Optimizing the dose of venetoclax with less intensive therapies for elderly patients with newly diagnosed AML

In patients over the age of 60, the prognosis of acute myeloid leukemia (AML) remains poor, often due to comorbid conditions and age-related changes in tumor biology that makes them refractory to, or less tolerant of intensive chemotherapy. There continues to be a need for novel treatment options for older patients with AML.

Venetoclax was recently approved by the US Food and Drug Administration (FDA) for the treatment of elderly patients with newly diagnosed AML, or for patients who have comorbidities, in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). First indicated for the treatment of patients with chronic lymphocytic leukemia (CLL), it is a potent, selective B-cell lymphoma-2 (BCL-2) inhibitor.

Suresh Agarwal, and colleagues, conducted a study to characterize the exposure-efficacy and exposure-safety relationships in order to identify the optimal dose of venetoclax combined with low-intensity therapies in elderly patients with newly diagnosed acute myeloid leukemia (AML). Low-intensity therapies consisted of a HMA (azacitidine or decitabine) or LDAC.

Study design

Patients were enrolled to either a phase Ib exposure-response analyses of venetoclax in combination with azacitidine or decitabine (NCT02203773, n=212) or a phase I/II study of venetoclax in combination with LDAC (NCT02287233, n=92). As food increases venetoclax plasma concentrations, it was administered orally once daily (QD) within 30 minutes after a meal, and before patients received HMA or LDAC therapies.

The starting dose of venetoclax was 20–100mg, which was then increased daily to mitigate the risk of tumor lysis syndrome (TLS). The target dose was 400–1200mg (venetoclax + HMA), or 600–800mg (venetoclax + LDAC). When the target dose was reached, it was continued daily in 28-day cycles.

Patient characteristics

• Median age, 74
• Majority of patients in the study were Caucasian (86% and 92% in both studies)

LDAC/HMA dosing

• Subcutaneous (SC) or intravenous (IV) azacitidine, 75mg/m² QD, administered on days 1–7 of each 28-day cycle
• IV decitabine, 20mg/m² QD, administered on days 1–5 of each 28-day cycle
• SC LDAC, 20mg/m² QD, administered on days 1–10 of each 28-day cycle

Analyses

• Pharmacokinetic samples were assayed for venetoclax concentrations using high-performance liquid chromatography with tandem mass spectrometric detection (LC-MS/MS)
• Efficacy assessments were performed using bone marrow and blood samples. Response variables were the probability to obtain a complete response (CR), CR + CR with partial hematologic recovery or a CR + CR with incomplete blood count recovery.
• Treatment-emergent adverse events (TEAEs) were summarised per the Medical Dictionary for Regulatory Activities and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). The response variables were the probability of grade 3 or worse neutropenia, the probability of grade 3 or worse infection, or the probability of a serious TEAE.

Results

Exposure-efficacy analysis

Data from all patients who had at least one efficacy assessment were included in the exposure-efficacy analyses (n=201 from HMA study; n=83 from LDAC study).

Venetoclax plus HMA

• Overall, no apparent exposure-response trend across the best responses
• Cumulative logistic regression analyses showed that increasing doses of venetoclax, up to 400mg, were associated with a statistically significant higher probability of response (p<0.05)Exposures of doses greater than 400mg achieved comparable response rates

Venetoclax plus LDAC

• Overall, no clear trend between venetoclax exposures and response rates
• Cumulative logistic regression analyses demonstrated a statistically significant higher probability (p<0.05) of increasing venetoclax doses to induce better responses
• Despite this, the recommended phase II dose of venetoclax was determined to be 600mg, as 4/5 patients experienced prolonged thrombocytopenia and dose interruption at a dose of 800mg

Exposure-safety analysis

Venetoclax plus HMA

No significant association between the probability of neutropenia or serious treatment-emergent adverse events (STEAEs) and venetoclax exposure. At 400mg and 800mg a slight increasing trend was identified in the probability of infections, with 51% (95% CI, 43%–58%) and 59% (95% CI, 50%–66%) respectively.

Venetoclax plus LDAC

Higher venetoclax exposures seemed to show a decreasing probability of STEAEs, but no relationship of venetoclax dosing with any of the evaluated AEs was identified.

Conclusion

The administration of 400mg venetoclax QD in combination with a HMA, and 600mg QD in combination with LDAC was supported by the exposure-response and exposure-safety analysis to safely maximize the probability of response in elderly patients with newly diagnosed AML.

These results provide the justification for the dose of venetoclax used the global, double-blind, phase III studies investigating venetoclax, in combination with azacitidine vs azacitidine alone (NCT02993523), and in combination with LDAC vs LDAC alone (NCT03069352). These studies will enroll elderly patients with AML who are unfit for standard induction therapy.