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Journal of Clinical Oncology, Vol 22, No 5 (March 1), 2004: pp. 963-964 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.274
Is the In Vitro Drug Resistance Profile the Strongest Prognostic Factor in Childhood Acute Lymphoblastic Leukemia?Department of Pediatric Hematology and Oncology, Medical University, Bydgoszcz, Poland To the Editor: Growing evidence supports the thesis of prognostic significance of the in vitro drug resistance profile in childhood acute lymphoblastic leukemia (ALL). Den Boer et al [1], using combined in vitro drug resistance profile to prednisolone, vincristine, and L-asparaginase (PVA score) as a measure of drug resistance profile, analyzed results of 202 children with de novo ALL, who were treated according to German Cooperative Group (COALL-92) protocol. With median follow-up of 6.2 years, they showed that the probability of disease-free survival (pDFS) for sensitive, intermediate sensitive, and resistant PVA profile was 84% ± 6.8%, 83% ± 4.4%, and 69% ± 7%, respectively. Despite being nondiscrimina-tive, resistant profile was the strongest prognostic factor in a multivariate analysis (P = .07). On the basis of the same methodologic background [2], but with different cutoff values for PVA score, we tested for in vitro drug resistance profile in 359 Polish children with newly diagnosed ALL. All patients were recruited between 1999 and 2002 and were stratified solely on the basis of WBC count into two risk groups: patients with WBC more than 50 G/L (n = 77) were treated as high risk according to the New York protocol [3], whereas all others were treated (n = 282) with ALL-BFM90 [4] protocol for standard-risk group. Patients with early deaths, those positive for bcr-abl rearrangement, those who were poor responders to in vivo prednisolone, and infants were excluded from this study. In 131 samples (36.5%), spontaneous apoptosis occurred during the 4-day incubation. This could be influenced either by disadvantages of overnight sample shipment or sensitivity of leukemic cells. In all other cases, PVA score was calculated and ranged from 3 to 9; the higher the score, the higher the resistance. All patients then were divided into three groups: those whose samples underwent spontaneous apoptosis were regarded as sensitive (S), those with PVA score from 3 to 7 were regarded as intermediately sensitive (M), and those with PVA score 8 to 9 were regarded as resistant (R). With median follow-up of 20 months, pDFS values were 0.90 ± 0.03, 0.82 ± 0.05, and 0.64 ± 0.11 (P = .023), for S, M, and R groups, respectively (Fig 1). Within subgroups characterized by initial WBC count, similar distribution was observed. For standard-risk patients, pDFS was 0.93 ± 0.03, 0.87 ± 0.04, and 0.71 ± 0.14 (not significant), whereas for high-risk patients, pDFS was 0.80 ± 0.09, 0.69 ± 0.10, and 0.36 ± 0.17 (not significant) for S, M, and R patients, respectively.
Multivariate analysis included following variables: resistance score, cell-biologic properties on leukemia diagnosis, prednisolone response by day 8 (in the standard-risk group only), bone marrow response by days 8 to 15, and bone marrow response by day 33 (only six children did not achieve remission by that day). In these analyses, two factors were significant: bone marrow response by day 33 (P < .001) and resistance score (P = .002) for the group of all patients (n = 359). When standard-risk patients (n = 282) were analyzed separately, resistance score (P = .038) and bone marrow response by day 33 (P = .031) were the only significant factors for pDFS. Because of limited follow-up, we were able to assess impact of early but not late relapses. However, in the group of in vitro sensitive and intermediately sensitive patients, plateau in survival curves was observed after 24 months. In conclusion, it seems possible that combined in vitro drug resistance profile to prednisolone, vincristine, and L-asparaginase is a potent prognostic factor in childhood de novo acute lymphoblastic leukemia. Our study, on the basis of results of therapy by BFM and New York protocols, confirms trends observed in COALL and Dutch Children Leukemia Study Group groups [1]. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
Acknowledgment We thank the Board of Polish Childhood Leukemia Study Group for providing patient samples and data. The board members are Anna Balcerska, Walentyna Balwierz, Alicja Chybicka, Jacek Wachowiak, Jerzy R. Kowalczyk, Michal Matysiak, Maryna Krawczuk-Rybak, Danuta Sonta-Jakimczyk, and Mariusz Wysocki. Supported by Polish State Committee for Scientific Research grant KBN 6 PO5E 082 21. REFERENCES
1. Den Boer ML, Harms DO, Pieters R, et al: Patient stratification based on prednisolone-vincristine-asparaginase profiles in children with acute lymphoblastic leukemia. J Clin Oncol 21:3262–3268, 2003 2. Styczynski J, Pieters R, Huismans DR, et al: In vitro drug resistance profiles in adult versus childhood acute lymphoblastic leukaemia. Br J Haematol 110:813–818, 2000[CrossRef][Medline] 3. Steinherz PG, Gaynon PS, Breneman JC, et al: Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic features: Randomized controlled trial from the Children's Cancer Group. Cancer 82:600–612, 1998[CrossRef][Medline]
4. Schrappe M, Reiter A, Ludwig WD, et al: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: Results of trial ALL-BFM 90—German-Austrian-Swiss ALL-BFM Study Group. Blood 95:3310–3322, 2000
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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