more tolerable alternative is needed for frail patients with multiple comorbidities. The addition of venetoclax to hypomethylating agents is approved and we share our experience in this patient population. Aims: We describe our experience in delivering Venetoclax and Azacitidine in AML patients who are ineligible for intensive chemotherapy, the majority of whom had adverse risk genetics and background of myelodysplasia. Methods: 15 consecutive patients with AML were initiated on a combination treatment with oral Venetoclax (at effective dose of 200-400mg/24hr for 14-28 days - Venetoclax at 100mg with Posaconazole gave an effective dose of 400mg) and a standard dose of subcutaneous Azacytidine (75mg/m2 for 5-7 days) at Royal Berkshire Hospital, UK between March 2020-December 2022. We reviewed disease characteristics and treatment response as per ELN 2022 criteria along with recorded adverse events as graded according to CTCAE. Results: The median age was 68 years (range 42-76). The patients were comorbid with a median Charlson Comoborbidity Index of 5 (range 2-9); most common comorbidities being cardiovascular (27%) and respiratory-related (33%). 5 patients (33%) had a baseline ECOG score of 2-3. The majority (11 patients) had secondary AML (73%). 13 patients (86%) were assigned adverse risk (2022 ELN). 40% patients had complex karyotype (13% had monosomy 7, 13% had trisomy 8 and 33% had TP53 variant/deletion). Our patients received a median of 2 cycles of treatment (range 1-4). Most received venetoclax dose of 400mg/24hr with a median duration of 14 days(range 1-28 days) and azacytidine at 75mg/m2. The median follow was 5 months (range 0.3-19.5), the median overall survival was 6.7 months (range 0.4-28.1). Overall Response Rate was 73% [47% Complete Response, 26% Partial Response). By the end of cycle 2, overall response were seen in 7 out of 8 patients still on treatment (87.5%). Responders to treatment had a median OS of 6.7 months (range 2.2-28.1) and those who managed to complete at least two cycles had a median OS of 6.3 months (2.2-28.1). Those with secondary AML had a median OS 7.1 months (range 3.6-19.5) compared to de-novo AML(median OS 3.3 months (range 0.4-28.1). The ORR for secondary AML was 70% with a CR rate of 50% compared to de-novo AML with ORR 60% and CR 40% respectively (OR for ORR=0.58; 95% CI 0.044–7.661, p=0.34, and CR=1.5; 95% CI 0.170–13.2, p=0.357). Patients with complex karyotype had poorer outcome with a median OS of 3.3 months (range 0.4-10) compared to those without complex karyotype (median OS 7.1 months (range 3.6-28.1)(Hazard Ratio for Death=3.46; 95% CI 0.881–13.647, p<0.05). The ORR in patients with complex karyotype was 57% with CR rate=33% compared with those without complex karyotype, ORR=78% and CR rate=56% (OR for ORR=0.57; 95% CI 0.057–5.775,p=0.317 and CR=0.40; 95% CI 0.047–3.4, p=0.2). Key adverse events were febrile neutropenia (87%), nausea (80%) and diarrhoea (53%) of any grade. Grade 3 bleeding occurred in 3 patients (20%). Summary/Conclusion: Venetoclax-Azacitidine was effective and well tolerated in frail patients with comorbidities, particularly secondary AML and standard risk karyotype.Keywords: Complex aberrant karyotype, Myelodysplasia, Venetoclax, AML