Vorinostat Combined With Gemtuzumab Ozogamicin, Idarubicin and Cytarabine in Acute Myeloid Leukemia
Status:
Unknown status
Trial end date:
1969-12-31
Target enrollment:
Participant gender:
Summary
The prognosis of elderly patients with relapsed or refractory acute myeloid leukemia (AML) is
grave. Because of their chronological age and/or the presence of multiple co-morbidities,
treatment-related mortality in elderly patients with AML is quite high although higher
intensive treatment is mandatory to overcome chemoresistant characteristic of their disease.
Several regimens have been evaluated as salvage chemotherapy for relapsed or refractory AML
such as Mitoxantrone/High dose Cytarabine or Amsacrine/High dose Cytarabine. These regimens
could achieve complete remission (CR) in a part of patients, but resulted in higher treatment
related mortality (TRM). Accordingly, less intensive salvage regimen is needed for elderly
patients with relapsed or refractory AML.
The activity of histone deacetylase (HDAC) inhibitor, Vorinostat or Suberoylanilide
hydroxamic acid (SAHA), against AML has been suggested in cell line models and in animal
model as well as in a phase 1 trial. The phase 1 study determined the MTD of oral Vorinostat
as 200mg twice daily or 250mg thrice daily. In addition, the phase 1 trial showed the
antitumor activity of Vorinostat with 17% of response rate in patients with advanced leukemia
or myelodysplastic syndrome (MDS). Accordingly, further study is recommended to demonstrate
the clinical activity of Vorinostat in AML.
In terms of the combining drug with Vorinostat, anthracycline is one of the best candidate. A
in vitro study demonstrated that the combination of anthracycline (esp. idarubicin) with HDAC
inhibitor have significant clinical activity against leukemia. Another candidate is
Gemtuzumab ozogamicin, which is a calicheamicin-conjugated antibody directed against CD33
antigen on AML blasts. The U.S. FDA also approved the use of GO in relapsed AML as a
monotherapy. A study also showed that the combinational therapy of GO with attenuated doses
of standard induction chemotherapy could successfully induce CR without increasing
treatment-related mortality in AML patients aged 55 or older. A in vitro study reported that
HDAC inhibitor valproic acid augmented the clinical activity of GO toward CD33+ AML cells.
The study demonstrated that the strategy using HDAC inhibitor together with GO could
potentially induce synergistic proapoptotic activity against AML blasts without increasing
toxicity. In our center, so far we treated relapsed or refractory AML patients using the
salvage regimen including GO (3mg/m2/dayx1day) plus attenuated Idarubicin/Cytarabine
(Idarubicin 12mg/m2/day for 2 days and intermediate dose Cytarabine). So far, the CR rate
from the regimen is around 50% without increasing TRM. Accordingly, we will determine the
efficacy and toxicity of Vorinostat-incorporating salvage regimen based on the GO+IA
chemotherapy in patients 50 years old or older with relapsed or refractory AML.