Practical Management of the Venetoclax-Treated Patient in Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia

Abstract

Venetoclax is a potent oral, highly selective small-molecule inhibitor of the antiapoptotic B-cell lymphoma 2 protein approved for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma in treatment-naive patients (in combination with obinutuzumab) or for patients with relapsed/refractory CLL (in combination with rituximab). Venetoclax, in combination with azacitidine, decitabine, or low-dose cytarabine, is also approved in the United States for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are ≥ 75 years or have comorbidities that preclude use of intensive induction chemotherapy. Clinical studies of patients with CLL or AML report both hematologic (e.g., neutropenia) and nonhematologic (e.g., gastrointestinal disorders and tumor lysis syndrome) adverse events associated with administration of venetoclax. It is therefore essential to provide information on the appropriate management of venetoclax-associated side effects. This article discusses the efficacy and safety of venetoclax administration and presents strategies specifically for the management of neutropenia and certain nonhematologic adverse events in patients receiving venetoclax for the treatment of AML and CLL.

Figure 1

Recommended venetoclax dose modifications or interruptions for neutropenia in CLL and AML. AML = acute myeloid leukemia; ANC = absolute neutrophil count; AZA = azacitidine; CLL = chronic lymphocytic leukemia; DAC = decitabine; G-CSF = granulocyte colony-stimulating factor; LDAC = low-dose cytarabine; VEN = venetoclax. ^aGrade 4 neutropenia with or without fever or infection, or grade 4 thrombocytopenia. ^bUnless due to underlying disease (e.g., relapse).

Figure 2

Recommended venetoclax dosage ramp-up schedule for CLL (left) and AML (right). AML = acute myeloid leukemia; CLL = chronic lymphocytic leukemia; HMA = hypomethylating agent; LDAC = low-dose cytarabine; TLS = tumor lysis syndrome; VEN = venetoclax.

Figure 3

Initiating the 5-week venetoclax dose ramp-up in patients with chronic lymphocytic leukemia. 1L = first line; ALC = absolute lymphocyte count; CrCl = creatinine clearance; IV = intravenous; LN = lymph node; TLS = tumor lysis syndrome; VEN = venetoclax. ^aStart allopurinol or xanthine oxidase inhibitor 2–3 days prior to initiation of VEN. ^b1.5–2 L of water (6–8 glasses) should be consumed every day starting 2 days before the first dose and throughout the ramp-up phase, especially the first day of each dose increase. Administer intravenous hydration for any patient who cannot tolerate oral hydration. ^cReview in real time. ^dFor patients at risk of TLS, monitor blood chemistries at 6–8 hr and at 24 hr at each subsequent ramp-up dose. ^ePotassium, uric acid, phosphorous, calcium, and creatinine; correct any pre-existing abnormalities. ^fStarting at 20 mg and escalating weekly to 50 mg, 100 mg, 200 mg, and then 400 mg once daily clearance.

Figure 4

Recommended dose reductions for patients who are on concurrent CYP3A and P-gp inhibitor. AML = acute myeloid leukemia; CLL = chronic lymphocytic leukemia; CYP3A = cytochrome P450, family 3, subfamily A; HMA = hypomethylating agent; LDAC = low-dose cytarabine; P-gp = P-glycoprotein; VEN = venetoclax. ^aPosaconazole and strong CYP3A inhibitors are contraindicated during ramp-up.