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Background: To evaluate the outcomes of first-line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML-CP) in real-world clinical practice., Methods: A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated., Results: Nilotinib-treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib-treated patients. However, there was no significant difference in 5-year overall survival (OS) or progression-free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib-treated patients had a higher failure-free survival (FFS) and event-free survival (EFS) than imatinib-treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025)., Conclusions: This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Therapeutic options used to be very limited for treatment-naïve elderly/comorbid patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) before the introduction of chemo-immunotherapy. Because dose-reduced fludarabine-based regimens yielded promising results, the Czech CLL Study Group initiated a prospective observational study to assess safety and efficacy of low-dose fludarabine and cyclophosphamide combined with rituximab (FCR) in elderly/comorbid patients. Between March 2009 and July 2012, we enrolled 107 patients considered ineligible for full-dose FCR (median age, 70 years; median Cumulative Illness Rating Scale score, 5; median creatinine clearance, 69 ml/min). Notably, 77% patients had unfavourable biological prognosis [unmutated immunoglobulin heavy-chain variable-region gene (IGHV), 74%; deletion 17p, 9%). Fludarabine was reduced to 12 mg/m 2 intravenously (iv) or 20 mg/m 2 orally on days 1-3 and cyclophosphamide to 150 mg/m 2 iv/orally on days 1-3. Grade 3-4 neutropenia occurred in 56% of the patients, but there were serious infections in only 15%. The median progression-free survival was 29 months, but was markedly longer in patients with mutated IGHV (median 53 months), especially in absence of del 11q or 17p (median 74 months). Low-dose FCR is a well-tolerated and effective first-line regimen for selected elderly/comorbid patients with CLL/SLL with favourable biology. The study was registered at clinicaltrials.gov (NCT02156726)., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

We retrospectively evaluated the role of age and dosage in 372 CML patients (170 women, 202 men) treated with first-line imatinib (IMA) from the records of the CAMELIA registry. The median follow-up of the patients was 82.3 (18.0-177.3) months. The treatment results of 80 elderly patients aged over 65 years at diagnosis were compared in analysis "A" with those of 292 younger patients and in analysis "B" with those of 90 patients younger than 40 and 202 patients aged 40-64. The elderly patients had statistically adverse values of the Sokal, ELTS, and ECOG scores and Charlson comorbidity index in both analyses (p from = 0.012 to ≤ 0.001). Despite a more frequent use of a daily dose lower than 400 mg - in 31 elderly patients (38.8%) than in 45 younger ones (15.4%) (p < 0.001), there were no statistically significant differences in the achievement of optimal haematological, cytogenetic, and molecular responses according to the ELN criteria in both the analyses, A and B. The comparisons of overall survival with CML-related death (OS CML ) and event-free survival (EFS) were insignificant inanalysis A (p = 0.07 and 0.396, respectively) but progression-free survival (PFS) differed significantly (p = 0.007). In analysis B OS CML and PFS differed significantly (p = 0.027 and 0.003) but EFS was similar (p = 0.351). Elderly patients with a sustained dose of IMA of 400 mg/day have insignificantly better OS, PFS, and EFS compared to patients treated with a lower dosage of IMA. The results in the treatment of the elderly CML patients were comparable with those of the younger ones in terms of the probabilities of the achievement of optimal ELN responses. However, the results for the survival probabilities were influenced by age and the IMA dosage., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Chemoimmunotherapy with bendamustine and rituximab is an alternative treatment for elderly patients with CLL. The aim of this observational multicenter study was to prospectively assess efficacy and safety of bendamustine and rituximab in front-line therapy in patients with CLL and significant comorbidities in real hematological practice. Eighty-three consecutive patients with cumulative illness rating scale (CIRS) >6 who received at least one cycle of BR as first-line treatment were included in the study. The median age was 71 years (range, 53-83), the median CIRS was 8 (range, 7-17), and 60.2% of patients had a creatinine clearance ≤70 mL/min. FISH analysis, available for 78 cases, showed a del(17p) in 11.5% and del(11q) in 20.5% of patients. Overall response rate was 88.0% with a complete response rate of 20.5%. With median follow-up time of 22 months, the estimated median progression free survival was 35.9 months. Progression free survival and overall survival rates at 2 years were 69.9% and 96.2%, respectively. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 40 (48.2%), 14 (16.9%), and 8 (9.6%) patients, respectively. Grade 3 or 4 infections occurred in 14.5% of patients. Chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities. ClinicalTrials.gov Identifier: NCT02381899., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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 × 10(9)/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 JAK2(V617F) 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., (© 2015 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)

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., (Copyright © 2013 Wiley Periodicals, Inc.)

