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Patient Stratification Based on Prednisolone-Vincristine-Asparaginase Resistance Profiles in Children With Acute Lymphoblastic Leukemia

M.L. Den Boer, D.O. Harms, R. Pieters, K.M. Kazemier, U. Göbel, D. Körholz, U. Graubner, R.J. Haas, N. Jorch, H.J. Spaar, G.J.L. Kaspers, W.A. Kamps, A. Van der Does-Van den Berg, E.R. Van Wering, A.J.P. Veerman, G.E. Janka-Schaub

From the Department of Pediatric Oncology and Hematology, Erasmus MC/Sophia Children’s Hospital, Rotterdam; The Dutch Childhood Leukemia Study Group, The Hague; Department of Pediatric Hematology/Oncology, VU University Medical Center, Amsterdam, the Netherlands; and The German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL), Hamburg, Germany.

Address reprint requests to M.L. Den Boer, PhD, Erasmus MC/Sophia Children’s Hospital, Department of Pediatric Oncology and Hematology, PO Box 2060, 3000 CB Rotterdam, the Netherlands; e-mail: m.l.denboer{at}erasmusmc.nl.

Purpose: To confirm the prognostic value of a drug resistance profile combining prednisolone, vincristine, and L-asparaginase (PVA) cytotoxicity in an independent group of children with acute lymphoblastic leukemia (ALL) treated with a different protocol and analyzed at longer follow-up compared with our previous study of patients treated according to the Dutch Childhood Leukemia Study Group (DCLSG) ALL VII/VIII protocol.

Patients and Methods: Drug resistance profiles were determined in 202 children (aged 1 to 18 years) with newly diagnosed ALL who were treated according to the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)-92 protocol.

Results: At a median follow-up of 6.2 years (range, 4.1 to 9.3 years), the 5-year disease-free survival probability (pDFS) rate ± SE was 69% ± 7.0%, 83% ± 4.4%, and 84% ± 6.8% for patients with resistant (PVA score 7 to 9), intermediate-sensitive (PVA score 5 to 6), and sensitive (SPVA score 3 to 4) profiles, respectively (sensitive and intermediate-sensitive v resistant, P .05). Resistant patients were at increased risk of an early event (nonresponse or relapse within 2.5 years of diagnosis) compared with sensitive and intermediate-sensitive patients (P = .03). The profile did not identify patients at higher risk of late relapse, which was also observed for DCLSG ALL-VII/VIII patients now analyzed at a median of 7.5 years of follow-up (range, 4.4 to 10.8 years). Despite being nondiscriminative for late relapses, the resistant profile was still the strongest prognostic factor for COALL-92 patients in a multivariate analysis including known risk factors (P = .07).

Conclusion: Drug resistance profiles identify patients at higher risk of early treatment failures and may, therefore, be used to improve risk-group stratification of children with ALL.

Supported by grant nos. VU 93-641 (M.L.D.B.) and IKA 89-06 (G.J.L.K.) from The Dutch Cancer Society, Amsterdam, the Netherlands.

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