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Molecular monitoring of response to imatinib (Glivec) in CML patients pretreated with interferon alpha. Low levels of residual disease are associated with continuous remission

Record type: Article

A significant proportion of chronic myeloid leukemia (CML) patients achieve a major cytogenetic remission (MCR) to imatinib therapy after failing interferon (IFN) alpha-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.

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Citation

Paschka, P., Muller, M.C., Merx, K., Kreil, S., Schoch, C., Lahaye, T., Weisser, A., Petzold, A., Konig, H., Berger, U., Gschaidmeier, H., Hehlmann, R. and Hochhaus, A. (2003) 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, (9), pp. 1687-1694. (doi:10.1038/sj.leu.2403033).

More information

Published date: 2003
Keywords: leukemia, rna, chronic, pathology, fluorescence, antagonists & inhibitors, drug resistance, residual, neoplasm, local, proteins, metabolism, neoplasm recurrence, Germany, methods, therapy, interferon-alpha, antineoplastic agents, polymerase chain reaction, bone, middle aged, messenger, alpha, humans, blast crisis, female, protein, research support, remission induction, bone marrow, comparative study, blood, reverse transcriptase polymerase chain reaction, fusion proteins, bcr-abl, in situ hybridization, aged, sensitivity and specificity, non-U.S.gov't, pyrimidines, drug therapy, piperazines, time, protein-tyrosine kinase, genetics, male, myeloid, cytogenetic analysis, survival rate, disease, adult, interphase, therapeutic use, diagnosis, prognosis, patients, analysis

Identifiers

Local EPrints ID: 60118
URI: http://eprints.soton.ac.uk/id/eprint/60118
ISSN: 0887-6924
PURE UUID: 86877dd1-7f19-4610-a7b9-b050657c3a9f

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Date deposited: 05 Sep 2008
Last modified: 17 Jul 2017 14:23

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Contributors

Author: P. Paschka
Author: M.C. Muller
Author: K. Merx
Author: S. Kreil
Author: C. Schoch
Author: T. Lahaye
Author: A. Weisser
Author: A. Petzold
Author: H. Konig
Author: U. Berger
Author: H. Gschaidmeier
Author: R. Hehlmann
Author: A. Hochhaus

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