Early minimal residual disease (MRD) analysis during treatment of Philadelphia chromosome/Bcr-Abl-positive acute lymphoblastic leukemia with the Abl-tyrosine kinase inhibitor imatinib (STI571).
The Abl kinase inhibitor imatinib mesylate (STI571) has significant and rapid antileukemic activity in Philadelphia chromosome/Bcr-Abl-positive acute lymphoblastic leukemia (Ph(+) ALL) but such activity is usually of short duration except for a small proportion of patients. To determine the prognostic significance of early Bcr-Abl levels and changes in peripheral blood (PB) and bone marrow (BM), serial samples of 56 patients with relapsed or refractory Ph(+) ALL treated in phase 2 trials of imatinib were analyzed by quantitative polymerase chain reaction (PCR). Imatinib induced a complete hematologic response (CHR) or complete marrow response (marrow-CR) in 40 patients (good responders) and a partial (n = 2) or no (n = 14) remission in the remaining patients (poor responders). Compared with baseline, the median Bcr-Abl/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) ratios decreased significantly in PB by 2.65, 2.64, and 3.11 log steps after 2 weeks, 4 weeks, and at the time of best response, respectively. In BM, the decline of median Bcr-Abl/GAPDH was 0.75, 1.37, and 2.78 logs, respectively. Thus, Bcr-Abl levels decreased more rapidly in PB than in BM (median time to best level 31 vs 39 days). Low Bcr-Abl/GAPDH ratios below 10(-4) in PB and below 10(-2) in BM after 2 weeks were significantly associated with good responses after 4 weeks. Moreover, Bcr-Abl levels (< 10(-2)) in BM of good responders after 4 weeks discriminated between 2 groups of patients with significantly different median time to progression (139 vs 22 days). The data show that Bcr-Abl levels in PB and BM after 2 weeks of imatinib treatment and in BM after 4 weeks have predictive relevance and may guide the application of additional therapies.
Scheuring
Urban J
UJ
Medizinische Klinik III, Abteilung für Hämatologie und Onkologie of the Johann Wolfgang Goethe-Universität, Frankfurt, Germany. scheuring@em.uni-frankfurt.de
Pfeifer
Heike
H
Wassmann
Barbara
B
Bruck
Patrick
P
Atta
Johannes
J
Petershofen
Eduard K
EK
Gehrke
Brigitte
B
Gschaidmeier
Harald
H
Hoelzer
Dieter
D
Ottmann
Oliver G
OG
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001549:Benzamides; D001853:Bone Marrow / Q000737:chemistry; D018572:Disease-Free Survival; D016044:Fusion Proteins, bcr-abl / Q000032:analysis* / Q000097:blood; D006801:Humans; D000068877:Imatinib Mesylate; D018365:Neoplasm, Residual / Q000175:diagnosis / Q000401:mortality; D010879:Piperazines / Q000008:administration & dosage*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D011379:Prognosis; D011743:Pyrimidines / Q000008:administration & dosage*; D012074:Remission Induction / Q000379:methods; D016879:Salvage Therapy
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl