The management of disease relapse after allogeneic BMT is challenging. DLI has traditionally been standard practice. Porter et al. [17
] identified recipients of unrelated DLI for the treatment of relapsed disease from the NMDP database. Unrelated DLI was administered for relapsed AML to 23 patients. Forty-two percent (8 out of 19) of assessable patients with AML achieved a complete response. The estimated probability of DFS at 1 year after a complete response was 23%. Acute and cGVHD were commonly seen in these patients. Huff et al. [2
] retrospectively analyzed 83 consecutive recipients of DLI after BMT. In relapsed acute myeloid leukemia (13 patients), DLI led to durable complete responses in 31% of patients. Grade II or higher acute GVHD (aGVHD) or cGVHD occurred in 43% patients and contributed to death in 16%. Schmid et al. [18
] analyzed the outcome of 399 patients in first hematologic relapse included in the European Group for Blood and Marrow Transplantation. Of these, 171 received DLI and 228 did not. At 2 years, 21% of those receiving DLI were alive versus 9% of those who did not.
The low likelihood of achieving prolonged survival without comorbid GVHD after DLI provides the rationale for novel investigations and approaches. There are emerging data suggesting activity for 5-azacytidine for relapse after allogeneic BMT. Jabbour et al. [11
] reported on 5-azacytidine (doses ranging from 16–40 mg/m2
) as salvage therapy and on 8 patients as maintenance after allogeneic. The treatment was well tolerated with no grade 3–4 toxicities, and 5 of 9 patients with recurrent disease responded without exacerbations of GVHD. After a median follow up of 16 months, 14 patients are alive including 7 in CR. Lübbert et al. [12
] administered 5-azacytidine for 3 days (100 mg/day) followed by DLI on day 10 every 21 days to patients relapsed after allogeneic BMT. The median survival for the 26 patients (who received a total of 60 courses of treatment) from the start of 5-azacytidine was 136 days. Toxicities related to the 5-azacytidine are hard to evaluate because of the addition for DLI.
In our cohort, treatment with 5-azacytidine was well tolerated, with sustained responses in many of the patients without exacerbations of GVHD. The potential immunologic antitumor effects of 5-azacytidine are still unclear. Hypomethylating agents including 5-azacytidine have been reported to reverse the loss of expression of tumor-specific, tumor-associated, or histocompatibility antigens on tumor cells, making them more susceptible to immune attack [19
]. Hypomethylating agents may also enhance presentation of tumor antigens [9
], which may be expected to generate a graft-versus-tumor reaction. The drug has also been reported to inhibit T cell proliferation and activation, decreasing the production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interferon-gamma (INF-γ), which may prevent GVHD and possibly graft-versus-tumor effects as well [25
]. It also induces FOXP3 expression in CD4+
T cells both in vitro and in vivo [26
Conversely, 5-azacytidine may induce cytotoxic T lymphocytes with activity against AML [27
]. Regardless of the exact mechanism of action, there are now several small studies that support the development of larger, prospective clinical trials to better characterize the safety and efficacy of 5-azacytidine after allogeneic BMT.