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)

Abstract

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 BcrAbl/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, BcrAbl levels (< 10 ؊2 ) in BM of good responders after 4 weeks discriminated between 2 groups of patients with significantly different median time to progression (

Standardized MRD quantification in European ALL trials: Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008

“…15,20 Introduction of novel treatment concepts for Ph þ ALL including MRD-guided therapy for adult ALL, for example, in protocols of the German Multicenter ALL SG (GMALL), has generated interest in quantitative analysis of this fusion gene. 14,15,18,20,21,27 Taken together, these data suggest that in Ph þ ALL, quantitative monitoring of residual leukemic cells is an essential diagnostic element for assisting in clinical decision making. Recent data comparing MRD levels obtained by quantitation of the BCR-ABL transcript and Ig/TCR rearrangements show that, in ALL, transcript monitoring might provide additional prognostic information compared with standard Ig/TCR follow-up.…”

“…34 Several studies have shown that levels of MRD in the bone marrow (BM) of patients with Ph þ ALL, assessed by RQ-PCR after induction and after consolidation treatment, is a powerful indicator of prognosis. 14,15,18,20,21,27 This also applies to the posttransplant setting, in which sequential analysis of patients who received allogeneic stem cell transplantation showed that repeated PCR positivity correlated with an increased risk of relapse. 15,20 Introduction of novel treatment concepts for Ph þ ALL including MRD-guided therapy for adult ALL, for example, in protocols of the German Multicenter ALL SG (GMALL), has generated interest in quantitative analysis of this fusion gene.…”

Serial minimal residual disease (MRD) analysis as a predictor of response duration in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) during imatinib treatment

“…Minimal residual disease (MRD) results of the initial phase of therapy with imatinib describing the degree of reduction have been published previously. 29 Of the 56 patients, 16 were refractory or with a PR and therefore not of interest for further MRD analysis. Since the present study intended to examine further MRD courses during imatinib therapy by monthly BM and PB samples, 10 of the remaining 40 patients with CHR or CMR were excluded from evaluation due to early transfer to SCT (28-67 days after starting imatinib therapy).…”

“…Since the present study intended to examine further MRD courses during imatinib therapy by monthly BM and PB samples, 10 of the remaining 40 patients with CHR or CMR were excluded from evaluation due to early transfer to SCT (28-67 days after starting imatinib therapy). Four of the remaining 30 patients suffered short-term relapse before or at 2 months of imatinib therapy (29,46, 55 and 64 days after start), thus not permitting predictive MRD analysis with a schedule of monthly sample collection. Another two patients were excluded from analysis since there was no regular sample collection or sufficient sensitivity at scheduled monthly time points (first patient: sensitivity too low at day 28; only valid sample at day 51; relapse at day 85; second patient: sensitivity too low at day 28; only valid sample at day 56, relapse at day 70).…”

“…29 In individual patients, however, the early reduction of Bcr-Abl transcripts does not necessarily predict the kinetics with which a resistant leukemic clone becomes the predominant cell population during subsequent imatinib therapy. Therefore, it is of practical relevance to determine whether the sensitivity and reproducibility of serial quantitative PCR are sufficient to define and detect clinically relevant MRD increments that are predictive of relapse, and whether such an analysis is clinically feasible.…”