Turning Away From 7 + 3
Venetoclax is a B-cell lymphoma 2 (BCL-2) protein inhibitor that is currently used in combination with azacitidine, decitabine, or low-dose cytarabine to treat adults with newly diagnosed AML or with chronic lymphocytic leukemia. Venetoclax in combination with azacitidine has shown a response rate of 70%, an early death rate of 3%, and a median OS that was not reached at 15 months of follow-up. Combination treatment with venetoclax is thus superior to 7 + 3, which has a 20% mortality rate and is only effective in patients with a favorable risk profile.
In the post-venetoclax era, where the availability of new drug regimens has increased considerably, assessment of fitness for induction must be modified. No patient should be considered “fit” for the 7 + 3 regimen, according to Dr Pollyea. It is therefore essential to question the relevance of intensive induction therapy as a standard of care, as only a small number of patients with favorable risk profiles may be eligible.
To assess response to treatment, current guidelines recommend conducting bone marrow biopsies after 28 days of induction chemotherapy, at which points patients have typically been treatment-free for 3 weeks. In patients with morphologic remission, peripheral recovery of blood counts is a prognostic factor for complete remission (CR), with incomplete peripheral count blood recovery (CRi) at 28 days considered a poor prognosis.
Dr Pollyea suggested a method of response assessment that is closer to real-world practice, where researchers document morphologic remission at 28 days, then hold therapy for 14 days, give growth factor if neutropenia persists, and reassess. In patients with morphologic remission, response should be upgraded from leukemia-free state to CRi and from CRi to CR. Furthermore, a 14-day hold period may promote count recovery and be helpful in preventing cytopenia-related side effects from continuous cycles of chemotherapy.
In addition, the prognostication criteria used today to classify low- and high-risk patients should be modified to allow risk stratification on a wider basis than simply in the induction setting. Venetoclax has maintained superior response in patients with high-risk molecular and cytogenetic profiles that are typically associated with poor prognosis. Mutations are no longer a concern with leukemia stem cell-targeting therapies or with venetoclax-based treatments.
“Going forward, new therapies will almost certainly have new associated prognostic features, and determining these will give us insight into the mechanisms of resistance,” Dr Pollyea wrote. He added that many patients may soon be classified as having “AML, relapsed after venetoclax,” and thus, prognostication ought to relate to resistance patterns against venetoclax in an effort to prevent relapse.
“More research is needed into the mechanisms of resistance and biomarkers of response for venetoclax,” Dr Pollyea told Hematology Advisor. Nonetheless, the approval of venetoclax brings with it a new era of treatment for patients with AML, wherein physicians and researchers ought to break away from the toxic 7 + 3 regimen and instead work with clinical end points that accurately reflect response and efficacy in all patients.
1. Pollyea, DA. Acute myeloid leukemia drug development in the post-venetoclax era [published online June 9, 2019]. Am J Hematol. doi:10.1002/ajh.25556