Prospective, randomized, multicenter Phase III trial of decitabine and venetoclax in combination with all-trans retinoic acid or placebo in patients with acute myeloid leukemia who are not candidates for induction chemotherapy

Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic system characterized by the uncontrolled proliferation of myeloid blasts (immature white blood cells) in the bone marrow and blood. Young patients (under 75 years of age) without serious comorbidities and in good overall health should receive intensive chemotherapy as standard treatment. In many cases, this treatment can achieve complete remission (no detectable cancer cells), but it may be accompanied by numerous side effects. For older and “less fit” patients with AML who are not suitable for intensive chemotherapy due to these severe side effects, a milder combination therapy consisting of venetoclax and a hypomethylating agent (HMA), such as azacitidine or decitabine, is already approved as an alternative. These HMAs lead to a “reprogramming” of the malignant cells, so that the cells’ control mechanisms resume their intended function. When combined with another drug (venetoclax), a so-called BCL-2 inhibitor that triggers programmed cell death in leukemia cells, this effect occurs more quickly and frequently. The combination of the two drugs thus targets leukemia cells more specifically while sparing healthy cells. As a result, side effects are generally less severe. However, this effect is only temporary. To prolong the duration of the treatment’s effect, this study also uses the vitamin A supplement all-trans retinoic acid (ATRA), which has already been shown in a preliminary study to have a positive effect when combined with decitabine. ATRA helps immature leukemia cells mature normally. ATRA is not yet approved for the treatment of AML, but it is already approved for a subtype known as acute promyelocytic leukemia (APL).

The goal of the DECIDER-2 study is to investigate whether patients who receive all-trans retinoic acid in addition to combination therapy with venetoclax and decitabine (milder standard therapy) live longer than those who receive a placebo in addition to the combination therapy.

To this end, patients will be randomly assigned to two arms. In the study arm, patients receive the combination therapy plus the study drug ATRA. The placebo group in the control arm receives the combination therapy plus a placebo (a pill that looks the same but contains no active ingredient). Neither the patient nor the healthcare provider knows whether they are receiving the study drug or the placebo (double-blind). Treatment is administered in 28-day cycles and continues until patients die or the disease progresses. Follow-up as part of the study continues for up to 12 months after the last person (256 in total) has been assigned to a group.

Women and men aged 18 and older with previously untreated AML are eligible to participate in the study. Prior treatment with hydroxyurea or cytarabine to reduce the number of leukemia cells at the time of initial diagnosis is permitted. Patients must not be eligible for standard induction therapy. Additionally, they must not have an allergy to soybeans or peanuts (due to ATRA excipients).