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Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3541-3550
By
From Saitama Cancer Center Research Institute, Saitama, Japan; and
the First Department of Internal Medicine, Toho University School of
Medicine, Tokyo, Japan.
The outcome of patients with non-Hodgkin's lymphoma has been
improved by current approaches to treatment. Nevertheless, many patients either do not have a complete remission or ultimately relapse.
To identify such patients, it is important to be able to predict the
outcome. We previously found that the differentiation inhibitory
factor/nm23 was correlated with the prognosis of acute myeloid
leukemia. To examine the prognostic effect of nm23 on non-Hodgkin's lymphoma, we established an enzyme-linked immunosorbent assay procedure to determine nm23-H1 protein levels in plasma and assessed the association of this protein level with the response to
chemotherapy, overall survival, and progression-free survival in
patients with aggressive non-Hodgkin's lymphoma. The plasma concentration of nm23-H1 was significantly higher in patients with malignant lymphoma than in normal controls, especially in aggressive non-Hodgkin's lymphoma. The complete remission rate in
patients with higher nm23-H1 levels was significantly worse than that in patients with lower nm23-H1 levels. Overall
survival and progression-free survival were also lower in patients with higher nm23-H1 levels than in those with lower levels. The
3-year survival rates in patients with low and high nm23-H1
levels were 79.5% and 6.7% (P = .0001). A multivariate
analysis of prognostic factors showed that the plasma nm23-H1
level was independently associated with the survival and
progression-free survival. An elevated plasma nm23-H1
concentration predicts a poor outcome of advanced non-Hodgkin's
lymphoma. Therefore, nm23-H1 in plasma may be useful for
identifying a distinct group of patients at very high risk.
WE FOUND THAT A differentiation
inhibitory factor purified from conditioned medium of a
differentiation-resistant mouse myeloid leukemia cell line was
identical to the nm23 protein.1-7 nm23
proteins are involved in tumor metastasis regulation and have
nucleoside diphosphate kinase enzyme activity that catalyzes the
ATP-dependent synthesis of nucleoside diphosphates.8,9 In
humans, 5 nm23 isotypes (nm23-H1, nm23-H2, DR-nm23,
nm23-H4, and nm23-H5) have been identified to
date.8-13 Among them, nm23-H1 and nm23-H2
show 88% amino acid sequence homology, and their genes are located on
the same region of chromosome 17q21 in tandem.10,14-17 An
inverse relationship between metastatic potential and the level of
nm23-H1 expression has been well established in various
cancers.9 nm23 homologs have been reported to be
involved in various cellular processes, such as stimulating
transcription, cell differentiation and proliferation, and
apoptosis.5,7,11,18 In addition, a
serine/threonine-specific protein phosphotransferase activity and a
histidine protein kinase activity have also been
detected.19,20 The nm23 protein inhibits the
differentiation of murine and human myeloid leukemia cells, although
the mechanism is unknown.1,2,21 The inhibition of
differentiation may be associated with the aggressive behavior of
leukemia. To clarify the role of nm23 in human myeloid leukemia, we investigated the relative levels of nm23 mRNA in bone marrow and blood samples from patients with acute myeloid leukemia
(AML) using the reverse transcriptase-polymerase chain reaction. We
reported that the mRNA expression levels of nm23 in bone marrow
and blood samples from AML patients were significantly higher than
those in normal blood cells, and a higher level of nm23-H1
expression was correlated with a poor prognosis in AML patients.3-5 An analysis of the correlation between
nm23 expression and clinical parameters demonstrated that
increased nm23-H1 mRNA levels were associated with resistance
to initial chemotherapy and reduced overall survival. A multivariate
analysis of putative prognostic factors showed that elevated
nm23-H1 mRNA levels significantly influenced the prognosis of
patients with AML.6 Furthermore, expression of
nm23-H1 mRNA was significantly higher in other hematological neoplasms, including acute lymphoblastic leukemia, myelodysplastic syndrome, and chronic myeloid leukemia in blastic crisis, than in
normal blood cells.6 It has been shown using
immunohistochemical analyses that high-grade non-Hodgkin's lymphoma
exhibits significantly higher levels of nm23-H1 expression than
does low-grade non-Hodgkin's lymphoma.22 Therefore,
nm23-H1 may have prognostic value in hematological malignancies.
Advances in combination chemotherapy and supportive therapy have made a
long-term survival rate of 60% to 70% possible for patients with
non-Hodgkin's lymphoma.23-25 The choice of treatment for
this lymphoma has become increasingly broad and now ranges from
first-generation to third-generation chemotherapy and further to
extremely potent therapy involving stem cell transplantation. Selection
of the appropriate therapy not only involves a consideration of the
complete remission (CR) rate, but also treating each patient neither
too much nor too little, so that the quality of life can be maintained
at a high level while the disease is cured. If intractable non-Hodgkin's lymphoma could be identified at diagnosis, this information would be useful for planning the best therapeutic strategy.
Therefore, effective prognostic factors are needed to select the
appropriate therapy. Many prognostic variables for predicting the
outcome have been identified, and prognostic models based on various
factors have been evaluated. Among them, the international prognostic
index (IPI) reported by Shipp in 199326 has been accepted
in many countries as a prognostic model that predicts fairly well the
clinical outcome for intermediate- and high-grade non-Hodgkin's
lymphoma. The IPI model is based on 5 independent prognostic factors
(age, performance status, number of extranodal sites, Ann Arbor stage,
and serum lactate dehydrogenase concentration) and can identify
patients with non-Hodgkin's lymphoma in 4 different risk groups (ie,
low [L], low-intermediate [L-I], high-intermediate [H-I], and
high [H] risk). In an attempt to use the IPI model for treatment
selection, peripheral blood stem cell transplantation has been
administered early in the treatment of the H-I and H risk groups to
improve the outcome of non-Hodgkin's lymphoma. However, more accurate
prognostic factors are required, because some patients in the L and L-I
risk groups have a poor outcome, whereas some in the H-I and H risk
groups have excellent results. Because prognostic factors need to be
assessed before treatment to design a therapeutic strategy, it is
essential that the tests should be easy to perform and provide results promptly.
With regard to the prognostic value of nm23-H1in malignant
lymphoma, we tried to use a quantitative assay system to detect nm23 protein in the plasma of patients, because it was
difficult to obtain lymphoma cells without contamination by normal
cells. nm23 proteins are basically intracellular proteins, but
these are sometimes found in the conditioned medium of certain tumor cells, although the secretion mechanism is unclear. We established a
method to determine the nm23-H1 protein in plasma of patients with malignant lymphomas by enzyme-linked immunosorbent assay (ELISA).
The plasma level of nm23-H1 was elevated in patients with
aggressive non-Hodgkin's lymphoma, and the plasma level was significantly correlated with the clinical outcome, suggesting that
nm23-H1 may be a valuable prognostic factor for predicting the
outcome in aggressive non-Hodgkin's lymphoma.
Patients.
nm23-H1 was measured in 201 consecutive untreated patients who
were diagnosed and treated at the First Department of Internal Medicine, Toho University School of Medicine (Tokyo, Japan) from 1987 to 1996. Of these 201 patients, 184 had non-Hodgkin's lymphoma. Thirty-five patients had low-grade, 147 had intermediate-grade, and 2 had high-grade lymphoma according to the Working Formulation scheme.27 Nine of the remaining cases had Hodgkin's
disease, and 8 had adult T-cell leukemia/lymphoma. Clinical staging was performed according to the Ann Arbor classification
system.28 Evaluation included a complete history and
physical examination: chest roentgenography; bone marrow aspiration and
biopsy; computed tomography of the chest, abdomen, and pelvis; hemogram
and differential counts; and routine biochemical tests. One hundred
eighty patients were treated with combination chemotherapy. Patients
with intermediate- or high-grade lymphoma and disseminated disease were
treated with cyclophosphamide, vincristine, prednisone, bleomycin,
doxorubicin, and procarbazine (COP-BLAM)29 or with biweekly
COP-BLAM with granulocyte colony-stimulating factor.30
Low-grade lymphoma was treated with cyclophosphamide, vincristine, and
prednisone (COP) or COP-BLAM. In addition to chemotherapy, 74 patients
received megavoltage radiotherapy. All patients were followed-up at
intervals of a few months at the department. Re-evaluation included
physical examination, hemogram and differential counts, biochemical
tests, and computed tomography of the chest, abdomen, and pelvis. The median follow-up time was 64 months (range, 24 to 120 months). Of the
149 patients with aggressive (intermediate- or high-grade) non-Hodgkin's lymphoma, 109 were alive after follow-up for 88 to 120 months (median, 68 months). The other 40 patients died from 1 to 34 months (median, 12 months) after diagnosis.
Venous blood samples.
Peripheral venous blood samples were collected into sterile test tubes
with heparin and placed on ice for at least 10 minutes to avoid
platelet activation. The samples were centrifuged at 2,000g for
15 minutes at 4°C, filtered through a 0.22-µm microfilter (Millipore, Molsheim, France), and stored at ELISA for human nm23-H1.
