Decitabine-cytarabine chemotherapy in elderly AML and high risk MDS patients (> 65 years) with high early mortality risk

Although considerable progress has been made the last decades in the treatment
of acute myeloid leukemia (AML), treatment of elderly patients (>= 60 years)
still remains a challenge. With standard induction chemotherapy no more than
50-60% of patients achieve a complete remission. When using only chemotherapy
treatment, long-term survival is poor due to high relapse rates.
However, cure is possible in elderly patients with AML using the
immunotherapeutic potential of allogeneic stem cell transplantation (alloSCT).
Non-myeloablative (NMA) or reduced intensity conditioning (RIC) regimens have
been developed which can be used in patients up to 75 years of age with long
term overall survival of 40-50% (2, 3).
One of the major problems in elderly patients is early mortality during
induction chemotherpay. Early mortality has been defined as death occurring
within the first month (or 30 days) after the start of induction chemotherapy.
In the last four decades the early mortality rate has dropped significantly
from 18.7% to 5.8% in younger patients with AML (< 65 years). In patients over
65 years early death rates remain high, ranging from 10-20%, and becoming even
higher in patients over 75 years (20-40%).
High early mortality rates are especially observed in patients with
co-morbidity. In our own center we have observed an early mortality rate of
37.5% in AML patients over 65 year with a HCT co-morbidity index value of >=2.
In AML patients over 65 years without or with low co-morbidity (HCT
co-morbidity index value of 0 or 1) iearly mortality rate was 7-8%.
A promising new therapeutic option is treatment with sequential
decitabine-cytarabine, which showed no early mortality in a very old AML
patient group with a median performance score of 1. This regimen also resulted
in an impressive CR rate of 70%.
In this study we want to treat AML patients over 65 years with a HCT
co-morbidity index of 2 and higher with sequential decitabine-intermediate dose
cytarabine. The aim of this study is to reach an early mortality rate of less
than 10%.

Primary objectives:
• To assess early mortality risk (first 30 days after start of induction
therapy) of treatment with decitabine-cytarabine in elderly patients with AML
or high risk myelodysplastic syndrome (IPSS >=1.5) with a high risk of early
mortality (HCT-CI score >=2)

Secondary objectives:
• To evaluate remission status after one and two cycles of
decitabine-cytarabine

Phase 1-2 interventional study

Patients will receive decitabine one time daily 20 mg/m2 during 5 days,
directly followed by cytarabine 100 mg/m2 per day as continuous infusion during
5 days. At day 28-35 after the start of chemotherapy, remission status will be
determined. In case of complete remission, complete remission with incomplete
recovery or morphologic leukemia-free state, patients will receive a second
cycle of decitabine-cytarabine. At day 28-35 after the start of the second
cycle, remission status will be determined.

Elderly patients with AML or high risk MDS (>=60 years) have a poor prognosis,
without treatment most patients die within weeks. With supportive care using
antibiotics and regular blood transfusions survival can be extended by weeks,
or a few months in a small subset of patients. Intensive chemotherapy can
induce complete remissions in 40-60% of patients, resulting in a return to
normal life for many months or even more than a year. Patients in complete
remission can also decide to undergo allogeneic stem cell transplantation with
the possibility of cure from the disease.
Induction chemotherapy is complicated by morbidity and early mortality, which
occurs mainly in the first month of treatment. However, mortality in patients
undergoing intensive chemotherapy is always lower than mortality occurring in
patients on supportive care.
Early mortality is especially high in patients aged over 65 years with
co-morbidity. These patients should not be treated with standard induction
chemotherapy. Because the decitabine-cytarabine treatment in this protocol is
less intensive than standard chemotherapy it is to be expected that
participation within this protocol will result in a high likelihood of
achieving a complete remission with a limited chance of early mortality.
Patients up to 75 years that achieve complete remission with this protocol will
next be offered allogeneic stem cell transplantation with the possibility of
cure.