Eduard Cmunt

Treatment of consecutive patients with chronic myeloid leukaemia in the cooperating centres from the Czech Republic and the whole of Slovakia after 2000 – a report from the population‐based CAMELIA Registry

Background: Most results on the treatment of chronic myeloid leukaemia (CML) with imatinib were obtained from clinical trials that may differ from the routine practice. We report the results of treatment of consecutive patients with CML at ten major centres during 2000–2008. Patients and methods: Data reporting was retrospective in 2000–2004 and prospective from 2005 on. A total of 661 patients [301 women and 360 men; median age 51 (range, 15–83)] with Ph + CML were registered. The median follow‐up was 46.1 months (0–122.2). Results: Most patients were treated with first‐ (379; 57.3%) or second‐line (193; 29.2%) imatinib; some of the patients underwent allogeneic hematopoietic stem cell transplantation (AHSCT) (83; 12.6%), but 6.1% were treated with other modalities [40 patients; median age 66 (range, 32–83)]. The probability of overall survival (OS) at 5 years, according to Kaplan and Meier, was 88.9%, 77.5% and 68.7% for chronic‐phase patients treated with first‐line imatinib, second‐line imatinib and first‐line AHSCT, respectively, but only 25.2% for patients receiving other modalities. The OS was dependent on the disease phase and Sokal, Hasford and European group for blood and marrow transplantation (EBMT) risk scores (P < 0.001; each). Only 46.2% of deaths in patients treated with other modalities were attributable to CML. Elderly patients over 65 years achieved similar response rates and progression‐free survival to the younger ones. There was a trend for inferior results of AHSCT performed after the failure of imatinib (P = 0.075), probably as a result of differences in EBMT risk scores (P < 0.001). Conclusions: The ability to achieve results comparable to those of previous clinical studies in our CML cohort was influenced by centralised care. Decisions not to initiate imatinib or to delay AHSCT may have a negative impact on OS, but comorbidities may limit the treatment potential of imatinib in the elderly.

Modern and conventional prognostic markers of chronic lymphocytic leukaemia in the everyday haematological practice

Objectives: The impact of modern prognostic markers on clinical course of chronic lymphocytic leukaemia (CLL) in everyday practice has been not yet well defined, especially in large series of patients. Therefore, the goal of this study was to assess the influence of conventional as well as modern prognostic factors on overall survival (OS) and time to therapy (TTT) of patients with CLL. Methods: We retrospectively analysed data of all patients consecutively entered into the databases of five large academic centres in the Czech Republic. The total of 1300 patients was included in the analysis. Results and conclusion: Through the use of uniparametric analysis, it was determined that gender, clinical stage Rai II–IV, unmutated IgVH status, deletion 17p (for both 5% and 20% cut‐off), deletion 11q, ZAP‐70 positivity and high expression of CD38 had significant negative influence on OS. TTT was significantly influenced by gender, Rai stage, IgVH status, deletion 11q, deletion 17p, deletion 13q and CD38 expression. Multiparametric analysis revealed that OS was significantly influenced by gender, age, IgVH status and deletion 17p. If only patients who died of CLL were included, gender, age, Rai stage, IgVH status and deletion 17p had significant influence on OS. Based on our results, the examination of biological prognostic markers can give an insight into the possible disease evolution in daily clinical practice. Biological prognostic markers are, however, not ready (maybe except deletion 17p in younger patients) to be used for guidance of therapy at least outside of clinical trials.

Thrombosis in thrombocythemic Ph-myeloproliferations is associated with higher platelet count prior to the event: results of analyses of prothrombotic risk factors from a registry of patients treated with anagrelide

Controversies still exist regarding definition of the thrombotic risks in Ph‐ (BCR/ABL1‐) myeloproliferative disorders with thrombocythemia (MPD‐T). Platelet counts at diagnosis are currently not taken as a risk factor of thrombosis. In our cohort of 1179 patients with MPD‐T, prospectively registered for anagrelide treatment, we found that the median platelet count prior to the thrombotic event was significantly higher than at time points without any ensuing thrombosis (453 vs. 400 × 109/L, P < 0.001), albeit higher platelet counts at diagnosis tended to be connected with fewer thrombotic events (in contrast to WBC counts at diagnosis). The JAK2V617F mutation predicted both arterial and venous events, while age >65 yr, hypertension, diabetes mellitus, smoking, elevated triglyceride and homocysteine levels predicted arterial events only. For venous events, the specific thrombophilic risk factors (factor V ‘Leiden’ and others), antiphospholipid antibodies, and elevated factor VIII levels played a major role. During anagrelide treatment (± aspirin), we documented a decrease in both venous (6.7‐fold) and arterial events (1.8‐fold), while bleeding (mostly minor events) increased twofold compared to history. Our results suggest that keeping platelet counts at low levels may be a meaningful therapeutic measure to prevent thrombosis, although their counts at diagnosis lack any prognostic value.

Current survival measures reliably reflect modern sequential treatment in CML: Correlation with prognostic stratifications

Using the data of 723 chronic myeloid leukemia (CML) patients in the chronic phase, we analyzed the prognostic value of the Sokal, Euro, and EUTOS scores as well as the level of BCR‐ABL1 and the achievement of complete cytogenetic response (CCgR) at 3 months of imatinib therapy in relation to the so‐called current survival measures: the current cumulative incidence (CCI) reflecting the probability of being alive and in CCgR after starting imatinib therapy; the current leukemia‐free survival (CLFS) reflecting the probability of being alive and in CCgR after achieving the first CCgR; and the overall survival. The greatest difference between the CCI curves at 5 years after initiating imatinib therapy was observed for the BCR‐ABL1 transcripts at 3 months. The 5‐year CCI was 94.3% in patients with BCR‐ABL1 transcripts ≤ 10% and 57.1% in patients with BCR‐ABL1 transcripts > 10% (P = 0.005). Therefore, the examination of BCR‐ABL1 transcripts at 3 months may help in early identification of patients who are likely to perform poorly with imatinib. On the other hand, CLFS was not significantly affected by the considered stratifications. In conclusion, our results indicate that once the CCgR is achieved, the prognosis is good irrespective of the starting prognostic risks. Am. J. Hematol. 88:790–797, 2013.

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.

Lenalidomide treatment in lower risk myelodysplastic syndromes—The experience of a Czech hematology center. (Positive effect of erythropoietin ± prednisone addition to lenalidomide in refractory or relapsed patients)

Lenalidomide therapy represents meaningful progress in the treatment of anemic patients with myelodysplastic syndromes with del(5q). We present our initial lenalidomide experience and the positive effect of combining erythropoietin and steroids with lenalidomide in refractory and relapsed patients. We treated by lenalidomide 55 (42 female; 13 male; median age 69) chronically transfused lower risk MDS patients with del(5q) (45) and non-del(5q) (10). Response, meaning transfusion independence (TI) lasting ≥ eight weeks, was achieved in 38 (90%) of analyzed patients with del(5q), of whom three achieved TI only by adding erythropoietin ± prednisone. Another five patients responded well to this combination when their anemia relapsed later during the treatment. In the non-del(5q) group only one patient with RARS-T reached TI. Cytogenetic response was reached in 64% (32% complete, 32% partial response). The TP53 mutation was detected in 7 (18%) patients; four patients progressed to higher grade MDS or acute myeloid leukemia (AML). All seven RAEB-1 patients cleared bone marrow blasts during lenalidomide treatment and reached complete remission (CR); however, three later progressed to higher grade MDS or AML. Lenalidomide represents effective treatment for del(5q) group and combination with prednisone and erythropoietin may be used for non-responders or therapy failures.