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High Expression Levels of X-Linked Inhibitor of Apoptosis Protein and Survivin Correlate with Poor Overall Survival in Childhood De Novo Acute Myeloid Leukemia

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High Expression Levels of X-Linked Inhibitor of Apoptosis Protein and Survivin Correlate with Poor Overall Survival in Childhood De Novo Acute Myeloid Leukemia Vol. 10, 3737–3744, June 1, 2004 Clinical Cancer Research 3737 High Expression Levels of X-Linked Inhibitor of Apoptosis Protein and Survivin Correlate with Poor Overall Survival in Childhood de Novo Acute Myeloid Leukemia Ingo Tamm,4 Stephan Richter,1 a mean follow-up of 34 months, a shorter overall survival ؍ Doreen Oltersdorf,1 Ursula Creutzig,2 was associated with high expression levels of XIAP [30 (n P < 0.05] and survivin [27 ;(34 ؍ versus 41 months (n (10 4 3 ؍ ؍ ,Jochen Harbott, Frank Scholz 1 1 (n 10) versus 41 months (n 34); P < 0.05]. Leonid Karawajew, Wolf-Dieter Ludwig, and Conclusions: We conclude that apoptosis-related mole- 1 Christian Wuchter cules are associated with maturation stage, cytogenetic risk 1HELIOS Klinikum Berlin, Robert-Ro¨ssle-Klinik, Department of groups, and therapy outcome in childhood de novo AML. Hematology, Oncology, and Tumor Immunology, Charite´, Campus 2 The observed association of XIAP with immature FAB Berlin-Buch, Universita¨tsmedizin Berlin, Berlin; Department of types, intermediate/poor cytogenetics, and poor overall sur- Pediatric Hematology/Oncology, University Children’s Hospital Mu¨nster, Munster; 3Oncogenetic Laboratory, Children’s Hospital, vival should be confirmed within prospective pediatric AML Justus-Liebig-University of Giessen, Giessen; and 4Department of trials. Hematology and Oncology, Charite´, Campus Virchow, Humboldt- University of Berlin, Berlin, Germany INTRODUCTION During the last years, it became evident that apoptosis- ABSTRACT related molecules may be useful as prognostic markers because Purpose: Apoptosis-related proteins are important mol- several antiapoptotic mechanisms are operational in acute leu- ecules for predicting chemotherapy response and prognosis kemias. Suppression of apoptosis contributes to leukemogenesis in adult acute myeloid leukemia (AML). However, data on by different mechanisms, including prolonging cell life span, the expression and prognostic impact of these molecules in thus facilitating the accumulation of gene mutations, permitting childhood AML are rare. growth factor-independent cell survival, promoting resistance to Experimental Design: Using flow cytometry and West- immune-based cytotoxicity, and allowing disobeyance of cell ern blot analysis, we, therefore, investigated 45 leukemic cell cycle checkpoints which would normally induce apoptosis. De- samples from children with de novo AML enrolled and fects in apoptotic mechanisms also play an important role in treated within the German AML-BFM93 study for the ex- resistance to chemotherapy (1–3). In adult acute myeloid leu- pression of apoptosis-regulating proteins [CD95, Bcl-2, Bax, kemia (AML), the expression patterns and prognostic role of Bcl-xL, procaspase-3, X-linked inhibitor of apoptosis pro- CD95 (Fas/APO-1), molecules of the Bcl-2 and caspase families tein (XIAP), cellular inhibitor of apoptosis protein–1 (cIAP- as well as members of the inhibitors of apoptosis proteins (IAPs) 1), survivin]. have been investigated in a variety of studies (4–15). In con- Results: XIAP (P < 0.002) but no other apoptosis reg- trast, systematic data on the expression and prognostic impact of ulators showed maturation-dependent expression differ- these molecules in pediatric AML are rare. ences as determined by French-American-British (FAB) Childhood AML has a better treatment outcome than adult morphology with the highest expression levels observed AML. For the current chemotherapy regimens, these prognostic within the immature M0/1 subtypes. XIAP (P < 0.01) and differences are true for response to induction chemotherapy, Bcl-xL (P < 0.01) expression was lower in patients with relapse frequency, and overall survival (16–19). It has been favorable rather than intermediate/poor cytogenetics. After speculated that differences in the maturation stage of the trans- formed progenitor cell clone contribute to the distinct prognosis of age-related AML groups. The leukemic cells in adult AML patients may arise from a transformed undifferentiated hemato- poietic stem cell, whereas in childhood AML, the malignant cell Received 11/25/03; revised 2/10/04; accepted 2/16/04. Grant support: This study was supported by grants from the Carreras- clone potentially arises from a more committed myeloid pro- Foundation, Mildred-Scheel-Stiftung fu¨r Krebsforschung, and Deutsche genitor cell. Different maturation stages of hematopoietic pro- Forschungsgemeinschaft. genitor cells differ in their intrinsic resistance toward chemo- The costs of publication of this article were defrayed in part by the therapy-induced cell death (i.e., immature stem cells are more payment of page charges. This article must therefore be hereby marked resistant than committed myeloid progenitor cells), and this fact advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. may contribute to the different treatment outcome of age-related Note: C. Wuchter is currently at PAREXEL Medical Services Europe, AML groups (20, 21). Thus, age-related acute leukemia groups Klinikum Westend, Haus 18, Spandauer Damm 130, 14050 Berlin, might be associated with distinct expression patterns of apopto- Germany. sis-related molecules leading to the distinct prognosis in adult Requests for reprints: Ingo Tamm, Department of Hematology and Oncology, Charite´, Campus Virchow, Universita¨tsmedizin Berlin; Au- and childhood acute leukemia (11, 22, 23). gustenburger Platz 1, 13353 Berlin, Germany. Phone: 49-30-450-559- The main aims of this study were to analyze the expression 438; Fax: 49-30-450-559-958; E-mail: [email protected]. patterns and prognostic relevance of apoptosis-related proteins Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2004 American Association for Cancer Research. 3738 Prognostic Impact of IAPs in Childhood de Novo AML Table 1 Characteristics of 45 examined children with de novo acute myeloid leukemia (AML) treated according to the AML-BFM93 protocol No. of patients 45 (21 males, 24 females) Age in years, mean (range) 9 (0–16) Initial hemoglobin g/dl, mean (range) 8.3 (3.7–14.4) Initial WBC ϫ 109/liter, mean (range) 71.739 (1.500–355.500) Initial platelet count ϫ 109/liter, mean (range) 61.104 (5.000–343.000) Initial LDHa units/liter, mean (range) 784 (192–2.584) FAB morphology M0 (n ϭ 3); M1 (n ϭ 7); M2 (n ϭ 9); M3 (n ϭ 5); M4 (n ϭ 11); M5 (n ϭ 6); M6 (n ϭ 1) Cytogenetics risk groups Good (n ϭ 7); intermediate/poor (n ϭ 30) a LDH, lactate dehydrogenase; FAB, French-American-British (morphology types). in childhood de novo AML; to correlate expression with karyo- mg/m2, days 4 and 5) either before or after standard consolida- type, maturation stage (FAB subtypes, immunophenotype), and tion therapy. Randomized scheduling of HAM after induction outcome (response to induction chemotherapy, relapse fre- did not reveal major differences in outcome. However, high-risk quency, overall survival) of pediatric AML cases who entered patients with ADE (ara-C, daunorubicin, etoposide) as induction the AML-BFM93 study and, thus, received standardized diag- therapy benefited especially from early HAM (18). After con- nostic work-up and therapy, and to assess the applicability of solidation therapy, all of the patients were treated with an these proteins as markers for treatment response. intensification block of high-dose ara-C and VP-16 (high-dose ara-C 3 g/m2 twice daily for 3 days and etoposide 125 mg/m2, MATERIALS AND METHODS day 2 to 5). This was followed by cranial irradiation with 18 Gy Patient Samples. Patient-derived cell samples (n ϭ 45; (standard dose in children Ն3 years) and maintenance therapy bone marrow n ϭ 35, peripheral blood n ϭ 10) were consecu- of thioguanine 40 mg/m2 p.o. and ara-C 40 mg/m2 s.c. for 4 days tively collected, ficoll-purified, and cryopreserved between monthly for a total of 18 months. 1997 and 1999 within the German multicenter AML-BFM93 Of the 45 patients in this series, 35 patients were treated study. Diagnosis of AML was made morphologically based on according to high-risk therapy regimen and 10 patients received FAB criteria (24, 25) and immunophenotypically according to standard-risk treatment. Three patients died during induction European Group for the Immunological Characterization of chemotherapy, 3 patients were nonresponders, and 39 patients Leukemias (EGIL) recommendations (26). All of the samples achieved complete remission (CR). Of the 39 patients with CR, contained more than 80% leukemic cells based on morpholog- 27 patients are in continuous CR (mean event-free survival: 42 ical and immunophenotypical criteria. All of the patients were months) and 12 patients suffered from relapse (mean event-free- children and had de novo AML. Clinical characteristics of these survival: 10 months). The mean overall survival follow up is 34 patients are summarized in Table 1. months. Treatment According to German AML-BFM93 Study Expression Analysis of Apoptosis-Related Molecules Protocol. Treatment modalities and risk stratification of the CD95, Bcl-2, and Bax by Flow Cytometry. Surface CD95 AML-BFM93 study are described in detail elsewhere (18). In expression and intracellular expression of Bcl-2 and Bax were brief, during induction phase, patients received either ADE determined as described previously using the phycoerythrin- (ara-C: 100 mg/m2, day 1 to 8; daunorubicin 30 mg/m2 twice conjugated anti-CD95 monoclonal antibody DX2, the FITC- daily, days 3 to 5; etoposide 150 mg/m2,day6to8)orAIE conjugated anti-Bcl-2 monoclonal antibody 124, and the poly- (idarubicin
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