10-day decitabine, fludarabine and 2 Gray TBI as conditioning strategy for poor and very poor risk AML in CR1. PLMA34 study

Acute myeloid leukemia (AML) is a heterogeneous group of malignant
hematological diseases with different molecular genetic abnormalities. These
are important in predicting respons 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. As these alterations are mainly outside the DNA itself, they
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 disease free survival was 46 weeks. The median survival was 55
weeks. Furthermore, this study showed that decitabine was well tolerated.
Despite a prolonged period of neutropenia, they did not develop a painful
mucositis. Earlier studies have showed that hypomethylating agents
pre-transplantation result in comparable survival as with toxic chemotherapy
(Damaj, JCO 2012). In contrast to the discussed studies, which solely used
hypomethylating agents to control the disease, in the current study the AML is
already in remission after intensive chemotherapy. For this study, we want to
add 10-day decitabine prior to NMA HCT by combining 10-day decitabine with the
Flu/TBI conditioning regimen in poor and very poor risk AML patients. The
hypothesis is that in this way we can extent the time the immune system of the
donor needs to create an adequate graft-versus-leukemia effect, at the cost of
low toxicity.

The primary objective of this study is to assess the feasibility (safety and
efficacy) of addition of 10-day decitabine to the standard Seattle
non-myeloablative conditioning regimen (3 days fludarabine 30 mg/m2 + 2 Gray
TBI) prior to allogeneic HCT in poor and very poor risk AML patients in CR1.
Safety will be assessed by adverse events and laboratory parameters; efficacy
will be assessed by (decrease of) relapse rate at 15 months (fixed time point)
after last-patient-in.

The secondary objectives of this study are:
1. To assess the safety profile: i.e. treatment related mortality (TRM) of the
transplantation procedure and toxicity, associated with this conditioning
regimen.
2. To assess transplant related parameters: i.e. acute and chronic
graft-versus-host disease (GVHD), rejection, engraftment kinetics (T-cell and
bone marrow chimerisms).
3. To assess the efficacy profile: i.e. relapse frequency after allogeneic HCT,
overall survival (OS), disease free survival (DFS) and event free survival (EFS)
4. To assess the social/economic impact both therapy regimens: i.e. Quality of
Life (QoL) (EORTC-Q30; t=0 and follow up), days staying in the hospital and
transfusion needs.
5. To assess the impact of this conditioning regimen on mucositis (citrulline
levels as biomarker of intestinal mucositis) and conditioning-induced
inflammation (soluble TNFR1, IL-8 and C-reactive protein levels).

Multicenter, phase II intervention study

The addition of 10 days (20 mg/m2) decitabine to the conditioningsregimen prior
to allogeneic hematopoiectic transplantation.

There is an addition of the hospital stay of 21 days. The neutropenic period
can be extended.

In this patient group, which consists of patients with (very) poor risk acute
myeloid leukemia, the chance of relapse is high despite current applied
treatment strategies. In case of relapse, the risk of death is high. In our
opinion it is very important to develop a strategy which lowers the risk of
relapse in this patient category.