Long-term outcome after hyper-CVAD and imatinib (IM) for de novo or minimally treated Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL).

Abstract

6506 Background: The selective ABL tyrosine kinase inhibitor (TKI) IM was added to hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone alternating with methotrexate and cytarabine) [Thomas, Blood 103:4396, 2004]. The final program dosed IM 600 mg days 1-14 of induction, 600 mg continuously courses 2-8, 800 mg during 24 mos of maintenance therapy with monthly VCR-prednisone interrupted by 2 intensifications (hyper-CVAD + IM), then IM indefinitely. Allogeneic stem cell transplant (aSCT) was performed in first CR as feasible. Methods: Fifty-four pts with IM naive de novo or minimally treated Ph-ALL were accrued from 2001-2006. Forty-five pts were untreated (n = 39) or refractory to 1 course (n = 6); 9 were in CR. Median age was 51 yrs (17–84); 13% had CNS disease. Results: CR rate was 93% (1 CRp, 1 PR, 1 ED). Molecular CR rate (MCR) prior to aSCT was 52%. 16 pts (33%) had aSCT in first CR within 5 mos (1-13). In the de novo group, 14 pts (med age 37 yrs) underwent aSCT in first CR whereas 33 pts (med age 53 yrs) did not. In de novo pts ≤ 60 yrs of age, 3-yr survival (OS) rates with or without aSCT were 77% vs. 57% (p = 0.1), respectively. In de novo pts ≤ 40 yrs of age, 3-yr OS rates were 90% with aSCT (n = 10) vs. 33% without aSCT (n = 6), p = 0.05. 3-yr CR duration (CRD) rate was 76% for 13 pts who achieved MCR prior to aSCT (2 had aSCT) compared with 63% for 31 pts who did not (14 had aSCT), p = 0.2. Neither CD20 expression nor additional chromosomal aberrancies influenced outcome. With median follow-up 77 mos (27-101+), 6 pts overtly relapsed on therapy after median 15 mos (8-42); 5 pts relapsed after change in TKI therapy for persistent Ph or increasing bcr-abl transcripts. Two relapsed after aSCT without IM maintenance. In the de novo group, 5 of 10 evaluable relapses had ABL kinase domain mutations [E459K, Y253H, Y253F, F359V, V338G]. Outcome with hyper-CVAD + IM remains favorable compared with hyper-CVAD; 3-yr CRD and OS rates were 68% vs. 24% and 54% vs. 15%, respectively, p < 0.001. Conclusions: Emerging data favors aSCT in 1st CR in the TKI era, particularly in younger pts. Substitution of IM with second- or later-generation TKIs may further improve outcome. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis