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Clinical significance of tissue polypeptide antigen in serum of acute nonlymphocytic leukemia
Leukemia Research Vol. 19, No. 6, pp. 407-409, 1995. Copyright 6 1995 Elsevier Science Ud Printed in Great Britain. AU rights reserved 0145-2126/95 $9.50 + 0.00
Pergamon 01452126(95)00006-2
CLINICAL SIGNIFICANCE OF TISSUE POLYPEPTIDE ANTIGEN IN SERUM OF ACUTE NONLYMPHOCYTIC LEUKEMIA Naoki Sadamori,* Mariko Mine,? Takako Kawachi,* Toshihisa Hayashibaraf, Takahiro Itoyama,* Ippei Sasagawa,* Hideo Nakamura* and Masao Tomonaga* *Department of Hematology, Atomic DiseaseInstitute, tScientific Data Center for Atomic Bomb Disaster; and fDepartment of Biochemistry, Nagasaki University School of Medicine, Nagasaki , Japan (Received 28 November 1994.Accepted 12 December 1994) Abstract-Tissue polypeptide antigen (TPA) in serum was measured at diagnosis in 27 patients with acute nonlymphocytic leukemia (ANLL) (I FAB MO, 1 Ml, 10 M2,7 M3,5 M4,l M5,l M6 and 1 MU). Statistical analysis disclosed a close correlation of TPA level with age (p < O.Ol), hemoglobin level (P < 0.05). therapeutic response (7’ < 0.01) and the length of survival after the initial diagnosis (P -C 0.02). A signficant difference in TPA level was present between patients with complete remission and those with poor response. To our knowledge, this is the first report to prove a correlation of TPA level with therapeutic response and the length of survival in ANLL. Key words: Acute nonlymphocytic
leukemia,
tissue polypeptide
antigen,
clinical
indicator.
with the median age of 45 years (range 15-78 years). The median value at diagnosis was 8.6 g/d1 (range 3.3-12.8 g/dl) for hemoglobin, 8.5 x 109/1(range 0.6-269.2x 109/1)leukocyte count, 63% (range O-100%) blasts in the blood, 57.5x109/l (range 6.0-200.0x 109/1) platelet count, and 48.6% (range O-90.8%) blasts in the bone marrow smear. The median survival after the initial diagnosis was 11.1 months (range O-54 months), although 15 patients are still alive. All patients in this series were given combination chemotherapyaccording mainly to the JapanAdult Leukemia Study (JALSG) protocol [ll]. Complete remission (CR) was defined as normal blood counts and less than 5% blasts in normocellular marrow. All other patients were classified as poor response(PR). The serumconcentration of TPA was measuredin duplicate using a double-antibody radioimmunoassay,the antigen being labelled with iodine-125 (Prolifigen TPA, Sangtec Medical, Bromma, Sweden). To examine any possible correlation betweenTPA and other items, the Wilcoxon rank sum test was used. The survival
Introduction Several useful parameters such as age [l], peripheral leukocyte count [2], initial blast cell count [3], lactic dehydrogenase(LDH) [3] and chromosome abnormalities [4], have been reported as the therapeutic and prognostic indicators for acute nonlymphocytic leukemia (ANLL). On the other hand, after extensive investigation, tissue polypeptide antigen (TPA) as a tumor marker has been found to be of equivocal value in predicting the presence,stage,recurrence and survival of various solid tumors [5-lo]. However, as far as we know, there has been no report on the clinical and biological significance of TPA in the serum of ANLL. In the present study, the correlation of TPA level with clinical and hematological data, therapeutic responseand the length of survival was statistically examined.
intervalwascalculatedfromthedateof diagnosisto thedateof last follow-up or death. Survival curves were obtained by the generalized Wilcoxon test [ 121.
Patients and Methods A total of 27 consecutive patients with ANLL were morphologically classified according to the French-American-British (FAB) system.One of the patients was subtypedas MO, 1 as Ml, 10 as M2, 7 as M3, 5 as M4, 1 as M5, 1 as M6 and 1 as unclassified (MU). The male:female ratio was 14:13,
Results In a control study of apparently healthy individuals, 95% were found to have TPA of lessthan 90 U/l, and the mean value was 43.9 + 24.8 U/l with no difference with age and sex. The median value of TPA at diagnosis in this series was 47 U/l (range 21.2-112.5 U/l). Figure 1 shows the TPA levels in respective FAB subtypes of ANLL.
