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

P. Paschka, M. C. Müller, K. Merx, S. Kreil, C. Schoch, T. Lahaye, A. Weisser, A. Petzold, H. König, U. Berger, H. Gschaidmeier, R. Hehlmann, A. Hochhaus

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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.

Original languageEnglish (US)
Pages (from-to)1687-1694
Number of pages8
JournalLeukemia
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2003

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Interferon-alpha
Cytogenetics
Reverse Transcriptase Polymerase Chain Reaction
Bone Marrow
Imatinib Mesylate
Leukemia, Myeloid, Chronic Phase
Blast Crisis
Recurrence
Cytogenetic Analysis
Interphase
Fluorescence In Situ Hybridization
Bone Marrow Cells
Interferons

Keywords

  • Chronic myelogenous leukemia
  • FISH
  • Imatinib
  • Minimal residual disease
  • Molecular cytogenetics
  • Quantitative RT-PCR

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Molecular monitoring of response to imatinib (Glivec®) in CML patients pretreated with interferon alpha. Low levels of residual disease are associated with continuous remission. / Paschka, P.; Müller, M. C.; Merx, K.; Kreil, S.; Schoch, C.; Lahaye, T.; Weisser, A.; Petzold, A.; König, H.; Berger, U.; Gschaidmeier, H.; Hehlmann, R.; Hochhaus, A.

In: Leukemia, Vol. 17, No. 9, 01.09.2003, p. 1687-1694.

Research output: Contribution to journalArticle

Paschka, P, Müller, MC, Merx, K, Kreil, S, Schoch, C, Lahaye, T, Weisser, A, Petzold, A, König, H, Berger, U, Gschaidmeier, H, Hehlmann, R & 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, vol. 17, no. 9, pp. 1687-1694. https://doi.org/10.1038/sj.leu.2403033
Paschka, P. ; Müller, M. C. ; Merx, K. ; Kreil, S. ; Schoch, C. ; Lahaye, T. ; Weisser, A. ; Petzold, A. ; König, H. ; Berger, U. ; Gschaidmeier, H. ; Hehlmann, R. ; Hochhaus, A. / Molecular monitoring of response to imatinib (Glivec®) in CML patients pretreated with interferon alpha. Low levels of residual disease are associated with continuous remission. In: Leukemia. 2003 ; Vol. 17, No. 9. pp. 1687-1694.
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AU - Paschka, P.

AU - Müller, M. C.

AU - Merx, K.

AU - Kreil, S.

AU - Schoch, C.

AU - Lahaye, T.

AU - Weisser, A.

AU - Petzold, A.

AU - König, H.

AU - Berger, U.

AU - Gschaidmeier, H.

AU - Hehlmann, R.

AU - Hochhaus, A.

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N2 - 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.

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KW - Chronic myelogenous leukemia

KW - FISH

KW - Imatinib

KW - Minimal residual disease

KW - Molecular cytogenetics

KW - Quantitative RT-PCR

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