Publications by authors named "Krzysztof Jamroziak"

93 Publications

Prompt Determination of the Mechanical Properties of Industrial Polypropylene Sandwich Pipes.

Materials (Basel) 2021 Apr 22;14(9). Epub 2021 Apr 22.

Department of Mechanics, Materials and Biomedical Engineering, Wroclaw University of Science and Technology, Smoluchowskiego 25 Str., 50-370 Wroclaw, Poland.

A simple and prompt method to determine the mechanical properties of industrial multilayer extrusion polypropylene pipes for a gravity sewer network is suggested. The engineering formulas included for calculating the permissible thickness and relative position of a foam core in the pipes are based on a linear-elastic approximation and the rule of mixtures. The applicability of the approximation was justified experimentally during investigation of the effective tensile characteristics of single- and multilayer pipes and each layer specimen by using traditional tests and finite-element calculations. The results obtained were used to formulate engineering recommendations for calculations of this type.
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http://dx.doi.org/10.3390/ma14092128DOI Listing
April 2021

Genetically determined telomere length and multiple myeloma risk and outcome.

Blood Cancer J 2021 Apr 14;11(4):74. Epub 2021 Apr 14.

Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.

Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 × 10 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.
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http://dx.doi.org/10.1038/s41408-021-00462-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046773PMC
April 2021

Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.

Int J Cancer 2021 Mar 6. Epub 2021 Mar 6.

Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.
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http://dx.doi.org/10.1002/ijc.33547DOI Listing
March 2021

Differential Function of a Novel Population of the CD19+CD24hiCD38hi Bregs in Psoriasis and Multiple Myeloma.

Cells 2021 Feb 16;10(2). Epub 2021 Feb 16.

Experimental Hematooncology Department, Medical University of Lublin, 20-093 Lublin, Poland.

Psoriasis (Ps), an autoimmune disease, and multiple myeloma (MM), a blood neoplasm, are characterized by immune dysregulation resulting from the imbalance between the effector and regulatory cells, including B regulatory (Breg) lymphocytes. Peripheral blood samples from 80 Ps patients, 17 relapsed/refractory MM patients before and after daratumumab (anti-CD38 monoclonal antibody) treatment, 23 healthy volunteers (HVs), and bone marrow samples from 59 MM patients were used in the study. Bregs were determined by flow cytometry using CD19, CD24, and CD38. Intracellular production of interleukin-10 (IL-10) was assessed by flow cytometry after CD40L, LPS, and CpG stimulation. IL-10 serum or plasma concentrations were tested using ELISA method. The percentage of CD19+CD24hiCD38hi Bregs was not different whereas the production of IL-10 in Bregs was significantly higher in Ps patients in comparison with HVs. The percentage of CD19+CD24hiCD38hi Bregs in MM patients was significantly higher than in HVs ( < 0.0001). The percentage of CD19+CD24hiCD38hi Bregs was significantly higher in MM patients with the ISS stage I ( = 0.0233) while IL-10 production in Bregs was significantly higher in ISS stage III (p = 0.0165). IL-10 serum or plasma concentration was significantly higher in Ps and MM patients when compared to HVs ( < 0.0001). Following the treatment with daratumumab the percentages of CD19+CD24hiCD38hi Bregs significantly decreased ( < 0.0003). Here, in the two opposite immune conditions, despite the differences in percentages of Bregs in Ps and MM we have identified some similarities in the IL-10 producing Bregs. Effective treatment of daratumumab besides the anti-myeloma effect was accompanied by the eradication of Bregs.
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http://dx.doi.org/10.3390/cells10020411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920433PMC
February 2021

Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility.

Int J Cancer 2021 Jun 3;148(11):2779-2788. Epub 2021 Feb 3.

Department of General Surgery, University of Heidelberg, Heidelberg, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.
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http://dx.doi.org/10.1002/ijc.33475DOI Listing
June 2021

Advances in diagnostics and therapy of systemic amyloidoses.

Reumatologia 2020 23;58(6):343-344. Epub 2020 Dec 23.

Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.

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http://dx.doi.org/10.5114/reum.2020.101998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792547PMC
December 2020

X-ray Computed Tomography for the Development of Ballistic Composite.

Materials (Basel) 2020 Dec 6;13(23). Epub 2020 Dec 6.

Department of Mechanics, Faculty of Mechanical Engineering, Materials Science and Engineering, Wroclaw University of Science and Technology, Smoluchowskiego 25, 50-370 Wroclaw, Poland.

This paper presents the results of research on ballistic panels made of polymer-matrix composites (PMCs). The analysis covers two types of composites produced by the authors based on high-density polyethylene (PEHD) and polypropylene (PP) reinforced with aramid fabric. Ballistic tests were carried out with the use of two types of projectile: 0.38 Special, and 9 × 19 Parabellum, which are characterized by different velocity and projectile energy. The study presents the X-ray computed tomography (XCT) analysis for structure assessment of ballistic panels and its impact behavior, further compared to the results of computer simulations conducted using the numerical analysis. The quality of the manufactured panels and their damage caused by a ballistic impact was assessed using a multi-scale geometry reconstruction. The mesoscale XCT allowed the internal composite geometry to be analyzed, as well as a unit cell of the representative volume element (RVE) model to be built. The RVE model was applied for homogenization and finite element (FEA) simulation of projectile penetration through the ballistic panel. The macroscale XCT investigation allowed for the quantitative description of the projectile's impact on the degree of delamination and deformation of the panels' geometry.
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http://dx.doi.org/10.3390/ma13235566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731439PMC
December 2020

Predictive significance of selected gene mutations in relapsed and refractory chronic lymphocytic leukemia patients treated with ibrutinib.

Eur J Haematol 2021 Mar 19;106(3):320-326. Epub 2020 Dec 19.

Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.

Background: Ibrutinib, an inhibitor of the Bruton's kinase (BTK), is characterized by high efficacy in the therapy of patients with relapsed and refractory chronic lymphocytic leukemia (RR-CLL).

Aims: To analyze the potential significance of the mutational status of selected 30 genes on the disease outcome in 45 patients with RR-CLL using custom-made gene panel and sequencing on Illumina MiSeq FGx platform.

Results: The highest rate of mutations was observed in TP53 (n = 18; 40.0%), NOTCH1 (n = 13; 28.8%), SF3B1 (n = 11; 24.4%), ATM (n = 7; 15.6%), MED12 (n = 6, 13.3%), CHD2 (n = 5; 11.1%), XPO1 (n = 5; 11.1%), NFKBIE (n = 5; 11.1%), BIRC3 (n = 4; 8.9%), SPEN (n = 4; 8.9%), POT1 (n = 4; 8.9%), EGR2 (n = 3; 6.7%), and RPS15 (n = 3; 6.7%). With a median observation time of 45.9 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. The 36-month estimated rate of PFS and OS were 64% and 68.2%, respectively. The overall response rate was noted in 23 patients (51.1%), while twenty (44.4%) patients achieved stability. Progression was noted in 2 (4.5%) cases. Analyzed molecular factors had no impact on PFS and OS.

Conclusion: Despite accumulation of several poor prognostic factors in our real-life cohort of heavily pretreated patients with CLL, ibrutinib treatment showed long-term clinical benefit.
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http://dx.doi.org/10.1111/ejh.13550DOI Listing
March 2021

Association between the CEBPA and c-MYC genes expression levels and acute myeloid leukemia pathogenesis and development.

Med Oncol 2020 Nov 10;37(12):109. Epub 2020 Nov 10.

Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, Muszynskiego 1 Street, 90-151, Lodz, Poland.

CEBPA and c-MYC genes belong to TF and play an essential role in hematologic malignancies development. Furthermore, these genes also co-regulate with RUNX1 and lead to bone marrow differentiation and may contribute to the leukemic transformation. Understanding the function and full characteristics of selected genes in the group of patients with AML can be helpful in assessing prognosis, and their usefulness as prognostic factors can be revealed. The aim of the study was to evaluate CEBPA and c-MYC mRNA expression level and to seek their association with demographical and clinical features of AML patients such as: age, gender, FAB classification, mortality or leukemia cell karyotype. Obtained results were also correlated with the expression level of the RUNX gene family. To assess of relative gene expression level the qPCR method was used. The expression levels of CEBPA and c-MYC gene varied among patients. Neither CEBPA nor c-MYC expression levels differed significantly between women and men (p=0.8325 and p=0.1698, respectively). No statistically significant correlation between age at the time of diagnosis and expression of CEBPA (p=0.4314) or c-MYC (p=0.9524) was stated. There were no significant associations between relative CEBPA (p=0.4247) or c-MYC (p=0.4655) expression level and FAB subtype and mortality among the enrolled patients (p=0.5858 and p=0.8437, respectively). However, it was observed that c-MYC and RUNX1 expression levels were significantly positively correlated (rS=0.328, p=0.0411). Overall, AML pathogenesis involves a complex interaction among CEBPA, c-MYC and RUNX family genes.
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http://dx.doi.org/10.1007/s12032-020-01436-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655568PMC
November 2020

Common gene variants within 3'-untranslated regions as modulators of multiple myeloma risk and survival.

Int J Cancer 2021 Apr 20;148(8):1887-1894. Epub 2020 Nov 20.

Laboratory of Clinical and Transplant Immunology and Genetics, Copernicus Memorial Hospital, Lodz, Poland.

We evaluated the association between germline genetic variants located within the 3'-untranlsated region (polymorphic 3'UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3'-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis.
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http://dx.doi.org/10.1002/ijc.33377DOI Listing
April 2021

Mean Platelet Volume Has Prognostic Value in Chronic Lymphocytic Leukemia.

Cancer Manag Res 2020 12;12:9977-9985. Epub 2020 Oct 12.

Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland; Hematology Department, St John's Cancer Center, Lublin, Poland.

Purpose: Mean platelet volume (MPV) is a readily accessible and commonly tested hematological indicator. Recent studies revealed a significant impact of MPV on the course and prognosis of many diseases, including some types of cancer, as well as on the incidence of atrial fibrillation and bleeding. The study aimed to perform a retrospective analysis of MPV in terms of time to first treatment (TTFT) and to determine its prognostic value in the group of patients with chronic lymphocytic leukemia (CLL). Moreover, the study includes a retrospective analysis of platelet parameters in patients treated with ibrutinib concerning bleeding and atrial fibrillation.

Patients And Methods: The study included 523 patients with CLL, for 344 the most important cytogenetic aberrations were reported. The Mann-Whitney, Kruskal-Wallis, Kaplan-Meier, chi-squared, log‑rank tests and multivariate Cox proportional hazard regression model were used to analyze collected data.

Results: The receiver operating characteristic curve analysis was performed to identify optimal cut-off value for MPV. The analysis of survival curves showed that in the group of patients with higher values of MPV TTFT was significantly longer than in the group with lower MPV (17.9 vs 36 months, p=0.0015, cut-off value for MPV= 10.4 fl). In multivariate Cox proportional hazard regression model low MPV, the presence of del11q and del13q provided independent prognostic value for TTFT (HR=0.69, 95%-CI, 0.5293 to 0.9081; p=0.0078; HR=1.76, 95%-CI, 1.3000 to 2.3882, p=0.0003, HR=0.74, 95%-Cl, 0.5674 to 0.9588, p=0.0229, respectively). In the group treated with ibrutinib, 59 patients had no significant correlation between MPV level and the incidence of therapy complications, although in the group of patients with low MPV there was a tendency for more frequent occurrence of atrial fibrillation (p=0.259).

Conclusion: Low MPV values are associated with unfavorable prognosis and might represent a novel, independent prognostic factor in CLL.
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http://dx.doi.org/10.2147/CMAR.S246385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567945PMC
October 2020

Allogeneic hematopoietic cell transplantation for multiple myeloma: A retrospective analysis of the Polish Myeloma Group.

Adv Med Sci 2020 Sep 10;65(2):429-436. Epub 2020 Sep 10.

Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.

Purpose: In this multicenter retrospective analysis of the Polish Myeloma Group we assessed the real-life application of allogeneic transplantations (alloHCT) in multiple myeloma (MM) outside clinical trials in Poland.

Methods: Anonymized clinical data of patients who underwent alloHCT were retrospectively collected from eight transplant centers and analyzed to identify factors affecting the outcome.

Results: Sixty patients (34 males, 26 females) at median age of 45 (22-59) years who received alloHCT between 1993 and 2016 were included. In this group, 16 (27%) patients underwent myeloablative conditioning and 44 (73%) reduced-intensity conditioning alloHCT. Acute graft versus host disease (GvHD) occurred in 27 (45%) patients, while chronic GvHD was diagnosed in 13 (22%) patients. With the median observation time after alloHCT of 10 months, the relapse rate was 38%. Median progression-free survival (PFS) reached 9 months (0-183) while median overall survival (OS) was 23 months (0-183). Main causes of death included disease progression in 16 (43%), infections in 10 (27%), and GvHD in 7 patients (19%). Presence of chronic GvHD was the only factor associated with prolonged PFS (28 vs. 6 months; p = 0.05), however its impact on OS was not statistically significant (73 vs. 8 months; p = 0.09).

Conclusions: In this relatively small and heterogeneous study we observed that alloHCT was associated with high risk of severe complications, but resulted in long-term survival in a proportion of patients. Decisions on optimal indications and timing of the alloHCT in MM need to be taken in the broader context of reported outcomes including data from large studies.
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http://dx.doi.org/10.1016/j.advms.2020.08.003DOI Listing
September 2020

Efficacy of high-dose corticosteroid-based treatment for chronic lymphocytic leukemia patients with p53 abnormalities in the era of B-cell receptor inhibitors.

Adv Med Sci 2020 Sep 10;65(2):371-377. Epub 2020 Jul 10.

Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.

Purpose: High-dose methylprednisolone (HDMP) with or without anti-CD20 antibody treatment in the pre B-cell receptor inhibitor (BCRi) era was used as potential salvage therapy for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (r/r CLL/SLL) patients bearing the 17p deletion.

Patients And Methods: Outcomes were compared in retrospect between r/r patients treated with HDMP (n = 20), ibrutinib (n = 39) and idelalisib with rituximab (n = 14).

Results: Higher overall response rates were found in those patients undergoing BCRi therapy compared to HDMP (79.2% vs. 0%; p < 0.0001), along with longer median progression-free survival (not reached vs. 24.1 months; p < 0.01). Nevertheless, there were no differences in the overall survival (HDMP 35.87 months vs. not reached; p = 0.58).

Conclusion: HDMP treatment was significantly inferior in terms of response rate and progression-free survival in r/r CLL/SLL patients with the 17p deletion, and may only be used whenever novel compounds are unavailable.
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http://dx.doi.org/10.1016/j.advms.2020.06.002DOI Listing
September 2020

Long-term Efficacy of Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of the Polish Adult Leukemia Study Group Observational Study.

Anticancer Res 2020 Jul;40(7):4059-4066

Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.

Background/aim: To study the long-term clinical efficacy and tolerability of ibrutinib monotherapy in real-world relapsed and refractory chronic lymphocytic leukemia (RR-CLL) patients outside clinical trials.

Patients And Methods: Clinical data of 171 RR-CLL patients treated with ibrutinib were collected within the observational study of the Polish Adult Leukemia Study Group.

Results: Median patient age was 64 years. Patients were pretreated with 3 (1-10) median lines of therapy, while 42 (24.6%) had 17p deletion. The median observation time was 40 months (range=1-59 months), while median ibrutinib monotherapy reached 37.5 months (range=0.4-59.2 months). Response was noted in 132 (77.2%) patients. The estimated 5-year progression-free survival (PFS) and overall survival (OS) rates were 61.1% (95%CI=49.3-70.9%) and 56.8% (95%CI=45.6-66.6%), respectively. At the time of analysis 97 (56.7%) remained under ibrutinib monotherapy.

Conclusion: Ibrutinib is clinically effective and tolerable as a monotherapy in real-world RR-CLL patients.
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http://dx.doi.org/10.21873/anticanres.14403DOI Listing
July 2020

Associations of ficolins and mannose-binding lectin with acute myeloid leukaemia in adults.

Sci Rep 2020 06 29;10(1):10561. Epub 2020 Jun 29.

Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232, Lodz, Poland.

We investigated clinical associations of ficolins and mannose-binding lectin (MBL) in 157 patients suffering from acute myeloid leukaemia (AML). Concentrations of ficolin-1, ficolin-2, ficolin-3 and MBL (before chemotherapy) in serum were determined as were selected polymorphisms of the corresponding genes (FCN1, FCN2, FCN3 and MBL2). The control group (C) consisted of 267 healthy unrelated individuals. Median level of ficolin-1 in patients was lower (p < 0.000001) while median levels of ficolin-2, ficolin-3 and MBL were higher (p < 0.000001, p < 0.000001 and p = 0.0016, respectively) compared with controls. These findings were generally associated with AML itself, however the highest MBL levels predicted higher risk of severe hospital infections (accompanied with bacteremia and/or fungaemia) (p = 0.012) while the lowest ficolin-1 concentrations tended to be associated with prolonged (> 7 days) fever (p = 0.026). Genotyping indicated an association of G/G homozygosity (corresponding to FCN1 gene - 542 G > A polymorphism) with malignancy [p = 0.004, OR = 2.95, 95% CI (1.41-6.16)]. Based on ROC analysis, ficolin-1, -2 and -3 may be considered candidate supplementary biomarkers of AML. Their high potential to differentiate between patients from non-malignant controls but also from persons suffering from other haematological cancers (multiple myeloma and lymphoma) was demonstrated.
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http://dx.doi.org/10.1038/s41598-020-67516-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324623PMC
June 2020

Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction.

J Med Genet 2020 Jun 26. Epub 2020 Jun 26.

Cancer Center Amsterdam, Amsterdam, The Netherlands.

Background: Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection.

Objective: We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score.

Methods: We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes.

Results: The scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10, highest vs lowest quintile of the weighted multifactorial score).

Conclusion: We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.
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http://dx.doi.org/10.1136/jmedgenet-2020-106961DOI Listing
June 2020

The impact of cytogenetic evolution and acquisition of del(17p) on the prognosis of patients with multiple myeloma.

Pol Arch Intern Med 2020 06 27;130(6):483-491. Epub 2020 Apr 27.

Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland

Introduction: Prognosis of patients with newly diagnosed multiple myeloma (MM), a third most common hematological cancer, is dependent on baseline cytogenetics. However, little is known about the prognostic significance of cytogenetic evolution (CE) at the time between the diagnosis and relapse of MM.

Objectives: Here, we retrospectively analyzed the prognostic impact of CE detected in a routine interphase fluorescence in situ hybridization (FISH) test in a cohort of patients with MM.

Patients And Methods: Among 650 patients evaluated with the FISH MM panel at our center between 2014 and 2019, we identified 29 individuals with MM who had been tested twice, at the time of diagnosis and relapse. Cytogenetic evolution was defined as the acquisition or loss of at least 1 cytogenetic abnormality at relapse (FISH2) compared with the baseline test result (FISH1).

Results: Cytogenetic evolution was seen in 14 patients (48%), whereas 15 had stable cytogenetics. Acquired chromosome 17p deletion (del[17p]) was the most common type of CE, found in 7 patients (24%). In univariable analysis, stable cytogenetics predicted longer overall survival (median not reached vs 3.8 years; hazard ratio [HR], 0.15; P = 0.04; median follow‑up of 3.1 years) and longer overall survival after FISH2 (median not reached vs 0.8 years; HR, 0.13; P = 0.002; median follow‑up of 0.6 years). In multivariable analysis, acquired del(17p) predicted shorter progression‑free survival and the overall survival after FISH2 (HR, 9.3 and 18.8; P = 0.005 and P = 0.004, respectively).

Conclusions: Presence of CE and, particularly, the acquisition of new del(17p) at relapse, negatively affect the outcome of MM. Therefore, re‑evaluation of FISH at MM relapse should be included in routine clinical practice.
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http://dx.doi.org/10.20452/pamw.15316DOI Listing
June 2020

Different MAF translocations confer similar prognosis in newly diagnosed multiple myeloma patients.

Leuk Lymphoma 2020 08 19;61(8):1885-1893. Epub 2020 Apr 19.

Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

The MAF translocations, t(14;16) and t(14;20), are considered as adverse prognostic factors based on few studies with small sample sizes. We report on their prognostic impact in a large group of 254 patients - 223 (87.8%) with t(14;16) and 31 (12.2%) with t(14;20). There were no intergroup differences in survival estimates. Median progression-free survival was 16.6 months for t(14;16) and 24.9 months for t(14;20) ( = 0.28). Median overall survival (OS) was 54.0 months and 49.0 months, respectively ( = 0.62). Median OS in patients who underwent double autologous stem cell transplantation (ASCT) was 107.0 months versus 60.0 months in patients who received single ASCT ( < 0.001). ISS 3 was associated with shorter OS (HR = 1.89; 95% CI 1.24-3.19;  = 0.005) in Cox analysis. Our study suggests that t(14;20) should be considered as an adverse factor of equal prognostic implication to t(14;16).
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http://dx.doi.org/10.1080/10428194.2020.1749605DOI Listing
August 2020

Genome-wide association study identifies an early onset pancreatic cancer risk locus.

Int J Cancer 2020 10 1;147(8):2065-2074. Epub 2020 May 1.

Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.

Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore, we performed a genome-wide association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset ≤60 years, of whom 198 with age of onset ≤50, and 3227 controls from PanScan I-II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P < 1 × 10 ). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset ≤60 years, of whom 265 with age of onset ≤50, and 4142 controls from the PANDoRA consortium while in the in silico data, we observed no statistically significant association. However, the resulting meta-analysis supported the association (P = 1.15 × 10 ). In conclusion, we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature.
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http://dx.doi.org/10.1002/ijc.33004DOI Listing
October 2020

A multicenter retrospective study of 223 patients with t(14;16) in multiple myeloma.

Am J Hematol 2020 05 29;95(5):503-509. Epub 2020 Feb 29.

Department of Hematology, UZ Leuven, Leuven, Belgium.

The t(14;16) translocation, found in 3%-5% of newly diagnosed (ND) multiple myeloma (MM), has been associated with adverse outcomes. However, the studies establishing the characteristics of t(14;16) included solely small cohorts. The goal of the current international, multicenter (n = 25 centers), retrospective study was to describe the characteristics and outcomes of t(14;16) patients in a large, real-world cohort (n = 223). A substantial fraction of patients had renal impairment (24%) and hemoglobin <10 g/dL (56%) on initial presentation. Combined therapy of both immunomodulatory drug and proteasome inhibitor (PI) in the first line was used in 35% of patients. Autologous stem cell transplantation was performed in 42% of patients. With a median follow up of 4.1 years (95% CI 3.7-18.7), the median progression-free survival (PFS) and overall survival (OS) from first line therapy were 2.1 years (95% CI 1.5-2.4) and 4.1 years (95% CI 3.3-5.5), respectively. Worse OS was predicted by age > 60 years (HR = 1.65, 95% CI [1.05-2.58]), as well as revised International Scoring System (R-ISS) 3 (vs R-ISS 2; HR = 2.59, 95% CI [1.59-4.24]). In conclusion, based on the largest reported cohort of t(14;16) patients, quarter of this subset of MM patients initially presents with renal failure, while older age and the R-ISS 3 predict poor survival.
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http://dx.doi.org/10.1002/ajh.25758DOI Listing
May 2020

Associations of Ficolins With Hematological Malignancies in Patients Receiving High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantations.

Front Immunol 2019 28;10:3097. Epub 2020 Jan 28.

Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland.

A prospective study of 312 patients [194 with multiple myeloma (MM) and 118 with lymphomas (LYMPH)] receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) was conducted. Ficolins are innate immune defense factors, able to distinguish between "self" "abnormal self," and "non-self" and contribute to the elimination of the last two by direct opsonization and/or initiation of complement activation the lectin pathway. Concentrations of ficolin-1, ficolin-2, and ficolin-3 in serially taken serum samples were determined as were the polymorphisms of the corresponding (, and ) genes. Serum samples were collected before conditioning chemotherapy, before HSCT, and once weekly post-HSCT (four to five samples in total); some patients were also sampled at 1 and/or 3 months post-transplantation. The control group (C) consisted of 267 healthy unrelated individuals. Median ficolin-1 and ficolin-2 (but not ficolin-3) levels in MM patients' sera taken before chemotherapy were lower (and correspondingly frequencies of the lowest concentrations were higher) compared with controls. That appeared to be associated with the malignant disease itself rather than with post-HSCT complications (febrile neutropenia, infections accompanied, or not with bacteremia). Higher frequencies of the genotype G/A-C/C-G/G (corresponding to polymorphisms at positions -542, -144, and +6658, respectively) and gene heterozygosity for the -857 C>A polymorphism were found among patients diagnosed with MM compared with the C group. Furthermore, G/G homozygosity (-557 A>G) was found more frequently and heterozygosity G/T at +6424 less frequently among LYMPH patients than among the healthy subjects. Heterozygosity for +1637delC mutation of the gene was more common among patients diagnosed with lymphomas who experienced hospital infections. Although no evidence for an association of low ficolin-1 or ficolin-2 with infections during neutropenia following chemotherapy before HSCT was found, we observed a possible protective effect of ficolins during follow-up.
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http://dx.doi.org/10.3389/fimmu.2019.03097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997528PMC
November 2020

Assessment of the Impact Resistance of a Composite Material with EN AW-7075 Matrix Reinforced with α-AlO Particles Using a 7.62 × 39 mm Projectile.

Materials (Basel) 2020 Feb 7;13(3). Epub 2020 Feb 7.

Wroclaw Center for Technology Transfer of Wroclaw University of Science and Technology, Smoluchowskiego 28, 50-372 Wroclaw, Poland.

The paper presents the results of studies on the effects of shooting composite materials produced by pressure infiltration with the EN AW-7075 alloy as a matrix and reinforcement in the form of preforms made of α-AlO particles. Composite materials were made with two reinforcement contents (i.e., 30% and 40% vol. of α-AlO particles). The composites produced in the form of 12 mm thick plates were subjected to impact loads from a 7.62 × 39 FMJ M43 projectile fired from a Kalashnikov. The samples of composites with different contents of strengthening particles were subjected to detailed microscopic examination to determine the mechanism of destruction. The effect of a projectile impact on the microstructure of the material within the perforation holes was identified. There were radial cracks found around the puncture holes and brittle fragmentation of the front surfaces of the specimens. The change in the volume of the reinforcement significantly affected the inlet, puncture and outlet diameters. The observations confirmed that brittle cracking dominated the destruction mechanism and the crack propagation front ran mainly in the matrix material and along the boundaries of the α-AlO particles. In turn, numerical tests were conducted to describe the physical phenomena occurring due to the erosion of a projectile hitting a composite casing. They were performed with the use of the ABAQUS program. Based on constitutive models, the material constants developed from the identification of material properties were modelled and the finite element was generated from homogenization in the form of a representative volume element (RVE). The results of microscopic investigations of the destruction mechanism and numerical investigations were combined. The conducted tests and analyses shed light on the application possibilities of aluminium composites reinforced with AlO particles in the construction of add-on-armour protective structures.
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http://dx.doi.org/10.3390/ma13030769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041378PMC
February 2020

Autologous stem cell transplantation in the treatment of multiple myeloma with 17p deletion.

Pol Arch Intern Med 2020 02 14;130(2):106-111. Epub 2020 Jan 14.

Department of Hematology, Oncology and Internal Disease, Medical University of Warsaw, Warsaw, Poland

Introduction: Deletion of chromosome 17p [del(17p)] in patients with multiple myeloma is associated with a poor prognosis. High‑dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains the standard of treatment in this population.

Objectives: The aim of the study was to compare the treatment outcomes with high‑dose chemotherapy and ASCT with standard treatment in patients with del(17p).

Patients And Methods: We collected data from 12 Polish centers between 2011 and 2017. The records of 97 patients with p53 deletion were assessed, including 29 individuals treated with ACST and 68 receiving standard treatment alone.

Results: During the follow‑up, 45 patients died and the overall survival (OS) for the whole group was 33 months (range, 1-66 months), with a median progression‑free survival (PFS) of 13 months (range, 1-46 months). The prognostic factors of OS in a multivariable analysis were calcium levels at diagnosis within the reference range (hazard ratio [HR], 0.24; 95% CI, 0.12-0.48) and at least partial remission achieved after the first‑line treatment (HR, 0.25; 95% CI, 0.12-0.51). Treatment with ASCT was an important factor in improving survival (HR, 3.23; 95% CI, 1.52-6.84). Abnormal kidney function at the time of diagnosis reduced the PFS (HR, 0.46; 95% CI, 0.22-0.94). When the analysis was limited only to patients who could be candidates for ASCT, the survival benefit of the procedure was lost (P = 0.21).

Conclusions: Patients with multiple myeloma with del(17p) do not benefit from high‑dose chemotherapy followed by ACST.
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http://dx.doi.org/10.20452/pamw.15139DOI Listing
February 2020

Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia.

Cancers (Basel) 2019 Nov 21;11(12). Epub 2019 Nov 21.

Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw 02-776, Poland.

Ibrutinib is the first Bruton's tyrosine kinase (BTK) inhibitor, which showed significant clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) patients regardless of cytogenetic risk factors. Recent results of phase III clinical trials in treatment-naïve CLL patients shift the importance of the agent to frontline therapy. Nevertheless, beside its clinical efficacy, ibrutinib possesses some off-target activity resulting in ibrutinib-characteristic adverse events including bleeding diathesis and arrhythmias. Furthermore, acquired and primary resistance to the drug have been described. As the use of ibrutinib in clinical practice increases, the problem of resistance is becoming apparent, and new methods of overcoming this clinical problem arise. In this review, we summarize the mechanisms of BTK inhibitors' resistance and discuss the post-ibrutinib treatment options.
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http://dx.doi.org/10.3390/cancers11121834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966427PMC
November 2019

Cereblon () gene polymorphisms predict clinical response and progression-free survival in relapsed/refractory multiple myeloma patients treated with lenalidomide: a pharmacogenetic study from the IMMEnSE consortium.

Leuk Lymphoma 2020 03 20;61(3):699-706. Epub 2019 Nov 20.

Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.

Cereblon (CRBN) is crucial for antiproliferative and immunomodulatory properties of immunomodulatory drugs. The objective of this study was to verify whether germline single nucleotide polymorphisms (SNPs) in the gene may influence response to lenalidomide in multiple myeloma (MM). Fourteen tagging SNPs covering the genetic variability in the gene region were genotyped in 167 Polish patients with refractory/relapsed MM treated with lenalidomide-based regimens. We found that carriers of minor alleles of two studied CRBN SNPs rs1714327G > C (OR = 0.26; 95% CI = 0.1-0.67;  = .0055, Bonferroni corrected  = .033) and rs1705814T > C (OR = 0.22; 95% CI = 0.07-0.65;  = .0063, Bonferroni corrected  = .037) were significantly associated with lower probability of achievement at least partial remission while treated with lenalidomide-based regimens, using the dominant inheritance model. Moreover, one of these SNPs, namely rs1705814T > C, was correlated with shorter progression-free survival (HR = 2.49; 95%CI = 1.31-4.74,  = .0054, Bonferroni corrected  = .033). It is suggested that selected germline CRBN allelic variants (rs1714327G > C and rs1705814T > C) affect lenalidomide efficacy in patients with relapsed/refractory MM.
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http://dx.doi.org/10.1080/10428194.2019.1689391DOI Listing
March 2020

Insights on Multiple Myeloma Treatment Strategies.

Hemasphere 2019 Feb 27;3(1):e163. Epub 2018 Dec 27.

Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

The introduction of new agents and management strategies over the past decade has resulted in a major step change in treatment outcomes with deepening responses and increased survival for patients with multiple myeloma. In daily clinical practice, healthcare professionals are now faced with challenges including, optimal treatment sequencing and changing treatment goals. In light of this, a group of experts met to discuss diagnostic and treatment guidelines, examine current clinical practice, and consider how new clinical trial data may be integrated into the management of multiple myeloma in the future.
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http://dx.doi.org/10.1097/HS9.0000000000000163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745941PMC
February 2019

Expression level of CEBPA gene in acute lymphoblastic leukemia individuals.

Sci Rep 2019 10 30;9(1):15640. Epub 2019 Oct 30.

Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, Lodz, Poland.

Currently, acute lymphoblastic leukemia (ALL) has an overall survival of nearly 80% when it occurs in children, however cure rates among adults are far reduced. Leukemogenesis can be driven up by a slight change in the expression or function of certain transcription factors. CCAAT Enhancer Binding Protein Alpha (CEBPA) is a transcription factor with role in cell cycle regulation, granulocytic differentiation and more. Some studies suggest its oncogenic function. The potential role of CEBPA as an oncogene in ALL development has not been completely elucidated so far. Therefore, the aim of the present study was to evaluate mRNA level of CEBPA gene in 60 adult patients diagnosed with ALL. Quantitative analysis was performed by qPCR reaction. Analysis revealed that men tended to have higher and more variable CEBPA expression levels (P = 0.032). No associations for other parameters (ALL subtype, age, leukocytosis, blast percentage, Philadelphia chromosome presence, CD10 marker presence) were found. When comparing the results of CEBPA expression with patients suffering from acute myeloid leukemia, ALL cases showed statistically significant lower levels of CEBPA (P < 0.0000). It may seem that CEBPA expression level itself has potentially no effect on arising and progression of acute lymphoblastic leukemia, although it is a matter that needs further investigation.
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http://dx.doi.org/10.1038/s41598-019-52104-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821811PMC
October 2019

Ibrutinib discontinuation in patients with relapsed or refractory chronic lymphocytic leukemia treated in a compassionate use program: A report from the Polish Adult Leukemia Study Group (PALG).

Adv Clin Exp Med 2019 Aug;28(8):1051-1057

Department of Hematology, Institute of Hematology and Transfusion Medicine, Warszawa, Poland.

Background: Development of a novel class of drugs, the B-cell receptor-signaling inhibitors, including ibrutinib, has been a major achievement in the therapy of refractory or relapsed chronic lymphocytic leukemia (CLL). However, the CLL patients who have discontinued the ibrutinib treatment in clinical trials have been reported to have poor prognosis.

Objectives: In this retrospective study by the Polish Adult Leukemia Group (PALG), we analyzed the reasons for ibrutinib cessation and outcomes after discontinuing ibrutinib in refractory or relapsed CLL patients treated in a compassionate use program in Poland.

Material And Methods: Polish CLL patients were included if they discontinued ibrutinib for any reason. The clinical data on the course of ibrutinib treatment was collected anonymously using electronic Case Report Forms (CRFs). The causes of discontinuation of ibrutinib as reported by the treating physicians were analyzed.

Results: Thirty-seven patients who discontinued ibrutinib were identified. The median duration of ibrutinib treatment in this group was 4.4 months (range: 0.2-25.2). The main reason for discontinuing ibrutinib was adverse events (n = 20, 54%), while 14 (38%) patients discontinued therapy due to disease progression and 3 (8%) due to other causes. The most common treatment complications that led to ibrutinib cessation were severe respiratory tract infections (9 patients, 24%). In the group discontinuing ibrutinib for progressive disease, 11 patients progressed with untransformed CLL, while in 3 patients, a rare type of Richter transformation to Hodgkin's lymphoma was diagnosed. Twenty-nine patients (78%) died during the follow-up period, and median overall survival (OS) reached 2.0 months (95% CI = 0.8-5.5 months). Importantly, no significant survival difference was detected between patients who discontinued ibrutinib due to disease progression and due to adverse events.

Conclusions: The results of this analysis indicate that ibrutinib discontinuation in relapsed or refractory CLL is associated with poor prognosis regardless of the reason for ibrutinib cessation.
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http://dx.doi.org/10.17219/acem/99911DOI Listing
August 2019

Efficacy of daratumumab monotherapy in real-world heavily pretreated patients with relapsed or refractory multiple myeloma.

Adv Med Sci 2019 Sep 21;64(2):349-355. Epub 2019 May 21.

Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.

Purpose: Daratumumab is a promising new agent for relapsed/refractory multiple myeloma (RRMM). However, there are limited data on its clinical activity and tolerability in the real-world patients. The purpose of this study is to determine the efficacy and toxicity profile of daratumumab monotherapy in the real-life setting.

Patients And Methods: Thirty RRMM patients treated with daratumumab who had previously received at least three treatment lines including a proteasome inhibitor and an immunomodulatory drug or had been double refractory (DRMM) were included to the Polish Myeloma Group observational study.

Results: The objective response rate to daratumumab was 42.8%. Median progression-free survival (PFS) and overall survival reached 9.5 and 13.8 months, respectively. Importantly, patients with DR-MM had a significantly shorter PFS than other patients (median PFS of 4.1 vs. 12.1 months). Daratumumab was generally well tolerated, however two patients had their therapy interrupted due to adverse events.

Conclusion: Daratumumab monotherapy has significant activity and good tolerance in heavily pretreated RRMM patients.
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http://dx.doi.org/10.1016/j.advms.2019.05.001DOI Listing
September 2019

Hodgkin lymphoma transformation of chronic lymphocytic leukemia-A real life data from the Polish Lymphoma Research Group.

Hematol Oncol 2019 Oct 14;37(4):383-391. Epub 2019 Jun 14.

Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.

Richter transformation (RT) of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to Hodgkin lymphoma (HL) is a rare and unexpected event in the course of the disease and data on this phenomenon is still limited. To better understand the clinical and histological characteristics and the outcomes of HL variant of RT (HvRS) the Polish Lymphoma Research Group performed a nationwide survey which identified 22 patients with histologically proven HvRS diagnosed between 2002 and 2016. There were 16 (73%) males. The median age at CLL/SLL and HvRS diagnosis was 59 (39-77) and 64 (40-77) years, respectively. The median interval between CLL/SLL and HvRS diagnosis was 38 months (range: 0-187). All patients had an advanced stage HL, and majority, 17 (77%), presented with B symptoms. The predominant subtypes of HL were nodular sclerosis (12; 55%) and mixed cellularity (9; 41%). Eighteen patients received non-palliative treatment, including 13 who received driamycin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen first line. Objective response was: 50%, with 33% complete remissions (61% and 46% for ABVD, respectively). Median overall survival reached 13.3 months (95% CI, 3.7-NA). The only adverse prognostic factor for survival was a higher number (≤1 versus ≥2) of prior lines of treatment given for CLL/SLL with HR 3.57 (95% CI, 1.16-10.92). We conclude, HvRS harbors a poor prognosis, especially in patients heavily pretreated for CLL/SLL. Response to standard first-line anti-HL chemotherapy is unsatisfactory, and new agents should be tested to improve the outcome.
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http://dx.doi.org/10.1002/hon.2624DOI Listing
October 2019