Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study

Abstract

Background: Recurrence is a major cause of treatment failure after allogeneic transplantation for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and treatment options are very limited. Azacitidine is a DNA methyltransferase inhibitor with activity in myeloid disease. The authors hypothesized that low-dose azacitidine administered after transplant would reduce recurrence rates, and conducted a study to determine a safe dose/schedule combination.

Methods: Forty-five high-risk patients were treated. Median age was 60 years; median number of comorbidities was 3; 67% were not in remission. By using a Bayesian adaptive method to determine the best dose/schedule combination based on time to toxicity, the authors investigated combinations of 5 daily azacitidine doses, 8, 16, 24, 32, and 40 mg/m2, and 4 schedules: 1, 2, 3, or 4 cycles, each with 5 days of drug and 25 days of rest. Cycle 1 started on Day +40.

Results: Reversible thrombocytopenia was the dose-limiting toxicity. The optimal combination was 32 mg/m2 given for 4 cycles. Median follow-up was 20.5 months. One-year event-free and overall survival were 58% and 77%, justifying further studies to estimate long-term clinical benefit. No dose significantly affected DNA global methylation.

Conclusions: Azacitidine at 32 mg/m2 given for 5 days is safe and can be administered after allogeneic transplant for at least 4 cycles to heavily pretreated AML/MDS patients. The trial also suggested that this treatment may prolong event-free and overall survival, and that more cycles may be associated with greater benefit.

Figure 1

Kaplan-Meier estimates of overall survival (n=45): (all patients: figure 1a – with 95% confidence band); by cytogenetics risk group (figure 1b); by donor type (figure 1c); by remission (CR) status at transplant (figure 1d). There is no significant difference among subgroups for any of the three variables, with log-rank p-values of 0.55, 0.50 and 0.10, respectively. Figure 1a​ Figure 1b. Cyto = cytogenetics. Figure 1c. Donor type (sib=sibling; MUD = unrelated donor). Figure 1d. CR= complete remission.

Figure 1

Kaplan-Meier estimates of overall survival (n=45): (all patients: figure 1a – with 95% confidence band); by cytogenetics risk group (figure 1b); by donor type (figure 1c); by remission (CR) status at transplant (figure 1d). There is no significant difference among subgroups for any of the three variables, with log-rank p-values of 0.55, 0.50 and 0.10, respectively. Figure 1a​ Figure 1b. Cyto = cytogenetics. Figure 1c. Donor type (sib=sibling; MUD = unrelated donor). Figure 1d. CR= complete remission.

Figure 2

Kaplan-Meier estimates of event-free survival (n=45): (all patients: figure 2a, with 95% confidence band ); by cytogenetics risk group (figure 2b); by donor type (figure 2c); by remission status at transplant (figure 2d). There was no significant difference among subgroups for cytogenetics or donor type (p=0.97 and p=0.50, log-rank test). However, there was a significant difference in EFS favoring patients in CR (six events; median of 27.2 months with lower 95% CI 12.1 months), versus those with active disease at HSCT (22 events; median of 12.0 months with 95% CI: 8.4 – 24.4 months; p=0.05; log-rank test). Figure 2a.​ Figure 2b. Cyto= cytogenetics. Figure 2c. Donor type: sib = sibling; MUD = unrelated donor. Figure 2d. Disease status at transplant (CR= complete remission; BMT = bone marrow transplant).

Figure 2

Kaplan-Meier estimates of event-free survival (n=45): (all patients: figure 2a, with 95% confidence band ); by cytogenetics risk group (figure 2b); by donor type (figure 2c); by remission status at transplant (figure 2d). There was no significant difference among subgroups for cytogenetics or donor type (p=0.97 and p=0.50, log-rank test). However, there was a significant difference in EFS favoring patients in CR (six events; median of 27.2 months with lower 95% CI 12.1 months), versus those with active disease at HSCT (22 events; median of 12.0 months with 95% CI: 8.4 – 24.4 months; p=0.05; log-rank test). Figure 2a.​ Figure 2b. Cyto= cytogenetics. Figure 2c. Donor type: sib = sibling; MUD = unrelated donor. Figure 2d. Disease status at transplant (CR= complete remission; BMT = bone marrow transplant).

Figure 3

Mononuclear cell DNA global methylation before and after azacitidine administration. Abbreviations: C = cycle; D=day of the administration cycle. Global hypomethylation induction was analyzed using the LINE bisulfite pyrosequencing assay. LINE methylation has measured on day 1 prior to therapy and on days 5 and 21 of therapy. As shown in panel A, when all patients and dose levels/schedules were analyzed, no evidence induction of LINE hypomethylation was observed. In B, the effect per dose level is shown: a non–significant hypomethylation trend was observed in patients treated at 8 mg/m².