Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study

Abstract

Cyclosporine A (CsA) inhibits P-glycoprotein (Pgp)-mediated cellular export of anthracyclines at clinically achievable concentrations. This randomized controlled trial was performed to test the benefit of CsA addition to treatment with cytarabine and daunorubicin (DNR) in patients with poor-risk acute myeloid leukemia (AML). A total of 226 patients were randomly assigned to sequential treatment with cytarabine and infusional DNR with or without intravenous CsA. Remitting patients received one course of consolidation chemotherapy that included DNR with or without CsA as assigned during induction. Addition of CsA significantly reduced the frequency of resistance to induction chemotherapy (31% versus 47%, P ‫؍‬ .0077). Whereas the rate of complete remission was not significantly improved (39% versus 33%, P ‫؍‬ .14), relapse-free survival (34% versus 9% at 2 years, P ‫؍‬ .031) and overall survival (22% versus 12%, P ‫؍‬ .046) were significantly increased with CsA. The effect of CsA on survival was greatest in patients with moderate or bright Pgp expression (median 12 months with CsA versus 4 months for controls) compared to patients with absent or low Pgp expression (median 6 months in both arms). The frequency of induction deaths was 15% with CsA and 18% in controls. Steady-state serum concentrations of DNR (P ‫؍‬ .0089) and daunorubicinol (P < .0001) were significantly higher in CsA-treated patients. Survival (P ‫؍‬ .0003) and induction response (P ‫؍‬ .028) improved with increasing DNR concentration in CsA-treated patients but not in controls, suggesting a targeted interaction by CsA to enhance anthracycline cytotoxicity. These results indicate that addition of CsA to an induction and consolidation regimen containing infusional DNR significantly reduces resistance to DNR, prolongs the duration of remission, and improves overall survival in patients with poor-risk AML. (Blood. 2001;98:3212-3220)

Gemtuzumab, fludarabine, cytarabine, and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high‐risk myelodysplastic syndromes

“…5,16,22,23 Our CSA regimen was based on data previously published by the SWOG on the use of CSA as an MDR modifier in patients with AML. 11 The CSA levels were not measured. Future studies of gemtuzumab -based regimens might incorporate different CSA schedules and/or CSA level monitoring, although the currently reported data would not indicate that any increase in clinically significant hepatotoxicity FIGURE 2.…”

“…High-dose (16 mg/kg daily) CSA has been reported by the Southwestern Oncology Group (SWOG) to prolong significantly the duration of survival and disease-free survival in high-risk patients with AML. 11 We conducted a Phase II study of a regimen combining gemtuzumab (Mylotarg) with fludarabine, ara-C, and CSA as a potential MDR modifier (MFAC) in patients with newly diagnosed AML, RAEB, or RAEBT.…”

New agents in acute myeloid leukemia and other myeloid disorders

“…36 Patients who were randomized to receive cyclosporine A had a slightly higher CR rate (40% vs. 33%; P ϭ 0.14) but a significantly better recurrence free rate (34% vs. 9% at 2 years; P ϭ 0.031) and overall survival rate (22% vs. 12%; P ϭ 0.046). 36 The cyclosporine effect was apparent in both MDR1 positive and MDR1 negative patients but was more significant in MDR1 positive patients (median survival, 12 months vs. 4 months). The steady-state daunorubicin serum concentrations were higher for cyclosporine-treated patients, possibly due to inhibition of hepatic metabolism of daunorubicin.…”

“…The steady-state daunorubicin serum concentrations were higher for cyclosporine-treated patients, possibly due to inhibition of hepatic metabolism of daunorubicin. 36 …”

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

“…Nevertheless, the discovery of new agents to inhibit P-gp is still ongoing, building on encouraging in vitro studies and individual clinical trials such as the Southwest Oncology Group (SWOG 9126) study that showed a strong benefit of the use of the P-gp inhibitor cyclosporine A (CSA) in patients with relapsed or refractory AML [98] . To date, three generations of P-gp inhibitors can be distinguished.…”