Abstract
A significant proportion of chronic myeloid leukemia (CML) patients achieve a major cytogenetic remission (MCR) to imatinib therapy after failing interferon (IFN) α-based protocols. We sought to determine levels of residual disease in patients with MCR using various molecular methods and to establish a relation between residual BCR-ABL transcript levels and rate of relapse in complete cytogenetic remission (CCR). Response was measured by conventional cytogenetic analysis, hypermetaphase and interphase fluorescence in situ hybridization (HM-FISH, IP-FISH) of bone marrow (BM) cells, qualitative nested and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL transcripts. We investigated 323 peripheral blood (PB) and BM samples from 48 CML patients who achieved a complete (Ph+ 0%; n=41) or partial (Ph+ 1–34%; n=7) cytogenetic remission after 3–20 months of imatinib therapy. Prior to imatinib, 35 patients were in chronic phase (CP), eight in accelerated phase (AP), four in myeloid and one in lymphoid blast crisis. HM-FISH results correlated with ratios BCR-ABL/ABL in PB and BM. In patients with CCR, residual disease was detectable by HM-FISH (31%), IP-FISH (18%), and RT-PCR (100%). During follow-up, BCR-ABL became undetectable in two patients (one CP, one AP) by both nested and quantitative RT-PCR. CCR is ongoing in 30 evaluable patients, 11 patients have relapsed. At the time of best response, median ratios BCR-ABL/ABL were 2.1% (range 0.82–7.8) in patients with subsequent relapse and 0.075% (range 0–3.9) in patients with ongoing remission (P=0.0011). All 16 CP patients, who achieved ratios BCR-ABL/ABL <0.1% as best molecular response are in continuous remission, while 6/13 patients (46%) with ratios ⩾0.1% have relapsed (P=0.0036). We conclude that: (i) in patients with CCR to imatinib, HM-FISH and RT-PCR usually reveal residual BCR-ABL+ cells; (ii) RT-PCR results derived from PB and BM are comparable in CP CML; and (iii) low levels of residual disease with ratios BCR-ABL/ABL <0.1% are associated with continuous remission.
This is a preview of subscription content, access via your institution
Relevant articles
Open Access articles citing this article.
-
Molecular measurement of BCR-ABL transcript variations in chronic myeloid leukemia patients in cytogenetic remission
BMC Hematology Open Access 18 November 2010
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Sawyers CL . Chronic myeloid leukemia. N Engl J Med 1999; 340: 1330–1340.
Deininger MWN, Goldman JM, Lydon N, Melo JV . The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 1997; 90: 3691–3698.
Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–566.
Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346: 645–652.
Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002; 99: 1928–1937.
Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002; 99: 3530–3539.
Hehlmann R, Heimpel H . Current aspects of drug therapy in Philadelphia-positive CML: correlation of tumor burden with survival. Leuk Lymphoma 1996; 22 (Suppl. 1): 161–167.
Kantarjian HM, O'Brien S, Cortes JE, Shan J, Giles FJ, Rios MB et al. Complete cytogenetic and molecular responses to interferon-alpha-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer 2003; 97: 1033–1041.
Bonifazi F, De Vivo A, Rosti G, Guilhot F, Guilhot J, Trabacchi E et al. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood 2001; 98: 3074–3081.
Hochhaus A, Reiter A, Saußele S, Reichert A, Emig M, Kaeda J et al. Molecular heterogeneity in complete cytogenetic responders after interferon-α therapy for chronic myeloid leukemia: low levels of minimal residual disease are associated with continuing remission. Blood 2000; 95: 62–66.
Cross NCP, Melo JV, Feng L, Goldman JM . An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders. Leukemia 1994; 8: 186–189.
Schoch C, Schnittger S, Bursch S, Gerstner D, Hochhaus A, Berger U et al. Comparison of chromosome banding analysis, interphase- and hypermetaphase-FISH, qualitative and quantitative PCR for diagnosis and follow up in chronic myeloid leukemia: study on 350 cases. Leukemia 2002; 16: 53–59.
Kantarjian HM, Smith TL, O'Brien S, Beran M, Pierce S, Talpaz M et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-α therapy. Ann Intern Med 1995; 122: 254–261.
Cross NCP, Feng L, Bungey J, Goldman JM . Minimal residual disease after bone marrow transplant for chronic myeloid leukaemia detected by the polymerase chain reaction. Leuk Lymphoma 1993; 11 (Suppl. 1): 39–43.
Emig M, Saussele S, Wittor H, Weisser A, Reiter A, Willer A et al. Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time quantitative RT-PCR. Leukemia 1999; 13: 1825–1832.
Cross NCP, Feng L, Chase A, Bungey J, Hughes TP, Goldman JM . Competitive polymerase chain reaction to estimate the number of BCR-ABL transcripts in chronic myeloid leukemia patients after bone marrow transplantation. Blood 1993; 82: 1929–1936.
Cross NCP . Assessing residual leukaemia. Baillieres Clin Haematol 1997; 10: 389–403.
Hochhaus A, Weisser A, La Rosée P, Emig M, Müller MC, Saußele S et al. Detection and quantification of residual disease in chronic myelogenous leukemia. Leukemia 2000; 14: 998–1005.
van der Velden VHJ, Hochhaus A, Cazzaniga G, Szczepanski T, Gabert J, van Dongen JJM . Detection of minimal residual disease in hematopoietic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects. Leukemia 2003; 17: 1013–1034.
Clarkson B, Strife A . Linkage of proliferative and maturational abnormalities in chronic myelogenous leukemia and relevance to treatment. Leukemia 1993; 7: 1683–1721.
Hook EB . Exclusion of chromosomal mosaicism: tables of 90%, 95%, and 99% confidence limits and comments on use. Am J Hum Genet 1977; 29: 94–97.
Cortes J, Talpaz M, O'Brien S, Rios MB, Majlis A, Keating M et al. Suppression on cytogenetic clonal evolution with interferon alfa therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. J Clin Oncol 1998; 16: 3279–3285.
Andersen MK, Pedersen-Bjergaard J, Kjeldsen L, Dufva IH, Brondum-Nielsen K . Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8. Leukemia 2002; 16: 1390–1393.
Meeus P, Demuynck H, Martiat P, Michaux L, Wouters E, Hagemeijer A . Sustained, clonal karyotype abnormalities in the Philadelphia chromosome negative cells of CML patients successfully treated with Imatinib. Leukemia 2003; 17: 465–467.
Bumm T, Muller C, Al Ali HK, Krohn K, Shepherd P, Schmidt E et al. Emergence of clonal cytogenetic abnormalities in Ph− cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003; 101: 1941–1949.
Seong DC, Kantarjian HM, Ro JY, Talpaz M, Xu J, Robinson JR et al. Hypermetaphase fluorescence in situ hybridization for quantitative monitoring of Philadelphia chromosome-positive cells in patients with chronic myelogenous leukemia during treatment. Blood 1995; 86: 2343–2349.
Bentz M, Cabot G, Moos M, Speicher MR, Ganser A, Lichter P et al. Detection of chimeric BCR-ABL genes on bone marrow samples and blood smears in chronic myeloid and acute lymphoblastic leukemia by in situ hybridization. Blood 1994; 83: 1922–1928.
Seong DC, Song MY, Henske EP, Zimmerman SO, Champlin RE, Deisseroth AB et al. Analysis of interphase cells for the Philadelphia translocation using painting probe made by inter-Alu-polymerase chain reaction from a radiation hybrid. Blood 1994; 83: 2268–2273.
Akel S, Kolialexi A, Mavrou A, Metaxotou C, Loukopoulos D, Yataganas X . Efficiency of interphase fluorescence in situ hybridization for BCR/ABL on peripheral blood smears for monitoring of CML patients: a comparison with bone marrow findings. Clin Lab Haematol 2002; 24: 361–367.
Branford S, Hughes TP, Rudzki Z . Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. Br J Haematol 1999; 107: 587–599.
