Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon α

Abstract

The degree of tumor load reduction as measured by cytogenetic response is an important prognostic factor for chronic myelogenous leukemia (CML) patients on therapy. We sought to determine whether BCR-ABL transcript levels can predict chromosomal response. Residual disease was evaluated in 120 CML patients in chronic phase (CP) treated with the selective tyrosine kinase inhibitor imatinib after resistance or intolerance to interferon ␣ ( RT-PCR data obtained after 1 and 2 months of therapy were compared with cytogenetic response at 6 months. BCR-ABL/ABL ratios after 1 month were not predictive, but results after 2 months correlated with the consecutive cytogenetic response (P = 0.0008). The probability for a major cytogenetic response was significantly higher in patients with a BCR-ABL/ABL ratio Ͻ20% after 2 months of imatinib therapy. We conclude that: (1) quantitative determination of residual disease with real time RT-PCR is a reliable and sensitive method to monitor CML patients on imatinib therapy; (2) BCR-ABL/ABL ratios correlate well with cytogenetic response; (3) in IFN-pretreated patients all complete responders to imatinib have evidence of residual disease with the limited follow-up available; and (4) cytogenetic response at 6 months of therapy in CP patients is predictable with real time RT-PCR at 2 months.

Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML)

“…[26][27][28] Our group has determined a BCR-ABL/ABL ratio o20% at 2 months as a predictor of MCyR in patients treated with imatinib after failure to IFN. 27 Gold standard remained CCyR by 12 or 18 months, which was shown to predict superior PFS and OS. 4 Our CML Study IV data revealed the 1% BCR-ABL IS cutoff at 12 months to predict PFS and OS so far.…”

Durability of molecular remission in chronic myeloid leukemia patients treated with imatinib vs allogeneic stem cell transplantation

“…3 Similar, in a study of 120 patients treated with imatinib in late chronic phase the rate of MR was 0%. 4 A recently published study in a comparable cohort of patients reported an MR rate of 11.5%. 5 Since none of these studies addressed the durability of imatinib-induced MR or provided a side-by-side comparison with allografting, we directly compared two cohorts of patients treated with imatinib or allografting who were monitored at a single center with identical assays.…”

“…It is indeed questionable whether in patients on imatinib a single negative RT-PCR test should be termed MR at all. It should be noted that we accepted a lower limit of GAPDH (6022 copies/ml Table 1 Sensitivity of tenfold replicate PCR compared to nested PCR in K562 cells and two patients with CML CP in complete hematologic remission to imatinib [2][3][4] Although the mechanisms of the occurrence of such mutations remain poorly understood, it has been shown that they can occur prior to the introduction of IM, suggesting the possibility of a clonal selection under IM therapy in some patients. 5 It is however possible that mutations could also occur during IM therapy.…”

Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – A Europe Against Cancer Program

“…31,121 In addition, quantification of BCR-ABL FG transcripts has also proven useful to monitor response to a-interferon-122 and imatinib-treated patients. 123,124 Despite many encouraging reports, monitoring of BCR-ABL FG transcripts with competitive RT-PCR has had limited clinical impact, partly due to the fact that this approach is difficult to standardize. Since the advent of real-time PCR, several groups have published reports that describe the feasibility of monitoring CML patients with this technique.…”