Ninety-six-well plates (Corning 25805-96; Corning, Corning,
NY) were coated with 50 µL of 2.5 µg/mL of monoclonal
anti-nm23-H1 antibody (Seikagaku Co, Tokyo, Japan) in 50 mmol/L bicarbonate buffer (pH 9.6) overnight, washed 4 times with
phosphate-buffered saline (PBS), and incubated with 200 µL of 25%
Block Ace (Dainihon Seiyaku, Oosaka, Japan) for 1 hour. Plasma samples
were diluted 2-fold with PBS, and then 50 µL aliquots were added to
the wells. After incubation at room temperature for 1 hour, the wells
were washed 4 times with PBS containing 0.05% Tween 20 (T-PBS). The samples were then incubated with polyclonal anti-nm23-H1
antibody (Santa Cruz Biotechnology, Inc, Santa Cruz, CA), washed 4 times with T-PBS, and incubated again with a 1:500 dilution of alkaline phosphatase-conjugated antirabbit IgG (Bio-Rad Lab, Richmond, CA) for 1 hour. After washing 4 times with T-PBS, alkaline phosphatase activity
was detected using diethanolamine as a substrate and an alkaline
phosphatase detection kit (Bio-Rad Lab). The absorbance was measured at
405 to 415 nm with a correction wavelength of 620 to 630 nm using a
microplate-ELISA reader. Recombinant nm23-H1-GST protein
(kindly provided by Prof H. Shiku, Nagasaki University, Nagasaki,
Japan) was used as the standard.31,32
Statistical analysis.
The response to treatment was documented on completion of chemotherapy.
CR was defined as the absence of detectable disease based on clinical,
radiologic, and histologic criteria. Partial remission (PR) required a
greater than 50% reduction of tumor volume. The duration of CR was
calculated from the completion of chemotherapy to relapse or the last
follow-up. Overall survival was the interval from the initiation of
therapy to the time of death or the last follow-up. Progression was
defined as a 25% increase in the product of the 2 largest diameters of
the tumor. Progression-free survival (PFS) was calculated from the date
of entry into the study to the date of the first physical or
radiographic evidence of disease progrssion, death, or the last
follow-up visit. Survival analysis was performed according to the
Kaplan-Meier method.36 The statistical significance of
differences among curves was determined by the log-rank and generalized
Wilcoxon's tests.37 Differences between groups were
evaluated by the Mann-Whitney U-test (nonparametric
analysis),38 and P < .05 indicated significance. A multivariate analysis of the prognosis was performed using Cox's proportional-hazards regression model.39 All calculations
were performed with SAS software, version 6.10 (SAS Institute, Cary, NC).
Measurement of nm23-H1 protein in plasma of patients and healthy
controls.
The plasma level of nm23-H1 was significantly elevated in
patients with malignant lymphoma (n = 201, mean ± SD; 42.91 ± 59.69 ng/mL) compared with that in the healthy controls (n = 21, 6.13 ± 4.13 ng/mL; P = .0001). The plasma levels of
nm23-H1 in Hodgkin's lymphoma (n = 9, 20.33 ± 17.15 ng/mL;
P = .0195), low-grade non-Hodgkin's lymphoma (n = 35, 18.93 ± 19.33 ng/mL; P = .0175 ), intermediate- and high-grade
non-Hodgkin's lymphoma (n = 149, 50.73 ± 66 ng/mL; P = .00001), and adult T-cell leukemia/lymphoma (n = 8, 27.65 ± 28.68 ng/mL; P = .0017) were significantly higher than those in the
healthy controls. The plasma level of nm23-H1 in intermediate- and high-grade non-Hodgkin's lymphoma was especially high and was
significantly higher than that in low-grade non-Hodgkin's lymphoma
(P = .007; Fig 2). However, there
was no significant difference in the nm23-H1 level between
high- and intermediate-grade (P = .94) or among the
subtypes of intermediate- and high-grade lymphoma such as diffuse
large, diffuse mixed, diffuse small cleaved cell, lymphoblastic, etc
(data not shown), indicating that the plasma level of nm23-H1
is independent of the Working Formulation grade in aggressive
non-Hodgkin's lymphoma.
nm23-H1 and clinical characteristics in aggressive lymphoma.
Table 1 shows the clinical characteristics
of the 149 patients with intermediate- and high-grade non-Hodgkin's
lymphoma. An elevated plasma level of nm23-H1 before treatment
was correlated with poor prognostic features, such as a poor
performance status, Ann Arbor stage III or IV, T-cell type, and an
elevated serum level of soluble IL-2 receptor (P < .02 for
all comparisons, Mann-Whitney U-test; Table 1). There was no
significant difference in the proportion of patients with high
nm23-H1 levels between the L + L-I risk group and the H-I + H
risk group according to the IPI score (P = .24; Table 1). The
plasma nm23-H1 level was 34.9 ± 40.6, 52.1 ± 66.7, 54.2 ± 81.9, and 78.8 ± 63.2 ng/mL in the L (n = 35), L-I (n = 65),
H-I (n = 37), and H (n = 12) risk groups according to the IPI scores,
respectively. The mean level tended to increase as the risk increased,
but there was no statistically significant difference (P = .065).
nm23-H1 and survival.
The 149 patients with aggressive (intermediate- and high-grade)
non-Hodgkin's lymphoma were divided into 2 groups with different plasma nm23-H1 levels. We tried to set the various cut-off
points over 14.39 ng/mL, which was the upper limit in controls plasma (6.13 +2 SD). The cut-off points used here were 14.39 ng/mL (<14.39 [n = 44] v
Prognostic factors in a univariate analysis in aggressive lymphoma.
The univariate analysis for intermediate- and high-grade non-Hodgkin's
lymphoma (n = 149) showed that the plasma nm23-H1 level, age,
performance status, lactate dehydrogenase level, IPI score, immunophenotype, soluble IL-2 receptor level, and soluble CD44 level
were significantly correlated with overall survival (P < .05;
Table 2); among these, the nm23-H1
level, age, performance status, lactate dehydrogenase level, IPI score,
immunophenotype, and soluble IL-2 receptor level were also
significantly correlated with PFS (P < .05; Table 2).
Multivariate analysis of prognostic factors in aggressive lymphoma.
The 8 prognostic factors (nm23-H1 level, age, performance
status, lactate dehydrogenase level, IPI score, immunophenotype, soluble IL-2 receptors level, and soluble CD44 level) that proved to be
significant in the univariate analysis were further evaluated for their
association with survival by a multivariate analysis using Cox's
proportional hazard model. This analysis showed that, in patients with
intermediate- and high-grade non-Hodgkin's lymphoma, the plasma
nm23-H1 level was the most important independent prognostic factor (Table 3). Regarding the association
with PFS, 7 factors (nm23-H1 level, age, performance status,
lactate dehydrogenase level, IPI score, immunophenotype, and soluble
IL-2 receptors level) were studied. An elevated plasma nm23-H1
level was identified as the most important prognostic determinant
similar to the performance status for poor PFS (Table 3). An additional
multivariate analysis was used to assess the association of the 5 prognostic factors used to calculate the IPI score and the plasma
nm23-H1 level with survival and PFS (data not shown). These
results indicated that the nm23-H1 level was an independent
prognostic factor that could predict both the overall survival and PFS.
Based on the biological activity of nm23 proteins for a
differentiation inhibitory factor, we previously investigated the relative levels of nm23-H1 and nm23-H2 transcripts in
AML cells. These transcripts were overexpressed in AML cells, and an
elevated nm23-H1 expression level predicted the prognosis of
AML.3,5,6 Most recently, it has been reported that
nm23-H1 overexpression (protein and mRNA) correlates with a
high relapse rate and a short survival in acute lymphoblastic
leukemia.40 In the present investigation, we found that an
elevated plasma nm23-H1 protein level had prognostic value in
aggressive non-Hodgkin's lymphoma. On the other hand, reduced
nm23-H1 expression has been associated with reduced survival or
with other histopathological indicators of a high metastatic potential
in cohorts of breast, ovarian, cervical, gastric, and hepatocellular
carcinoma and melanoma.9 However, an opposite trend has
been identified in neuroblastoma and pancreatic carcinoma.9 Although the reason for these differences is unknown, it might be worth
examining the prognostic value of the plasma nm23-H1 level in
several solid tumors in which nm23-H1 is overexpressed, as in
acute leukemias.
Submitted April 12, 1999; accepted July 14, 1999.
Supported in part by a grant from the Ministry of Health and Welfare,
and Grants-in-Aid for Scientific Research (C) and Cancer Research, from
The Ministry of Education, Science, Sports and Culture, Japan.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Junko Okabe-Kado, PhD, Saitama Cancer
Center Research Institute, 818 Komuro, Ina, Kita-adachi, Saitama
362-0806, Japan; e-mail: jkado{at}cancer-c.pref.saitama.jp.
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Nademanee A, Molina A, O'Donnell MR, Dagis A, Snyder DS, Parker P, Stein A, Smith E, Planas I, Kashyap A, Spielberger R, Fung H, Wong KK, Somlo G, Margolin K, Chow W, Sniecinski I, Vora N, Blume KG, Niland J, Forman SJ:
Results of high-dose therapy and autologous bone marrow/ stem cell transplantation during remission in poor-risk intermediate- and high-grade lymphoma: International index high and high-intermediate risk group.
Blood
90:3844, 1997 |
TOP
ABSTRACT
INTRODUCTION
80°C.
), 21 healthy controls (
), and blood
red cell extracts with various amounts of free hemoglobin (
).
14.39 [n = 105]), 50 ng/mL (<50 [n = 103]
v 
