Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1985 Jul;76(1):319–324. doi: 10.1172/JCI111964

Pretreatment of cytokinetics in acute myelogenous leukemia. Age-related prognostic implications.

H M Kantarjian, B Barlogie, M J Keating, R R Hall, T L Smith, K B McCredie, E J Freireich
PMCID: PMC423776  PMID: 3860508

Abstract

To determine the clinical and biologic relevance of cellular kinetics in leukemia, DNA flow cytometric analysis was performed on bone marrow biopsy specimens from 148 previously untreated adult patients with acute myelogenous leukemia. The proportion of cells in synthesis, second growth, and mitosis (S + G2M) ranged from 4% to 33% with a median of 14%. The overall incidence of complete remission was not affected by the pretreatment cell cycle distribution. As in earlier studies, there was a marked decline in remission rate with advancing age from 73% for patients age less than or equal to 50 yr to 50% for those greater than 50 (P less than 0.01). Although not affecting remission induction overall, an increasing proportion of cells in S + G2M phase was favorable in patients under the age of 50 yr, but was associated with a progressive decline in remission rate in older patients (P = 0.01). This age-related divergent effect of cell cycle kinetics on initial response to therapy was confined to the less favorable subgroup of patients with karyotypic abnormalities, whereas patients with normal diploid cytogenetics had a consistently higher response rate regardless of proliferative activity. A positive correlation was also observed between percent of S + G2M cells and the proportion of diploid metaphases in young patients, contrasting with a negative correlation in the older age group. Our observations strongly suggest that the well-recognized prognostic effect of age on remission induction is not entirely host-mediated, but is at least partly an expression of disease-intrinsic differences between young and older patients.

