Search

Imatinib induces remissions in approximately 30% of patients with chronic myeloid leukemia (CML) in myeloid blast crisis (M-BC). Because most patients eventually relapse, allogeneic stem cell transplantation (SCT) in remission offers the best chance for cure. Remission induction with imatinib alone would seem ideal because it is less toxic than conventional chemotherapy. Conversely, patients unlikely to respond may benefit from combination therapy up front. To identify prognostic factors, we studied the mRNA expression of genes related to drug resistance and apoptosis in leukemic cells from patients with M-BC and their in vitro sensitivity to imatinib, and analyzed the results with other baseline factors for their impact on response. We show that high levels of BAX, low levels of MRP-1, and a high platelet count are independently predictive of response to imatinib. Combined into a score, these parameters may be clinically useful for risk-adapted patient stratification.

Imatinib induces remissions in approximately 30% of patients with chronic myeloid leukemia (CML) in myeloid blast crisis (M-BC). Because most patients eventually relapse, allogeneic stem cell transplantation (SCT) in remission offers the best chance for cure. Remission induction with imatinib alone would seem ideal because it is less toxic than conventional chemotherapy. Conversely, patients unlikely to respond may benefit from combination therapy up front. To identify prognostic factors, we studied the mRNA expression of genes related to drug resistance and apoptosis in leukemic cells from patients with M-BC and their in vitro sensitivity to imatinib, and analyzed the results with other baseline factors for their impact on response. We show that high levels of BAX, low levels of MRP-1, and a high platelet count are independently predictive of response to imatinib. Combined into a score, these parameters may be clinically useful for risk-adapted patient stratification.

Objectives:Patients with CML who achieve molecular remission (MR, defined as a RT-PCR negativity for BCR-ABL transcripts) after myeloablative stem cell transplantation (SCT) have a low risk of relapse, and the majority may be cured. The frequency of MR on imatinib varies greatly and the durability of these responses has not been reported. To investigate if MR after SCT and on imatinib are equally stable, we directly compared two cohorts of patients treated with imatinib or SCT, respectively, from the time of their first negative RT-PCR result.

Objectives: Patients with CML who achieve molecular remission (MR, defined as a RT-PCR negativity for BCR-ABL transcripts) after myeloablative stem cell transplantation (SCT) have a low risk of relapse, and the majority may be cured. The frequency of MR on imatinib varies greatly and the durability of these responses has not been reported. To investigate if MR after SCT and on imatinib are equally stable, we directly compared two cohorts of patients treated with imatinib or SCT, respectively, from the time of their first negative RT-PCR result. Patients and Methods: One hundred and forty-four CML patients in chronic (n=104) or accelerated phase (n=40) treated with standard dose imatinib were routinely monitored by conventional cytogenetics, quantitative RT-PCR (qPCR) and conventional nested PCR in case of negative qPCR results. Nineteen patients (13.2%) had at least 1 negative nested PCR. To assess the level of residual disease in patients with a single negative RT-PCR result, 10 replicate reactions were performed, each corresponding to > 106 white bone marrow cells. Thirty-six samples (median 3, range 1–4) from patients in MR on imatinib and 45 samples (median 2, range 1–3) from patients in MR after SCT were available. Twenty samples from healthy individuals were tested as controls. Results: The first negative result was noted after a median of 16.8 months (range 11.5–36.1) of imatinib therapy and 6.6 months (range 4.7–9.5) after SCT, respectively. The projected risk of molecular relapse at 12 months after the first negative RT-PCR result was 83% in patients on imatinib but only 20% in patients after SCT (P = 0.0001). Only two patients on imatinib remained in molecular remission at 13.8 and 16.6 months. While none of the patients with molecular relapse after allograft lost CCyR, one patient on imatinib progressed to cytogenetic relapse. The replicate assay was positive in 18/36 samples (50%) from patients on imatinib, 8/46 (17.4%) after allografting and 4/20 (20%) from healthy individuals. These differences were significant between patients on imatinib and after allografting (P = 0.003) and between patients on imatinib and healthy individuals (P = 0.005), but not between patients after allografting and healthy individuals (P = 0.9). Negativity by replicate testing was more stable in patients after allografting, although, even in these patients, positive replicate reactions continued to occur with longer follow-up. Conclusion: Imatinib-induced MR is usually not durable, in contrast to MR after transplant. Consistent with this, the level of residual disease in samples negative by single nested PCR is higher in patients on imatinib compared to patients after SCT. These results suggest that disease eradication with imatinib monotherapy may be rare. Patients on imatinib followed by PCR should be made aware of the fact that a single negative test does not have the same significance as in patients after SCT.