Omission of Venetoclax Ramp-up Dosing during Induction Therapy for Acute Myeloid Leukemia in Combination with DNA Hypomethylating Agents Is Safe and Well-Tolerated
Authors: Parkin Brian , Escobar Caralyn , Patel Roma , Smith Tori , Browning Amy , Pancari Philip A. , Gayle Arlene A. , Mori Shahram 
Published: December 2024

Introduction:

In the treatment of acute myeloid leukemia (AML), the combination of venetoclax, a BH3 mimetic, with DNA hypomethylating agents (HMA+ven) has demonstrated significant efficacy and has been established as the standard-of-care for patients unfit for intensive induction chemotherapy. However, use of venetoclax in the treatment of chronic lymphocytic leukemia (CLL) commonly induces tumor lysis syndrome (TLS), a potentially life-threatening complication. A “ramp-up” of venetoclax dosing in the treatment of CLL often mitigates TLS and is the standard practice during initiation of treatment. This practice was carried over to trials of venetoclax in AML, but it is unclear if the incidence of TLS is higher in AML treated with full dosing of venetoclax that omits the ramp-up phase. This study seeks to assess the safety and efficacy of treatment of AML patients with HMA+ven without venetoclax ramp-up dosing.

Methods:

A retrospective chart review was performed to identify all patients with AML treated at AdventHealth Orlando with HMA+ven for front line induction therapy, salvage after failure of intensive induction therapy, or treatment of relapsed disease during 2019 and 2020. Comparisons of TLS incidence and cumulative response rates were assessed with Fisher's exact test and time to neutrophil and platelet recovery was determined using the log-rank test with the R survminer package.

Results:

108 patients were treated with HMA+ven with 13% (n=14) receiving venetoclax with a dose ramp-up in accordance with the package insert and 87% (n=94) initiating venetoclax at full dose adjusted for concomitant administration of strong CYP3A4 inhibitor azole antifungals. Of the latter, 91% (n=86) received an initial venetoclax dose of 100 mg daily with concurrent posaconazole. Venetoclax was given for 28 days to 13% (n=14) and 21 days to 87% (n=94) of patients. All but two patients (98%, n=106) received decitabine as the companion HMA with 42% receiving &gt;5 days of treatment (n=44, median 10 days [range 7-10]) and 58% receiving ≤5 days (n=62, median 5 days [range 4-5]). The median age of the cohort was 67 years (range 20-84), and indications for treatment included front line induction therapy (67%, n=72), salvage after failure of intensive induction therapy (11%, n=12), and treatment of relapsed disease (22%, n=24).

TLS occurred in 7% (n=1) and 2% (n=2) of patients after initiation of ramp-up dosing and full dosing of venetoclax (p=0.34), respectively. All cases resolved with administration of rasburicase and without end-organ damage. In the combined cohort (n=108) at any time after initiating HMA+ven treatment, patients experienced reversible increases ≥2x the upper limit of normal (ULN) in aspartate aminotransferase (AST) in 23% (n=25, median 3.0x ULN [range 2.0-12.4x]), alanine aminotransferase (ALT) in 19% (n=21, median 2.3x ULN [range 2.0-6.8x]), and total bilirubin in 13% (n=14, median 3.3x ULN [range 2.1-21.7x]) of cases. Venetoclax dosing was temporarily interrupted in 10% (n=11) of cases and was increased in 15% (n=16) of cases, typically due to discontinuation of posaconazole due to liver function test abnormalities.

The median time to recovery of absolute neutrophil count (&gt;500/uL) with venetoclax 100 mg (with concurrent posaconazole) combined with 5 or 10 days of an HMA was 37 and 38 days (p=0.82), respectively, while the median time to platelet recovery (&gt;100,000/uL) was 29 and 28 days (p=0.98), respectively. Bone marrow biopsy results at the end of the first cycle of HMA+ven were available for 85 patients. The composite complete remission rate (CR+CRi) was 62% (28 of 45) and 72% (29 of 40) for patients treated with venetoclax combined with 5 or 10 days of an HMA (p=0.36), respectively.

Conclusions:

The omission of the ramp-up phase in HMA+ven dosing in AML patients was safe with a very low incidence of TLS at similar rates to ramp-up dosing. Hepatic toxicity was observed at reasonable rates, requiring infrequent and temporary dosing adjustments of venetoclax. Recovery times for neutrophils and platelets and composite remission rates after 1 cycle of treatment were similar regardless of HMA duration when combined with venetoclax. These retrospective, single institution findings suggest that venetoclax can be safely administered at a dose of 100 mg daily with concurrent posaconazole and HMA and initiated without venetoclax ramp-up dosing.