Azacytidine treatment after discontinuation of immunosuppressants in patients with myelodysplastic syndrome and relapse after allo-SCT at a single center

Although newly developed drugs are available for myelodysplastic syndrome (MDS), the only reliable curative treatment strategy for MDS is an allo-SCT. However, the therapeutic options for patients who relapse after transplantation are limited.1 Attempts to maximize the GVL effects by donor lymphocyte infusion have been generally unsuccessful for restoration of a CR.2 Trials of donor lymphocyte infusion in combination with chemotherapy have shown increased response rates, but the long-term survival of relapsed patients is low.3 Some explanations for the unsatisfactory outcome are treatment-related mortality caused by regimen-related toxicity, life-threatening GVHD and the associated infections. Hypomethylating agents have an advantage over conventional cytotoxic chemotherapeutic agents in terms of regimen-related toxicity and OS in high-risk MDS patients.4 With regard to transplantation, recent studies have suggested that hypomethylating agents may potentiate GVL effects.5, 6, 7, 8 Therefore, a pilot study of azacytidine treatment after discontinuation of immunosuppressants was performed in MDS patients who relapsed after transplantation. All study patients underwent PBSCT with a fludarabine-based conditioning regimen. The interval from transplantation to relapse ranged from 3.6 to 23.1 months. All patients discontinued immunosuppressants when a relapse was diagnosed. After discontinuation of the immunosuppressants, we treated four patients with four cycles of azacytidine (75 mg/m2 for 7 consecutive days) at 4- to 5-week intervals. Responses were evaluated after each cycle of azacytidine using the criteria of the international working group.9 Toxicity was evaluated using the toxicity criteria version 2.0 of the National Cancer Institute. Three patients responded to azacytidine treatment and one did not. Two patients achieved a CR and a restoration of complete donor chimerism (Table 1). One patient achieved a PR with complete donor chimerism. All treated patients developed grade III–IV neutropenia and grade IV thrombocytopenia during the treatment. Two patients had a grade III infection and two patients a grade IV infection during the neutropenic period; however, none of the study patients died due to the azacytidine treatment. All treated patients completed four cycles of azacytidine. The follow-up duration of patients was 11.3–35.4 months from the initiation of azacytidine treatment. One patient who achieved a CR has survived for 31.4 months after the last cycle of azacytidine, with a sustained CR. The other patient relapsed 8.3 months after completion of the last cycle of azacytidine; he received a donor lymphocytes infusion but died from GVHD and an associated infection. In the patient with a partial response, the disease started to progress 2 months after the fourth cycle of azacytidine; he died of infection 4 months after the onset of disease progression. The nonresponder received a second transplantation 10 months after the last cycle of azacytidine and is still alive. There was no association between the treatment response and emergence of chronic GVHD. One patient developed chronic GVHD after treatment but he did not show any improvement in the blood counts; one of the two patients who achieved a CR had no GVHD. The remaining two patients who achieved a PR and a CR had re-emergence of chronic GVHD or newly developed chronic GVHD. However, compared with nontransplanted patients, the response rate to azacytidine treatment in the study patients was considerable. The findings suggest that GVL had a role, at least in part, in the transplanted patients. Because all patients discontinued immunosuppressants, it is impossible to determine whether azacytidine potentiated the GVL effects. Taking into consideration the limitation of the small number of cases reported in this pilot study, the results suggest that treatment of patients with MDS, after relapse post-transplantation, with hypomethylating agents is feasible and the additional GVL effects might significantly affect patient outcome. However, the limited treatment cycles with these agents could reduce the likelihood of long-term responses in such patients. Further clinical trials using additional cycles of azacytidine are required to obtain long-term responses to hypomethylating agents in MDS patients who relapse after transplantation. The authors declared no conflict of interest.