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Insulin-Like Growth Factor Binding Protein-2 at Diagnosis of Childhood Acute Lymphoblastic Leukemia and the Prediction of Relapse Risk

Department of Pediatric Hematology/Oncology (P.V., H.W., U.M.), Department of General Pediatrics (K.M.), Institute of Biometrics and Medical Informatics (F.-W.R.), University Otto von Guericke Magdeburg, D-39112 Magdeburg, Germany; Department of Pediatric Hematology/Oncology (M.Z.), Hannover Medical School, D-30625 Hannover, Germany; Eli Lilly and Company (W.F.B.), 61350 Bad Homburg, Germany; and University Children’s Hospital (W.F.B.), D-35385 Gießen, Germany

Address all correspondence and requests for reprints to: Dr. Peter Vorwerk, Department of Pediatric Hematology/Oncology, University Otto von Guericke, E.-Larisch-Weg 17-19, D-39112 Magdeburg, Germany. E-mail: Peter.Vorwerk{at}medizin.uni-magdeburg.de.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Despite remarkable advances in the clinical outcome of most children with acute lymphoblastic leukemia, a substantial number of patients ultimately relapse or suffer from side effects of treatment. In the present study, we investigated components of the IGF system for their predictive value to identify patients with an increased risk of relapse.

Serum levels of IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-2, and IGFBP-3 were measured in 162 children with acute lymphoblastic leukemia treated by the Berlin Frankfurt Münster Study Group. At diagnosis we found elevated IGFBP-2, low IGFBP-3, low IGF-I, and low normal IGF-II, but normal IGFBP-1 levels. Highly elevated IGFBP-2 and low IGFBP-3 at the time of diagnosis correlated with a higher risk of an event such as lack of remission or a relapse. Serum IGFBP-2 was identified as an independent factor that adds additional information for the prediction of events (relapse or treatment failure) to the conventional prognostic factors such as white blood cell count and platelet count at diagnosis.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
CHEMOTHERAPY HAS CONSIDERABLY improved the outcome for children with acute lymphoblastic leukemia (ALL). However, a number of patients still die from relapse and others suffer from side effects of treatment. Therefore, reliable prognostic factors at the time of diagnosis are required to select patients for appropriate therapeutic strategies. At present, various biological features, e.g. age and white blood cell count (WBC) at diagnosis, cytogenetic aberrations, and response to therapy, are used to identify subgroups of patients who need intensified or, alternatively, less toxic treatment (1, 2, 3).

The IGF system is known to be involved in the regulation of cell proliferation and apoptosis of a variety of normal and malignant cell types (4, 5). It has been shown that normal lymphocytes and lymphoblast cell lines express and secrete IGFs and IGF-binding proteins (IGFBP) (6, 7, 8, 9) and the presence of a functional type 1 IGF receptor (IGF-IR) was demonstrated in hematopoietic cells (10, 11). In addition, inhibition of the IGF-IR by a specific antibody or use of antisense oligonucleotides to IGF-IR mRNA has been shown to interfere with proliferation of lymphoblasts (12).

Previously, we described altered serum levels of IGF-I, IGF-II, IGFBP-2, and IGFBP-3 in children with ALL at the time of diagnosis (13). To further evaluate the clinical significance of these findings, especially of elevated serum IGFBP-2 at diagnosis, we continued to study these patients after the end of therapy.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

