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Leukemia (2001) 15, 1165–1170  2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu

Plasma hepatocyte growth factor is a prognostic factor in patients with acute myeloid leukemia but not in patients with myelodysplastic syndrome S Verstovsek1, H Kantarjian1, E Estey1, A Aguayo1, FJ Giles1, T Manshouri2, C Koller1, Z Estrov3, E Freireich1, M Keating1 and M Albitar3 Departments of 1Leukemia, 2Hematopathology, and 3Bioimmunotherapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Hepatocyte growth factor (HGF) is a potent angiogenic factor. The aim of our study was to evaluate plasma HGF levels and their prognostic significance in patients with newly diagnosed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The sandwich enzyme immunoassay technique was used to quantify HGF in stored samples obtained before treatment from patients with AML (59 patients) and MDS (42 patients) treated at The University of Texas MD Anderson Cancer Center. HGF levels were significantly higher in patients with AML or MDS than in healthy individuals (P ⬍ 0.0001). Higher HGF levels in both AML and MDS correlated significantly with white blood cell (P = 0.000001 for both groups) and monocyte counts (P = 0.0004 and 0.003, respectively), and with poor performance status (P = 0.03 and 0.001, respectively). Using Cox proportional hazard model and HGF levels as a continuous variable, plasma levels of HGF correlated with shorter survival of AML (P = 0.001), but not MDS (P = 0.34) patients. No significant correlation was observed between HGF levels and complete remission rate or duration. In the multivariate analysis HGF retained its significance as prognostic factor in AML (P = 0.02), along with age (P = 0.0005). Leukemia (2001) 15, 1165– 1170. Keywords: hepatocyte growth factor; prognosis; AML; MDS; angiogenesis

Introduction Several studies examined angiogenic indices in specimens from patients with hematological malignancies because of the possibility that increased angiogenesis is important in the pathophysiology of these cancers. The risk of active disease in patients with multiple myeloma increased in parallel with marrow microvessel density and was accompanied by increased plasma cell angiogenic potential and matrix-degrading enzyme levels, bone marrow mast cell density, plasma cell adhesion molecule expression, and plasma cell proliferation index.1–4 Increased lymph node and bone marrow angiogenesis was found in patients with lymphoma, with progression from benign lymphadenopathies to low-grade and intermediate-grade lymphomas, and accompanied by simultaneous increases in macrophage and mast cell bone marrow density.5–7 Increased marrow vascularity was reported in patients with acute lymphoblastic and myelogenous leukemias, myelodysplastic syndrome, and myeloproliferative diseases.8–11 Our own study found increased vascularity in bone marrow from patients with myelodysplastic syndrome (MDS) and all types of leukemia, except chronic lymphocytic leukemia.12 Many angiogenic factors have been identified,13 but so far in leukemia the significance of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have received most attention.8–17 We have recently reported that Correspondence: M Albitar, University of Texas, MD Anderson Cancer Center, Department of Hematopathology, 1515 Holcombe Blvd., Box 72, Houston, TX 77030, USA; Fax: 713 794 1800 Received 7 November 2000; accepted 27 March 2001

the level of another angiogenic factor, hepatocyte growth factor (HGF), is elevated in all types of leukemia, as well as in myelodysplastic syndrome (MDS).12 In vitro and in vivo angiogenesis assays have established HGF to be a powerful angiogenic factor.18–20 Initially identified as a stimulator of hepatocyte growth in vitro, it has since then been characterized as a cytokine with mitogenic, motogenic, and morphogenic effects, involved in various normal developmental and homeostatic processes of the body.21 HGF is produced mainly by mesenchymal cells, like fibroblasts and vascular smooth muscle cells. A variety of HGF production stimulators have so far been identified,21 including bFGF.22 The cellular responses to HGF are mediated by the Met, a cell surface receptor encoded by the c-met proto-oncogene. Regulation of neovasculature by HGF may occur in both autocrine and paracrine mechanisms as both HGF and the Met are expressed in vascular tissue, including vascular smooth muscle cells and endothelial cells.21 HGF is believed to increase angiogenesis by multiple mechanisms, including effects on proliferation, motility, and adhesion of endothelial cells, effects on morphogenesis of new vessels, and possibly also by the production of angiogenic factors by stromal and other cells.21 One recent study, reporting that HGF upregulated the expression of VEGF in vascular smooth muscle cells, supported paracrine amplification of angiogenesis as an operating mechanism.23 A substantial body of experimental evidence establishes HGF and its receptor, the Met, as regulators of carcinogenesis, cancer invasion, and metastasis of solid tumors.24 Correlation between increased HGF levels/expression and cancer progression or poor prognosis has been reported in patients with a variety of solid tumors.24 Based on these findings, potential HGF antagonists/inhibitors are being screened, developed, and tested as anticancer agents.25,26 The significance of HGF in the pathogenesis of hematological malignancies has only recently become the focus of more extensive research. Strong evidence for the role of HGF and its receptor has been reported in multiple myeloma.27,28 The role of HGF in the pathophysiology of lymphomas and leukemias has not been fully evaluated.29 Here we report the results of our study of HGF plasma levels and their prognostic significance in newly diagnosed, untreated patients with AML and MDS. Materials and methods

Study group HGF concentrations were measured in plasma samples of 101 patients with newly diagnosed AML (59 patients) or MDS (42 patients) seen at the MD Anderson Cancer Center between 1994 and 1998. Patient characteristics are shown in Table 1. Patients with acute promyelocytic leukemia were excluded because of the distinctive clinical course of this disease. All

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Table 1

Patients’ clinical characteristics

Characteristics

AML No. (% of total)

Age ⬎60 years Performance status 0–2 AHD Yes Hemoglobin ⬍10 g/dl White blood cells ⬎20 × 109/l Platelets ⬍50 × 109/l Monocytes ⬎10 × 109/l

59 37 (63) 55 (93) 33 (56) 57 (97) 18 (30) 29 (49) 21 (36)

Cytogenetics (prognosis) Diploid (intermediate) −5, −7, 11q23 or +8 (bad) t(8;21) or inv16 (good) FAB classification M 0–2 M 4–5 M 6–7 RA RAEB RAEB-T CMML

MDS

No. (% of category) with HGF ⬎1500 pg/ml 16 11 14 5 16 12 11 9

No. (% of total)

No. (% of category) with HGF ⬎1500 pg/ml

(27) (30) (25) (15) (28) (67) (38) (43)

42 31 (73) 41 (98) 30 (71) 36 (86) 11 (26) 27 (64) 19 (45)

24 (41) 14 (24) 5 (8)

7 (29) 3 (21) 3 (60)

24 (57) 14 (33) 1 (2)

8 (33) 3 (21) 0

34 (58) 20 (34) 5 (8)

6 (18) 8 (40) 2 (40) 1 14 16 11

0 0 6 (37) 6 (55)

(2) (33) (38) (26)

12 7 11 8 11 9 10 6

(29) (23) (26) (27) (31) (82) (37) (32)

AHD, antecedent hematological disorder; FAB, French–American–British; RA, refractory anemia; RAEB, refractory anemia with elevated blasts; RAEB-T, refractory anemia with elevated blasts in transformation; CMML, chronic myelomonocytic leukemia.

patients were treated on frontline AML-type chemotherapy clinical research protocols (cytarabine/idarubicin- or cytarabine/topotecan-based chemotherapy combinations). Although treated with different chemotherapy regimens, patient outcome of such a diverse group does not differ significantly,30 minimizing the possibility that treatment allocations influenced the results reported here. All patients were regularly followed up in the Leukemia Department outpatient clinic.

(Elx808; Bio-Tek Instruments, Inc., Winooski, VT, USA). The standard curve was created, using the KC3 computer program (Bio-Tek Instruments), by plotting the logarithm of the mean absorbency of each standard vs the logarithm of the HGF concentration. The HGF concentration in each sample was then calculated. Each patient sample was evaluated in triplicate and median value was used in statistical analysis. The reproducibility of ELISA has previously been verified.12

Statistical analysis Samples Peripheral venous blood samples were collected in sterile test tubes 1–2 days before patients started therapy. On the same day, plasma was separated from each specimen and stored at −70°C. All samples were obtained under protocols approved by the hospital Internal Review Board and with patients’ written informed consent. Samples from 11 healthy individuals were collected and used as controls.

All data were collected by reviewing patients’ records and compiled in the Leukemia Department database. Statistical analysis was performed using the Kruskal–Wallis or Fisher exact test for comparing groups. Survival was plotted using Kaplan–Meier plots and compared by log-rank test, as well as using Cox proportional hazard model and HGF levels as a continuous variable. Spearman analysis was used for correlation testing. Multivariate analysis was performed using Cox proportional hazard model with variables used as continuous variables rather than using cutoff point.

Plasma HGF immunoassay HGF concentrations in plasma were determined as HGF immunoreactivity using a quantitative sandwich enzyme immunoassay technique (Quantikine Human Hepatocyte Growth Factor Immunoassay; R&D Systems, Minneapolis, MN, USA). The system uses a solid-phase monoclonal antibody and an enzyme-linked polyclonal antibody raised against recombinant HGF. For each sample, 50 ␮l of plasma was analyzed as suggested by the manufacturer. The calibrations on each microtiter plate included recombinant human HGF. Optical densities were determined, as suggested by the manufacturer, by using a microtiter plate reader Leukemia

Results

Increased HGF levels in plasma of patients with newly diagnosed AML and MDS Among 59 patients with newly diagnosed AML, HGF concentrations ranged from 101.9 to 12 819.5 pg/ml (median value 854.8 pg/ml). Among 42 patients with newly diagnosed MDS, HGF concentrations ranged from 192.3 to 8657.4 pg/ml (median value 843.5 pg/ml). HGF concentrations in 11 normal controls ranged from 164.0 to 522.3 pg/ml (median value

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364.2 pg/ml). HGF levels were significantly higher in patients with AML and MDS than in normal subjects (P ⬍ 0.0001; Figure 1). Plasma concentrations of HGF did not differ between MDS and AML patients (P = 0.49). The mean value for the whole study group (101 patients) was 1500 pg/ml. The median age of normal control group was 35 years (range: 19–60), different from that of AML/MDS patients. However, there was no correlation between HGF and age (see below). Furthermore, using Fisher exact test we tested whether HGF levels were different in older vs younger AML/MDS patients. We found no difference between groups even when cut-off point of 60 (P = 0.5), 50 (P = 0.09) or 40 (P = 0.3) years was used.

High plasma HGF levels correlate with shorter survival in patients with newly diagnosed AML but not MDS Using mean as a cutoff value to separate HGF levels into two groups, we found that AML patients with HGF concentrations higher than 1500 pg/ml had medium survival of 42 weeks compared with 84 weeks for patients with HGF levels lower than 1500 pg/ml (P = 0.05; Figure 2a). In patients with MDS, HGF levels were not associated with differences in survival outcome (P = NS; Figure 2b). The use of different cutoff points did not yield significant finding. We then used HGF levels as a continuous variable and used the Cox proportional hazard model to assess its significance. We found significant correlation between increasing plasma levels of HGF and shorter survival of AML (P = 0.001) but not MDS (P = 0.34) patients. We evaluated survival of patients with refractory anemia with elevated blasts in transformation (RAEB-T) separately and found no correlation between HGF levels and survival (P = 0.5). Using Cox proportional hazard model for analysis, HGF level remained predictive of survival in AML group even after including RAEB-T patients in the AML group (P ⬍ 0.001); HGF was not predictive of survival in MDS group even when we excluded RAEB-T patients from this group (P = 0.72). Correlation between HGF plasma levels and the characteristics of AML and MDS patients are shown in Table 2. High HGF levels in both AML and MDS patients correlated significantly with elevated white blood cell (P = 0.000001 for both

Figure 2 Survival of patients with AML and MDS based on pretreatment plasma HGF concentration. HGF concentrations were measured in plasma of 59 patients with AML and 42 patients with MDS. Survival times of patients with AML (a) and with MDS (b) are presented in relation to their HGF level. Table 2 Spearman correlation between HGF concentration and various characteristics of AML and MDS patients

Patient characteristics

R Age Performance status Antecedent hematological disorder Hemoglobin level White blood cell count Monocyte count Platelet count Poor prognosis cytogenetics

Figure 1 Comparison of HGF plasma levels in patients with AML, MDS and normal controls. HGF concentrations (pg/ml) were measured in plasma of 59 patients with AML, 42 patients with MDS, and 11 normal subjects. Data are presented as means with standard deviations. HGF levels were significantly higher in patients with AML and MDS than in normal controls.

Correlation with HGF

0.17 0.29

AML P value 0.20 0.03

−0.17 −0.25 0.60 0.44 −0.11

0.21 0.05 0.000001 0.0004 0.39

−0.08

0.52

R 0.03 0.49 −0.02 −0.12 0.67 0.44 −0.28 0.23

MDS P value 0.85 0.001 0.91 0.45 0.000001 0.003 0.07 0.14

groups) and monocyte counts (P = 0.0004 and 0.003, respectively) and with poor performance status (P = 0.03 and 0.001, respectively). Prediction of survival based on individual characteristics of AML and MDS patients is shown in Table 3. For AML patients survival correlated significantly with variables known to affect prognosis, including age (P = 0.0001), performance status (P = 0.02), and poor cytogenetic characteristics (P = 0.05), as well as treatment in a protected environment (P = 0.03). No significant correlation was found between Leukemia

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Table 3 Prediction of survival as determined by various patient characteristics

Variable

P value for prediction of survival

Age Performance status Treatment in protected environment Hemoglobin White blood cell count Platelet count Monocyte count Poor prognosis cytogenetics

AML

MDS

0.0001 0.02 0.03 0.79 0.15 0.87 0.62 0.05

0.19 0.34 0.27 0.28 0.70 0.85 0.08 0.08

Table 4 Multivariate analysis of correlation between various patient characteristics and survival

Variable

HGF Age Performance status Hemoglobin White blood cell count Platelet count Monocyte count

P value AML

MDS

0.02 0.0005 0.9 0.4 0.6 0.9 0.7

0.4 0.1 0.2 0.1 0.3 0.6 0.01

HGF plasma concentrations in patients with AML or MDS and the incidence of complete remission or remission duration. In the multivariate analysis (Table 3) HGF level retained its significance as prognostic factor in AML (P = 0.02), along with age (P = 0.0005). Discussion Expression and production of HGF, and expression of its receptor, have been reported in a number of leukemic cell lines.31,32 Initial studies on samples from leukemic patients showed elevated HGF blood and bone marrow plasma levels in AML patients, but these did not reach statistical significance.33 A subsequent comparison with normal controls showed, however, that HGF levels were significantly higher in bone marrow plasma, but not blood plasma, of 20 AML and five chronic myeloid leukemia patients.34 We also found elevated levels of HGF in plasma of patients with AML (and also MDS).12 Recently, HGF levels in blood serum samples from 60 newly diagnosed AML patients showed statistically significant elevation, compared to those of normal controls, but no significant correlation was found between HGF levels and patient survival.35 In our study, plasma HGF levels were significantly higher in newly diagnosed AML patients than in normal controls. We also found plasma HGF levels to be as high in newly diagnosed MDS as in AML patients, significantly higher than in normal controls. In contrast to a previous report, we found high HGF levels to be associated with significantly worse survival of newly diagnosed AML patients. This may be due to the sample source. We chose to analyze plasma rather than Leukemia

serum levels because of observed variations in the level of angiogenic factors in serum, which might be caused by the release of angiogenic factors from platelets into the serum during serum isolation.12,36 Moreover, HGF was initially isolated and purified from normal rat platelets,37 and removal of platelets greatly reduced the HGF activity of normal rat serum.38 Sakon et al39 recently compared HGF measurements in plasma and serum samples and concluded that HGF plasma levels yield more valid and precise measures than HGF serum levels. In contrast to the findings in AML, we found no significant correlation between HGF levels and outcome in newly diagnosed MDS patients. The mechanisms underlying this difference are unknown, but the finding may suggest that AML and MDS are biologically dissimilar entities and follow different pathophysiologic processes. Certainly, repeating the study in a significantly larger number of patients would help clarify this issue. HGF was recently shown to promote proliferation and migration of blood mononuclear cells obtained from patients with AML and MDS with elevated blasts.40 Furthermore, the possibility that HGF was produced by leukemic cells in vivo was suggested by the detection of HGF expression and production by freshly prepared AML blasts. Based on these observations, it is not surprising that HGF plasma levels in our study group correlated strongly with the white blood cell counts. More intriguing is the strong correlation between HGF plasma levels and monocyte counts. Beilmann et al41 reported that activated monocytes expressed c-met, and HGF promoted the viability of activated monocytes. Thus, the observed correlation may be the result of a direct stimulation of monocytes by HGF in patients with AML and MDS. For the group of patients with AML it is important to note that despite correlation between HGF and monocyte and white blood cell counts, as well as with performance status, in the multivariate analysis HGF was shown to have independent statistical significance for patient survival. Several factors are known to augment the production of HGF in normal tissues,21 but such a relationship has not been evaluated in leukemia, nor is it known whether any factors involved in HGF action are active in leukemia. In normal tissues, bFGF is a known inducer of HGF22 and HGF induces VEGF production.23 Both bFGF and VEGF may have significant roles in the pathophysiology of leukemia. When we evaluated bFGF and VEGF plasma levels in relation to HGF plasma levels in AML patients, we found a strong correlation between plasma concentrations of HGF and VEGF, but not between HGF and bFGF (preliminary results; data not shown). More investigations are needed to confirm these findings, but the correlation may elucidate one of the more important cytokine combinations operable in the propagation of AML, similar to such findings in solid tumors.42 This may then also help us understand better how HGF level affects patient survival. For example, based on our experience that a significant number of AML patients who die early in the course of treatment die of hemorrhage,43 it is possible that HGF as an angiogenic agent contributes to this fatal event. In summary, our study demonstrated elevated plasma HGF levels in patients with newly diagnosed AML and MDS. High HGF levels were associated with significantly shorter survival of newly diagnosed AML, but not MDS patients. The mechanisms by which high plasma HGF levels confer shorter survival in AML are unclear; augmentation of angiogenesis may be involved. Although antiangiogenic therapy in patients with hematologic malignancies is already undergoing evaluation,44

HGF is a prognostic factor in AML S Verstovsek et al

the development of more specific and potent antiangiogenic agents will require a better understanding of the role and action of each angiogenic factor.

Acknowledgements

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18

SV is supported by grant T32-CA09666 from the National Institute of Health, USA. 19

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