Abstract
Of 93 consecutively treated patients with acute myeloid leukemia 36 (39%) achieved complete remission (CR). Thirty-five patients were randomized to receive either maintenance chemotherapy alone (C) or a combination of active nonspecific immunotherapy with Corynebacterium parvum and chemotherapy (C + I). Maintenance therapy was given monthly for 1 year or until relapse. The median survival time was 21 months for patients treated with chemotherapy alone, compared with 30 months for patients treated with chemotherapy and immunotherapy. The median remission duration was 15 months for patients treated with chemotherapy, compared with 18 months for chemotherapy and immunotherapy group. While no statistically significant difference in remission duration or survival time could be attributed to the use of immune stimulation, a plateau of 40% long-term time survivors was defined in the chemotherapy and immunotherapy group. Age and sex were found to be the major prognostic factors for achivement of CR. No difference was found in remission duration or survival between the two different induction schedules. Neither did the morphological subtype of AML (FAB classification) or the leukocyte count at diagnosis correlate with remission rate or survival.
Keywords: Acute Myeloid Leukemia, Complete Remission, Myeloid Leukemia, Maintenance Therapy, Median Survival Time
References
- 1.Bennet JM, Catovsky D, Daniel M, Flandrin G, Galton DAG, Gralnick HR, Sultan C. Proposals for the classification of the acute leukaemias. Br J Haematol. 1976;33:451–485. doi: 10.1111/j.1365-2141.1976.tb03563.x. [DOI] [PubMed] [Google Scholar]
- 2.Berd DA, Mitchell MS. Immunologic enhancement of leukemia by Corynebacterium parvum in allogeneic mice. Cancer Res. 1976;36:4119–4124. [PubMed] [Google Scholar]
- 3.Björnsson S, Preisler H, Pavelic Z. Effects of Corynebacterium parvum on murine myeloid leukaemia. Br J Cancer. 1978;38:703–708. doi: 10.1038/bjc.1978.276. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Bomford R. Active specific immunotherapy of mouse methylcholantren induced tumors with Corynebacterium parvum and irradiated tumor cells. Br J Cancer. 1975;32:551–557. doi: 10.1038/bjc.1975.260. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Brennan DC, Lewis JP. Remission-induction regimens in acute non-lymphocytic leukemia. West J Med. 1980;133:279–288. [PMC free article] [PubMed] [Google Scholar]
- 6.Curie DC, Bagshawe KD. Active immunotherapy with Corynebacterium parvum and chemotherapy in murine fibrosarcomas. Br Med. 1970;I:541–544. doi: 10.1136/bmj.1.5695.541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Ellegaard J, Starklint H, Kragballe K, Dimitrov NV. Immunoproliferative alterations in lymphoid tissues and liver in mice stimulated with Corynebacterium parvum . Acta Pathol Microbiol Scand [C] 1978;86:79–88. doi: 10.1111/j.1699-0463.1978.tb02562.x. [DOI] [PubMed] [Google Scholar]
- 8.Eppinger-Helft M, Pavlovsky S, Hidalgo G, Muriel FS, Suarez A, Garay G, Russo C, Santos M, Macchi A, Lein J. Chemoimmunotherapy with Corynebacterium parvum in acute myeloid leukemia. Cancer. 1980;45:280–284. doi: 10.1002/1097-0142(19800115)45:2<280::aid-cncr2820450213>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
- 9.Foon KA, Zighelboim J, Yale C, Gale RP. Intensive chemotherapy is the treatment of choice for elderly patients with acute myelogenous leukemia. Blood. 1981;58:467–470. [PubMed] [Google Scholar]
- 10.Gale RP. Chemoimmunotherapy in acute myelogenous leukemia (AML) Proc Am Assoc Cancer Res. 1977;18:555. [Google Scholar]
- 11.Gale RP, Cline MJ. High remission-induction rate in acute myeloid leukaemia. Lancet. 1977;I:497–499. doi: 10.1016/s0140-6736(77)91366-6. [DOI] [PubMed] [Google Scholar]
- 12.Gale RP, Foon KA, Cline MJ, Zighelboim J, the UGLA Acute Leukemia Study Group Intensive chemotherapy for acute myelogenous leukemia. Ann Intern Med. 1981;94:753–757. doi: 10.7326/0003-4819-94-6-753. [DOI] [PubMed] [Google Scholar]
- 13.Galton DAG, Peto R. Immunotherapy of acute myeloid leukaemia. Br J Cancer. 1978;37:1–14. doi: 10.1038/bjc.1978.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Gehan E. Statistical methods for survival time studies. In: Staqueb MJ, editor. Cancer therapy: Prognostic factors and criteria of response. New York: Raven Press; 1975. [Google Scholar]
- 15.Gehan FA, Smith TL, Freireich EJ, Bodey G, Rodriques J, McCredie K. Prognostic factors in acute leukaemia. Semin Oncol. 1976;3:271–282. [PubMed] [Google Scholar]
- 16.Halpern B, Biozzi G, Stiffel C, Mouton D. Inhibition of tumor growth by administration of killed Corynebacterium parvum . Nature. 1966;212:853–856. doi: 10.1038/212853a0. [DOI] [PubMed] [Google Scholar]