One hundred sixty-two patients, 88 boys and 74 girls (Table 1) with newly diagnosed ALL, from 23 Berlin Frankfurt Münster (BFM) trial centers were included. Diagnosis was evaluated (14) and treatment was stratified according to the relapse risk. The study was approved by the ethics committees of the various study centers as part of the trial protocol, and written informed consent was obtained from the patients’ parents or legal guardians. Inclusion criteria were the patient’s treatment according to the ALL-BFM protocols 90 or 95 (study patients) and the availability of an additional serum sample for hormone measurements at diagnosis. The patients were treated according to protocol ALL-BFM 90 (n = 33, diagnosis between April 1990 and November 1995) or according to protocol ALL-BFM 95 (n = 129, diagnosis after December 1995). The median follow-up was 5.5 yr (range, 1.4–11 yr). Treatment by the ALL-BFM protocols includes an induction therapy followed by a consolidation phase, a reintensification, and a maintenance therapy (15). The protocol ALL-BFM 95 is based on the protocol ALL-BFM 90. The main differences between both protocols were a slightly different risk group stratification in the 95 trial (Table 2), less anthracyclines in the induction of standard risk (SR), and 12 more months of additional maintenance (16). For the analysis of survival, we reclassified the 33 ALL-BFM 90 study patients according to the ALL-BFM 95 risk group criteria (Table 2).

Serum samples were stored at –20 C until analyses. IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3 were determined by specific RIAs as described previously in detail (17). IGF-I and IGF-II were measured by IGFBP-blocked assays in the presence of a large excess of the nonmeasured IGF. Whereas the IGFBP-3 assay detects various IGFBP-3 fragments besides the complete protein, no such detection of IGFBP-1 or IGFBP-2 fragments have been observed. Because of the age and sex dependence of the normal ranges during childhood, the absolute values of all five analytes were converted to SD scores (SDS) (18) adjusting for age and sex.

Statistics

Cox regression was used to test whether different factors influenced the event-free survival (EFS) of the patients. Correlation analysis was used to test whether serum levels of IGFs and IGFBPs had independent effects compared with conventional prognostic factors such as age, immunologial phenotype, WBC, hemoglobin, platelet count, and blast count at d 8. To define the cutoff points of IGFBP-2 and IGFBP-3, sensitivity and specificity were calculated as receiver operating characteristic curves. The optimum was confirmed by Cox regression with relative risk as the criterion. Discrimination analysis by cross-validation was performed to assess the event risk and to test whether these parameters improve the prediction at the time of diagnosis. Missing data were inferred by calculating the mean values of all patients.

EFS was defined as the time from diagnosis until the date of the first event; when no event occurred, the time until the last date of follow-up was used. Probabilities of EFS according to IGFBP-2 and IGFBP-3 at diagnosis were estimated by the method of Kaplan and Meier and were compared with the Log-Rank test.

For statistical evaluation, the SAS program system (version 8.2; SAS Institute, Cary, NC) was used. All statistical decisions were made with a critical probability of 5% without -adjustment. Therefore, all results should be interpreted in an explorative manner.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Serum concentrations of IGF and IGFBP at diagnosis

Clinical characteristics of patients and the SDS values of IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3 at diagnosis are shown in Table 1. In accordance with our previous report on 28 patients (13), serum concentrations less than –2.0 SDS were found for IGF-I in 57.4%, for IGF-II in 23.5%, and for IGFBP-3 in 31.5% of the patients. In contrast, serum IGFBP-2 was elevated to more than +2.0 SDS in 67.3% of the patients. Serum IGFBP-1 was normal (±2.0 SDS) in 98.1% of the patients.

Frequency of immunophenotypes and classification of risk according to the BFM protocols is shown in Table 2. Comparing patients with T-immunophenotype ALL (T-ALL) and common immunophenotype ALL (c-ALL), significant differences were obtained for serum concentrations of IGF-I and IGFBP-2, and a trend was observed for IGFBP-3, whereas significant differences between the SR and high risk (HR) groups were only found for IGFBP-3 (Table 3).

Prognostic value

From all 162 studied patients, 29 presented with an event. Patients with T-immunology and B-precursor immunology showed the highest event rate (25%), whereas only 13.8% of patients with c-ALL had events (Table 2).

The Cox regression was used to test whether the studied parameters had independent effects on EFS of our patients. Significant results were obtained for initial WBC (P < 0.001), IGFBP-2 (P = 0.019), age (P = 0.019), and blast count at d 8 (P = 0.02).

