From the Journals

Guadecitabine may be option for certain MDS/AML patients



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.

Human cells with acute myelocytic leukemia (AML) in the pericardial fluid, shown with an esterase stain at 400x. National Institutes of Health/Wikimedia Commons/Public Domain

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.

Marie Sébert, MD, of Hôpital Saint Louis in Paris and her colleagues conducted this trial and reported the results in Haematologica.

The trial (NCT02197676) 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).

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