Demethylating Agents As a Salvage Treatment in Relapsed Myeloid Diseases Following Allogeneic Bone Marrow Transplantation

Abstract ⁴²¹⁶

Patients who relapse after allogeneic bone marrow transplant (BMT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) have a poor prognosis. Salvage treatments rely on further chemotherapy, donor lymphocyte infusions (DLI) and experimental therapies. However, the treatments are often toxic and the prognosis grim particularly in patients over the age of 60 years. More recently, DNMT3A inhibition such as 5-Azacytidine (5-Aza) and Decitabine have been shown not only to have an antileukemic activity, but are also capable of inducing an antileukemic cytotoxic T lymphocyte response as well as reversal in the ratio of Tregs to Th17 CD4 cellular reactions. We therefore evaluated the role of these agents in 17 patients who have relapsed post-transplant.

The indications for transplant were AML (n=13), of whom 9 had transformed from either MDS (n=5), aplastic anaemia (n=1), MDS/MPD (n=1), myelofibrosis (n=1) or CML (n=1); Of the remainder: Refractory anaemia with excess blasts II (n=2); plasmacytoid dendritic cell leukemia (n=1); MPD/MDS with trisomy 21 (n=1). 13 were treated with 5-Aza; 6 Decitabine and 2 had both 5-Aza and Decitabine as separate courses. In total, there were 20 courses of treatment, each comprising of a variable number of cycles of 5-Aza or Decitabine. 5-Aza was administered at a standard dosage of 75mg/m2 for 7 days every 28 days and Decitabine 20mg/m2 for 5 days every 28 days. There was no toxicity from the treatment such that patients required a dose reduction.

Responses were categorized as stable disease (SD), partial response (PR), morphological (MR) or complete cytogenetic remission (CCR) and were seen in 11 of 20 courses of treatment (55%) of which SD = 2, PR = 2, MR = 7, CCR = 0. Specifically 2 patients had SD whilst they remained on 5-Azacytidine. Of the 2 with PR, 1 had a drop in blast percentage but did not enter into remission. The other with plasmacytoid dendritic cell leukemia relapsed with recurrence of biopsy proven skin lesions had a transient response on 5-Azacytidine but progressed during the 5^th cycle. 7 achieved a MR (<5% bone marrow blasts), none went into cytogenetic remission. Amongst the group of responders, 5 out of 9 patients (55%) had AML, 4 out of the 5 achieved MR and 1 PR. The mean duration of morphological remission was 186 days. Of the remainder 9 courses of treatment that did not respond, all had a pre-transplant diagnsosis of AML, of which 6 had pre-existing MDS and I myelofibrosis. There was no difference in response according to the pre-treatment blast percentage in the marrow. Conversely, one patient achieved a morphological remission after 3 cycles of Decitabine with a pre-treatment blast percentage of 89%. Equally there was no difference in response according to cytogenetic risk at first presentation or pre-treatment relapse between responders and non-responders. Importantly, 30% of patients treated with DNMT3A inhibitors are alive.

In the majority of patients, donor chimersm remained unchanged pre and post 5-Aza and Dec. 2 patients received DLI immediately post 5-Azacyditine as consolidation. Out of the 17 patients, 5 had graft-versus-host-disease (GVHD) temporally associated with commencing 5-Aza or Decitabine. 2 in this group had GVHD (grade 1–3) and 3 chronic GVHD (grade 1–3).

These results suggest that demethylating agents are effective following allogeneic BMT. It is encouraging that of the patients who responded, over half had a pre-transplant diagnosis of AML however more numbers are required to support this. The effect of these agents are thought to be both antileukemic for example by increasing expression of tumour associated antigens, and immunomodulatory by delaying the effect on the methylation pattern of genes that result in a significant decrease in Tregs.