Full text

PDF
319

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amadori S., Petti M. C., De Francesco A., Chierichini A., Mastrovincenzo C., Testa M. G., Mandelli F. Lack of prognostic significance of the pretreatment labeling and mitotic indices of marrow blasts in acute nonlymphocytic leukemia (ANLL). Cancer. 1978 Mar;41(3):1154–1160. doi: 10.1002/1097-0142(197803)41:3<1154::aid-cncr2820410353>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
  2. Arlin Z. A., Fried J., Clarkson B. D. Therapeutic role of cell kinetics in acute leukaemia. Clin Haematol. 1978 Jun;7(2):339–362. doi: 10.1016/s0308-2261(78)80009-5. [DOI] [PubMed] [Google Scholar]
  3. BASERGA R., KISIELESKI W. E. Comparative study of the kinetics of cellular proliferation of normal and tumorous tissues with the use of tritiated thymidine. I. Dilution of the label and migration of labeled cells. J Natl Cancer Inst. 1962 Feb;28:331–339. [PubMed] [Google Scholar]
  4. Barlogie B., Latreille J., Freireich E. J., Fu C. T., Mellard D., Meistrich M., Andreeff M. Characterization of hematologic malignancies by flow cytometry. Blood Cells. 1980;6(4):719–744. [PubMed] [Google Scholar]
  5. Bhuyan B. K., Scheidt L. G., Fraser T. J. Cell cycle phase specificity of antitumor agents. Cancer Res. 1972 Feb;32(2):398–407. [PubMed] [Google Scholar]
  6. Boll I. T., Sterry K., Maurer H. R. Evidence for a rat granulocyte chalone effect on the proliferation of normal human bone marrow and of myeloid leukemias. Acta Haematol. 1979;61(3):130–137. doi: 10.1159/000207645. [DOI] [PubMed] [Google Scholar]
  7. Braylan R. C., Diamond L. W., Powell M. L., Harty-Golder B. Percentage of cells in the S phase of the cell cycle in human lymphoma determined by flow cytometry. Cytometry. 1980 Nov;1(3):171–174. doi: 10.1002/cyto.990010302. [DOI] [PubMed] [Google Scholar]
  8. Broxmeyer H. E., Grossbard E., Jacobsen N., Moore M. A. Persistence of inhibitory activity against normal bone-marrow cells during remission of acute leukemia. N Engl J Med. 1979 Aug 16;301(7):346–351. doi: 10.1056/NEJM197908163010702. [DOI] [PubMed] [Google Scholar]
  9. Bruce W. R., Meeker B. E., Valeriote F. A. Comparison of the sensitivity of normal hematopoietic and transplanted lymphoma colony-forming cells to chemotherapeutic agents administered in vivo. J Natl Cancer Inst. 1966 Aug;37(2):233–245. [PubMed] [Google Scholar]
  10. Burke P. J., Karp J. E., Braine H. G., Vaughan W. P. Timed sequential therapy of human leukemia based upon the response of leukemic cells to humoral growth factors. Cancer Res. 1977 Jul;37(7 Pt 1):2138–2146. [PubMed] [Google Scholar]
  11. Crowther D., Beard M. E., Bateman C. J., Sewell R. L. Factors influencing prognosis in adults with acute myelogenous leukaemia. Br J Cancer. 1975 Oct;32(4):456–464. doi: 10.1038/bjc.1975.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dosik G. M., Barlogie B., Göhde W., Johnston D., Tekell J. L., Drewinko B. Flow cytometry of DNA content in human bone marrow: a critical reappraisal. Blood. 1980 May;55(5):734–740. [PubMed] [Google Scholar]
  13. Dosik G. M., Barlogie B., Smith T. L., Gehan E. A., Keating M. J., McCredie K. B., Freireich E. J. Pretreatment flow cytometry of DNA content in adult acute leukemia. Blood. 1980 Mar;55(3):474–482. [PubMed] [Google Scholar]
  14. Durie B. G., Salmon S. E., Moon T. E. Pretreatment tumor mass, cell kinetics, and prognosis in multiple myeloma. Blood. 1980 Mar;55(3):364–372. [PubMed] [Google Scholar]
  15. Fabrikant J. I. The kinetics of cellular proliferation in normal and malignant tissues: a review of methodology and the analysis of cell population kinetics in human tissues. Am J Roentgenol Radium Ther Nucl Med. 1971 Apr;111(4):700–711. doi: 10.2214/ajr.111.4.700. [DOI] [PubMed] [Google Scholar]
  16. Fabrikant J. I., Wisseman C. L., 3rd, Vitak M. J. The kinetics of cellular proliferation in normal and malignant tissues. II. An in vitro method for incorporation of tritiated thymidine in human tissues. Radiology. 1969 May;92(6):1309–1320. doi: 10.1148/92.6.1309. [DOI] [PubMed] [Google Scholar]
  17. Ford S. S., Shackney S. E. Lethal and sublethal effects of hydroxyurea in relation to drug concentration and duration of drug exposure in sarcoma 180 in vitro. Cancer Res. 1977 Aug;37(8 Pt 1):2628–2637. [PubMed] [Google Scholar]
  18. Freireich E. J., Keating M. J., Gehan E. A., McCredie K. B., Bodey G. P., Smith T. Therapy of acute myelogeneous leukemia. Cancer. 1978 Aug;42(2 Suppl):874–882. doi: 10.1002/1097-0142(197808)42:2+<874::aid-cncr2820420709>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  19. GEHAN E. A. A GENERALIZED WILCOXON TEST FOR COMPARING ARBITRARILY SINGLY-CENSORED SAMPLES. Biometrika. 1965 Jun;52:203–223. [PubMed] [Google Scholar]
  20. Gale R. P., Foon K. A., Cline M. J., Zighelboim J. Intensive chemotherapy for acute myelogenous leukemia. Ann Intern Med. 1981 Jun;94(6):753–757. doi: 10.7326/0003-4819-94-6-753. [DOI] [PubMed] [Google Scholar]
