Prospective monitoring of BCR‐ABL1 transcript levels in patients with Philadelphia chromosome‐positive acute lymphoblastic leukaemia undergoing imatinib‐combined chemotherapy

Abstract

Summary The clinical significance of minimal residual disease (MRD) is uncertain in patients with Philadelphia chromosome‐positive acute lymphoblastic leukaemia (Ph+ ALL) treated with imatinib‐combined chemotherapy. Here we report the results of prospective MRD monitoring in 100 adult patients. Three hundred and sixty‐seven follow‐up bone marrow samples, collected at predefined time points during a uniform treatment protocol, were analysed for BCR‐ABL1 transcripts by quantitative reverse transcription polymerase chain reaction. Ninety‐seven patients (97%) achieved complete remission (CR), and the relapse‐free survival (RFS) rate was 46% at 3 years. Negative MRD at the end of induction therapy was not associated with longer RFS or a lower relapse rate (P = 0·800 and P = 0·964 respectively). Twenty‐nine patients showed MRD elevation during haematological CR. Of these, 10 of the 16 who had undergone allogeneic haematopoietic stem cell transplantation (HSCT) in first CR were alive without relapse at a median of 2·9 years after transplantation, whereas 12 of the 13 who had not undergone allogeneic HSCT experienced a relapse. These results demonstrate that, in Ph+ ALL patients treated with imatinib‐combined chemotherapy, rapid molecular response is not associated with a favourable prognosis, and that a single observation of elevated MRD is predictive of subsequent relapse, but allogeneic HSCT can override its adverse effect.

Presence of CD34+CD38−CD58− leukemia-propagating cells at diagnosis identifies patients at high risk of relapse with Ph chromosome-positive ALL after allo-hematopoietic SCT

“…25,26 However, it remains controversial whether BCR/ABL-based MRD monitoring pre and post HSCT continues to serve as an efficient tool for risk stratification after HSCT. [27][28][29][30] Our study demonstrates the prognostic relevance of MRD kinetics to relapse and strongly supports a prior report from the GMALL Study Group, 28 which found that patients with the appearance of BCR/ABL transcripts early ( o100 days) and/or at higher levels (410 − 3 ) after allo-HSCT show a limited benefit from imatinib treatment. Unlike a previous study by Lee et al, 27 our data indicate that MRD status pre HSCT is not significantly correlated with recurrence post HSCT.…”

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

“…These results confirm the observations made in our previous study based on the use of dasatinib in induction, 16 and are in line with the current general knowledge on the prognostic impact of MRD. 12,19,[37][38][39][40][41][42][43] Furthermore, they strengthen the notion that MRD negativity should be regarded as a major goal in Ph + ALL treatment. Indeed, with few exceptions, 20,38 it is now well established that BCR-ABL1 transcript levels correlate with response.…”

“…12,19,[37][38][39][40][41][42][43] Furthermore, they strengthen the notion that MRD negativity should be regarded as a major goal in Ph + ALL treatment. Indeed, with few exceptions, 20,38 it is now well established that BCR-ABL1 transcript levels correlate with response. Lee et al 37 were able to demonstrate that a 3-log reduction in BCR-ABL1 transcripts after one month of imatinib treatment strongly predicted a reduced risk of relapse and confirmed these results in a subsequent study.…”

Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia

“…In the imatinib era, only limited information is available regarding the prognostic impact of MRD level on treatment outcome in adult Ph-positive ALL. Yanada et al 26 conducted a prospective MRD monitoring in adults with Ph-positive ALL treated with imatinib-combined chemotherapy (including both transplants and non-transplants) and reported upon the prognostic significance of MRD level at the end of induction (n ¼ 86 (day 28) and n ¼ 85 (day 63)) and after first consolidation (n ¼ 75). However, in their study, neither PCR negativity at the end of induction nor after consolidation was associated with a lower relapse rate or survival advantage (median follow-up 3.2 years), although patients whose MRD levels exceeded 1000 copies per mg had trends toward a higher relapse rate (P ¼ 0.070).…”