Novel Target: RARA Agonist plus Azacitidine Active in Relapsed or Refractory Acute Myeloid Leukemia

February 2021, Vol 12, No 1

The selective, oral retinoic acid receptor alpha (RARA) agonist, SY-1425, combined with azacitidine showed encouraging activity in patients with relapsed or refractory acute myeloid leukemia (AML) that is overexpressing the RARA gene in a phase 2 clinical trial presented at ASH 2020. The RARA gene is a novel target in patients with AML.

“There are hints here that this is a therapy that may find a place with the right patient population who has relapsed and refractory AML,” said lead investigator Eytan M. Stein, MD, Hematologic Oncologist, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Discussing the combination of SY-1425 and azacitidine, Dr Stein noted, “Generally speaking, the combination was well-tolerated, with no increased toxicity compared with expected toxicity from either agent as monotherapy. The majority of nonhematologic events were low-grade and reversible.”

“We think that the clinical activity really does support the ongoing development of SY-1425 in RARA-positive myeloid malignancies,” Dr Stein stated.

New effective therapies represent a high unmet need for patients with relapsed or refractory AML. Survival is poor, particularly for patients whose disease progresses after treatment with a combination of venetoclax (Venclexta) and a hypomethylating agent (HMA).

Oral SY-1425 may provide hope for the 30% of patients with RARA-positive AML. Preclinical studies have shown that the combination of SY-1425 and azacitidine has synergy in malignancies overexpressing the RARA gene. Among 18 response-evaluable unfit patients with newly diagnosed AML and RARA overexpression, an early study showed an overall response rate of 67% (12 of 18 patients), with 61% of the patients achieving complete responses, and 6% of patients having morphological leukemia-free state.

Promising Results

The current phase 2, multicenter, open-label clinical trial enrolled 28 patients (median age, 74 years) with relapsed or refractory AML and RARA overexpression in the peripheral blood. Patients received treatment with azacitidine 75 mg/m2 intravenously or subcutaneously on days 1 to 7, followed by SY-1425 6 mg/m2 daily, orally, on days 8 to 18 for 28-day cycles.

Patients received a median of 2 previous therapies (range, 1-9); 66% of patients received HMA monotherapy; 32% received venetoclax plus HMA combinations; 11% had favorable-risk status according to cytogenetics; 29% had intermediate-risk status; and 21% had poor-risk status (cytogenetic data were missing for 39% of the patients). Of the patients, 14 (50%) had previously received intensive induction treatment, and 6 (21%) had previously undergone stem-cell transplant.

In all, 23 patients discontinued therapy, including 10 patients because of progressive disease, 4 because of adverse events, 4 died, 2 did not respond to treatment, 1 was nonadherent, and 2 because of other reasons.

The primary end point was overall response rate according to the International Working Group criteria. Among 21 patients evaluable for response, 4 patients responded to treatment, for an overall response rate of 19% (including 1 complete response, 2 complete responses with incomplete hematologic recovery, and 1 morphological leukemia-free state).

“Although the numbers are small, we saw responses in these heavily pretreated relapsed or refractory AML patients,” Dr Stein said.

The time to response was a median of 1.4 months, and 2 of the patients were still receiving treatment with the novel combination as of December 2020. Responses occurred in 3 of 7 (43%) patients naïve to venetoclax and to HMA agents before study entry.

The SY-1425 plus azacitidine combination resulted in transfusion-independence in 6 of 20 (30%) patients in the study, who did not require blood-cell and platelet transfusion for an ≥8-week interval during treatment. In addition, 3 of 11 (27%) patients who were transfusion-dependent at baseline converted to transfusion-independence during treatment. The median overall survival was 5.9 months.

“Looking at a swimmer plot, all patients with stable disease seem to be surviving longer. We know these patients typically have very low survival. We are analyzing stable disease patients to see if improvement in blood count allowed them to survive longer without meeting the formal criteria for response,” Dr Stein said.

Adverse Events

The most common nonhematologic adverse events in 20% or more of patients were pruritus, arthralgia, decreased appetite, vomiting, diarrhea, hypertriglyceridemia, constipation, fatigue, pyrexia, and nausea.

“What stands out is that 21% of patients had grade 3 or higher hypertriglyceridemia, which is a known adverse event with SY-1425,” said Dr Stein.

Hematologic adverse events were all grade ≥3 in severity and included neutropenia (4%), leukopenia (7%), thrombocytopenia (14%), anemia (14%), and febrile neutropenia (36%).

Serious adverse events occurred in 19 patients; the most common events were febrile neutropenia (N = 7) and sepsis (N = 3).

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