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The immune dysregulation during SARS-CoV-2 has the potential to worsen immune homeostasis after recovery. Patients with hematological malignancies with COVID-19 have changes both in the innate and adaptive immune responses. Little is known about the severity of immune dysfunction following recovery from COVID-19 in hematological patients.Here, we performed a comprehensive analysis of the lymphocyte subsets in peripheral blood mononuclear cells by FACS Canto II in 55 patients, including 42 with hematological malignancies 4-6 weeks after COVID-19.Hematological COVID-19 convalescents had deep reduction in CD3+ T cells, including helper T cells (CD3 + CD4+), naïve helper T cells (CD3 + CD4 + CD45RA+), and memory CD4+ T cells among with extremely low levels of Treg cells and decreased expression of both TCRα/β and TCRγ/δ. Severe immune dysregulation in hematological convalescents was expressed by increased activation of T lymphocytes, both as elevated levels of activated T cells (CD3 + HLA-DR+) and activated cytotoxic T cells (CD3 + CD8 + HLA-DR+).Our findings showed a profound impairment of the adaptive immune response in hematological convalescents which might be a result of persistent activation of T cells. Convalescents with lymphoid malignancies showed more pronounced depletion of key T lymphocytes subpopulations in creating an effective adaptive response and immune memory.

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients have increased morbidity and mortality rates of COVID-19 due to immunosuppression associated with the disease and ongoing therapy. The same immune impairment accompanying CLL and MM also affects suboptimal vaccine response. The study assessed the effectiveness of the humoral and T cell-mediated immunity following mRNA COVID-19 vaccination (using either BNT162b2 or mRNA-1273) in short-term (2-5 weeks after second dose) and long-term follow-up (12 weeks after vaccination). Between March and August 2021, blood samples were obtained from 62 CLL and 60 MM patients from eight different hematology departments in Poland. Total anti-RBD antibodies were detected in 37% MM patients before vaccination, increased to 91% and 94% in short- and long-term follow-up, respectively. In CLL, serological responses were detectable in 21% of patients before vaccination and increased to 45% in the short-term and 71% in long-term observation. We detected a tendency to higher frequencies of specific CD8+ T cells against SARS-CoV-2 after vaccination compared to samples before vaccination in MM patients and no changes in frequencies of specific T cells in CLL patients. Our study provides novel insights into mRNA vaccination efficacy in immunocompromised MM and CLL patients, and our findings highlight that specific CD8+ T cells against SARS-CoV-2 might be induced by vaccination but do not correlate positively with serological responses.

Background Autologous peripheral blood marrow stem cell transplantation (auto-PBSCT) preceded by high-dose chemotherapy is a well-known method of treatment for patients with hematological cancers. Performing the procedure entails obtaining from the patient their own stem cells from peripheral blood using G-CSF. Currently, various filgrastim biosimilars are widely used. Aim of the study The purpose of this study is to compare the efficacy and safety of three different biosimilars of filgrastim in PBSC mobilization in patients with hematological malignancies. Materials and methods This is a retrospective analysis of 282 patients (118 women and 164 men) who underwent stem cells mobilization for auto-PBSCT in the Department of Hematology in Wroclaw in 2012-2014. Three filgrastim biosimilars were used: Tevagrastim (95), Nivestim (92), and Zarzio (95). Ninety patients (32%) were diagnosed with multiple myeloma, 55 (19%) with Hodgkin's lymphoma, 90 (32%) with NHLs, 20 (7%) with acute myeloid leukemia, and 27 (10%) with another hematological cancer. Results The mean number of CD34+ cells collected during the first leukapheresis was 5.95 × 106 /kg for Tevagrastim, 7.08 × 106 /kg for Nivestim, and 6.8 × 106 /kg for Zarzio (P > .05). The necessary number of leukapheresis for patients receiving Zarzio, Nivestim, and Tevagrastim was 1.32, 1.37, and 1.66, respectively (P > .05). The percentage of effective mobilizations was 88.2% for Zarzio, 86.2% for Nivestim, and 84.9% for Tevagrastim. The side effects included bone pain and headache. Conclusion All tested biosimilars demonstrated similar effectiveness and safety profiles in patients with hematological tumors undergoing PBSC mobilization; therefore, they can be used interchangeably.

