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To determine whether a lower imatinib dose could minimize toxicity while maintaining the molecular response (MR), imatinib dose was reduced to 300 mg daily in 43 patients with chronic myeloid leukemia (CML) in sustained deep molecular response to first-line imatinib 400 mg daily. At the time of dose reduction, median duration of the deep response was 4.1 (interquartile range (IQR) 2.2–5.9) years; molecular response was MR4, MR4.5, and MR5 of the international scale in 6, 28, and 9 patients, respectively. Toxicity grade was 1, 2, and 3 in 28, 8, and 1 patients, respectively; 6 patients underwent dose reduction without having side effects. With a median of 1.6 (IQR 0.7–3.2) years on imatinib 300 mg daily, only one patient lost the deep molecular response to MR3. At the last follow-up, response was MR3, MR4, MR4.5, and MR5 in 1, 3, 9, and 30 patients, respectively. Toxicity improvement was observed in 23 (62.2 %) of the 37 patients with side effects, decreasing to grade 0 in 20 of them. All but one anemic patients improved (p = 0.01), the median Hb increase in this subgroup of patients being 1 g/dL. In CML patients with sustained deep response to the standard imatinib dose, reducing to 300 mg daily significantly improves tolerability and preserves efficacy.

The level of BCR-ABL1 reached after treatment with tyrosine kinase inhibitors is an effective marker of the therapeutic response and a good survival predictor in chronic myeloid leukemia (CML) patients. However, no agreement has yet been achieved about either the standardization of the technique to determine BCR-ABL1 or the interpretation of the results. The aim of this study was to compare the method currently recommended by the European Leukemia Net, which includes the application of a conversion factor to express the results in international scale, with an automated method (Xpert BCR-ABL™, Cepheid). BCR-ABL1 transcript quantification was performed in 117 samples from CML patients in two different laboratories by both methods, and the results were compared by statistical procedures. A high linear correlation was obtained in the results between the two methods. The concordance at logarithmic intervals reached 62 %. When the major molecular response (MMR) was analyzed, 85 % agreement was achieved. The automated method provides reproducible results and does not show significant differences compared with the traditional method. As a clinical tool, Xpert correctly classified the patients in MMR and can be considered a useful alternative for the molecular follow-up of CML patients.

Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood (PB) is increasingly selected as a source of stem cells for allogeneic transplantation.1 The shift from using bone marrow (BM) to PB stem cells is based on the faster haematological recovery and lower transplant-related mortality (TRM) in patients with advanced disease observed after transplantation with PB.2 However, it remains unclear whether the use of PB is associated with an increased incidence of acute graft-versus-host disease (GvHD). Several retrospective and randomized prospective studies comparing BM and PB found a similar incidence of acute GvHD,2, 3 except the European Group for Blood and Marrow Transplantation (EBMT) study, which seems to indicate that PB transplants are associated with an increased cumulative incidence of acute GvHD.4 This association was recently confirmed by a meta-analysis of nine randomized trials.5 Nevertheless, it seems clear that PB transplants have an increased risk of chronic GvHD.2, 3, 4, 5

We have analyzed the regulation and expression of ASPP members, genes implicated in the regulation of the apoptotic function of the TP53 tumor-suppressor gene, in acute lymphoblastic leukemia (ALL). Expression of ASPP1 was significantly reduced in ALL and was dependent on hypermethylation of the ASPP1 gene promoter. Abnormal ASPP1 expression was associated with normal function of the tumor-suppressor gene TP53 in ALL. The analyses of 180 patients with ALL at diagnosis showed that the ASPP1 promoter was hypermethylated in 25% of cases with decreased mRNA expression. Methylation was significantly higher in adult ALL vs childhood ALL (32 vs 17%, P¼0.03) and T-ALL vs B-ALL (50 vs 9%, P¼0.001). Relapse rate (62 vs 44%, P¼0.05) and mortality (59 vs 43%, P¼0.05) were significantly higher in patients with methylated ASPP1. DFS and OS were 32.8 and 33.7% for patients with unmethylated ASPP1 and 6.1 and 9.9% for methylated patients (Po0.001 y Po0.02, respectively). On the multivariate analysis, methylation of the ASPP1 gene promoter was an independent poor prognosis factor in ALL patients. Our results demonstrate that decreased expression of ASPP1 in patients with ALL is due to an abnormal methylation o

Increasing mixed chimerism (MC) after allogeneic stem cell transplantation (SCT) has been associated with a high risk of relapse in acute leukemia. We evaluated a new method for chimerism detection, based on the quantitative real-time PCR (qrt-PCR) amplification of null alleles or insertion/deletion polymorphisms (indels). All qrt-PCR assays with null alleles and indels attained a sensitivity of at least 10(-4), as well as good intra- and interassay concordance, and a high accuracy in experiments with cell mixtures. Informativeness was found in 80.3% of the 61 donor/recipient pairs tested. Nonrelapsed patients showed a progressive decrease in peripheral blood chimerism to values below 0.01% (complete chimerism (CC)). Bone marrow chimerism failed to reach CC more than 4 years after SCT. Increasing MC was observed prior to relapse in 88.2% of patients. Compared with conventional PCR amplification of variable number of tandem repeats, qrt-PCR predicted a significantly higher number of relapses (88.2 vs 44.4%) with a median anticipation period of 58 days. In conclusion, chimerism determination by qrt-PCR amplification of null alleles and indels constitutes a useful tool for the follow-up of patients with acute leukemia after SCT, showing better results than those obtained with conventional PCR.

Promoter hypermethylation and global hypomethylation are independent epigenetic events in lymphoid leukemogenesis with opposing effects on clinical outcome