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Modifications of Growth Velocity and the Insulin-Like Growth Factor System in Children with Acute Lymphoblastic Leukemia: A Longitudinal Study¹

Universidad Autónoma, Department of Pediatrics, Division of Pediatric Endocrinology, Laboratory of Research, Hospital Universitario Niño Jesús, 28009 Madrid, Spain

Address all correspondence and requests for reprints to: Jesús Argente, M.D., Ph.D., Division of Pediatric Endocrinology, Laboratory of Research, Hospital Niño Jesús, Avenida. Menéndez Pelayo 65, 28009 Madrid, Spain. E-mail: argentefen{at}teleline.es

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The basis of impaired growth in children with acute lymphoblastic leukemia (ALL) is multifactorial, including the disease itself, infections, undernutrition, and adverse effects of therapy. Because growth is regulated by the GH-insulin-like growth factor (IGF) system, which may be altered in catabolic states, we studied serum IGF-I, free IGF-I, IGF-II, the IGF-binding proteins (IGFBP-1 to -3), and total and free acid-labile subunit (ALS) levels in 26 prepubertal children with ALL at diagnosis (n = 26) and 6 (n = 21), 12 (n = 21), 18 (n = 21), 24 (n = 20), 30 (n = 16), and 36 months (n = 16) after beginning treatment to investigate the effects of disease and therapy on this system and its relationship with growth in these patients. Intensive chemotherapy compromised growth, with a catch-up period beginning when maintenance therapy began and increased growth after stopping therapy. Weight increased 6 months after chemotherapy withdrawal, whereas the body mass index was increased both at 6 months after diagnosis and 6 months after therapy suppression. Serum IGF-I, IGF-II, IGFBP-3, and total and free ALS levels were significantly decreased at diagnosis. Normalization of IGF-II and IGFBP-3 occurred 6 months after diagnosis, and normalization of IGF-I and total and free ALS occurred 1 yr after terminating therapy. IGFBP-1 and IGFBP-2 levels were significantly increased at diagnosis and decreased after stopping therapy. Free IGF-I was elevated throughout the study. IGF and IGFBP-3 levels showed a close relationship to growth velocity at the end of chemotherapy, with this correlation remaining until at least 1 yr after therapy withdrawal. In conclusion, intensive chemotherapy compromises linear growth in prepubertal ALL patients, and this phenomenon is associated with alterations in the IGF system. However, when therapy is reduced or stopped, catch-up growth occurs, but various parameters of the GH-IGF axis remain impaired. This suggests the need for a longer period of follow-up to assess the long-term risks of therapy and disease on this system.

	Introduction

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GROWTH RETARDATION is a common finding in children successfully treated for acute lymphoblastic leukemia (ALL). Various factors that may contribute to this attenuation of growth include the disease itself, cortisone and cytotoxic drug treatment, infections, poor nutrition during therapy, and CNS irradiation (1). It is well recognized that high doses of cranial irradiation can cause neurological sequelae and a significant loss in height, mainly by impairing GH secretion. Hence, in recent years the use of cranial irradiation has been restricted to patients with high risk leukemia and the dose to 12 Gy or less, but the effect of this radiation dose on growth remains controversial (2, 3).

Longitudinal growth is regulated mainly by the insulin-like growth factors (IGFs) (4). IGF-I and IGF-II are peptide mitogens that share structural homology with proinsulin, stimulate cellular proliferation in many tissues, and may contribute to the autocrine stimulation of cell growth in a variety of tumors (5). More than 95% of the IGFs is complexed to a family of at least six IGF-binding proteins (IGFBPs), which may modulate the effects of these growth factors on target tissues (6). There is evidence that IGFBP-2 and IGFBP-4, unlike IGFBP-1 and IGFBP-3, modulate the intracellular actions of the IGFs (7). In postnatal animals IGFBP-3 is the major carrier of IGFs in serum, and 90–95% of it is found in a ternary complex of approximately 140 kDa, comprised of an acid-labile subunit (ALS), IGFBP-3, and IGF-I or -II (8). In contrast, during fetal life the most abundant binding protein is IGFBP-2. A great number of tumor cell lines have been reported to express IGFBP-2, but the effects of this protein on tumor and normal cells are still unknown (9). Measurements of these components of the IGF system in a group of children with ALL at different points of disease evolution have not been reported previously.

We report here the results of a longitudinal, prospective study in which serial measurements of various components of the peripheral GH-IGF axis and auxological parameters were made and correlated in children with ALL. This was done to determine whether the changes in this system were related to the disease or its therapy.

	Subjects and Methods

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Subjects

The study population included 26 prepubertal children with ALL without CNS involvement and 37 healthy age-matched controls. The definitions and requirements for diagnosis of ALL were made according to the German cooperative group BFM (Berlin-Frankfurt-Münster) (10). The patients were studied at seven different points: at diagnosis (n = 26) and 6 (n = 21), 12 (n = 21), 18 (n = 21), 24 (n = 20), 30 (n = 16), and 36 months (n = 16) after beginning therapy. The distribution by risk groups was 11 standard risk, 11 intermediate risk, and 4 high risk. During the study period 6 patients died (2 intermediate risk and 4 high risk). The therapy used was that stipulated by the BFM-90 protocol.

All normal subjects were referred to the Division of Endocrinology for suspected endocrine abnormalities and were found to be normal, with height and body mass index (BMI) between -1 and 1 SD according to Spanish standards (11). This study was approved by the ethics committee of the Hospital Universitario Niño Jesús.

The BFM-90 treatment schedule

Protocol I. This therapeutic phase was common to all risk groups. It had a duration of 64 days, and the drugs used were prednisone, vincristine, daunorubicine, L-asparaginase, cyclophosphamide, arabinoside C, 6-mercaptopurine, and intrathecal methotrexate.

Protocol M. The duration was 56 days. The drugs used were 6-mercaptopurine, L-asparaginase, high dose methotrexate, and intrathecal methotrexate.

Protocol II. The duration was 49 days. Dexamethasone, vincristine, adriamicin, L-asparaginase, cyclophosphamide, arabinoside C, 6-thioguanine, and intrathecal methotrexate were the drugs employed.

High risk blocks. Therapeutic blocks 1, 2, and 3 lasted 6 days each. They were administered consecutively, with an interval of 15 days, and were repeated three times each.

Maintenance therapy. In this period, oral 6-mercaptopurine (50 mg/m²) was administered daily, and oral methotrexate (20 mg/m²) was given weekly for 24 months from the beginning of therapy.

Prophylactic cranial irradiation. Cranial irradiation was only administered to the patients of the intermediate risk and high risk groups. This was applied in eight fractions delivered in 2 weeks to reach a total dose of 12 Gy.

Auxology

Height was measured in the morning by the same experienced staff using a wall stadiometer (Holtain Ltd., Crymych, UK). In children with ALL, measurements were taken at diagnosis and at 6-month intervals up to 3 yr after diagnosis. Height SD scores were calculated as (h- mean)/SD, where h is the actual measurement, mean is the mean of the standard for age and sex, and SD is the corresponding SD (10). Growth velocity was calculated once a year and is expressed as the SD. Bone age was determined annually according to the Greulich and Pyle method. Weight and BMI at all study points were calculated and expressed as the SD score. The SD scores were based upon normative data from Spanish children (11).

Biochemical measurements

Total IGF-I was performed by RIA after acid-ethanol extraction (Nichols Institute Diagnostics, San Juan Capistrano, CA). Intra- and interassay coefficients of variation were 4.9% and 8.9%, respectively. Free IGF-I was measured by immunoradiometric assay (Diagnostic Systems Laboratories, Inc., Webster, TX). Intra- and interassay coefficients of variation were 6.2% and 7.3%, respectively. Serum IGFBP-3 levels were determined by RIA (Mediagnost, Tubingen, Germany). Intra- and interassay coefficients of variation were 3.56% and 6.05%, respectively. Total and free ALS were measured by enzyme-linked immunosorbent assays (Diagnostic Systems Laboratories, Inc.). Intra- and interassay coefficients of variation were 5.6% and 7% for total ALS, and 6.1% and 7.2% for free ALS, respectively. IGFBP-1 was performed by enzyme-linked immunosorbent assay (Medix Biochemica, Kauniainen, Finland). Intra- and interassay coefficients of variation were 4.6% and 9.8%, respectively. Serum IGFBP-2 levels were measured by RIA (Diagnostic Systems Laboratories, Inc.). Intra- and interassay coefficients of variation were 5.7% and 7.2%, respectively.

Statistics

All data are reported as the mean ± SEM, expressed as the SD score. These values were determined by using reference values from a large Spanish population (12, 13). Changes in the different parameters were assessed for seven periods: diagnosis and 6, 12, 18, 24, 30, and 36 months after beginning treatment. The significance of these changes was analyzed by the Wilcoxon signed-rank test. Analyses were performed by one-way ANOVA, followed by Scheffe’s F test. Correlations were performed using simple regression analyses. P < 0.05 was chosen as the level of significance.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Auxological parameters

The mean age at diagnosis for the 26 study patients with ALL was 5.12 yr (range, 1.66–10.0 yr). The mean age at the end of the study was 7.09 yr (range, 5.5–9.0 yr). The sex distribution was 19 boys and 7 girls.

The mean height of the 26 children was 0.55 SD at diagnosis, 0.40 at 6 months of treatment, and 0.97 at 24 months of treatment. The height SD score at the end of therapy was significantly increased compared with that at diagnosis (by ANOVA, P < 0.05). Weights were 0.79, 1.10, and 1.26 SD score for the same periods. These children had significantly increased BMIs (Fig. 1 and Table 1) 6 months after diagnosis and 6 and 12 months after treatment suspension (by ANOVA, P < 0.05). Growth velocity (Table 2) was significantly elevated during the third year compared with those during the first and second years (by ANOVA, P < 0.05). When we compared this auxological parameter in patients who received or did not receive radiotherapy, we found slightly higher values during the first and second years in nonirradiated patients and lower values in this group during the third year, but these differences did not reach statistical significance (Table 2). The bone age corresponded to the chronological age throughout the study.

View larger version (43K): [in this window] [in a new window]   Figure 1. Mean (±SEM) SD score for BMI of patients with ALL at diagnosis (Dx) and throughout a 3-yr treatment and follow-up period. *, P < 0.05 by ANOVA.

Biochemical parameters

IGF-I, free IGF-I (fIGF-I), and IGF-II. The SD scores of the components of the peripheral GH-IGF axis are expressed in Table 3. Total serum IGF-I levels (Fig. 2A) were decreased significantly in patients with ALL at diagnosis and during the first year (by ANOVA, P < 0.01). They were significantly increased with respect to diagnosis at 12, 18, 24, and 30 months and did not return to normal values until 36 months after diagnosis (by ANOVA, P < 0.05). There were no differences between irradiated and nonirradiated children. Free IGF-I levels (Fig. 2B) were significantly increased in patients with ALL at diagnosis and remained so throughout the study (by ANOVA, P < 0.05), including 1 yr after suspension of therapy.

View larger version (59K): [in this window] [in a new window]   Figure 2. Schematic representation of the mean (±SEM) SD score for serum levels of IGF-I (A), free IGF-I (B), IGF-II (C), IGFBP-1 (D), IGFBP-2 (E), IGFBP-3 (F), total ALS (G), and free ALS (H) in controls (C) and in patients with ALL at diagnosis (Dx) and throughout a 3-yr period. *, P < 0.05; **, P < 0.01 (by ANOVA).

IGFBP-1, IGFBP-2, and IGFBP-3. Serum IGFBP-1 (Fig. 2D) and IGFBP-2 (Fig. 2E) levels were significantly elevated in ALL patients at diagnosis and did not change during the first 18 months after treatment was started, but returned to normal values 24 months after diagnosis (by ANOVA, P < 0.05).

Serum IGFBP-3 levels (Fig. 2F) were significantly lower than control values at diagnosis. They returned to normal by 6 months and remained stable throughout the rest of the study period (by ANOVA, P < 0.01).

Total and free ALS. As shown in Fig. 2, G and H, serum ALS and free ALS levels in patients with ALL were significantly lower than those in normal subjects from the time of diagnosis up until 30 months after beginning the study (by ANOVA, P < 0.01), returning to normal at 36 months.

Ratio of IGFBP-2/IGF-I. Patients with ALL have a significantly higher IGFBP-2/IGF-I ratio than controls at diagnosis (7.31 ± 1.64 vs. 1.55 ± 0.36, respectively; P < 0.05). This ratio remained significantly elevated 6 months after diagnosis (6.07 ± 1.87; P < 0.05 vs. control group), but returned to control values at 24 months (2.21 ± 0.45).

Regression analyses

The results of all regression analyses performed between auxological and biochemical parameters are represented in Table 4. Growth velocity showed a close relationship with IGF-I, IGF-II, and IGFBP-3 at 24 and 36 months after diagnosis. BMI correlated negatively with IGFBP-2 at 6 and 36 months and positively with IGF-I, IGFBP-3, and total and free ALS 1 yr after therapy withdrawal. When we analyzed the relationship between the components of the GH-IGF system, a significant positive correlation was found between serum total ALS levels and all components of the ternary complex, including IGF-I, free IGF-I, IGFBP-3, and free ALS. Furthermore, serum IGF-I levels correlated significantly with free IGF-I, IGFBP-3, and total and free ALS values, except for IGFBP-3 after stopping therapy.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Although a few reports indicate normal growth in children treated for ALL with chemotherapy alone (16, 17), others studies suggest that chemotherapy has a negative influence on growth (3, 18). The mechanism by which chemotherapy influences growth has received little attention to date, although some data suggest that cytotoxic drugs impair the production of IGF-I by the liver and the action of IGF-I on the cartilage growth plate (19).

Our data support previous observations (20, 21) that linear growth is compromised during chemotherapy, but is then followed by a catch-up period, suggesting that intense chemotherapy could be directly involved in growth retardation. All of our patients had a significant decline in height SD scores during the first 6 months of treatment, confirming the findings of other investigators (20, 21). The exact cause of this decrease in growth rate remains unknown. These children have an elevated IGFBP-2/IGF-I ratio at diagnosis and at 6 months, which suggests a catabolic state (22). After 1 yr, a slight increase in growth velocity occurred in these children during continuation treatment, which employs only methotrexate and 6-mercaptopurine. It has been reported that methotrexate has no discernible effect on height velocity in ALL patients (23), and Mohnike et al. reported that the BFM protocol does not affect final height (3).

The effects of leukemia and its treatment on weight gain are less well documented than their influence on linear growth. However, around 50% of survivors of leukemia are overweight (24). Factors such as cranial irradiation, chemotherapy, corticosteroids, and lack of exercise could contribute to the weight gain in these children (24). However, BMI was increased both 6 months after diagnosis, when height was still in the normal range, and 6 and 12 months after therapy withdrawal, when height was increased. The use of corticosteroids during the first phase of therapy could explain the increase in BMI, but the rise after chemotherapy suspension, also observed by other researchers (25), would indicate an effect of treatment on body composition or an improvement in nutrient intake and assimilation when therapy is removed.

The mechanism by which the GH-IGF-I axis is altered in children with ALL is multifactorial. Children with cancer are severely catabolic, as shown by an increase in protein breakdown and protein synthesis (26). One consequence of this may be modulation of the GH-IGF axis. In addition, malignant diseases lead to alterations in the IGF signaling system, and leukemic T cell lines secrete IGF-II and express high levels of IGFBP-2 messenger ribonucleic acid and protein (27). Finally, some studies suggest that cytotoxic drugs impair the production of IGF-I by the liver and its action on the cartilage growth plate (19).

Our results are consistent with those of previous studies (9, 28), and clearly demonstrate that at diagnosis, serum IGF-I, IGF-II, and IGFBP-3 levels in ALL patients are significantly reduced. Serum total and free ALS levels were also diminished at diagnosis. Hence, the proliferation of malignant lymphoblasts occurs in the presence of decreased serum levels of IGF-I, IGF-II, IGFBP-3, and free and total ALS. The decrease in these peptides might contribute to impaired growth. In general, these changes in the IGF regulatory pathway are comparable to those observed in malnutrition and other catabolic conditions (29). The differential recuperation of the ternary complex components could be secondary to the differential response of hepatic cell types, as IGF-I and ALS are produced by hepatocytes, whereas IGFBP-3 is produced by Kupffer cells (30). Furthermore, at diagnosis, IGFBP-3 proteolysis is increased in serum samples of children with solid tumors or acute leukemia, and this activity is normalized when patients reach complete remission (31).

In children with ALL, serum IGFBP-1 and IGFBP-2 levels were increased at the time of diagnosis and throughout the acute phase of chemotherapy. IGFBP-2 may be a good biochemical marker in growth and nutritional disorders during childhood, because its levels are not modified by nutrient ingestion. Leukemic cells secrete IGFBP-2; hence, Wex et al. (32) suggest that the increased serum IGFBP-2 levels originate from the tumor itself and, therefore, might be a useful parameter for early detection of a relapse of leukemia (9). Our findings are not in agreement with this, because serum IGFBP-2 levels remained elevated until therapy was suppressed, even though the patients had been in remission for many months. Therefore, tumor proliferation could not account for the elevated serum IGFBP-2 in these children and suggest that these changes are controlled mainly by the catabolic state.

If fIGF-I is the biologically active fraction of this factor, these children, although having low overall IGF levels, may not be deficient in biologically active IGF-I (33). fIGF-I levels were elevated, suggesting that the diminution in total IGF-I is due to a decrease in the bound IGF-I fraction. As IGFBP-3 is the main transporter of IGF-I in serum, the higher level of fIGF-I may be related to the significant reduction in this binding protein. Hence, the possible increase in proteolytic activity could explain the rise in fIGF-I (33).

In summary, this study demonstrates that linear growth in prepubertal children with ALL is compromised mainly during intensive chemotherapy, but is then followed by a catch-up period. On the other hand, the GH-IGF axis is altered not only during the treatment period, but also when therapy is withdrawn, suggesting that some of the GH-IGF axis components are more sensitive than auxological data in following some aspects of this disease.

	Acknowledgments

 
We thank Dr. Julie A. Chowen for the critical review of the manuscript.

	Footnotes

 
¹ This work was supported by Fundación Endocrinología y Nutrición.

Received December 16, 1999.

Revised March 18, 2000.

Revised June 26, 2000.

Accepted July 28, 2000.

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