Novel Venetoclax/Decitabine Dosing Schedule Demonstrates Safety, Efficacy in Older Patients With Newly Diagnosed AML

The combination of 10-day decitabine with venetoclax elicited responses and was found to be well tolerated in older patients with newly diagnosed acute myeloid leukemia who are ineligible for chemotherapy.

The combination of 10-day decitabine with venetoclax (Venclexta) elicited responses and was found to be well tolerated in older patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for chemotherapy, according to results of a single-center, phase 2 trial.1

In the entire study population of patients with AML, results showed that the overall response rate (ORR) with the regimen was 74% (95% CI, 67%-80%), with 61% of patients having a complete response (CR) or CR with incomplete blood count recovery (CRi; 95% CI, 54%-68%).

Specifically, in older patients with newly diagnosed AML, the ORR was 89% (95% CI, 79%-94%). Patients with untreated secondary disease saw an ORR of 80% (95% CI, 55%-93%), while the ORR was 61% (95% CI, 42%-76%) in those with treated secondary disease. In a cohort of patients with relapsed/refractory disease, the ORR was 62% (95% CI, 49%-74%).

"Preclinical studies have shown a synergism between hypomethylating agents and venetoclax that has a capability to eradicate leukemic stem cells," lead study author Courtney DiNardo, MD, of The University of Texas MD Anderson Cancer Center, and co-investigators wrote. "Therefore, we hypothesized that 10-day decitabine with venetoclax might offer superior activity in patients with high-risk newly diagnosed and relapsed or refractory AML."

AML most commonly occurs in adult patients, with a median age of at least 65 years at presentation. Due to increased adverse-risk features, older patients are often unable to tolerate intensive chemotherapy regimens. Moreover, older patients with AML have additionally been found to have a high rate of early mortality when treated with induction therapy (5%-40%) and are often undertreated. This potentially plays into the poor 3-year overall survival (OS) rate of 10% to 30%.2,3 

In the phase 2 study, which was conducted at The University of Texas MD Anderson Cancer Center, investigators evaluated the effects of the 10-day regimen in the following patient subgroups: patients over 60 years old with newly diagnosed AML who cannot undergo intensive chemotherapy (42%); those over the age 18 years with secondary AML and a history of antecedent hematological disorder, such as myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML; 9%); patients over 18 years old with relapsed/refractory disease (33%); patients with high-risk MDS or CMML with 10% to 20% bone marrow blasts or relapsed/refractory disease following treatment with hypomethylating agents (17%).

Exclusion factors included patients with favorable-risk cytogenetics or prior treatment with a BCL-2 inhibitor.

Patients enrolled received 20 mg/m2 of decitabine intravenously for 10 days along with oral venetoclax at 400 mg daily as induction. After that, patients were given the same dose of decitabine as a consolidation regimen for 5 days per cycle. If bone marrow samples showed aplasia on day 21, or if remission was achieved with 5% or fewer blasts, venetoclax was stopped on day 21. Following remission, venetoclax was given on days 1 to 21 during the second cycle.

Duration of venetoclax was additionally reduced to 21 days or less in 93% of patients in the newly diagnosed cohort, 93% in the untreated secondary disease cohort, 71% in the treated secondary disease cohort, and 80% in the relapsed/refractory cohort.

Among patients who had an evaluable cycle 1 and day 21 bone marrow sample (n = 119), 55% had 5% or fewer blasts (95% CI, 46%-63%), 67% (n = 33) of whom had newly diagnosed disease. Flowcytometry–based minimal residual disease (MRD) negativity was achieved in 58% (95% CI, 49%-67%) of patients who responded to treatment.

The median duration of follow-up was 16 months. There was also a correlation between patients who achieved a CR and had improved overall survival (22.1 months; 95% CI, 13.4–not reached) vs CRi (8.0 months; 95% CI, 5.8-12.4), morphological leukemia-free state (MLFS; 8.2 months; 95% CI, 5.6-14.1), or no response (3.3 months; 95% CI, 2.1-4.9; P < .0001), ultimately demonstrating a 65% reduction in the risk of death (HR, 0.35; 95% CI, 0.16-0.75; P < .001). An additional association was found between CR and improved duration of response (DOR; 95% CI, 9.7–not reached [NR]) vs CRi (NR; 95% CI, 3.3–NR), or MLFS (1.5 months; 95% CI, 1.1–6.3; P < .0001). Here, the hazard ratio was 0.46 (95% CI, 0.20-1.07; P = .032).

Regarding safety, the most common grade 3/4 treatment-related adverse effects (TRAE) included neutropenia (47%) and febrile neutropenia (29%). The most common infections were observed to be pneumonia (n = 34), sepsis or bacteremia (n = 23), and cellulitis (n = 14). Among those who experienced serious AEs (83%), the most common were neutropenic fever (38%) pneumonia (10%), and sepsis (10%). Five deaths were related to neutropenic infections, with an additional death that was related to renal failure due to acute tubular necrosis.

In all patients, the 30- and 60-day mortality rates were 3.6% and 10.7%, respectivel. Patients with newly diagnosed disease had a 30-day mortality rate of 1.4% and a 60-day mortality rate of 7.1%.

“…Venetoclax with 10-day decitabine has a manageable safety profile and offers effective therapy for older patients with newly diagnosed AML and some patients with relapsed or refractory AML with venetoclax sensitive genomics,” the investigators concluded. “[It] can be a potential salvage approach before hematopoietic stem cell transplant.”


  1. DiNardo CD, Maiti A, Rausch CR, et al. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Lancet Haem. 2020;7(10):e724-e736. doi:10.1016/S2352-3026(20)30210-6
  2. Juliusson G, Antunovic P, Serolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113(18):4179-4187. doi:10.1182/blood-2008-07-172007
  3. Cashen AF, Schiller GJ, O'Donnell MR, et al. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2009;28(4):556-561. doi: 10.1200/JCO.2009.23.9178
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