- 17.Hedley DW, Nyholm RE, Currie GA. Monocytes and macrophages in malignant melanoma. IV. Effects of C. parvum on monocyte function. Br J Cancer. 1979;39:558–565. doi: 10.1038/bjc.1979.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Herberman RB. NK cells and other natural effector cells. New York: Academic Press; 1982. [Google Scholar]
- 19.Hokland P, Ellegaard J. In vivo effects of Corynebacterium parvum on natural cell-mediated immunity in acute myeloid leukemia patients. In: Herberman RB, editor. NK cells and other natural effector cells. New York: Academic Press; 1982. pp. 1285–1290. [Google Scholar]
- 20.Hokland P, Ellegaard J, Heron I. Immunomodulation by Corynebacterium parvum in normal humans. J Immunol. 1980;124:2180–2185. [PubMed] [Google Scholar]
- 21.Kaplan R, Meier P. Non-parametric estimation from incomplete observation. J Am Stat Assoc. 1958;53:457–481. [Google Scholar]
- 22.Kirschner H, Holden HT, Herberman RB. Splenic suppressor macrophages induced in mice by injections of Corynebacterium parvum . J Immunol. 1975;115:1212–1217. [PubMed] [Google Scholar]
- 23.Lee SK, Oliver RTD. Leukaemic specific T cell-mediated lymphocytotoxicity. J Exp Med. 1978;197:912–922. doi: 10.1084/jem.147.3.912. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Leventhal BG, Mirro J, Konior Yarbro GS. Immune reactivity to tumor antigens in leukemia and lymphoma. Semin Hematol. 1978;15:157–179. [PubMed] [Google Scholar]
- 25.Lewis JP, Linman JW, Marshall GT. Randomized clinical trial of cytosine arabinoside and 6-thioguanine in remission induction and consolidation of adult non-lymphocytic acute leukemia. Cancer. 1977;39:1387–1396. doi: 10.1002/1097-0142(197704)39:4<1387::aid-cncr2820390406>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
- 26.Lischer TA, Whitehou JMA, Oliver TD, Bell R, Johnson SAN, Wrighley PFM, Ford JM, Cullen MH, Gregory W, Paxton AM, Malpas JS. Chemotherapy and immunotherapy for acute myelogenous leukemia. Cancer. 1980;46:2142–2148. doi: 10.1002/1097-0142(19801115)46:10<2142::aid-cncr2820461005>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
- 27.Mertelsman R, Thaler HT, Yo L, Gee TS, McKenzie S, Schaver P, Friedman A, Arlan Z, Cirrinciane C, Clarkson B. Morphological classification, response to therapy and survival in 263 adult patients with acute non-lymphoblastic leukemia. Blood. 1970;56:773–781. [PubMed] [Google Scholar]
- 28.Milas L, Gutterman JU, Baśić I, Hunter N, Mavligit GM, Hersh EM, Withers HR. Immunophylaxis and immunotherapy for a murine fibrosarcoma with C. granulosum and C. parvum . Int J Cancer. 1974;14:493–503. doi: 10.1002/ijc.2910140409. [DOI] [PubMed] [Google Scholar]
- 29.M R C Working Party on Leukaemia in Adults Br J Haematol. 1974;27:373–389. doi: 10.1111/j.1365-2141.1974.tb06805.x. [DOI] [PubMed] [Google Scholar]
- 30.Muharata RI, Zighelboim J. Inhibition of memory cell-mediated cytotoxic response by systemic administration of Corynebacterium parvum . Cell Immunol. 1979;42:289–297. doi: 10.1016/0008-8749(79)90194-1. [DOI] [PubMed] [Google Scholar]
- 31.Nossal GJV (1980) The case history of Mr. T. I. Terminal patient or still curable? Immunology Today: 5–9 [DOI] [PubMed]
- 32.Rees JKH, Sandler RM, Challener J, Hayhoe FGJ. Treatment of acute myeloid leukaemia with a triple cytotoxic regime: DAT. Br J Cancer. 1977;36:770–776. doi: 10.1038/bjc.1977.260. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Smith T, Gehan A computer program for estimating survival functions for the lifetable. Comput Prog Biomed. 1970;1:58. [Google Scholar]
- 34.Sugiyama M, Epstein LB. Effect of Corynebacterium parvum on human T-lymphocyte interferon production and T-lymphocyte proliferation in vitro. Cancer Res. 1978;38:4467–4473. [PubMed] [Google Scholar]
- 35.Thatcher N, Swindell R, Crowther D. Effects of Corynebacterium parvum and BCG therapy on immune parameters in patients with disseminated melanoma. A sequential study over 28 days. II. Changes in non-specific (NK, K and T-cell) lymphocytoxicity and delayed hypersensitivity skin reactions. Clin Exp Immunol. 1979;35:171–179. [PMC free article] [PubMed] [Google Scholar]
- 36.Vaughan WP, Karl JE, Burke PJ. Long chemotherapy free remissions after single-cycle timed-sequential chemotherapy for acute myelocytic leukemia. Cancer. 1980;45:859–865. doi: 10.1002/1097-0142(19800301)45:5<859::aid-cncr2820450506>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
- 37.Whittaker JA. Annotation: Immunotherapy in the treatment of acute leukaemia. Br J Haematol. 1980;45:187–193. doi: 10.1111/j.1365-2141.1980.tb07137.x. [DOI] [PubMed] [Google Scholar]
- 38.Whittaker JA, Bailay-Wood R, Hutchins S. Active immunotherapy for the treatment of acute myelogenous leukaemia: Report of two controlled trials. Br J Haematol. 1980;45:389–400. doi: 10.1111/j.1365-2141.1980.tb07159.x. [DOI] [PubMed] [Google Scholar]