Correspondence to: Naoki Sadamori, Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, 12-4 Sakamoto 1-chome, Nagasaki 852, Japan(Tel: 0958-47 2111, ext. 2376; Fax: 0958-43-6867). 407
N. Sadamoriet al.
408
TPA (U/I) 120110loogo80-
fr” ol.,.... 0 10
t
7060-
20
30
40
50
60
Months 4
50-
Fig. 2. Actuarial survival after the initial diagnosis in 27 patients with acute nonlymphocytic leukemia divided into two subgroups of a higher level than median value of TPA (247 U/l) (n=14) and relatively low level of TPA (<47 U/l) (n = 13). A statistical difference was present between these two groups (P < 0.03).
40304
2010-
MO
Ml
M2
M3
MC
MS
M6
MU
Fig. 1. Pretreatment TPA levels in 27 patients with acute nonlymphocytic leukemia and the responseto treatment. 0, complete remission; 0, failure to achieve completeremission.
Following combination chemotherapy, 20 out of 27 patients in this series achieved CR and seven showed PR. A total of 12 patients were dead at the time of writing. The median survival after the initial diagnosis was 20.6 months (range 1.6-54.0 months) in CR patients and 2 months (range O-18.3 months) in PR patients. To clarify the clinical and biological significance of TPA in ANLL, we investigated any possible correlation of pretreatment TPA level with age, hemoglobin level, percentage of blasts in the blood, platelet count, percentage of blasts in the bone marrow smear at diagnosis, therapeutic response and the length of survival after the initial diagnosis. Statistical analysis disclosed a close correlation of TPA level with age (I’< O.Ol), hemoglobin level (P < 0.05), therapeutic response (I’< 0.01) and the length of survival (P
of the antigen are found in the serum of patients with various tumors. SerumTPA seemsto be characteristic of carcinomaproliferation, and increasedlevels of TPA are closely related to the progression of tumor. TPA is a general cancer analyte, often reflecting malignant growth in many different organs. Monitoring TPA values over a long period hasbeen found to be clinically useful in controlling the effectivenessof treatment and detecting recurrence in cancers of the breast [5], liver [6], lung [7], bladder [B], prostate [9] and ovary [lo]. Nevertheless,no information on TPA is as yet available with respect to hematological malignancies. The aim of the present study was to investigate how
the pretreatment level of TPA is correlated to clinical and hematological data, the therapeutic responseand the length of survival. The results showed that there was a close correlation between TPA level and age (P < O.Ol), hemoglobin level (I’ < 0.05), therapeutic response (P < 0.01) and the length of survival (PcO.02). Age has been recognized as a good indicator of therapeutic response and survival [l]. A significant difference in TPA level was present between patients with CR and those with PR (I’< 0.02) in this series. Thus, the TPA level appearsto indicate the aggressivenessof leukemic cells, and the pretreatmentserumTPA value may predict the responseto the treatment and the length of survival in ANLL as well as in other solid tumors. However, further studies will be necessary before any final conclusion can be reached.
two groups (P
1. Preisler H. D., Priore R., Azarnia N., Barcos M., Raza A., Rakowski I., Volger R., Winton E. L., Browman G., Goldberg J., Gottlieb A. J., Grunwald H., Rai K., Miller K., Brennan J., Chervenick P., Joyce R. & Tricot G. (1986) Prediction of responseof patients with acute nonlympho-
Tissuepolypeptideantigenin serumof ANLL cytic leukemia to remission induction therapy: use of clinical measurements.Br. J. Huematol. 63, 625. 2. Schwartz R. S., Mackintosh F. R., Halpem J., Schrier S. L. & GreenbergP. L. (1984) Multivariate analysis of factors associatedwith outcome of treatmentfor adults with acute myelogenous leukemia. Cancer 54, 1672. 3. Keating M. J., Smith T. L., Gehan E. A., McCredie K. B., Bodey G. P., Spitzer G., Hersh E., Gutterman J. & Freireich E. J. (1980) Factorsrelated to length of complete remission in adult acute leukemia. Cancer 45, 2017. 4. SamuelsB. L., Larson R. A., LeBeau M. M., Daly K. M., Bitter M. A., Vardiman J. W., Barker C. M., Rowley J. D. ACGolomb H. M. (1988) Specitic chromosomal abnormalities in acute nonlymphocytic leukemia correlate with drug susceptibility in vivo. Leukemia 2, 79. 5. Liithgens M. & Schlegel G. (1980) CEAtTPA in clinical tumor diagnostics with special reference to breast cancer. Tumor Diagnostik 1, 63.
6. Kew M. C. & Berger E. L. (1986) The value of serum concentrations of tissue polypeptide antigen in the diagnosis of hepatocellular carcinoma. Cancer 58, 127. 7. Lilthgens M. & Schlegel G. (1985) Surveilance of lung cancer patients by tissue polypeptide antigen and carcinoembryonic antigen. Tumor Diagnostik Therapie 6, 1. 8. Adolphs H. D. & Oehr P. (1984) Significance of plasma
409
tissue polypeptide antigen determination for diagnosis and follow-up of urothelial bladder cancer. Uro. Dot. 12, 125. 9. Oehr P., Molitor D. & Winkler C. (1984) Diagnostic significance of a new methodfor combined use of TPA and PAP as tumor markers in patients with prostatic cancer. Verh. Dtsch Krebsges 5, 634.
10. Inoue M., Inoue Y., Hiramatsu K. & Ueda G. (1985) The clinical value of tissue polypeptide antigen in patients with gynecological tumors. Cancer 55, 2618. 11. Ohno R., Kobayashi T., Tanimoto M., Hiraoka A., Imai K., Asou N., Tomonaga M., Tsubaki K., Takahashi I., Kodera Y., Yoshida M., Murakami H., Naoe T., Shimoyama M., TsukadaT., Take0 T., Teshima H., Onozawa Y., Fujimoto K., Kuriyama K., Horiuchi A., Kimura I., Minami S., Miura Y., Kageyama S., Tahara T., Masaoka T., Shirakawa S. & Saito H. (1993) Randomized study of individualized induction therapy with or without vincristine, and of maintenance-intensificationtherapy between 4 or 12 coursesin adult acute myeloid leukemia. Cancer 71, 3888.
12. Gehan E. (1965) A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52, 203.
13. Bjiirklund B. (1980) On the nature and clinical use of tissue polypeptide antigen (TPA). Tumor Diugnostik 1, 9.
Pergamon 01452126(95)00006-2
CLINICAL SIGNIFICANCE OF TISSUE POLYPEPTIDE ANTIGEN IN SERUM OF ACUTE NONLYMPHOCYTIC LEUKEMIA Naoki Sadamori,* Mariko Mine,? Takako Kawachi,* Toshihisa Hayashibaraf, Takahiro Itoyama,* Ippei Sasagawa,* Hideo Nakamura* and Masao Tomonaga* *Department of Hematology, Atomic DiseaseInstitute, tScientific Data Center for Atomic Bomb Disaster; and fDepartment of Biochemistry, Nagasaki University School of Medicine, Nagasaki , Japan (Received 28 November 1994.Accepted 12 December 1994) Abstract-Tissue polypeptide antigen (TPA) in serum was measured at diagnosis in 27 patients with acute nonlymphocytic leukemia (ANLL) (I FAB MO, 1 Ml, 10 M2,7 M3,5 M4,l M5,l M6 and 1 MU). Statistical analysis disclosed a close correlation of TPA level with age (p < O.Ol), hemoglobin level (P < 0.05). therapeutic response (7’ < 0.01) and the length of survival after the initial diagnosis (P -C 0.02). A signficant difference in TPA level was present between patients with complete remission and those with poor response. To our knowledge, this is the first report to prove a correlation of TPA level with therapeutic response and the length of survival in ANLL. Key words: Acute nonlymphocytic
leukemia,
tissue polypeptide
antigen,
clinical
indicator.
with the median age of 45 years (range 15-78 years). The median value at diagnosis was 8.6 g/d1 (range 3.3-12.8 g/dl) for hemoglobin, 8.5 x 109/1(range 0.6-269.2x 109/1)leukocyte count, 63% (range O-100%) blasts in the blood, 57.5x109/l (range 6.0-200.0x 109/1) platelet count, and 48.6% (range O-90.8%) blasts in the bone marrow smear. The median survival after the initial diagnosis was 11.1 months (range O-54 months), although 15 patients are still alive. All patients in this series were given combination chemotherapyaccording mainly to the JapanAdult Leukemia Study (JALSG) protocol [ll]. Complete remission (CR) was defined as normal blood counts and less than 5% blasts in normocellular marrow. All other patients were classified as poor response(PR). The serumconcentration of TPA was measuredin duplicate using a double-antibody radioimmunoassay,the antigen being labelled with iodine-125 (Prolifigen TPA, Sangtec Medical, Bromma, Sweden). To examine any possible correlation betweenTPA and other items, the Wilcoxon rank sum test was used. The survival
Introduction Several useful parameters such as age [l], peripheral leukocyte count [2], initial blast cell count [3], lactic dehydrogenase(LDH) [3] and chromosome abnormalities [4], have been reported as the therapeutic and prognostic indicators for acute nonlymphocytic leukemia (ANLL). On the other hand, after extensive investigation, tissue polypeptide antigen (TPA) as a tumor marker has been found to be of equivocal value in predicting the presence,stage,recurrence and survival of various solid tumors [5-lo]. However, as far as we know, there has been no report on the clinical and biological significance of TPA in the serum of ANLL. In the present study, the correlation of TPA level with clinical and hematological data, therapeutic responseand the length of survival was statistically examined.
intervalwascalculatedfromthedateof diagnosisto thedateof last follow-up or death. Survival curves were obtained by the generalized Wilcoxon test [ 121.
Patients and Methods A total of 27 consecutive patients with ANLL were morphologically classified according to the French-American-British (FAB) system.One of the patients was subtypedas MO, 1 as Ml, 10 as M2, 7 as M3, 5 as M4, 1 as M5, 1 as M6 and 1 as unclassified (MU). The male:female ratio was 14:13,
Results In a control study of apparently healthy individuals, 95% were found to have TPA of lessthan 90 U/l, and the mean value was 43.9 + 24.8 U/l with no difference with age and sex. The median value of TPA at diagnosis in this series was 47 U/l (range 21.2-112.5 U/l). Figure 1 shows the TPA levels in respective FAB subtypes of ANLL.
Correspondence to: Naoki Sadamori, Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, 12-4 Sakamoto 1-chome, Nagasaki 852, Japan(Tel: 0958-47 2111, ext. 2376; Fax: 0958-43-6867). 407
N. Sadamoriet al.
408
TPA (U/I) 120110loogo80-
fr” ol.,.... 0 10
t
7060-
20
30
40
50
60
Months 4
50-
Fig. 2. Actuarial survival after the initial diagnosis in 27 patients with acute nonlymphocytic leukemia divided into two subgroups of a higher level than median value of TPA (247 U/l) (n=14) and relatively low level of TPA (<47 U/l) (n = 13). A statistical difference was present between these two groups (P < 0.03).
40304
2010-
MO
Ml
M2
M3
MC
MS
M6
MU
Fig. 1. Pretreatment TPA levels in 27 patients with acute nonlymphocytic leukemia and the responseto treatment. 0, complete remission; 0, failure to achieve completeremission.
Following combination chemotherapy, 20 out of 27 patients in this series achieved CR and seven showed PR. A total of 12 patients were dead at the time of writing. The median survival after the initial diagnosis was 20.6 months (range 1.6-54.0 months) in CR patients and 2 months (range O-18.3 months) in PR patients. To clarify the clinical and biological significance of TPA in ANLL, we investigated any possible correlation of pretreatment TPA level with age, hemoglobin level, percentage of blasts in the blood, platelet count, percentage of blasts in the bone marrow smear at diagnosis, therapeutic response and the length of survival after the initial diagnosis. Statistical analysis disclosed a close correlation of TPA level with age (I’< O.Ol), hemoglobin level (P < 0.05), therapeutic response (I’< 0.01) and the length of survival (P
of the antigen are found in the serum of patients with various tumors. SerumTPA seemsto be characteristic of carcinomaproliferation, and increasedlevels of TPA are closely related to the progression of tumor. TPA is a general cancer analyte, often reflecting malignant growth in many different organs. Monitoring TPA values over a long period hasbeen found to be clinically useful in controlling the effectivenessof treatment and detecting recurrence in cancers of the breast [5], liver [6], lung [7], bladder [B], prostate [9] and ovary [lo]. Nevertheless,no information on TPA is as yet available with respect to hematological malignancies. The aim of the present study was to investigate how
the pretreatment level of TPA is correlated to clinical and hematological data, the therapeutic responseand the length of survival. The results showed that there was a close correlation between TPA level and age (P < O.Ol), hemoglobin level (I’ < 0.05), therapeutic response (P < 0.01) and the length of survival (PcO.02). Age has been recognized as a good indicator of therapeutic response and survival [l]. A significant difference in TPA level was present between patients with CR and those with PR (I’< 0.02) in this series. Thus, the TPA level appearsto indicate the aggressivenessof leukemic cells, and the pretreatmentserumTPA value may predict the responseto the treatment and the length of survival in ANLL as well as in other solid tumors. However, further studies will be necessary before any final conclusion can be reached.
