Daniela Žáčková

Constant BCR-ABL transcript level ≥0.1% (IS) in patients with CML responding to imatinib with complete cytogenetic remission may indicate mutation analysis

OBJECTIVE Of 140 chronic myeloid leukemia patients responding to imatinib with complete cytogenetic remission, 32 exhibited a plateau of BCR-ABL values at >or=0.1% level in a minimum of three subsequent samples (minimal duration, 6 - 9 months). Median follow-up of unchanged BCR-ABL transcript level was 12 months (range, 6 - 64). We tested this group of patient for BCR-ABL mutations to reveal resistance development and to evaluate the risk of disease progression. MATERIALS AND METHODS Altogether, 134 samples of peripheral blood of these 32 patients were tested for mutation in BCR-ABL kinase domain. RESULTS Mutation was detected by direct sequencing in 9 of 32 patients (28%). Loss of complete cytogenetic remission or 1 log rise of BCR-ABL was observed in five of nine patients at a median of 5 months (range, 4-17) since first detection of mutation. One patient with no mutation relapsed 12 months after the start of the BCR-ABL plateau. In 5 of 32 patients without mutation (16%), BCR-ABL level significantly decreased after the first plateau to levels that stayed unchanged for a median of 11 months (range, 7-28). CONCLUSION We show here that the BCR-ABL constant levels >or=0.1% (BCR-ABL plateau) in imatinib-responding patients may indicate mutation analysis. This approach highly reduces the number of examinations for mutation in chronic myeloid leukemia responders and may present cost-effective alternative applicable in clinical practice.

Assessment of adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) mRNA expression in patients with de novo chronic myelogenous leukemia: the role of different cell types

In this study, we investigated differences in ABCB1 mRNA expression measured in peripheral blood (PB) leukocytes (LEU) as well as polymorphonuclear (PMNCs) and mononuclear cells (MNCs) of PB LEU obtained from healthy volunteers and patients with de novo CML. In addition, we analyzed the relationship between the percentage of individual cells that comprise the total LEU count and ABCB1 mRNA expression assessed from the total LEU. We have shown that ABCB1 mRNA transcript levels are significantly higher in PB MNCs than in PB PMNCs and are lower in patients with de novo CML compared to healthy individuals. Moreover, we have demonstrated the importance of the cell composition of analyzed samples in ABCB1 mRNA expression analysis.

Estimation of current cumulative incidence of leukaemia-free patients and current leukaemia-free survival in chronic myeloid leukaemia in the era of modern pharmacotherapy

BackgroundThe current situation in the treatment of chronic myeloid leukaemia (CML) presents a new challenge for attempts to measure the therapeutic results, as the CML patients can experience multiple leukaemia-free periods during the course of their treatment. Traditional measures of treatment efficacy such as leukaemia-free survival and cumulative incidence are unable to cope with multiple events in time, e.g. disease remissions or progressions, and as such are inappropriate for the efficacy assessment of the recent CML treatment.MethodsStandard nonparametric statistical methods are used for estimating two principal characteristics of the current CML treatment: the probability of being alive and leukaemia-free in time after CML therapy initiation, denoted as the current cumulative incidence of leukaemia-free patients; and the probability that a patient is alive and in any leukaemia-free period in time after achieving the first leukaemia-free period on the CML treatment, denoted as the current leukaemia-free survival. The validity of the proposed methods is further documented in the data of the Czech CML patients consecutively recorded between July 2003 and July 2009 as well as in simulated data.ResultsThe results have shown a difference between the estimates of the current cumulative incidence function and the common cumulative incidence of leukaemia-free patients, as well as between the estimates of the current leukaemia-free survival and the common leukaemia-free survival. Regarding the currently available follow-up period, both differences have reached the maximum (12.8% and 20.8%, respectively) at 3 years after the start of follow-up, i.e. after the CML therapy initiation in the former case and after the first achievement of the disease remission in the latter.ConclusionsTwo quantities for the evaluation of the efficacy of current CML therapy that may be estimated with standard nonparametric methods have been proposed in this paper. Both quantities reliably illustrate a patients disease status in time because they account for the proportion of patients in the second and subsequent disease remissions. Moreover, the model is also applicable in the future, regardless of what the progress in the CML treatment will be and how many treatment options will be available, respectively.

Treatment of chronic myeloid leukemia with autologous transplantation using peripheral blood stem cells or bone marrow cultured in IL-2 followed by IL-2, GM-CSF, and IFN-alpha administration.

Interleukin-2 (IL-2) is able to generate nonspecific cytotoxic effectors from hematopoietic precursors. We evaluated the feasibility and efficacy of chronic myeloid leukemia (CML) treatment with autologous hematopoietic stem cell transplantation (HSCT) using grafts cultured in IL-2 followed by immunotherapy with IL-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon (IFN)-α. Eight patients with CML were enrolled: five in an accelerated phase and three in a chronic phase. They received peripheral blood stem cells (PBSC) or bone marrow (BM) cultured in a medium containing IL-2 for 24 h. A median of 1.29 × 106 CD34+ cells/kg were infused after conditioning with busulfan (12–16 mg/kg) in PBSC recipients. BM was infused without prior myeloablative therapy. The engraftment occurred with a median of 15 d. Engraftment failure developed in one patient. The transplantation was followed by a 1-mo regimen of IL-2 (0.5 × 106 IU/m2 daily) and GM-CSF, and 6 mo of IFN-α. One complete and one transient minor cytogenetic remission were observed. At 24 mo after transplantation, two patients had died of progressive disease and one of infection. Five patients had stable disease in the chronic phase. Autologous transplantation using IL-2-activated graft is feasible and the subsequent IL-2, GM-CSF, and IFN-α administration has acceptable toxicity. However, no benefits in comparison with conventional autologous transplantation for CML were identified in our study.

Evaluation of 5-year imatinib treatment of 458 patients with CP-CML in routine clinical practice and prognostic impact of different BCR-ABL cutoff levels

We evaluated responses to the treatment and long‐term outcomes of chronic myeloid leukemia patients treated with imatinib as first‐line treatment in routine clinical setting from two countries with centralized tyrosine kinase inhibitors (TKIs) treatment. We assessed prognostic significance of European LeukemiaNet (ELN) 2006‐ and 2009‐defined responses and the prognostic value of molecular responses at defined time points on 5‐year survivals. Among the cumulative rates of incidence of hematologic, cytogenetic, and molecular responses and all important survival parameters, we evaluated the prognostic significance of different BCR‐ABL transcript‐level ratios (≤1%; >1%–≤10%; >10%) at 3, 6, 12, and 18 months (n = 199). The ELN optimal response criteria and their predictive role were significantly beneficial for event‐free survival at all given time points. We found significant improvement in survivals of patients with BCR‐ABL lower than 10% in the 6th and 12th months. Significantly better outcome was found in patients who achieved major molecular response (MMR) in the 12th month. The cumulative incidences of complete cytogenetic response (CCyR) and MMR were significantly associated with the molecular response in the 3rd month. The ELN response criteria and their predictive role were helpful at given time points; however, the 2009 definition did not significantly alter the prognostic accuracy compared with that of the 2006 definition. The significant value was observed for cytogenetic responses at the 6th and 12th month. Moreover, progression‐free and event‐free survivals were improved with MMR at the 12th month.

The effect of imatinib treatment duration on the quality of the life of patients with chronic myeloid leukemia

Purpose: The objective of this study was to evaluate the quality of life (QL) as well as the frequency and severity of depression in patients with chronic phase chronic myeloid leukemia (CP-CML) in relation to the duration of Imatinib treatment. Methods: A detailed analysis of 56 adult patients with CP CML divided into groups according to the length of Imatinib treatment was performed as follows: Group A (n=28)- patients treated for 15 months (median); and Group B (n=28)-patients treated for 50 months (median). All used questionnaires EORTC QLQ-C30 (version 2), SF 36 and BDI were localized and validated. Results: The results from the QL questionnaires found a trend in the improvement in the QL of patients treated with Imatinib for 50 months (median) compared to patients treated for 15 months (median) only. However, a statistically significant improvement in the QL of patients with longer Imatinib treatment was found only in patients without co-existing invalidity and/or rheumatic disease. Moreover, these two comorbidities increased the level of depressive symptoms in patients with CML during the early period of Imatinib therapy. Conclusion: We found a trend in the improvement in the QL of patients with CML in relation to the duration of Imatinib therapy. Statistically significant improvement in the QL of patients with longer Imatinib treatment was found in patients without co-existing invalidity and/or rheumatic disease only.

Efficacy and tolerance of dasatinib after imatinib failure or intolerance for patients with chronic myeloid leukemia treated in three different hospitals compare well with results achievable in formal clinical trials.

Efficacy and tolerance of dasatinib after imatinib failure or intolerance for patients with chronic myeloid leukemia treated in three different hospitals compare well with results achievable in formal clinical trials. Efficacy and tolerance of dasatinib after imatinib failure or intolerance for patients with chronic myeloid leukemia treated in three different hospitals compare well with results achievable in formal clinical trials.