Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia

Abstract

Disease relapse is the most common cause of treatment failure after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes, yet treatment options for such patients remain extremely limited. Azacitidine is an important new therapy in high-risk myelodysplastic syndromes and acute myeloid leukemia but its role in patients who relapse post allograft has not been defined. We studied the tolerability and activity of azacitidine in 181 patients who relapsed after an allograft for acute myeloid leukemia (n=116) or myelodysplastic syndromes (n=65). Sixtynine patients received additional donor lymphocyte infusions. Forty-six of 157 (25%) assessable patients responded to azacitidine therapy: 24 (15%) achieved a complete remission and 22 a partial remission. Response rates were higher in patients transplanted in complete remission (P=0.04) and those transplanted for myelodysplastic syndromes (P=0.023). In patients who achieved a complete remission, the 2-year overall survival was 48% versus 12% for the whole population. Overall survival was determined by time to relapse post transplant more than six months (P=0.001) and percentage of blasts in the bone marrow at time of relapse (P=0.01). The concurrent administration of donor lymphocyte infusion did not improve either response rates or overall survival in patients treated with azacitidine. An azacitidine relapse prognostic score was developed which predicted 2-year overall survival ranging from 3%-37% (P=0.00001). We conclude that azacitidine represents an important new therapy in selected patients with acute myeloid leukemia/myelodysplastic syndromes who relapse after allogeneic stem cell transplantation. Prospective studies to confirm optimal treatment options in this challenging patient population are required.

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

“…These issues were also addressed in another retrospective analysis of a similar-sized patient group (n = 181) by Craddock et al within the EBMT [16]. They also identified the diagnosis of MDS instead of AML and in addition transplantation in remission as predictors for response.…”

“…In the recent retrospective EBMT analysis, only those 39 patients who received DLI within 2 months of commencing AZA salvage and in the absence of a clinical response were included in multivariate analysis [16]. Probably as a result of this methodological limitation, the administration of DLI had no impact on either response or on 2-year overall survival in this register-based analysis.…”

“…Table 1 summarizes the publications regarding the use of Aza as salvage treatment for relapse after allo-SCT: until now a total of 601 patients with AML, MDS and other related myeloid malignancies have been published with varying schedules and dosages of Aza. These included 3 prospective, non-randomized trials and the majority of patients reported retrospectively [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Furthermore, Aza was the first treatment of relapse and combined with DLI in some of these patients, while other patients had previously received other salvage therapies or did not receive DLI.…”

Mutational analysis in serial marrow samples during azacitidine treatment in patients with post-transplant relapse of acute myeloid leukemia or myelodysplastic syndromes

“…[2][3][4] We recently presented the results of a prospective phase II trial of azacitidine in patients with MDS or AML with persistent disease or early relapse after hematopoietic cell transplantation (HCT). 5 The trial enrolled 39 patients with MDS or AML, as defined by World Health Organization (WHO) criteria, who had undergone allogeneic HCT from related or unrelated donors following conditioning with various high intensity or reduced intensity regimens.…”

Hypomethylating agents after allogeneic blood stem cell transplantation

“…In general, some of the findings were recently confirmed by results from a retrospective EBMT analysis investigating a similar-sized patient group (n=181) (24). Here, Craddock and colleagues identified the diagnosis of MDS instead of AML and transplantation in remission as predictors for response.…”