Stepwise multivariate analysis was used to select factors that provide the best discrimination between both groups (event vs. continuous complete remission). WBC, platelet count, and IGFBP-2 were identified as critical prognostic factors in both forward and backward analysis of all studied parameters (sensitivity, 55.2%; specificity, 80.4%). Using only the IGF peptides for discrimination, age, IGFBP-2 and IGFBP-3 were identified as critical factors (sensitivity, 51.7%; specificity, 66.9%). Using conventional risk factors alone (age, WBC, and platelet count at diagnosis, hemoglobin and blast count at d 8), only WBC and platelet count at diagnosis contributed to the discrimination of both groups (sensitivity, 48.2%; specificity, 81.2%).

A negative correlation between IGFBP-2 serum levels at diagnosis and EFS of all patients (r = –0.216; P = 0.002) was found. Taking into consideration only patients with an event (n = 29, the correlation (r = –0.286) was slightly higher but not significant (P = 0.133). This is in line with the results from the Cox regression and the multivariate analysis: IGFBP-2 alone is not strong enough as a prognostic parameter, but shows additional impact in combination with other parameters.

All patients with poor prednisone response at d 8 of therapy or no remission at d 33 of therapy were classified as HR patients (n = 23) (Table 2). The negative correlation between EFS and IGFBP-2 was clearly higher in the HR group (r = –0.413; P = 0.05) than with SR and medium risk (MR) patients (total n = 139; r = –0.21; P = 0.013).

To select suitable cutoff points for IGFBP-2 and IGFBP-3, sensitivity and specificity were calculated for different values and displayed as receiver operating characteristic curves. The optimum was defined as the point where the sum of specificity and sensitivity was maximal, and was confirmed by Cox regression with relative risk as criterion. With this procedure, cutoff points of +3.10 SDS for IGFBP-2 and –2.35 SDS for IGFBP-3 were selected.

The Kaplan-Meier plots show the EFS of all patients classified according to IGFBP-2 with a cutoff point of 3.10 SDS (Fig. 1) and according to IGFBP-3 with a cutoff point of –2.35 SDS (Fig. 2).

View larger version (15K): [in this window] [in a new window]   FIG. 1. Five-year probability of EFS in relation to serum IGFBP-2 concentration at diagnosis. Patients were divided into two groups according to their initial serum IGFBP-2. Patients with IGFBP-2 levels 3.10 SDS or less (solid line; n = 82; 10 events) had a significantly better outcome (P = 0.044) than patients with IGFBP-2 levels greater than 3.10 SDS (broken line; n = 80, 19 events).

View larger version (15K): [in this window] [in a new window]   FIG. 2. Five-year probability of EFS in relation to IGFBP-3 serum concentrations at diagnosis. Patients were divided into two groups according to their initial serum IGFBP-3. Patients with IGFBP-3 levels at least –2.35 SDS (solid line; n = 119; 15 events) had a significantly better outcome (P = 0.003) than patients with IGFBP-3 less than –2.35 SDS (broken line; n = 42, 14 events).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

The aim of the present study was to investigate whether components of the IGF system can be used to improve the prediction of survival or to identify risk groups for a risk-adapted treatment in children with ALL. Significantly higher serum IGFBP-2 levels and decreased IGFBP-3 levels at diagnosis were seen in patients with an event compared with those in continuous complete remission. Similarly, the use of IGFBP-3 for prediction of survival has been described in children with ALL (22). Changes in serum IGF and IGFBP concentrations in these patients exceeded those seen in nonmalignant conditions, e.g. after protein restriction or in GH deficiency (31). Under physiological circumstances, the liver is the main source of circulating IGFs and the binding proteins evaluated in this study. However, we have shown in patients with ALL that up-regulation of IGFBP-2 gene transcription in mononuclear cells is a possible source of elevated serum IGFBP-2 (32), which is in line with cell culture studies (6, 7, 33, 34).

