Low-dose Venetoclax and Azacitidine as Front-line Therapy in Newly Diagnosed AML

Venetoclax plus azacitidine are effective in treating newly diagnosed AML in patients who cannot recieve intensive chemotherapy. However there is no clinical data rewarding the efficacy and safety of low-dose venetoclax and azacitidine as first-line therapy. This phase 2 clinical trial will explore the efficacy and safety of low-dose venetoclax (100mg /day/21 days) and a fixed dose of azacitidine (75mg/m2, maximun dose 100mg, SC for seven consecutive days) for a maximun of two cycles.

• Venetoclax 100 MG (Drug), also known as Venclexta: Patients will receive oral Venetoclax at a fixed dose of 100mg/day from day 1 to day 21 per cycle for a maximum of 2 cycles.
• Itraconazole capsule (Drug): Patients will receive oral itraconazole at a dose of 100 mg every 12 hours from day 1 to day 21.
• Azacitidine Injection (Drug), also known as Vidaza: Patients will receive a maximum of two cycles of daily subcutaneous Azacitidine at a dose of 75 mg/m2 (maximum 100 mg) from day 1 to day 7.

Primary outcomes

• Feasibility will be address by obtaining the proportion of patients who need hospitalization [1 month]: If therapy is feasible >50% of patients will recieve their first cycle of treatment without hospitalization
• Safety will be defined by the number of patients deceased before 14 days of initiating treatment [2 weeks]: If therapy is safe then <10% of patients will die in the first 14 days of treatment
• Safety will be defined by the number of patients deceased before 30 days of initiating treatment [1 month]: If therapy is safe then <20% of patients will die in the first 30 days of treatment

Secondary outcomes

• Efficacy will be achieved if the overall response rate is similar to standard of care (7+3) [2 months]: If the therapy is effective then overall response rates will be similar to those reported with standard of care (7+3)

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Age >18 years
2. Both genders
3. Diagnosis of non-m3 AML by the WHO 2016 diagnostic criteria
4. Patients eligible and not eligible for transplant
5. AML secondary to treatment or associated to myelodisplasia

Exclusion Criteria:

1. AML with PML/RAR-alfa translocation t(15;17)
2. Central nervous system involvement
3. Poor functional status (ECOG>2)
4. Organic dysfunction (Marshall score ≥2)
5. Active infection
6. Use of other CYP3A4 inhibitors
7. Pregnancy
8. GFR <30 ml/min/1.72m2

• Dohner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015 Sep 17;373(12):1136-52. doi: 10.1056/NEJMra1406184. No abstract available. PMID 26376137
• Guerra VA, DiNardo C, Konopleva M. Venetoclax-based therapies for acute myeloid leukemia. Best Pract Res Clin Haematol. 2019 Jun;32(2):145-153. doi: 10.1016/j.beha.2019.05.008. Epub 2019 May 24. PMID 31203996
• Pollyea DA, Amaya M, Strati P, Konopleva MY. Venetoclax for AML: changing the treatment paradigm. Blood Adv. 2019 Dec 23;3(24):4326-4335. doi: 10.1182/bloodadvances.2019000937. PMID 31869416
• DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, Letai A. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019 Jan 3;133(1):7-17. doi: 10.1182/blood-2018-08-868752. Epub 2018 Oct 25. PMID 30361262
• Results publication: De la Garza-Salazar F, Colunga-Pedraza PR, Gomez-Almaguer D, Garcia-Zarate VA, Gomez-De Leon A. Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study. Leuk Res. 2023 Oct;133:107373. doi: 10.1016/j.leukres.2023.107373. Epub 2023 Aug 22. PMID 37633156

• David Gomez-Almaguer, Principal investigator, Universidad Autonoma de Nuevo Leon