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.

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients’ outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37–0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.

The dysregulation of both the innate and adaptive responses to SARS-CoV-2 have an impact on the course of COVID-19, and play a role in the clinical outcome of the disease. Here, we performed a comprehensive analysis of peripheral blood lymphocyte subpopulations in 82 patients with COVID-19, including 31 patients with a critical course of the disease. In COVID-19 patients who required hospitalization we analyzed T cell subsets, including Treg cells, as well as TCRα/β and γ/δ, NK cells, and B cells, during the first two weeks after admission to hospital due to the SARS-CoV-2 infection, with marked reductions in leukocytes subpopulations, especially in critically ill COVID-19 patients. We showed decreased levels of Th, Ts cells, Treg cells (both naïve and induced), TCRα/β and γ/δ cells, as well as CD16+CD56+NK cells in ICU compared to non-ICU COVID-19 patients. We observed impaired function of T and NK cells in critically ill COVID-19 patients with extremely low levels of secreted cytokines. We found that the IL-2/INFγ ratio was the strongest indicator of a critical course of COVID-19, and was associated with fatal outcomes. Our findings showed markedly impaired innate and adaptive responses in critically ill COVID-19 patients, and suggest that the immunosuppressive state in the case of a critical course of SARS-CoV-2 infection might reflect subsequent clinical deterioration and predict a fatal outcome.

Highlights • Patients with haematological malignancies and COVID-19 are characterized by T lymphopenia and reduction in NK cell numbers. • T lymphopenia in haematological patients with COVID-19 include reduction in CD4+ T cells numbers and lowered CD4/CD8 ratio. • Increase in activated T cells with low CD4/CD8 ratio are crucial for the early stages of COVID-19 in haematological patients. • Low levels of both TCRγ/δ and CD3+CD25+ T cells may indicate impaired cellular response to COVID-19 in haematological patients., The role of immune dysregulation in the course and prognosis of COVID-19 is not clearly established. In particular, immune status in specific populations such as haematological patients, who have an impaired immunological system, has not been described so far. Here, we performed a comprehensive analysis of peripheral blood lymphocyte subsets in 27 SARS-CoV-2-infected patients, including 16 patients with haematological malignancies. We identified T cell subpopulations, B cells, NK cells and TCR α/ß and ɣ/ƍ-expressing T cells during COVID-19 infection, with significant changes observed in immune profiles during the course of disease, especially in haematological patients. We observed an increase in activated T lymphocytes (CD3+HLA-DR+ and CD3+CD8+HLA-DR+) in the early stages of SARS-CoV-2 infection with a concomitant decrease in the CD4/CD8 ratio in haematological patients compared to non-haematological patients affected by COVID-19. We also found a decrease in ɣ/ƍ T cells in both studied groups of patients, with lower numbers of CD25+ T cells and CD16+CD56+ NK cells in haematological patients compared to non-haematological patients with COVID-19. Our findings demonstrate, for the first time, impaired adaptive immunity in patients with haematological malignancies infected with COVID-19, resulting in impaired cellular immune responses to SARS-CoV-2. This warrants further investigation of this disease group in COVID-19 patient cohorts

Background: Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor.\ud \ud Methods: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life.\ud \ud Results: A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P

Monocytes are important cells of the innate system. They are a heterogeneous type of cells consisting of phenotypically and functionally distinct subpopulations, which play a specific role in the control, development and escalation of the immunological processes. Based on the expression of superficial CD14 and CD16 in flow cytometry, they can be divided into three subsets: classical, intermediate and non-classical. Variation in the levels of human monocyte subsets in the blood can be observed in patients in numerous pathological states, such as infections, cardiovascular and inflammatory diseases, cancer and autoimmune diseases. The aim of this review is to summarize current knowledge of human monocyte subsets and their significance in homeostasis and in pathological conditions.

Anti-CD20 monoclonal antibodies (mAbs) in combination with chemotherapies have changed the treatment landscape for chronic lymphocytic leukemia (CLL) [1]. Rituximab added to fludarabine with cyclop...

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

Patients with hematological malignancies (HM) require intensive chemotherapy with curative intent, especially in case of AML that results in more frequent admissions to Intensive Care Units (ICU). Due to our knowledge, this study is the first multicenter retrospective analysis in Polish population. A total of 200 patients with HM hospitalized in 4 Polish hematological centers. Data concerning clinical indices and outcomes during admission and ICU stay were collected retrospectively. The most common hematological malignancy was acute leukemia (55%). The main cause of ICU admission was respiratory failure (88.5%), often accompanied by sepsis (58.5%) and acute renal failure (51.5%). In patients with hematological malignancies, the following factors were associated with ICU mortality: prolonged ICU stay (odd ratio [OR] = 6.98, 95% confidence interval [CI]: 1.38-35.33, χ2 = 5.61, p = 0.02), the presence of acute respiratory failure (odd ratio [OR] = 5.35, 95% confidence interval [CI]: 1.01–28.46, χ2 = 3.93, p = 0.04), and the need for renal replacement therapy (odd ratio [OR] = 8.75, 95% confidence interval [CI]: 1.23–62.11, χ2 = 4.78, p = 0.03). There were following associations with in-hospital mortality in patients with hematological malignancies: prolonged ICU stay (odd ratio [OR] = 10.12, 95% confidence interval [CI]: 1.85–55.37, χ2 = 7.21, p = 0.008), the presence of acute respiratory failure (odd ratio [OR] =5.24, 95% confidence interval [CI]: 1.36–20.16, χ2 = 5.87, p = 0.02), the need for catecholamine support (odd ratio [OR] =3.43, 95% confidence interval [CI]: 1.06–11.05, χ2 = 4.32, p = 0.04), and renal replacement therapy (odd ratio [OR] =5.55, 95% confidence interval [CI]: 1.14–26.92, χ2 = 4.59, p = 0.03). We have demonstrated that ICU and in-hospital mortalities among patients with hematological malignancies are still poor, but easier access to the intensive care unit and close cooperation between hematologists and intensivists may improve outcomes. We have found that acute failure of key organs (acute respiratory failure, end-stage renal failure requires renal replacement therapy) and length of ICU stay (but probably no comorbidities and illness severity) may have impact on mortality (both ICU and in-hospital).

Anticoagulant rodenticides are a group of substances used in rodent poisoning. Intake of these compounds can cause severe and life-threatening poisoning in humans. This article describes the case of patient with chronic hemorrhagic manifestations and a complex deficiency of coagulation factors caused by chronic rodenticide using.

