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. 1990 Jan;87(2):563–567. doi: 10.1073/pnas.87.2.563

Molecular relapse in chronic myelogenous leukemia patients after bone marrow transplantation detected by polymerase chain reaction.

C L Sawyers 1, L Timson 1, E S Kawasaki 1, S S Clark 1, O N Witte 1, R Champlin 1
PMCID: PMC53305  PMID: 2405384

Abstract

Relapse of chronic myelogenous leukemia after bone marrow transplantation can be detected by using clinical, cytogenetic, or molecular tools. A modification of the polymerase chain reaction can be used in patients to detect low levels of the BCR-ABL-encoded mRNA transcript, a specific marker for chronic myelogenous leukemia. Early detection of relapse after bone marrow transplantation could potentially alter treatment decisions. We prospectively evaluated 19 patients for evidence of molecular relapse, cytogenetic relapse, and clinical relapse after bone marrow transplantation. We used the polymerase chain reaction to detect residual BCR-ABL mRNA in patients followed up to 45 months after treatment (median, 15 months; range, 6-45 months) and found 4 patients with BCR-ABL mRNA expression following bone marrow transplantation. In 2 patients BCR-ABL mRNA was detected in all samples, and both have developed cytogenetic relapse. In 1 patient BCR-ABL mRNA was detected transiently during the first month after transplant but was undetectable thereafter. The fourth patient had BCR-ABL mRNA 6 months after bone marrow transplantation but not in prior samples. Fifteen patients did not express detectable BCR-ABL mRNA. All 19 patients remain in clinical remission. In this prospective study of chronic myelogenous leukemia patients treated with bone marrow transplantation, molecular relapse preceded cytogenetic relapse in those patients who persistently express BCR-ABL mRNA. We recommend using standard clinical and cytogenetic testing to make patient care decisions until further follow-up determines the clinical outcome of those patients with residual BCR-ABL mRNA transcripts detected by polymerase chain reaction.

