New research suggests guadecitabine may be an option for select patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have failed treatment with azacitidine.
In a phase 2 trial, eight of 56 patients with high-risk MDS or low-blast-count AML responded to guadecitabine after azacitidine failure. Patients were significantly more likely to respond if they had few or no somatic mutations.
, of Hôpital Saint Louis in Paris and her colleagues conducted this trial and reported the results in .
The trial () included 56 patients with the following disease types:
- Refractory anemia with excess blasts (RAEB) type 2 (n = 31; 55%).
- RAEB type 1 (n = 11; 20%).
- Low-blast-count AML (n = 11; 20%).
- Refractory cytopenias with multilineage dysplasia (RCMD; n = 2; 4%).
- Chronic myelomonocytic leukemia (n = 1; 2%).
The patients had a median age of 75 years (range, 70-79) at baseline, and 37 (66%) were men. Thirty-four patients (61%) had very-high-risk disease according to the revised International Prognostic Scoring System. Forty-nine patients (87.5%) had at least one somatic mutation. The most commonly mutated genes were ASXL1, RUNX1, TP53, U2AF1, and DNMT3A.
Most patients (n = 41, 73%) had relapsed after azacitidine, and 15 (27%) had primary resistance to the drug. Patients had received a median of 13 azacitidine cycles (range, 6-23).
The patients received guadecitabine subcutaneously at 60 mg/m2 on days 1-5 of a 28-day cycle. They were treated until progression, death, unacceptable toxicity, or no response after six to nine cycles. Patients received a median of three cycles (range, 0-27). One patient died of infection before receiving guadecitabine, but the remaining 55 patients received at least one cycle of treatment. Eighteen patients had a dose reduction.
Eight patients (14.3%) responded to guadecitabine. Two patients achieved a complete response (CR) – one who had RAEB-2 and one with AML. Two patients with RAEB-1 had marrow CRs. Two patients – one with RAEB-2 and one with AML – had marrow CRs with hematologic improvement. A patient with RCMD had hematologic improvement, and a patient with RAEB-2 had a partial response.
The researchers said mutation frequency was the only significant predictor of response. The response rate was significantly higher in patients who did not have somatic mutations (P = .036). The median number of mutations was one (range, zero to three) in responders and two (range, zero to six) in nonresponders (P = .035). None of the patients with TP53 mutations achieved a response.
The median duration of response was 11.5 months. The median overall survival was 17.9 months in responders and 7.1 months in the overall population.
In a multivariate analysis, the following factors were significantly associated with longer survival:
- Having low- to high-risk (vs. very-high-risk) disease (P = .03).
- Having experienced primary (vs. secondary) azacitidine failure (P = .01).
- Having a high rate of demethylation in blood during the first treatment cycle (P = .03).