Do Patients With Lower-Risk MDS Benefit From Low-Dose Hypomethylating Agents?

The hypomethylating agents (HMAs) azacitidine and decitabine have been shown to improve survival and/or delay disease progression in patients with higher-risk myelodysplastic syndromes (MDS), but outcomes in lower-risk disease have not been as systematically reported. In a randomized study published in Blood, HMAs could be administered in doses lower than what is approved, and are safe and effective in patients with less severe MDS.

Elias Jabbour, MD, from The University of Texas MD Anderson Cancer Center in Houston, and co-authors on behalf of the U.S. MDS Clinical Research Consortium enrolled 113 adult patients (median age =70 years; range = 44-84 years) with low or intermediate-1 risk MDS or chronic myelomonocytic leukemia (CMML; per the International Prognostic Scoring System [IPSS]) between November 2012 and February 2016. Patients with other active and uncontrolled infection or intercurrent illnesses, or who had received any prior therapy with HMAs were excluded. Most patients (90%) had good or intermediate-risk cytogenetics. The majority of patients had MDS (n=97), including 20 (18%) with therapy-related MDS; six patients (5%) had an overlap MDS/myeloproliferative neoplasm (MPN) other than CMML, and 16 (14%) had CMML.

Using a Bayesian response-adaptive design, investigators randomized patients to receive:

  • decitabine 20 mg/m2 intravenously daily for 3 days (n=73)
  • azacitidine 75 mg/m2 intravenously daily for 3 days (n=40)

The imbalance in treatment groups was “due to a higher response rate seen with decitabine, which contributed to the skewed randomization,” the authors noted. Usually, decitabine is given for five days, azacitidine for seven days.

Bone marrow aspiration and/or biopsy were performed at the end of the second course and every three months during the first year of follow-up, then every three to six months thereafter. Patients whose disease responded to treatment could continue therapy indefinitely.

Most patients (n=109; 96%) received at least two cycles of treatment and were eligible for evaluation. After a median follow-up of 20 months (range = 2-43 months), the overall response rate (ORR; primary endpoint) for all patients receiving either HMA was 62 percent (n=68), including the 37 percent of patients (n=40) who achieved a complete response (CR).

Overall, the median time to best response was two months (range = 1-20 months), and the median number of cycles patients received was nine (range = 1-41 cycles). The median duration of response was 18 months in both the decitabine and azacitidine cohorts (range = 2->40 months and 2->30 months, respectively).

The median event-free survival (EFS) was 18 months (95% CI 14-22) – 20 months in the decitabine group and 13 months in the azacitidine group (p=0.1). The median overall survival (OS) had not been reached.

In the entire population, the one-year EFS rate was 65 percent (74% in the decitabine group and 55% in the azacitidine group) and the one-year median OS rate was 85 percent (87% and 83%, respectively).

Of the 57 evaluable patients who were red blood cell or platelet transfusion–dependent at baseline (38 treated with decitabine and 19 with azacitidine), 15 patients (26%) became transfusion-independent (12 in the decitabine group and 3 in the azacitidine group; p=0.2).

“Decitabine was found to be superior mainly in patients with advanced [disease] features, including patients with ≥5 percent bone marrow blasts, adverse mutation profile, and higher-risk disease,” the authors wrote. The ORR was 70 percent with decitabine and 49 percent with azacitidine (p=0.03), but CR rates were similar: 37 percent and 36 percent, respectively (p=0.9). “The underperformance of azacitidine could be due to the lower dose,” the authors noted.

When the authors conducted univariate subgroup analyses to determine if any patient subgroups in particular would benefit from low-dose HMAs, they found that the likelihood of achieving four-year OS was “unfavorably impacted” by:

  • transfusion-dependence at baseline (hazard ratio [HR] = 2.3; 95% CI 1.1-4.9; p=0.033)
  • the presence of 2 or more cytopenias (HR=2.2; 95% CI 1.0-4.9; p=0.046)
  • the presence of a DNMT3A mutation (HR=5.7; 95% CI 1.6-20.2; p=0.007)
  • the presence of a TP53 mutation (HR=3.7; 95% CI 1.2-11.0; p=0.02)
  • the presence of a ZRSR2 mutation (HR=45.5; 95% CI 2.8-727.3; p=0.007)

However, achievement of CR was associated with favorable survival (HR=0.38; 95% CI 0.2-0.9; p=0.026).

In multivariate analysis, only the presence of the TP53 (HR=136.76; 95% CI 5.3-3,534.4; p=0.003) and ZRSR2 mutations (HR=94.87; 95% CI 2.53-3,559.7; p=0.014) had a statistically significant negative effect on OS.

“Our study indicates that the use of HMA at low dose is relatively safe, as no treatment-related early deaths or high-grade adverse events (AEs) were encountered,” the researchers reported. Most AEs were mild (grade 1 or 2), and grade 3 non-hematologic AEs were rare, according to the authors. Infection or neutropenic fever occurred in 7 percent and 5 percent of patients treated with decitabine and azacitidine, respectively.

Treatment delays or dose reductions were required in 38 percent and 12 percent, respectively, of patients treated with decitabine and 20 percent and 5 percent, respectively, of patients treated with azacitidine. Most of these modifications were due to myelosuppression.

“The impact on the natural history of lower-risk disease needs to be further studied,” the authors noted, adding that, while survival benefits were “more pronounced in patients with higher-risk features, [it] is unknown whether [the results] translate to meaningful changes in survival or quality of life, compared [with] intervening when patients have higher-risk disease.”

The study is limited by its open-label design, small patient population, and the use of ORR as the primary endpoint. “The skewing of this study’s patient population to a relatively ‘higher-risk’ group of IPSS lower-risk patients may also limit the generalizability of these results to the broader population of lower-risk patients with MDS,” the authors noted.

The authors report no conflicts.


Reference

Jabbour E, Short NJ, Montalban-Bravo G, et al. A randomized phase II study of low-dose decitabine versus low-dose azacytidine in lower risk MDS and MDS/MPN. Blood. 2017 August 3. [Epub ahead of print]

 

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