Recent advances in the understanding of IGF regulatory pathways has increased our knowledge of the regulation of proliferation and apoptosis. In many cell types, including hematopoietic cells, carcinomas, and neuroblastomas (9, 35, 36), activation of the IGF-IR has been identified as a crucial step in control of the cell cycle (12, 35, 36, 37). It was shown that mutations in mitotic checkpoint genes cause aneuploidy and contribute to increased mutability (38). Therefore, it was postulated that defects in other mitotic checkpoints may contribute to chromosomal instability (39). Various alterations of the IGF signaling pathway have been described in malignant diseases including leukemia, in which mutations of IGF-IR (11) and altered expression of the IGF-II (40, 41) and M6P/IGF-2R genes (42) have been discovered. In view of the transcriptional activation of IGFBP-3 by p53 (43), mutations of p53 in T-ALL patients (44) might be an additional link to altered function of the IGF regulatory system in malignant diseases.

It has been shown that extracellular matrix-associated IGFBP-2 regulates local IGF availability (45, 46) and limited proteolysis of IGFBP-2 increases bioavailability of IGFs and mitosis (47). Therefore, we hypothesize that hematopoetic stem cells secrete IGFBP-2 (32) and build up a local reservoir of IGFs at the time when IGFs are low in circulation, favoring clonal expansion both at sites of normal lymphopoesis (bone marrow, lymph nodes) or of leukemic infiltration at extramedullary organs (testes, central nervous system).

In several in vitro studies, the effects of IGFBP-2 in tumorigenesis were investigated and both inhibitory and stimulatory consequences on cell proliferation have been described (48). In general, IGF ligand binding to IGFBP-2 result in an inhibition of the IGF-induced IGF-1R stimulation on the cell membrane. Proteolytic cleavage of cell surface-bound IGFBP-2 with subsequent decreased affinity for IGF, however, result in stimulation of IGF effects and supports also the concept of IGF-dependent growth-inhibitory effects of IGFBP-2 (47). On the other hand, a number of in vitro studies show also a positive association between IGFBP-2 expression, cell proliferation, and degree of malignancy (49, 50) and IGF-independent effects of IGFBP-2 have been assumed. Furthermore, permanently IGFBP-2 transfected epidermoid carcinoma cells developed faster large tumors when injected sc in nude mice than they did after injection of control clones. Because this effect was not observed in vitro, and an increased IGFBP-3 proteolysis was found in the tumors, increased IGFBP-3 proteolysis might be the mechanism responsible for the enhanced growth of IGFBP-2-overexpressing tumors in vivo (51).

It has been suggested that the cure for ALL may not require elimination of all leukemic cells (52) and that other mechanisms control the proliferation of persisting leukemic cells. If different local concentrations of IGF/IGFBP complexes are responsible either for sensitivity or resistance to chemotherapy, new therapeutic options in leukemia may include the interaction with the IGF regulatory pathway.

Our results show that components of the IGF system are linked to the outcome of childhood ALL. We were able to demonstrate an improvement in the prediction of EFS by including IGFBP-2 serum levels at diagnosis with the conventional risk factors. However, prediction models using only components from the IGF system (22) need to be critically examined. The weak correlations between conventional risk factors and components of the IGF system indicate the existence of different classes of variables with little interaction. This may encourage the search for additional factors that could provide better information for the optimal treatment of these patients.

	Acknowledgments

 
We thank the members of the BFM Study Group for sending us patient material and providing us with important clinical information.

	Footnotes

 
This work was supported by Deutsche Leukämie Forschungshilfe, Germany; Ministry of Culture of Saxonia-Anhalt, Germany; W. A. Drenckmann-Foundation, Germany; and Magdeburger Förderkreis Krebskranker Kinder e.V., Germany.

First Published Online February 1, 2005

Abbreviations: ALL, Acute lymphoblastic leukemia; BFM, Berlin Frankfurt Münster; c-ALL, common immunophenotype ALL; EFS, event-free survival; HR, high risk; IGFBP, IGF binding protein; IGF-IR, type 1 IGF receptor; MR, medium risk; SDS, SD score; SR, standard risk; T-ALL, T immunophenotype ALL; WBC, white blood cell count.

Received March 8, 2004.

Accepted January 26, 2005.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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