10-day Decitabine, Fludarabine and 2 Gray TBI as Conditioning Strategy for Poor and Very Poor Risk AML in CR1

Acute myeloid leukemia (AML) is a heterogeneous group of malignant hematological diseases with different molecular genetic abnormalities. These are important in predicting response to treatment. Recently, an analysis of 424 AML patients treated in various HOVON protocols showed a 5 year overall survival for patients in good, intermediate, poor and very poor risk groups of 65%, 51%, 25% and 7% respectively (HOVON 102 protocol). This shows that especially for patients in the (very) poor risk group, the outcome is very disappointing, despite the current treatment strategies. For patients with intermediate, poor and very poor risk cytogenetics postconsolidation treatment with an allogeneic hematopoietic cell transplantation (allo HCT) is standard practice after myeloablative (MAB HCT) or non-myeloablative (NMA HCT) conditioning.

Unfortunately, mortality after MAB conditioning is still considerable, mainly due to therapy related mortality, graft-versus-host disease, infections, or relapse. Currently, the NMA conditioning is used more frequently, which is far less toxic. Nonmyeloablative regimens have relied on the immunological anti-leukemia effect (graft-versus-leukemia), to prevent relapsing disease. This anti-leukemia effect, however, needs time to develop, which makes it necessary to be in control over the disease pre-transplantation as much as possible. This extends the time the immune system of the donor has to develop an adequate anti-leukemia effect, which is especially important in the (very) poor risk group patients since they have the highest chance of relapse.

Epigenetic alterations are increasingly recognised for their roles in oncogenesis. These alterations can for example 'silence'genes by hypermethylation. These alterations are potentially reversible.

The hypomethylating agent decitabine is one of the therapeutic approaches which can reactivate silenced genes by its interaction on the epigenetics. A phase II study (Blum, Proc Natl Acad Sci 2010) with 53 AML patients who received 10 days decitabine, showed a complete remission rate (CR) in 47% of patients. This percentage corresponds to the CR of intensive chemotherapy in elderly AML patients. The median survival was 55 weeks. Furthermore, this study showed that decitabine was well tolerated.

Earlier studies have shown that patients whose disease was controlled with hypomethylating agents pre-transplantation had comparable survival compared with patients whose disease was controlled with intensive chemotherapy(Damaj, Journal of Clinical Oncology, 2012).