FLAG/VEN as a frontline induction therapy for AML: A multi-centre experience of  Anthracycline free approach from India Free

Introduction: Acute myeloid leukemia (AML) is a life-threatening hematological malignancy with reported 5-year OS of 40% to 50% with 3+7 therapy. CR/CRi rates of 76% were reported with FLAG-IDA albeit with increased toxicity. Chepsy et al. reported an induction mortality of 24.7% with 3 + 7 regimen from India. Indian registry Hematology Cancer Consortium reported (n = 392) induction mortality rate of 16.9% (range - 6.1–43%) with 3 + 7 protocol. Jain et al. reported that 63% of patients present with baseline infections and sepsis was the most common cause of induction mortality. FLAG-IDA-VEN approach leads to CR+CRi rates of 89% with prolonged neutropenia which restricts its adaptability to LMICs in view high prevalence of multi drug resistant organism related infections. FLAG/VEN is a novel approach adapted by us. We have previously reported increased tolerability and efficacy of this approach in comparison with 3+7 as a proof of concept. We report outcomes of FLAG/VEN therapy as a frontline induction therapy at two centres in India.

Methods: Baseline variables included age, gender, ECOG PS, baseline organ function, karyotype, targeted next generation sequencing were collected from the electronic health record of the institutions. Clinical variables included data with regards to tolerance of therapy and response assessment. All patients received azole antifungals either prophylactic or therapeutic. Venetoclax dose was adjusted as per azole antifungals. This study was granted ethical approval by the Institutional Review Board No. RGCIRC/IRB-BHR/04/2023 dated 4th February 2023.

Induction therapy: All patients received tumor lysis syndrome prophylaxis with intravenous hydration and Tab Febuxostat. Inj. Fludarabine 30 mg/m2 IV once daily for 4 days, Cytarabine 1500 mg/m2 IV once daily for 4 days. Inj. Filgrastim (biosimilar) 5 mcg/kg s/c once daily from day −1 to ANC > 500 cells/ µL. Tab Venetoclax was added as per treating physician discretion. Venetoclax was given as 50 mg for day 1 and 2 followed by 100 mg once daily. It was given for 7 days.

Consolidation therapy:

Patients underwent Allogeneic HSCT as a consolidation therapy based on feasibility. Patients [except core binding factor (CBF) AML and not a candidate of Allogeneic HSCT] in CR1 at day 28 received Cytarabine 1500 mg/m2 twice daily for 3 days every 28 days for 3 cycles as consolidation therapy. CBF AML patients in CR1 at day 28 in both arms received FLAG with Gemtuzumab Ozogamicin (GO) based consolidation therapy for 4 cycles. GO (3 mg/m2 capped at 4.5 mg) was administered in any two of the four consolidation cycles. Patients not in CR underwent re-induction with regimen of choice as per physician discretion.

Results: A total of 44 patients received FLAG/VEN as frontline induction therapy since 2022 in two centres. 16 patients in centre A and 28 patients in centre B. Median age of patients was 40 years (18-62). 21(44%) of them were males and 23(56%) were females. 8 patients had co -morbidities. 5 patients had more than one co- morbidity and one patient had mitral valve replacement. One patient had a ECOG PS of 2, 43 patients had PS of 0-1.

As per the ELN 2022 risk stratification n=10 (23%), n=18 (41%), n=13 (30%) belonged to standard, intermediate and adverse risk profile respectively. n=3 (6%) could not be risk stratified in view of culture failure on conventional karyotype and no mutations were captured in the NGS panel. There was no incidence of induction mortality. Twenty-eight (63%) patients developed febrile neutropenia. n=14 (31%) patients had fungal pneumonia. n=2 (4.5%) patients had tuberculosis. n=6 (14%) patients had carbapenem resistant organism related sepsis.

Forty-one (93%) patients achieved CR at day 28 Bone Marrow assessment. Among 3(6.8%) patients who did not respond two had TP53 mutations and one patient had complex karyotype.

Nine patients relapsed at the last recorded follow up. Fourteen patients (32%) underwent Allogeneic HSCT as a consolidation therapy. 1-year PFS is 76 % and 1-year OS is 92% for the entire cohort.

Conclusions: Our results suggests that FLAG/VEN approach can decrease induction mortality rate which is anywhere about 20-25 % in a lower middle-income country like India. FLAG/VEN achieves high CR rates of 93% which is comparable to FLAG/IDA/VEN approach without added toxicity in the real-world scenario. This approach needs to be tested in a randomized controlled trial to establish it as a standard therapy for AML.