Single Centre Experience in Treating Elderly Patients with Acute Myeloid Leukaemia or High Risk Myelodysplastic Syndrome with a Combination of Low Dose Cytarabine, Venetoclax and Fluconazole (VeLDAC-F)
Authors: Child Lauren , Chan Henry , Henderson Ross Alistair , Elinder Anna , Merriman Eileen , Hanna Merit , Simpson David 
Published: October 2019

Introduction

Acute myeloid leukaemia (AML), high risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukaemia (CMML) are bone marrow disorders that predominately affect the elderly population. The treatment options for this patient group have been limited and those unable to undergo intensive chemotherapy have historically had a poor prognosis.

Low dose cytarabine (LDAC) is an accepted treatment option in patients who are ineligible for intensive therapy. LDAC has been shown to achieve a complete response (CR) and complete response with incomplete count recovery (CRi) in 11-18% of patients with a median overall survival of 5- 12 months. Recent evidence suggests that venetoclax (VEN) has a synergistic effect with LDAC with a phase I/II trial reporting a CR +CRi of 33/61 (54%) with this combination.

Antifungal agents are commonly used in AML treatment protocols due to the increased risk of invasive fungal infections in this population. Fluconazole, a moderate CYP3A4 inhibitor, increases the maximum concentration (Cmax) of VEN resulting in a 2-5-fold increase in the area under the curve (AUC), thereby significantly increasing drug exposure. When using an azole antifungal, a dose reduction of VEN is recommended to maintain safe therapeutic levels. Here, we present our experience with using a lower dose of VEN in combination with fluconazole and LDAC (VeLDAC-F) in patients with AML, high risk MDS and CMML.

Methods

Patients with a diagnosis of AML, high risk MDS or CMML that required treatment but were not candidates for high intensity chemotherapy were offered the combination of VeLDAC-F. In cycle 1, VEN was started at 100mg daily and ramped up over the first 4 days to 200mg. This dose was continued from days 4-10. Fluconazole was started on day 3 and continued at 200mg until day 10. On subsequent cycles, VEN was administered at 200mg daily on days 1-10 with 200mg of fluconazole. Subcutaneous LDAC 20 mg/m2/day was given on days 1-10 of each cycle. Treatment cycles were repeated every 4-6 weeks. Patients were not routinely admitted for initiation of chemotherapy, unless the circulating blast count was high.

Patients who received at least one dose of VeLDAC-F were included. Event-free survival was the time to either treatment termination, disease progression or death; overall survival was the time to death from all cause. Patients who achieved a haemoglobin > 100g/L, platelets >100 x 109/L and neutrophils > 1 x 109/L were said to have reached a modified haematological response (HR), and time to modified haematological response was analysed using competing risk model with death as the competing factor. All statistical analysis was done using IBM SPSS version 20 and R Statistics.

Results

Nineteen patients received at least one dose of VeLDAC-F between the 1st of June 2017 and the 1st of June 2018. The majority of patients were male (89.5%). 14/19 (73.7%) had an ECOG performance status of 0 or 1 and the median Charleston co-morbidity index was 6. The median age at diagnosis was 77 years (range 64.4- 87.7 years). The cohort included 9 patients with AML (47.4%), 7 with high risk MDS (36.8%) and 2 with CMML (15.8%). Twelve patients were still alive at the time of analysis (63.2%). The median follow-up was 182 days.

Ten patients achieved a modified HR (52.6%). The median duration of response in these patients was 210 days and the 100 day probability of achieving a modified HR was 50.1%. The majority of patients who achieved a modified HR did so within 2 cycles of treatment with only one patient achieving a modified HR after 100 days.

Seven patients died over the follow-up period (36.8%) with one patient dying within 30 days of commencing treatment (5.3%). Four patients died of progressive disease, 2 from sepsis and 1 from catastrophic bleeding. The median OS had not been reached at the time of analysis. The 180-day OS was 61%. The median event free survival was 217 days. There were no cases of clinical tumour lysis and three cases of biochemical tumour lysis (15.8%). Only 10 patients were admitted to hospital with neutropenic fever over the course of the follow up period (52.6%).

Discussion

The combination of VeLDAC-F appears to be an effective regimen for elderly patients with AML, high grade MDS and CMML who are otherwise ineligible for intense chemotherapy. The risk of tumour-lysis is low in this real-world cohort, but ongoing follow-up and further clinical trials are needed to establish the longer-term outcomes of this regime.

Figure. Figure.

Disclosures

Chan: Amgen: Honoraria; Karyopharm: Research Funding. Simpson:Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta: Research Funding; Merck: Honoraria, Research Funding; MSD: Honoraria; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding.