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

Abstract

Patients with refractory or relapsed Philadelphia chromosomepositive acute lymphoblastic leukemia (Ph+ALL) rarely have prolonged responses to salvage therapy, including imatinib, resulting in a short opportunity for potentially curative stem cell transplantation. To identify minimal residual disease (MRD) parameters predictive of imminent relapse, we quantitated BcrAbl expression by real-time PCR in peripheral blood (PB) and bone marrow (BM) of 24 Ph+ALL patients after achieving a complete response and MRD minimum. The ratio of Bcr-Abl and glyceraldehyde-3-phosphate dehydrogenase copies, magnitude of increase and velocity of increase were evaluated regarding subsequent time intervals to relapse, death or censoring. High Bcr-Abl levels X5 Â 10 À4 in PB (n ¼ 23) and X10 À4 in BM (n ¼ 18) were significantly associated with short time periods to relapse. Bcr-Abl increases 42 logarithmic units (log) in PB, but not in BM preceded short-term relapse. The velocity of Bcr-Abl increases predicted response duration in PB (cutoff: 1.25 log/30 days) and BM (0.6). Bcr-Abl level and velocity of increase in BM as well as magnitude of increase in PB correlated with remaining periods of survival and predicted relapse within 2 months in nine of 10, 10 of 11 and four of four patients, respectively. Thus, these MRD parameters may guide timing and intensity of therapeutic modifications.

Imatinib Mesylate in Conjunction with Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Philadelphia Chromosome Positive Leukemias: Report of 4 Cases

“…1). Although the previous report suggested that BM samples were shown to be the more discriminatory and reliable materials as compared to PB in case of Ph+ ALL (Scheuring et al 2003), we speculate that more frequent sampling of PB may increase the ability to detect significant increase of MRD. Since early relapse is common and predicts a poor outcome in Ph+ ALL, MRD quantification at a very early stage of SCT should be important for the stratification of high risk patients who need further treatment intervention.…”

“…Several approaches to treat relapsed leukemia after SCT, including donor lymphocyte infusion, second SCT and chemotherapy, do not benefit significant proportion of patients because of toxicity associated with the procedure or disease progression. Therefore, imatinib, which is well tolerated and has a manageable side-effect profile (Kantarjian et al 2002;Olavarria et al 2002Olavarria et al , 2003Ottmann et al 2002;Wassmann et al 2002;Scheuring et al 2003;Shimoni et al 2003), might be a useful strategy to be used in conjunction with SCT. However, the clinical role of imatinib in Ph+ leukemia in the setting of SCT remains to be defined.…”

“…He achieved CR after 3 courses of induction therapy, and subsequently 2 courses of consolidation therapy were performed. He was referred to our hospital for Imatinib mesylate (STI571, Gleevec), a selective BCR-ABL tyrosine-kinase inhibitor, has shown significant activity against Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) (Kantarjian et al 2002;Olavarria et al 2002Olavarria et al , 2003Ottmann et al 2002;Wassmann et al 2002;Scheuring et al 2003;Shimoni et al 2003). To date, allogeneic stem cell transplantation (SCT) has been the only established approach capable of completely eliminating BCR-ABL positive cell population.…”

Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission – experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG)

“…In future trials, it has to be prospectively assessed whether MRD analysis in peripheral blood which is more convenient and costeffective mirrors changes in bone marrow samples, as has been shown for MRD assessment in other leukemia entities. [40][41][42] Although based on a few patients due to incomplete accrual, a significant trend towards longer PFS for alemtuzumab-treated patients was seen at a median follow-up of almost 2 years. We are fully aware that these results have to be taken cautiously and that this trend needs to be confirmed after a longer follow-up, especially in light of residual splenomegaly and/or lymphadenopathy in most patients.…”

Why and how to quantify minimal residual disease in acute lymphoblastic leukemia?

“…29 With the addition of targeted treatment such as imatinib mesylate to current chemotherapy regimens for BCR-ABL þ ALL, BCR-ABL transcripts have become the first-choice marker for MRD monitoring by RT-RQ-PCR. 30,31 In contrast, TEL-AML1 fusion gene occurring in approximately 25% of children with ALL identifies a subgroup with a very good prognosis for which the advantage of MRD monitoring is not yet fully proven.…”