  21. Hart J. S., George S. L., Frei E., 3rd, Bodey G. P., Nickerson R. C., Freireich E. J. Prognotic significance of pretreatment proliferative activity in adult acute leukemia. Cancer. 1977 Apr;39(4):1603–1617. doi: 10.1002/1097-0142(197704)39:4<1603::aid-cncr2820390435>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  22. Hiddemann W., Büchner T., Andreeff M., Wörmann B., Melamed M. R., Clarkson B. D. Bone marrow biopsy instead of 'marrow juice' for cell kinetic analysis. Comparison of bone marrow biopsy and aspiration material. Leuk Res. 1982;6(4):601–612. doi: 10.1016/0145-2126(82)90016-9. [DOI] [PubMed] [Google Scholar]
  23. Hiddemann W., Büchner T., Andreeff M., Wörmann B., Melamed M. R., Clarkson B. D. Cell kinetics in acute leukemia: a critical reevaluation based on new data. Cancer. 1982 Jul 15;50(2):250–258. doi: 10.1002/1097-0142(19820715)50:2<250::aid-cncr2820500215>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  24. Hillen H., Wessels J., Haanen C. Bone-marrow-profileration patterns in acute myeloblastic leukaemia determined by pulse cytophotometry. Lancet. 1975 Mar 15;1(7907):609–611. doi: 10.1016/s0140-6736(75)91887-5. [DOI] [PubMed] [Google Scholar]
  25. Keating M. J., Smith T. L., Gehan E. A., McCredie K. B., Bodey G. P., Freireich E. J. A prognostic factor analysis for use in development of predictive models for response in adult acute leukemia. Cancer. 1982 Aug 1;50(3):457–465. doi: 10.1002/1097-0142(19820801)50:3<457::aid-cncr2820500313>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  26. Keating M. J., Smith T. L., Gehan E. A., McCredie K. B., Bodey G. P., Spitzer G., Hersh E., Gutterman J., Freireich E. J. Factors related to length of complete remission in adult acute leukemia. Cancer. 1980 Apr 15;45(8):2017–2029. doi: 10.1002/1097-0142(19800415)45:8<2017::aid-cncr2820450806>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  27. Keating M. J., Smith T. L., McCredie K. B., Bodey G. P., Hersh E. M., Gutterman J. U., Gehan E., Freireich E. J. A four-year experience with anthracycline, cytosine arabinoside, vincristine and prednisone combination chemotherapy in 325 adults with acute leukemia. Cancer. 1981 Jun 15;47(12):2779–2788. doi: 10.1002/1097-0142(19810615)47:12<2779::aid-cncr2820471204>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  28. Latreille J., Barlogie B., Johnston D., Drewinko B., Alexanian R. Ploidy and proliferative characteristics in monoclonal gammopathies. Blood. 1982 Jan;59(1):43–51. [PubMed] [Google Scholar]
  29. Mauro F., Madoc-Jones H. Age responses of cultured mammalian cells to cytotoxic drugs. Cancer Res. 1970 May;30(5):1397–1408. [PubMed] [Google Scholar]
  30. Mayer R. J., Weinstein H. J., Coral F. S., Rosenthal D. S., Frei E., 3rd The role of intensive postinduction chemotherapy in the management of patients with acute myelogenous leukemia. Cancer Treat Rep. 1982 Jul;66(7):1455–1462. [PubMed] [Google Scholar]
  31. Mertelsmann R., Tzvi Thaler H., To L., Gee T. S., McKenzie S., Schauer P., Friedman A., Arlin Z., Cirrincione C., Clarkson B. Morphological classification, response to therapy, and survival in 263 adult patients with acute nonlymphoblastic leukemia. Blood. 1980 Nov;56(5):773–781. [PubMed] [Google Scholar]
  32. Murphy S. B., Aur R. J., Simone J. V., George S., Mauer A. M. Pretreatment cytokinetic studies in 94 children with acute leukemia. Relationship to other variables at diagnosis and to outcome of standard treatment. Blood. 1977 May;49(5):683–691. [PubMed] [Google Scholar]
  33. Preisler H. D. Therapy for patients with acute myelocytic leukemia who enter remission: bone marrow transplantation or chemotherapy? Cancer Treat Rep. 1982 Jul;66(7):1467–1473. [PubMed] [Google Scholar]
  34. Rowley J. D. Association of specific chromosome abnormalities with type of acute leukemia and with patient age. Cancer Res. 1981 Sep;41(9 Pt 1):3407–3410. [PubMed] [Google Scholar]
  35. Traganos F., Darzynkiewicz Z., Sharpless T., Melamed M. R. Simultaneous staining of ribonucleic and deoxyribonucleic acids in unfixed cells using acridine orange in a flow cytofluorometric system. J Histochem Cytochem. 1977 Jan;25(1):46–56. doi: 10.1177/25.1.64567. [DOI] [PubMed] [Google Scholar]
  36. Wolberg W. H., Ansfield F. J. The relation of thymidine labeling index in human tumors in vitro to the effectiveness of 5-fluorouracil chemotherapy. Cancer Res. 1971 Apr;31(4):448–450. [PubMed] [Google Scholar]
  37. Zittoun R., Bouchard M., Facquet-Danis J., Percie-du-Sert M., Bousser J. Prediction of the response to chemotherapy in acute leukemia. Cancer. 1975 Feb;35(2):507–513. doi: 10.1002/1097-0142(197502)35:2<507::aid-cncr2820350232>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  38. van Putten L. M. Are cell kinetic data relevant for the design of tumour chemotherapy schedules? Cell Tissue Kinet. 1974 Sep;7(5):493–504. doi: 10.1111/j.1365-2184.1974.tb00432.x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES