Effectiveness and safety of different azacitidine dosage regimens in patients with myelodysplastic syndromes or acute myeloid leukemia

Abstract

We investigated the effectiveness and tolerability of azacitidine in patients with World Health Organization-defined myelodysplastic syndromes, or acute myeloid leukemia with 20-30% bone marrow blasts. Patients were treated with azacitidine, with one of three dosage regimens: for 5 days (AZA 5); 7 days including a 2-day break (AZA 5-2-2); or 7 days (AZA 7); all 28-day cycles. Overall response rates were 39.4%, 67.9%, and 51.3%, respectively, and median overall survival (OS) durations were 13.2, 19.1, and 14.9 months. Neutropenia was the most common grade 3-4 adverse event. These results suggest better effectiveness-tolerability profiles for 7-day schedules.

Comparison of risk stratification tools in predicting outcomes of patients with higher-risk myelodysplastic syndromes treated with azanucleosides

“…27,37–39 For example, a report from the Spanish Compassionate use registry of 200 azacitidine-treated patients with all IPSS risk groups estimated an overall median OS of 16.5 months (95% CI, 12.4 – 19.1 months). 38 A report from the Dutch compassionate patient-named program of 90 azacitidine-treated patients estimated a median OS of 13 months. 39 The Groupe Francophone des Myelodysplasies reported a median OS of 13.5 months for 282 patients with HR-MDS treated with azacitidine in the French compassionate, patient-named program.…”

“…In addition, the details of routes and doses of azanucleoside therapy were not collected, though previous studies have shown little difference in response rates with variation in these parameters. 20,38,45 Compared with this analysis, other studies have calculated survival from date of initiation of the azanucleoside rather than from date of diagnosis. However, since this analysis was limited to patients who presented with HR-MDS, most of whom were symptomatic and were started on azanucleoside therapy soon after diagnosis.…”

A call for action: Increasing enrollment of untreated patients with higher‐risk myelodysplastic syndromes in first‐line clinical trials

“…Indeed, the AVIDA registry study in the United States indicated that only 15% of patients with MDS who receive azacitidine use the consecutive 7-day administration schedule used in AZA-001, which to our knowledge is the only schedule that has been associated with an OS advantage. 22 It is interesting to note that, in contrast to these observations with azacitidine, the OS observed in real-life and registry analyses of patients with HR-MDS treated with decitabine does not appear to differ substantially from the OS observed in the large 2 randomized clinical trials. 20 Similarly, in the Spanish MDS Registry study, there were no differences in survival noted between in the standard 7-day schedule of azacitidine and less intensive regimens.…”

“…15 Patients with HR-MDS usually are referred to tertiary centers early in the disease course only if alloHSCT is considered or after HMA failure; the rare younger patient with MDS and those with unusual presentations such as MDS/myeloproliferative neoplasm overlapping syndromes also are more likely to be referred. [8][9][10][11][18][19][20][21][22][23][24][25][26][27] For example, investigators in the MDS Clinical Research Consortium recently described the outcomes of patients in what to our knowledge is the largest reported cohort of patients with HR-MDS treated with HMAs in the United States. 16 Lenalidomide also is often attempted before specialty center referral, despite the limited efficacy of lenalidomide in the non-del5q setting and almost complete absence of activity in patients with HR-MDS.…”

“…17 We argue that instead, nearly every patient diagnosed with HR-MDS should be considered for clinical trial enrollment at community-based or at tertiary centers, especially for patients who are not candidates for alloHSCT. 22 In another report from the Spanish MDS Registry of 821 patients with HR-MDS who did not undergo alloHSCT, the median OS for patients treated with azacitidine (251 patients) was 13.4 months (95% CI, 11.8-16 months) (Table 1) 19 and, in contrast to the AZA-001 trial, the survival of those patients was not significantly different from that of those treated with conventional care treatments, who had a median OS of 12.2 months (95% CI, 11-14.1 months; P 5 .41). The rationale for this recommendation is outlined below.…”