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.

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., (© 2011 John Wiley & Sons A/S.)

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., (© 2011 John Wiley & Sons A/S.)

Interphase fluorescence in situ hybridization was used to detect common deletions in B-CLL patients as well as trisomy 12 and aberrations of IgH gene complex at 14q32.33 where we evaluated not only translocation-like signal pattern but also deletions. 120 (82%) patients showed genetic changes - del(13)(q14) 95 (62%), deletion of ATM gene 22 (15%), deletion of p53 gene 25 (17%) and trisomy 12 was proved in 18 (12%) cases. IgH rearrangements were detected in 45 (31%), split of the signals in 11 (8%), deletion of 3' segment flanking IgH gene in 5 (3%) and deletions of variable segment in 29 (20%) patients. Although deletions of 3' segment flanking IgH gene complex are supposed to have an adverse prognostic impact and the genetic background of variable segment deletions is believed to be most probably physiological, we assumed a detailed mapping of the 14q32.33 region will be needed to unravel these mysteries.

B-chronic lymphocytic leukemia (B-CLL) is the most common adult leukemia. Molecular genetic characterization of B-CLL has made significant progress and typical chromosomal anomalies have been assessed. The most frequent chromosomal abnormalities are deletions at 13q14, 17p13, and 11q22 approximately q23 and trisomy 12. The aim of this study was to establish incidence of chromosomal changes in bone marrow or peripheral blood cells (or both) of B-CLL patients using a molecular cytogenetic method, interphase fluorescence in situ hybridization (I-FISH), and to evaluate the prognostic implications. We performed I-FISH on bone marrow and blood smears from 217 B-CLL patients (124 male, 93 female). Trisomy 12 was found in 35 of the 217 (16%); deletion 13q14 was analyzed in 207 patients and found in 112 (54%). Deletion 17p13 was found in 34 (16%) out of 206 examined. Deletion of 11q23 was analyzed in 56 patients and was present in 7 (12%). Statistical analyses were performed to correlate the molecular-cytogenetic findings with disease status (stable versus progressive), Rai stage, CD38/CD19 antigen coexpression, immunoglobulin variable heavy chain (IgV(H)) mutational pattern, and other clinical and laboratory parameters. No apparent differences in distribution were noted for anomalies +12, del(13)(q14), or del(17)(p13) among patients with stable and progressive disease, and no consistent pattern in the distribution of type of genomic changes were found among various Rai stages and in CD38/CD19-positive or -negative patients. Patients without IgV(H) mutation had a worse prognosis; however, distribution of chromosomal abnormalities identified with FISH was the same for patients with and without IgV(H) mutations.

Background: The B-chronic lymphocytic leukemia (B-CLL) has highly variable prognosis. Possibility of more relevant prognosis has a great impact for the beginning and mode of therapy., Methods and Results: One hundred patients diagnosed as having B-CLL were included into the study. Beside usual examinations necessary to establish the diagnosis, cytogenetic examination for the detection of deletion 13q14, 17p13, 11q23 and trisomy 12 and immunophenotyping was done. The mean age of the patients was 58.2 years, there were 62 men and 38 women. 91 evaluated patients were divided into two groups--those with the steady disease (55 pts) and those with progressive disease (36 pts). No relation between the number of cytogenetic abnormalities and the Rai stage of the disease was found. We identified a relation between the bone marrow infiltration pattern (diffuse) and the number of cytogenetic abnormalities and the del 13q14 (p.05). Using the immunophenotyping of the lymphocytes we found a relation between the expression of CD38 and CD11c and the disease progression (p < 0.05). Neither of the method (FISH and immunophenotyping) revealed differences between results from bone marrow samples and those from peripheral blood., Conclusions: Though the cytogenetic (FISH) and immunophenotype evaluation at the time of diagnosis did not improve the ability to define better the clinical course of the B-CLL, we suggest to use both methods routinely as an important tool to identify patients who would develop the progressive disease.

