De novo accelerated phase of chronic myeloid leukemia should be recognized even in the era of tyrosine kinase inhibitors.

Overall survival of patients classified according to the European LeukemiaNet 2020 classification. Chronic phase (CP), accelerated phase (AP), blast crisis (BC), low risk (LR), intermediate risk (IR), high risk (HR).

COVID-19 in patients with chronic lymphocytic leukemia: a multicenter analysis by the Czech CLL study group.

Patients with chronic lymphocytic leukemia (CLL) have a high risk of poor outcomes related to coronavirus disease 2019 (COVID-19). This multicenter cohort study evaluated the impact of COVID-19 infection on the population of CLL patients in the Czech Republic. Between March 2020 and May 2021, 341 patients (237 males) with CLL and COVID-19 disease were identified. The median age was 69 years (range 38-91). Out of the 214 (63%) patients with the history of therapy for CLL, 97 (45%) were receiving CLL-directed treatment at diagnosis of COVID-19: 29% Bruton tyrosine kinase inhibitor (BTKi), 16% chemoimmunotherapy (CIT), 11% Bcl-2 inhibitor, and 4% phosphoinositide 3-kinase inhibitor. Regarding the severity of COVID-19, 60% pts required admission to the hospital, 21% pts were admitted to the intensive care unit (ICU), and 12% received invasive mechanical ventilation. The overall case fatality rate was 28%. Major comorbidities, age over 72, male gender, CLL treatment in history, CLL-directed treatment at COVID-19 diagnosis were associated with increased risk of death. Of note, concurrent therapy with BTKi compared to CIT was not associated with better outcome of COVID-19.

Successful early use of anti-SARS-CoV-2 monoclonal neutralizing antibodies in SARS-CoV-2 infected hematological patients - A Czech multicenter experience.

COVID-19 significantly impairs survival rates among hematological patients when compared to the general population. Our prospective multicentre project analyzed early administration of anti-SARS-CoV-2 spike protein neutralizing monoclonal antibodies (NmAbs) - bamlanivimab (72%) and casirivimab/imdevimab (28%) - efficacy among hematological patients with early-stage COVID-19. Mortality rate was compared to a control cohort of 575 SARS-CoV-2 positive hematological patients untreated with any specific anti-COVID-19 therapy. 88 hematological patients with lymphomas, acute leukemias, and myeloma as their most frequent underlying diagnoses (72%) were evaluated with a 97 days median follow-up after NmAb administration. One third of patients (32%) were treated with an anti-CD20 monoclonal antibody before COVID-19 diagnosis. Median time between first COVID-19 symptom and NmAb administration was 2 days. When administering NmAb, 29%, 57%, 11%, 2%, and 1% of our patients had asymptomatic, mild, moderate, severe, and critical degrees of COVID-19, respectively. 80% of baseline asymptomatic patients remained asymptomatic following NmAb administration. Median duration of COVID-19 symptoms after NmAb administration was 2.5 days. Progression to severe/critical COVID-19 occurred among a total of 17% (15/88) of our cases and numerically higher with bamlanivimab versus casirivimab/imdevimab (21% vs. 8%; p = 0.215), and myelomas (29%), lymphomas (17%) and acute leukemias (18%), respectively. During final follow-up, nine deaths (10%) were recorded - all after bamlanivimab (p = 0.056) with 8% attributed to COVID-19. Regarding "remdesivir/convalescent plasma naïve" patients, COVID-19 mortality rates were significantly lower in our NmAbs treated cohort compared to the control cohort of untreated SARS-CoV-2 positive hematological patients (6% vs. 16%, p = 0.020), respectively. Our study validated the safety and efficacy of NmAbs early use among hematological patients with newly diagnosed early-stage COVID-19 in terms of alleviating infection course and decreasing mortality. Results confirmed a more positive effect of a casirivimab/imdevimab combination versus bamlanivimab monotherapy.

Hierarchical distribution of somatic variants in newly diagnosed chronic myeloid leukaemia at diagnosis and early follow-up.

There is an emerging body of evidence that patients with chronic myeloid leukaemia (CML) may carry not only breakpoint cluster region-Abelson murine leukaemia viral oncogene homologue 1 (BCR-ABL1) kinase domain mutations (BCR-ABL1 KD mutations), but also mutations in other genes. Their occurrence is highest during progression or at failure, but their impact at diagnosis is unclear. In the present study, we prospectively screened for mutations in 18 myeloid neoplasm-associated genes and BCR-ABL1 KD in the following populations: bulk leucocytes, CD34+ CD38+ progenitors and CD34+ CD38- stem cells, at diagnosis and early follow-up. In our cohort of chronic phase CML patients, nine of 49 patients harboured somatic mutations in the following genes: six ASXL1 mutations, one SETBP1, one TP53, one JAK2, but no BCR-ABL1 KD mutations. In seven of the nine patients, mutations were detected in multiple hierarchical populations including bulk leucocytes at diagnosis. The mutation dynamics reflected the BCR-ABL1 transcript decline induced by treatment in eight of the nine cases, suggesting that mutations were acquired in the Philadelphia chromosome (Ph)-positive clone. In one patient, the JAK2 V617F mutation correlated with a concomitant Ph-negative myeloproliferative neoplasm and persisted despite a 5-log reduction of the BCR-ABL1 transcript. Only two of the nine patients with mutations failed first-line therapy. No correlation was found between the mutation status and survival or response outcomes.

Low-dose fludarabine and cyclophosphamide combined with rituximab in the first-line treatment of elderly/comorbid patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL): long-term results of project Q-lite by the Czech CLL Study Group.

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/m2 intravenously (iv) or 20 mg/m2 orally on days 1-3 and cyclophosphamide to 150 mg/m2 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).

Survival benefit of ixazomib, lenalidomide and dexamethasone (IRD) over lenalidomide and dexamethasone (Rd) in relapsed and refractory multiple myeloma patients in routine clinical practice.

BACKGROUND: We have performed a head to head comparison of all-oral triplet combination of ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and refractory multiple myeloma (RRMM) in the routine clinical practice. METHODS: A total of 344 patients treated with IRD (N = 127) or RD (N = 217) were selected for analysis from the Czech Registry of Monoclonal Gammopathies (RMG). Descriptive statistics were used to assess patient's characteristics associated with the respective therapy. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS). Survival endpoints were plotted using Kaplan-Meier methodology at 95% Greenwood confidence interval. Univariable and multivariable Cox proportional hazards models were used to evaluate the effect of treatment regimens and the significance of uneven variables. Statistical tests were performed at significance level 0.05. RESULTS: In the whole cohort, median PFS for IRD was 17.5 and for RD was 11.5 months favoring the all-oral triplet, p = 0.005; in patients within relapse 1-3, the median PFS was 23.1 vs 11.6 months, p = 0.001. The hazard ratio for PFS was 0.67 (95% confidence interval [CI] 0.51-0.89, p = 0.006). The PFS advantage translated into improved OS for patients treated with IRD, median 36.6 months vs 26.0 months (p = 0.008). The overall response rate (ORR) was 73.0% in the IRD group vs 66.2% in the RD group with a complete response rate (CR) of 11.1% vs 8.8%, and very good partial response (VGPR) 22.2% vs 13.9%, IRD vs RD respectively. The IRD regimen was most beneficial in patients ≤75 years with ISS I, II, and in the first and second relapse. Patients with the presence of extramedullary disease did not benefit from IRD treatment (median PFS 6.5 months). Both regimens were well tolerated, and the incidence of total as well as grade 3/4 toxicities was comparable. CONCLUSIONS: Our analysis confirms the results of the TOURMALINE-MM1 study and shows benefit of all-oral triplet IRD treatment versus RD doublet. It demonstrates that the addition of ixazomib to RD improves key survival endpoints in patients with RRMM in a routine clinical setting.

Bortezomib-based therapy for newly diagnosed multiple myeloma patients ineligible for autologous stem cell transplantation: Czech Registry Data.

OBJECTIVES: This study compared the use of bortezomib in different combination regimens in newly diagnosed multiple myeloma (NDMM) patients who were transplant ineligible. PATIENTS AND METHODS: We analyzed data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group (CMG) to provide real-world evidence of outcome for 794 newly diagnosed MM transplant ineligible patients. The most frequently used regimen was VCd (bortezomib-cyclophosphamide-dexamethasone) (47.5%) over VMP (bortezomib-melphalan-prednisone) (21.7%), BDd (bortezomib-doxorubicin-dexamethasone) (9.8%), and VTd (bortezomib-thalidomide-dexamethasone) (2.9%). RESULTS: The overall response rate (ORR) was 69.2% (478/691), including 12.6% (≥ CR); 34.7% very good partial responses (VGPR); and 21.9% partial responses (PR). Among triplet regimens, VMP was the most effective regimen compared to VCd, BDd, and VTd. Median PFS was 22.3 vs. 18.5 vs. 13.7 vs. 13.8 mo, (P = .275), respectively, and median OS was 49 vs. 41.7 vs. 37.9 vs. 32.2 mo (P = .004), respectively. The most common grade 3-4 toxicities were anemia in 17.4% and infections in 18% of patients. CONCLUSION: Our study confirmed that bortezomib-based treatment is effective and safe in NDMM transplant ineligible patients, especially VMP, which was identified as superior between bortezomib-based induction regimens not only in clinical trials, but also in real clinical practice.

Identification of patients with smouldering multiple myeloma at ultra-high risk of progression using serum parameters: the Czech Myeloma Group model.

Smouldering multiple myeloma (SMM) presents without MM defining symptoms. We aimed to identify patients with SMM with an 80% risk of progression within 2 years using only serum parameters. In total, 527 patients with SMM were included and divided into a training group (287 patients from the Czech Myeloma Group [CMG]) and an independent validation group (240 patients from Heidelberg). The median follow-up was 2·4 and 2·5 years, respectively. Progression to MM occurred in 51·9% of the CMG and 38·8% of the Heidelberg patients, respectively. The median risk of progression was 11·0% (CMG) and 9·7% (Heidelberg) per year, during the 5 years after diagnosis. A serum involved/uninvolved free light-chain ratio of >30, immunoparesis, and serum monoclonal (M) protein of ≥2·3 g/dl emerged as powerful predictors of 2-year progression rate with a hazard ratio (HR) of 2·49 (95% confidence interval [CI] 1·49-4·17), HR of 2·01 (95% CI 1·36-2·96) and HR of 2·00 (95% CI 1·44-2·79) (P < 0·001) in univariate Cox regression analysis, respectively. Based on this, the CMG model identified patients with SMM with a 2-year risk of progression of 78·7% (95% CI 53·1-95·7; HR 6·8; P < 0·001, CMG) and 81·3% (95% CI 47·1-98·8; HR 38·63; P < 0·001, Heidelberg). Serum parameters in the CMG model allow identification of patients with SMM with an 80% risk of progression to symptomatic MM within 2 years.

Clinical efficacy and safety of first-line nilotinib or imatinib therapy in patients with chronic myeloid leukemia-Nationwide real life data.

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.

Clinical characteristics and outcomes in risk-stratified patients with smoldering multiple myeloma: data from the Czech Republic Registry of Monoclonal Gammopathies.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor to active multiple myeloma (MM). The aim of this study was to report clinical characteristics and outcomes of patients with SMM stratified based on their risk of progression to MM using the Mayo 20/2/20 criteria. Data were leveraged from the Czech Myeloma Group Registry of Monoclonal Gammopathies (RMG). Key outcomes included progression-free survival from SMM diagnosis to active MM diagnosis or death (PFS), progression-free survival from SMM diagnosis to progression on first line (1 L) MM treatment or death (PFS2), and overall survival (OS). Of 498 patients, 174 (34.9%) were classified as high risk and 324 (65.1%) as non-high risk. Median follow-up was approximately 65 months. During follow-up, more patients in the high-risk vs non-high-risk group received 1 L MM treatment (76.4% vs 46.6%, p < 0.001). PFS, PFS2, and OS were significantly shorter in high-risk vs non-high-risk patients (13.2 vs 56.6 months, p < 0.001; 49.9 vs 84.9 months, p < 0.001; 93.2 vs 131.1 months, p = 0.012, respectively). The results of this study add to the growing body of evidence that patients with high-risk vs non-high-risk SMM have significantly worse outcomes, including OS.

Dasatinib treatment long-term results among imatinib-resistant/intolerant patients with chronic phase chronic myeloid leukemia are favorable in daily clinical practice.

To evaluate long-term real-life results of dasatinib therapy among chronic phase chronic myeloid leukemia patients resistant or intolerant to imatinib, we retrospectively analyzed data of 118 patients treated in centers participating in the database INFINITY. With median follow-up of 37 months, estimated 5-year cumulative incidences of complete cytogenetic and major molecular responses were 78% and 68%, respectively. The estimated 5-year probability of overall survival (OS) and event-free survival (EFS) were 86% and 83%, respectively. Both OS and EFS were significantly improved among patients with BCR-ABL1 transcript level ≤10% at 3 months. Dasatinib toxicity was tolerable however persistent in almost half our patients, even after years of therapy. Pleural effusion occurred in 29% of patients and was responsible for 30% of dasatinib discontinuations. Our results confirmed very good efficacy and acceptable toxicity of dasatinib in second line setting and support the evidence and importance of high-quality real-life CML patient management.

Validation of multiple myeloma risk stratification indices in routine clinical practice: Analysis of data from the Czech Myeloma Group Registry of Monoclonal Gammopathies.

This study used data from the Czech Myeloma Group Registry of Monoclonal Gammopathies to validate the International Myeloma Working Group (IMWG) and revised International Staging System (R-ISS) indices for risk stratification in patients with multiple myeloma (MM) in clinical practice. Patients were included if they had symptomatic MM, complete data allowing R-ISS and IMWG staging (including cytogenetic information regarding t(4;14), t(14;16), and del(17p)), and key parameters for treatment evaluation. Median overall survival (OS) in included patients (n = 550) was 47.7 (95% CI: 39.5-55.9) and 46.2 (95% CI: 38.9-53.5) months from diagnosis and initiation of first-line therapy, respectively. Patients categorized as higher vs lower risk had reduced survival; median OS from diagnosis was 35.4 (95% CI: 30.5-40.3) vs 58.3 (95% CI: 53.8-62.9) months in high-risk vs other patients (IMWG; P = .001) and 34.1 (95% CI: 30.2-38.0) vs 47.2 (95% CI: 43.4-51.0) months in Stage III vs Stage II patients (R-ISS; P < .001). In conclusion, IMWG and R-ISS risk stratification indices are applicable to patients with MM in a real-world setting.