Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421

Abstract

Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P = ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P = .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.

Figure 1.

Chemotherapy regimens. DAT 3 + 7 indicates daunorubicin 45 mg/m² intravenous push (over 15 minutes) on days 1, 2, and 3; Ara-C 100 mg/m² continuous 24-hour intravenous infusion on days 1-7 (168 hours); and thioguanine 100 mg/m² by mouth, single daily dose on days 1-7. HDAT 3 + 7 indicates daunorubicin 45 mg/m² intravenous push (over 15 minutes) on days 1, 2, and 3; Ara-C 1 g/m² intravenous 1-hour infusion every 12 hours for 7 days (14 doses); and thioguanine 100 mg/m² by mouth, single daily dose on days 1-7. HA indicates Ara-C 1 g/m² intravenous 1-hour infusion every 12 hours for 5 days (10 doses). EM - CSA indicates etoposide 100 mg/m² intravenous 45 minutes-1 hour infusion on days 1-5 and mitoxantrone 10 mg/m² intravenous 30-minute infusion on days 1-4. EM + CSA indicates etoposide 100 mg/m² intravenous 45 minutes-1 hour infusion on days 1-5; mitoxantrone 10 mg/m² intravenous 30-minute infusion on days 1-4; and CsA 10 mg/kg intravenous 2-hour loading dose followed by 30 mg/kg continuous infusion for 98 hours (total 100 hours).

Figure 2.

Distribution and outcome of patients. ^*5 patients withdrawn in less than 14 days of treatment; ^**12 patients received nonprotocol BMT; ^***7 patients received nonprotocol BMT.

Figure 3.

Panel A shows the frequency distribution of the KS-D value, and panel B shows the comparison with percent expression of MRK16, which showed tight correlation (r = 0.952).

Figure 4.

565 randomized patients excluding 57 with DS. OS (—) 53.6% ± 2.2% versus EFS (- - -) 36.3% ± 2.2%.

Figure 5.

EFS for DAT (—; n = 284) 35.2% ± 3% versus HDAT (- - -; n = 281) 40.1% ± 3.2% P = .28.

Figure 6.

DFS for patients in remission randomized to no CsA (—; n = 209) 33.9% ± 3.5%, CsA (- - -; (n = 209) 40.6% ± 3.6% (P = .24).

Figure 7.

EFS for DAT/no CsA (—; n = 103) 22.7% ± 3.8% and for HDAT/CsA (- - -; n = 103) 36% ± 5.7% (P = .08).

Figure 8.

OS for 4 randomized groups excluding BMT patients: DAT/no CsA (n = 127) 51.2% ± 4.5%; DAT/CsA (n = 118) 50.2% ± 4.9%; for HDAT/no CsA (n = 122) 49.9% ± 4.6%; and for HDAT/CsA (n = 115) 51.6% ± 4.8%.

Figure 9.

DFS for DAT/no CsA (—; n = 39) 69% ± 38.4% versus HDAT/CsA (- - -; n = 44) 61% ± 22% (P = .4).