A number of prognostic scoring systems for patients with myelodysplastic syndrome (MDS) have been introduced since FAB classification of the MDS in 1982. Recently, the International Prognostic Scoring System (IPSS), published in 1997 by Greenberg et al. [9] is based on the percentage of bone marrow (BM) blasts, cytogenetic abnormalities and number of cytopenias. We applied criteria of the IPSS on 205 patients (pts) with primary MDS (RA = 82, RARS = 49, RAEB = 42, RAEB-t = 8, CMML = 24 pts). IPSS discriminated within each of the FAB-subgroups: RA pts were present in low risk and intermediate (Int) I and II risk subgroups, RARS pts were separated into low and Int I, RAEB were distributed predominantly between Int I and Int II risk groups, RAEB-t in high-risk group, and CMML pts were distributed in all groups. In contrary to Greenberg's group of the MDS patients there are only three risk-groups in our study: low risk (score 0-0.5), intermediate (1-2) and high risk (> 2); the median survival and the risk of the evolution to the acute leukemia (p = 0.0001) are significantly different.

Background: B-chronic lymphocytic leukemia (B-CLL) is the most common adult leukemia in the Western countries. Any routinely used staging system does not distinguish exactly the probable course of the disease at the time of diagnosis. Therefore the new prognostic factors, which help to assess the optimal therapeutic plan of patients, are searched intensively., Methods and Results: We evaluated 154 patients with the B-CLL at the time of diagnosis--133 of them were retrospectively divided into two groups--one with stable form and the other with progressive form of the disease. We compared these two groups of patients with some of the prognostic factors (absolute lymphocyte count, the level of C-reactive protein, lactatdehydrogenase, beta-2-microglobulin, tumour necrosis factor, the immunoglobulin levels, the expression of CD38, FMC7, surface immunoglobulins, the type of bone marrow infiltration, and the cytogenetic abnormalities (trisomy 12, del(13)(q14), del(17)(p13) a del(11)(q23)). We found higher absolute lymphocyte count, level of beta-2-mikroglobulin, tumour necrosis factor, expression of CD38, light chains lambda, lower expression of FMC7 and less frequent nodular type of bone marrow infiltration by the patients with progressive disease. The correlation of the cytogenetic abnormalities and the course of the disease or stage according to the RAI et al. [27] staging system were not significant may be due to the small number of evaluated patients and short period of follow up., Conclusion: The routine evaluation of some risk factors in patients with B-chronic lymphocytic leukemia at the time of diagnosis helps to distinguish those with the probable more aggressive course of the disease and have the implication for the design of risk-adapted treatment strategies. The prognostic impact of the cytogenetic abnormalities and other risk factors has to be evaluated on larger group of patients during longer follow up period and repeated evaluations.

Background: Trisomy 12 was found to be the most frequent chromosomal aberration identified by conventional cytogenetic studies of bone marrow cells and peripheral lymphocytes of patients with CLL. Molecular-cytogenetic techniques which enable examination of dividing and/or non-diving interphase nuclei (I-FISH), proved existence of other chromosomal abnormalities, mainly deletions, which could have in CLL patients relation to the origin, course and prognosis of the disease., Methods and Results: During the last two years bone marrow chromosomes of all patients with CLL were examined by G-banding and by I-FISH. The numerical changes of chromosome 12 were followed by centromeric DNA probe in dividing and non-dividing cells. The small deletions were ascertained by locus specific probes for 13q14 (Rb gene), 17p13 (p53 protein) and 11q23 (MLL gene). These genes are responsible for cell division and their function is probably in connection with neoplastic process. It is of interest whether numerical and structural chromosomal rearrangements are primary or secondary changes and what is their impact on etiology of CLL. 93 patients were examined by DNA prove CEP12 and trisomy 12 was found in 24 of them (25.8%), the range of the clone was 2.5-75.5% of the screened cells. Deletion del(13)(q14) was examined by probe D13S319 in 73 patients and proved in 24 of them (32.8%), pathological clone ranged 2.5-80.0% of the cells. Deletion del(17)(p13) was found in 14 patients out of 61 examined by probe LSI p53 (22.9%). The extent of the clone was 2.5-34.0% of examined cells. Deletion 11q23 was not ascertained in any of 11 patients by means of probe LSI 11q23 (MLL). All probes used for FISH were manufactured by VYSIS., Conclusions: FISH is very sensitive method, suitable for molecular-cytogenetic examination of leukemic patients. With I-FISH the deletion of 13q14 was ascertained as the most frequent chromosomal aberration in series of 73 patients with CLL. We continue to increase the number of patients screened by I-FISH with all eligible DNA probes and start the prospective study on patients with chromosomal pathology. We will correlate the immunophenotype, morphology, clinical course and prognosis with karyotypic findings.