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Selected References

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

  1. Arrigo S. J., Weitsman S., Rosenblatt J. D., Chen I. S. Analysis of rev gene function on human immunodeficiency virus type 1 replication in lymphoid cells by using a quantitative polymerase chain reaction method. J Virol. 1989 Nov;63(11):4875–4881. doi: 10.1128/jvi.63.11.4875-4881.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arthur C. K., Apperley J. F., Guo A. P., Rassool F., Gao L. M., Goldman J. M. Cytogenetic events after bone marrow transplantation for chronic myeloid leukemia in chronic phase. Blood. 1988 May;71(5):1179–1186. [PubMed] [Google Scholar]
  3. Bertheas M. F., Maraninchi D., Lafage M., Fraisse J., Blaise D., Stoppa A. M., Michel G., Brizard C. P., Gaspard M. H., Novakovitch G. Partial chimerism after T-cell-depleted allogeneic bone marrow transplantation in leukemic HLA-matched patients: a cytogenetic documentation. Blood. 1988 Jul;72(1):89–93. [PubMed] [Google Scholar]
  4. Champlin R., Gajewski J., Feig S., Giorgi J., Lyddane N., Lee K., Schmidt I., Winston D., Ho W., Reichert T. Selective depletion of CD8 positive T-lymphocytes for prevention of graft-versus-host disease following allogeneic bone marrow transplantation. Transplant Proc. 1989 Feb;21(1 Pt 3):2947–2948. [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Dobrovic A., Trainor K. J., Morley A. A. Detection of the molecular abnormality in chronic myeloid leukemia by use of the polymerase chain reaction. Blood. 1988 Dec;72(6):2063–2065. [PubMed] [Google Scholar]
  7. Goldman J. M., Apperley J. F., Jones L., Marcus R., Goolden A. W., Batchelor R., Hale G., Waldmann H., Reid C. D., Hows J. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med. 1986 Jan 23;314(4):202–207. doi: 10.1056/NEJM198601233140403. [DOI] [PubMed] [Google Scholar]
  8. Goldman J. M., Gale R. P., Horowitz M. M., Biggs J. C., Champlin R. E., Gluckman E., Hoffmann R. G., Jacobsen S. J., Marmont A. M., McGlave P. B. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Ann Intern Med. 1988 Jun;108(6):806–814. doi: 10.7326/0003-4819-108-6-806. [DOI] [PubMed] [Google Scholar]
  9. Groffen J., Stephenson J. R., Heisterkamp N., de Klein A., Bartram C. R., Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984 Jan;36(1):93–99. doi: 10.1016/0092-8674(84)90077-1. [DOI] [PubMed] [Google Scholar]
  10. Kawasaki E. S., Clark S. S., Coyne M. Y., Smith S. D., Champlin R., Witte O. N., McCormick F. P. Diagnosis of chronic myeloid and acute lymphocytic leukemias by detection of leukemia-specific mRNA sequences amplified in vitro. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5698–5702. doi: 10.1073/pnas.85.15.5698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Konopka J. B., Watanabe S. M., Singer J. W., Collins S. J., Witte O. N. Cell lines and clinical isolates derived from Ph1-positive chronic myelogenous leukemia patients express c-abl proteins with a common structural alteration. Proc Natl Acad Sci U S A. 1985 Mar;82(6):1810–1814. doi: 10.1073/pnas.82.6.1810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kurzrock R., Gutterman J. U., Talpaz M. The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med. 1988 Oct 13;319(15):990–998. doi: 10.1056/NEJM198810133191506. [DOI] [PubMed] [Google Scholar]
  13. Lange W., Snyder D. S., Castro R., Rossi J. J., Blume K. G. Detection by enzymatic amplification of bcr-abl mRNA in peripheral blood and bone marrow cells of patients with chronic myelogenous leukemia. Blood. 1989 May 1;73(6):1735–1741. [PubMed] [Google Scholar]
  14. Lee M. S., LeMaistre A., Kantarjian H. M., Talpaz M., Freireich E. J., Trujillo J. M., Stass S. A. Detection of two alternative bcr/abl mRNA junctions and minimal residual disease in Philadelphia chromosome positive chronic myelogenous leukemia by polymerase chain reaction. Blood. 1989 Jun;73(8):2165–2170. [PubMed] [Google Scholar]
  15. Mitsuyasu R. T., Champlin R. E., Gale R. P., Ho W. G., Lenarsky C., Winston D., Selch M., Elashoff R., Giorgi J. V., Wells J. Treatment of donor bone marrow with monoclonal anti-T-cell antibody and complement for the prevention of graft-versus-host disease. A prospective, randomized, double-blind trial. Ann Intern Med. 1986 Jul;105(1):20–26. doi: 10.7326/0003-4819-105-1-20. [DOI] [PubMed] [Google Scholar]
  16. Morgan G. J., Hughes T., Janssen J. W., Gow J., Guo A. P., Goldman J. M., Wiedemann L. M., Bartram C. R. Polymerase chain reaction for detection of residual leukaemia. Lancet. 1989 Apr 29;1(8644):928–929. doi: 10.1016/s0140-6736(89)92508-7. [DOI] [PubMed] [Google Scholar]
  17. NOWELL P. C., HUNGERFORD D. A. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst. 1960 Jul;25:85–109. [PubMed] [Google Scholar]
  18. Petz L. D., Yam P., Wallace R. B., Stock A. D., de Lange G., Knowlton R. G., Brown V. A., Donis-Keller H., Hill L. R., Forman S. J. Mixed hematopoietic chimerism following bone marrow transplantation for hematologic malignancies. Blood. 1987 Nov;70(5):1331–1337. [PubMed] [Google Scholar]
  19. Ringdén O., Horowitz M. M. Graft-versus-leukemia reactions in humans. The Advisory Committee of the International Bone Marrow Transplant Registry. Transplant Proc. 1989 Feb;21(1 Pt 3):2989–2992. [PubMed] [Google Scholar]
  20. Roth M. S., Antin J. H., Bingham E. L., Ginsburg D. Detection of Philadelphia chromosome-positive cells by the polymerase chain reaction following bone marrow transplant for chronic myelogenous leukemia. Blood. 1989 Aug 1;74(2):882–885. [PubMed] [Google Scholar]
  21. Rowley J. D. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973 Jun 1;243(5405):290–293. doi: 10.1038/243290a0. [DOI] [PubMed] [Google Scholar]
  22. Thomas E. D., Clift R. A., Fefer A., Appelbaum F. R., Beatty P., Bensinger W. I., Buckner C. D., Cheever M. A., Deeg H. J., Doney K. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med. 1986 Feb;104(2):155–163. doi: 10.7326/0003-4819-104-2-155. [DOI] [PubMed] [Google Scholar]
  23. Yam P. Y., Petz L. D., Knowlton R. G., Wallace R. B., Stock A. D., de Lange G., Brown V. A., Donis-Keller H., Blume K. G. Use of DNA restriction fragment length polymorphisms to document marrow engraftment and mixed hematopoietic chimerism following bone marrow transplantation. Transplantation. 1987 Mar;43(3):399–407. doi: 10.1097/00007890-198703000-00016. [DOI] [PubMed] [Google Scholar]
  24. Yoffe G., Blick M., Kantarjian H., Spitzer G., Gutterman J., Talpaz M. Molecular analysis of interferon-induced suppression of Philadelphia chromosome in patients with chronic myeloid leukemia. Blood. 1987 Mar;69(3):961–963. [PubMed] [Google Scholar]
  25. de Klein A., van Kessel A. G., Grosveld G., Bartram C. R., Hagemeijer A., Bootsma D., Spurr N. K., Heisterkamp N., Groffen J., Stephenson J. R. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1982 Dec 23;300(5894):765–767. doi: 10.1038/300765a0. [DOI] [PubMed] [Google Scholar]

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