Imatinib in Philadelphia chromosome-positive chronic phase CML patients: molecular and cytogenetic response rates and prediction of clinical outcome.
Previous clinical trials with the tyrosine kinase inhibitor imatinib in chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia (CML) resulted in 95% of hematologic and 60% major cytogenetic remissions in patients who failed a previous interferon-alpha-containing regimen. In an identical clinical trial setting with 39 chronic-phase CML patients we achieved comparable cytogenetic response rates after a median follow up of 30.1 weeks, with an almost identical toxicity profile. In order to identify predictive markers for the therapeutical use of imatinib, we monitored apart from standard hematology parameters bcr/abl fusion transcripts by quantitative real-time fluorescence RT-PCR. As previous investigations demonstrated that the plasma protein alpha-1 acid glycoprotein might inactivate circulating levels of free imatinib by protein binding with high affinity, we assessed plasma alpha-1 acid glycoprotein concentrations in our study cohort as well. Median bcr/abl fusion transcripts declined gradually over the entire treatment period and became significantly lowered at month 3 after initiation of imatinib therapy. Further, we observed elevated pretreatment levels of alpha-1 acid glycoprotein in patients who relapsed with leukemia, whereas initial bcr/abl mRNA copy numbers were not of predictive value. In addition, we provide data showing molecular response to this therapy in the vast majority of patients. Finally, our results support the hypothesis, that initially elevated plasma levels of alpha-1 acid glycoprotein might serve as a predictive marker for the clinical outcome of treatment with imatinib.
Le Coutre
Philipp
P
Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Campus Virchow, Charité, Humboldt Universität Berlin, Germany. lecoutrep@aol.com
Kreuzer
Karl-Anton
KA
Na
Il-Kang
IK
Schwarz
Michaela
M
Lupberger
Joachim
J
Holdhoff
Matthias
M
Baskaynak
Gökben
G
Gschaidmeier
Harald
H
Platzbecker
Uwe
U
Ehninger
Gerhard
G
Prejzner
Witold
W
Huhn
Dieter
D
Schmidt
Christian A
CA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D001549:Benzamides; D015415:Biomarkers / Q000097:blood; D020732:Cytogenetic Analysis; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D009961:Orosomucoid / Q000032:analysis; D010879:Piperazines / Q000627:therapeutic use* / Q000633:toxicity; D011379:Prognosis; D011743:Pyrimidines / Q000627:therapeutic use* / Q000633:toxicity; D012333:RNA, Messenger / Q000032:analysis; D012008:Recurrence; D012074:Remission Induction; D013997:Time Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D015415:Biomarkers; D009961:Orosomucoid; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl