TUCSONCyclosporine (Sandimmune) significantly reduces
resistance to daunorubicin (Cerubidine), prolongs the duration of
remission, and improves overall survival of patients with high-risk
acute myelogenous leukemia (AML), Alan F. List, MD, of the University
of Arizona, said at the ASH meeting. Dr. Lists observations
were based on a randomized trial conducted with the Southwest
The 226 study patients had relapsed, refractory, treatment-related,
or secondary AML, or refractory anemia with excess blasts in
After stratification by age and disease category, patients were
randomized to receive either induction therapy with cytarabine, 3
g/m²/d on days 1 through 5, and daunorubicin, 45 mg/m2/d as a
continuous infusion on days 6 through 8, or the same induction
therapy plus cyclosporine, beginning on day 6 in a loading dose of 6
mg/kg over 6 hours, followed by 16 mg/kg/d as a continuous infusion,
concurrently with daunorubicin for 72 hours.
Patients who went into remission received one course of consolidation
with the same regimen but with three doses of cytarabine rather than five.
The investigators found that cyclosporine-treated patients had
significantly better documented complete remission and relapse-free
survival rates. At 2 years, 44% of these patients remained in a
sustained complete remission vs 5% of the controls (P = .012).
A similar trend was seen for overall survival: At 2 years, 25% of
patients in the cyclosporine arm remained alive vs 12% of controls (P
There was a significant elevation of steady-state daunorubicin levels
on the cyclosporine arm; the daunorubicin level on day 9 was
approximately double that of the control arm, Dr. List said, and
overall daunorubicinol levels were approximately fourfold higher with cyclosporine.
If the increase in daunorubicin exposure contributed to the
treatment benefit with cyclosporine, then we would expect to see an
improvement in all outcome parameters on both arms of the study with
rising daunorubicin steady-state levels, Dr. List said. In
fact, that was not the case.
As daunorubicin steady-state levels in the control arm increased, the
complete response rate actually decreased, with a trend for
increasing resistance, whereas the opposite was true among
cyclosporine-treated patients. With rising daunorubicin levels in the
cyclosporine arm, there was an increasing frequency of remission and
a trend toward decreasing frequency of resistance.
The same pattern was seen for overall survival and relapse-free
survival, independent of MDR1 (multidrug resistant) phenotype and
across all cytogenetic risk groups. These results confirm a targeted
interaction between cyclosporine and daunorubicin, which Dr. List
called the most important observation of the study.
Despite the associated rise in steady-state daunorubicin blood
levels, cyclosporine generally did not augment treatment-related
toxicity. The only significant difference in toxicity was the
frequency of hyperbilirubinemia (grade 3 or more), which was more
common in the cyclosporine arm (43% vs 12%, P = .0001).