Molecular monitoring of response to imatinib (Glivec) in CML patients pretreated with interferon alpha. Low levels of residual disease are associated with continuous remission.
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.
Paschka
P
P
III. Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany.
Müller
M C
MC
Merx
K
K
Kreil
S
S
Schoch
C
C
Lahaye
T
T
Weisser
A
A
Petzold
A
A
König
H
H
Berger
U
U
Gschaidmeier
H
H
Hehlmann
R
R
Hochhaus
A
A
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D016898:Interferon-alpha / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018365:Neoplasm, Residual / Q000175:diagnosis*; D010879:Piperazines / Q000627:therapeutic use*; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000235:genetics; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D015996:Survival Rate
D000970:Antineoplastic Agents; D001549:Benzamides; D016898:Interferon-alpha; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl