Tony was an 80-year-old man who presented to Dana-Farber with pancytopenia, fever, and a nodular skin rash. He was hospitalized, and a bone marrow biopsy confirmed the diagnosis of acute myeloid leukemia (AML). The skin rash was also biopsied and consistent with leukemia cutis. His age precluded him from intensive anthracycline/cytarabine-based induction chemotherapy due to the potential for treatment-related toxicity and lower possibility of achieving remission.
We discussed with Tony the poor prognosis of leukemia at this age with current available therapies, with survival typically less than one year. I offered Tony a promising phase 1b (early phase) clinical trial combining the DNA hypomethylating agent azacitidine (commonly used to treat high-risk myelodysplastic syndromes, or AML in elderly patients) with an orally available selective BCL-2 inhibitor, venetoclax (Venclexta; a drug approved for chronic lymphocytic leukemia). Tony bravely consented and enrolled onto this clinical study.
Over the course of the next couple of days, his leukemia cells were no longer detectable in his blood and in the next two weeks, his rash disappeared. Tony achieved a complete remission (CR) (clearance of leukemia) after one cycle of treatment. Tony continued on treatment and remained in a CR for over 15 months, longer than is typical for azacitidine alone in this setting. During that time, notably, his disease and treatment did not result in any further hospitalization. He made it to his 50th wedding anniversary and his 82nd birthday.
When his AML eventually relapsed, Tony moved on to another clinical trial and lived for another 7 months. Tony is just one example of many others who benefitted from this novel combination. One of my colleagues had an 85-year-old patient who enjoyed 26 months of remission while on this clinical trial.
Results from the dose escalation cohort of the trial combining azacitidine or decitabine plus venetoclax were recently published (Lancet Oncology, 2018) with 61% achieving a CR or CR with incomplete marrow recovery, considerably higher than would be expected with azacitidine or decitabine alone. The maximum tolerated dose of venetoclax was not reached, and common toxicities included febrile neutropenia, nausea, and neutropenia. Tumor lysis, common in lymphoid neoplasms treated with venetoclax, is rare in myeloid neoplasms. The FDA recently granted Venetoclax breakthrough designation for AML.
The dose-escalation study led to the development of a randomized, double-blind Phase 3 clinical trial for patients ineligible for intensive chemotherapy with previously untreated AML (NCT02993523). This exciting combination is also being assessed in upfront (NCT02942290) and after hypomethylating agent failure for patients with high-risk myelodysplastic syndrome (NCT02966782). We are actively accruing patients at Dana-Farber Cancer Institute for these three studies.
Venetoclax is a highly selective, orally bioavailable BCL2 inhibitor. When Venetoclax binds to BCL2, proapoptotic (or “pro” cell death) proteins such as BIM and BAX are released and facilitates induction of apoptosis. Cytochrome c release is a critical initial event signaling cell death.