Cyclosporine Reduces Daunorubicin Resistance and Improves Treatment Outcome in High-Risk AML Patients

TUCSON—Cyclosporine (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. List’s observations were based on a randomized trial conducted with the Southwest Oncology Group.

The 226 study patients had relapsed, refractory, treatment-related, or secondary AML, or refractory anemia with excess blasts in transformation (RAEB-t).

Randomization

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 = .036).

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.

Targeted Interaction

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).