Venetoclax-induced neutropenia in leukemic patients: underlying causes, risk factors and management

Venetoclax (ABT-199, Venclexta) is the only member of a novel drug class currently approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) in combination with established frontline therapies, and its therapeutic potential in the treatment of other lymphoid malignancies such as Waldenstrom Macroglobulinemia and Mantle Cell Lymphoma is currently being investigated. As an orally bioavailable BH3 mimetic, it has proven to be highly effective in reinstating the apoptotic potential of leukemic cells through highly selective inhibition of the anti-apoptotic protein BCL-2. Clinically, venetoclax has provided lasting remissions and durable responses through rapid cytoreduction of CLL and AML blasts. However, this activity has often come at the cost of myelosuppression and Grade III/IV neutropenia due to the dependence of healthy hematopoietic cells on BCL-2 for survival. As life-threatening infections are an important complication risk in this patient group, effective management of neutropenia is indispensable to maximizing patient outcomes. While there is general consensus over dose reduction and scheduling modifications to minimize the risk of neutropenia, the impact of these modifications on survival outcomes is uncertain. Moreover, these guidelines do not yet adequately account for patient-specific and disease-specific risk factors that may predict toxicity or the synergistic role combination treatment and chemotherapy intensity play in exacerbating neutropenia. However, there are already measures for venetoclax dosage modulation in the presence of prophylactic concomitant antimicrobials in order to mitigate toxicity as a biproduct of drug interactions. Furthermore, we are beginning to understand mechanisms of resistance to venetoclax, and how measures to combat it may be dually beneficial in terms of retaining sensitivity to the BH3 mimetic while curbing the development of neutropenia. The objective of this thesis is to clarify the mechanism of hematological toxicity induced by venetoclax, identify potential predictive risk factors that impact patient vulnerability to neutropenia, determine the aspects of managing venetoclax-induced hematological toxicity that currently have consensus, and explore opportunities for enhancing management strategies.