Eder M, Battner K, Kafert S, Stucki A, Ganser A, Hertenstein B . Monitoring of BCR-ABL expression using real-time RT-PCR in CML after bone marrow or peripheral blood stem cell transplantation. Leukemia 1999; 13: 1383–1389.
Lion T, Izraeli S, Henn T, Gaiger A, Mor W, Gadner H . Monitoring of residual disease in chronic myelogenous leukemia by quantitative polymerase chain reaction. Leukemia 1992; 6: 495–499.
Mensink E, van de Locht A, Schattenberg A, Linders E, Schaap N, Guerts van Kessel A et al. Quantitation of minimal residual disease in Philadelphia chromosome positive chronic myeloid leukaemia patients using real-time quantitative RT-PCR. Br J Haematol 1998; 102: 768–774.
Preudhomme C, Révillion F, Merlat A, Hornez L, Roumier C, Duflos-Grardel N et al. Detection of BCR-ABL transcripts in chronic myeloid leukemia (CML) using a ‘real time’ quantitative RT-PCR assay. Leukemia 1999; 13: 957–964.
Hochhaus A, Lin F, Reiter A, Skladny H, Mason PJ, van Rhee F et al. Quantification of residual disease in chronic myelogenous leukemia patients on interferon-α therapy by competitive polymerase chain reaction. Blood 1996; 87: 1549–1555.
Gabert J, Beillard E, van der Velden VHJ, Bi W, Grimwade D, Pallisgaard N et al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) of fusion gene transcripts for residual disease detection in leukaemia – an Europe Against Cancer Program. Leukemia 2003; 17: in press.
Guo JQ, Lin H, Kantarjian H, Talpaz M, Champlin R, Andreeff M et al. Comparison of competitive-nested PCR and real-time PCR in detecting BCR-ABL fusion transcripts in chronic myeloid leukemia patients. Leukemia 2002; 16: 2447–2453.
Merx K, Müller MC, Kreil S, Lahaye T, Paschka P, Schoch C et al. Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha. Leukemia 2002; 16: 1579–1583.
Kantarjian HM, Talpaz M, Cortes J, O'Brien S, Faderl S, Thomas D et al. Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with imatinib mesylate (STI571; Gleevec) in chronic-phase chronic myelogenous leukemia. Clin Cancer Res 2003; 9: 160–166.
Szczepanski T, Orfao A, van der Velden V, San Miguel JF, van Dongen JJ . Minimal residual disease in leukaemia patients. Lancet Oncol 2001; 2: 409–417.
Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 2002; 100: 1965–1971.
Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002; 16: 2190–2196.
Acknowledgements
We are grateful to all colleagues and nursing staff from the referring centers for participating in this study. This work was supported by the Deutsche José-Carreras-Stiftung eV, the Forschungsfonds der Fakultät für Klinische Medizin, Mannheim and the competence network ‘Acute and chronic leukemias’, sponsored by the German Bundesministerium für Bildung und Forschung (Projektträger Gesundheitsforschung; DLR e.V.).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Paschka, P., Müller, M., Merx, K. et al. Molecular monitoring of response to imatinib (Glivec®) in CML patients pretreated with interferon alpha. Low levels of residual disease are associated with continuous remission. Leukemia 17, 1687–1694 (2003). https://doi.org/10.1038/sj.leu.2403033
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2403033
Keywords
This article is cited by
-
Measurable residual disease testing in acute myeloid leukaemia
Leukemia (2017)
-
Molecular measurement of BCR-ABL transcript variations in chronic myeloid leukemia patients in cytogenetic remission
BMC Hematology (2010)
-
Dasatinib-associated major molecular responses in patients with chronic myeloid leukemia in chronic phase following imatinib failure: response dynamics and predictive value
Leukemia (2009)
-
Molecular responses of late chronic phase chronic myeloid leukemia patients after achieving complete cytogenetic responses with imatinib treatment: a 6-year follow-up
Annals of Hematology (2009)
-
Leukämien des Erwachsenen
Der Onkologe (2009)