two groups (P
1. Preisler H. D., Priore R., Azarnia N., Barcos M., Raza A., Rakowski I., Volger R., Winton E. L., Browman G., Goldberg J., Gottlieb A. J., Grunwald H., Rai K., Miller K., Brennan J., Chervenick P., Joyce R. & Tricot G. (1986) Prediction of responseof patients with acute nonlympho-
Tissuepolypeptideantigenin serumof ANLL cytic leukemia to remission induction therapy: use of clinical measurements.Br. J. Huematol. 63, 625. 2. Schwartz R. S., Mackintosh F. R., Halpem J., Schrier S. L. & GreenbergP. L. (1984) Multivariate analysis of factors associatedwith outcome of treatmentfor adults with acute myelogenous leukemia. Cancer 54, 1672. 3. Keating M. J., Smith T. L., Gehan E. A., McCredie K. B., Bodey G. P., Spitzer G., Hersh E., Gutterman J. & Freireich E. J. (1980) Factorsrelated to length of complete remission in adult acute leukemia. Cancer 45, 2017. 4. SamuelsB. L., Larson R. A., LeBeau M. M., Daly K. M., Bitter M. A., Vardiman J. W., Barker C. M., Rowley J. D. ACGolomb H. M. (1988) Specitic chromosomal abnormalities in acute nonlymphocytic leukemia correlate with drug susceptibility in vivo. Leukemia 2, 79. 5. Liithgens M. & Schlegel G. (1980) CEAtTPA in clinical tumor diagnostics with special reference to breast cancer. Tumor Diagnostik 1, 63.
6. Kew M. C. & Berger E. L. (1986) The value of serum concentrations of tissue polypeptide antigen in the diagnosis of hepatocellular carcinoma. Cancer 58, 127. 7. Lilthgens M. & Schlegel G. (1985) Surveilance of lung cancer patients by tissue polypeptide antigen and carcinoembryonic antigen. Tumor Diagnostik Therapie 6, 1. 8. Adolphs H. D. & Oehr P. (1984) Significance of plasma
409
tissue polypeptide antigen determination for diagnosis and follow-up of urothelial bladder cancer. Uro. Dot. 12, 125. 9. Oehr P., Molitor D. & Winkler C. (1984) Diagnostic significance of a new methodfor combined use of TPA and PAP as tumor markers in patients with prostatic cancer. Verh. Dtsch Krebsges 5, 634.
10. Inoue M., Inoue Y., Hiramatsu K. & Ueda G. (1985) The clinical value of tissue polypeptide antigen in patients with gynecological tumors. Cancer 55, 2618. 11. Ohno R., Kobayashi T., Tanimoto M., Hiraoka A., Imai K., Asou N., Tomonaga M., Tsubaki K., Takahashi I., Kodera Y., Yoshida M., Murakami H., Naoe T., Shimoyama M., TsukadaT., Take0 T., Teshima H., Onozawa Y., Fujimoto K., Kuriyama K., Horiuchi A., Kimura I., Minami S., Miura Y., Kageyama S., Tahara T., Masaoka T., Shirakawa S. & Saito H. (1993) Randomized study of individualized induction therapy with or without vincristine, and of maintenance-intensificationtherapy between 4 or 12 coursesin adult acute myeloid leukemia. Cancer 71, 3888.
12. Gehan E. (1965) A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52, 203.
13. Bjiirklund B. (1980) On the nature and clinical use of tissue polypeptide antigen (TPA). Tumor Diugnostik 1, 9.