Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study

Abstract

Purpose: Imatinib mesylate is a targeted agent that may be used against Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), one of the highest risk pediatric ALL groups.

Patients and methods: We evaluated whether imatinib (340 mg/m(2)/d) with an intensive chemotherapy regimen improved outcome in children ages 1 to 21 years with Ph+ ALL (N = 92) and compared toxicities to Ph- ALL patients (N = 65) given the same chemotherapy without imatinib. Exposure to imatinib was increased progressively in five patient cohorts that received imatinib from 42 (cohort 1; n = 7) to 280 continuous days (cohort 5; n = 50) before maintenance therapy. Patients with human leukocyte antigen (HLA) -identical sibling donors underwent blood and marrow transplantation (BMT) with imatinib given for 6 months following BMT.

Results: Continuous imatinib exposure improved outcome in cohort 5 patients with a 3-year event-free survival (EFS) of 80% +/- 11% (95% CI, 64% to 90%), more than twice historical controls (35% +/- 4%; P < .0001). Three-year EFS was similar for patients in cohort 5 treated with chemotherapy plus imatinib (88% +/- 11%; 95% CI, 66% to 96%) or sibling donor BMT (57% +/- 22%; 95% CI, 30.4% to 76.1%). There were no significant toxicities associated with adding imatinib to intensive chemotherapy. The higher imatinib dosing in cohort 5 appears to improve survival by having an impact on the outcome of children with a higher burden of minimal residual disease after induction.

Conclusion: Imatinib plus intensive chemotherapy improved 3-year EFS in children and adolescents with Ph+ ALL, with no appreciable increase in toxicity. BMT plus imatinib offered no advantage over BMT alone. Additional follow-up is required to determine the impact of this treatment on long-term EFS and determine whether chemotherapy plus imatinib can replace BMT.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Treatment schema for Children's Oncology Group (COG) protocol AALL0031. At enrollment onto AALL0031, patients had completed 4 to 6 weeks of three-drug or four-drug induction therapy consistent with a front-line pediatric cooperative group (Children's Cancer Group [CCG] or Pediatric Oncology Group [POG]) regimen. MRD, minimal residual disease; IV, intravenous; IT, intrathecal; PH+, Philadelphia chromosome–positive; ALL, acute lymphoblastic leukemia; HD, high dose; TBI, total body irradiation; IM, intramuscular; PO, oral.

Fig 2.

Integration of imatinib into successive blocks of therapy. Imatinib was given at 340 mg/m2/d (blue blocks) for 21 days (cohorts 1 to 4). Maintenance Blocks 1 through 4 consisted of 3-week blocks and Maintenance Blocks 5 through 12 consisted of 2-week blocks every 4 weeks. In cohort 5, dosing was continuous except for 2 weeks every 4 weeks during Maintenance Blocks 5 through 12. All boxes shaded blue received imatinib during that cycle of therapy. Cons, Consolidation Block; Reind, Reinduction Block; Intens, Intensification Block; Maint, Maintenance Block.

Fig 3.

Early event-free survival in Philadelphia chromosome–positive acute lymphoblastic leukemia patients treated with imatinib. Treated patients in cohort 5 (n = 44) were compared with patients previously treated on Pediatric Oncology Group (POG) protocols ALinC 14, 15, and 16 from January 1986 through November 1999 (N = 120).

Fig 4.

Comparison of event-free survival (EFS) for Cohort 5 chemotherapy only versus related-donor bone marrow transplantation (BMT) versus unrelated-donor BMT. Cohort 5 patients were compared with human leukocyte antigen (HLA) –identical sibling BMT (8 of 39 in cohorts 1-4; 13 of 44 in cohort 5) and 11 of the total 83 patients removed from protocol for an alternative-donor BMT. Patients treated on protocol were given imatinib 340 mg/m2/d for 6 months starting 4 to 6 months after BMT.

Fig 5.

Comparison of event-free survival for Philadelphia chromosome–positive (Ph+) induction failures (IFs) at study entry versus Ph+ non–induction failures (Non IF). Ph+ patients who were classified as IFs (n = 9; all cohorts) at end of induction (> 25 blasts) were compared with Ph+ patients treated on all cohorts (N = 82).

Fig 6.

Impact of minimal residual disease (MRD) at study entry on outcome in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). (A) Event-free survival (EFS) by MRD at study entry (≤ 0.01% v > 0.01%) for cohorts 3 and 4 (100% v 38.6% ± 15.1%; P = .02). (B) EFS by MRD at study entry for cohort 5 (88.2% ± 17.5% v 75.9% ± 14.1%; P = .41). Induction failures were excluded from these analyses.