Acute myeloid leukemia (AML) is a bone marrow malignancy characterized by uncontrolled proliferation of transformed myeloid precursors. It is the most common acute leukemia and is a highly heterogeneous disease. AML leads to impaired hematopoiesis, which may result in increased risk of infection. Toll-like receptors (TLRs) are major elements of the innate immune system which recognize pathogen-associated molecular patterns. They also have a role in autoimmune diseases and cancer through their recognition of endogenous danger-associated molecular patterns. Various TLRs were found to be expressed in AML cells, and their expression was found to affect growth, differentiation, and immunostimulatory capacity in AML. We retrospectively analysed 90 patients (48 females and 42 males) with diagnosis of AML, hospitalized in Department and Clinic of Hematology, Blood Neoplasms and Bone Marrow Transplantation of Wroclaw Medical University. The median age of patients was 62 (range:18-81). Infectious complications after induction chemotherapy occurred in 62 patients. In the present study, we detected the effect of seven single nucleotide polymorphisms (SNPs) located in the genes coding for TLR3 (rs5743305, rs3775296, 3775291), TLR4 (rs4986791, rs4986790) and TLR9 (rs187084, rs5743836). DNA was isolated from samples of peripheral blood taken on EDTA. Melting curve genotyping with the use of LightSNiP asays(TIB MOLBIOL, Germany) was employed to determining TLR3, TLR4 and TLR9 genotypes, and the reactions were performed LightCycler 480 device (Roche Applied Science, Germany).Statistical analyses were performer using Real Statistics Resource Pack for Microsoft Excel. We found that TLR3 rs5743305 AA homozygosity was more common in AML patients with infectious complications than in patients unaffected by infections (p=0.015). TLR4 rs4986791 C and TLR9 rs5743836 C were associated with lower levels of the inflammation marker CRP (p=0.015 and p=0.048, for rs4986791 and rs5743836, respectively), TLR4 rs4986791 C and was less frequently detected among patients with CRP>5 (p=0.028). We also found TLR9 rs187084 C to be more common in patients with adverse cytogenetic risk according to ELN criteria (0.012). Additionally, a trend for higher prevalence of extramedullary disease was observed for carriers of TLR3 rs3775296 T (p=0.054), TLR3 3775291 GG (p=0.068), TLR4 rs4986790 G (p=0.078), as well as TLR9 rs187084 TT (p=0.053). In conclusion, our results suggest that SNPs in the genes coding for TLR3, TLR4 and TLR9 may be implicated in clinical outcome of AML and is related with increased risk of infectious complications. Disclosures Wróbel: BMS: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria.

COVID-19, as a disease involving the endothelium of multiple organs, is characterized by high mortality rates among hospitalized patients. Patients with hematological malignancies are particularly at risk of an unfavorable course of COVID-19. The endothelial activation and stress index (EASIX) score has been used as a simple predictor of overall survival (OS) in specific groups of hematological cancer patients. EASIX, as a biomarker of endothelial dysfunction, might play a prognostic role in patients with COVID-19. Here, we performed a comprehensive retrospective analysis of the EASIX score in 523 hospitalized COVID-19 patients with or without coexisting hematological cancer. Hematological cancer COVID-19 patients had higher EASIX scores compared to the overall population with COVID-19. In hematological patients, EASIX was a strong predictor of the occurrence of sepsis during COVID-19. Our findings demonstrated EASIX as a strong predictor of intensive care unit admission, in-hospital mortality, the occurrence of acute renal failure and the need for hemodialysis, both in hematological and non-hematological COVID-19 patients. Patients with a high EASIX score on COVID-19 diagnosis had significantly inferior OS compared to patients with low EASIX. We showed for the first time that EASIX might serve as a simple, universal prognostic tool of OS in both hematological and non-hematological COVID-19 patients.

Bendamustine and ibrutinib are commonly used in the treatment of patients suffering from chronic lymphocytic leukemia (CLL). In this study we compare efficacy and safety bendamustine versus ibrutinib therapy in previously untreated patients with CLL. Because there are no head-to-head comparisons between bendamustine and ibrutinib, we performed indirect comparison using Bucher method. A systematic literature review was performed and 2 studies published before June 2016 were taken into analysis. Treatment with ibrutinib significantly improves PFS determined by investigator (HR of 0.3; P = .01) and OS (HR of 0.21; P < .001. Our study indicates that ibrutinib therapy improves PFS, OS and is superior in terms of safety comparing with bendamustine therapy in CLL patients.

BACKGROUND/AIM Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) play an important role in the initiation of angiogenesis. We aimed to assess whether polymorphisms within the genes coding for these angiogenic activators (VEGF (rs3025039;C>T) and bFGF (rs308395;G>C)) contribute to susceptibility and/or progression in multiple myeloma patients (MM) and to chemotherapy. PATIENTS AND METHODS One hundred and thirty-two patients with MM and 122 controls were genotyped for the VEGF and bFGF alleles by the PCR-RFLP technique. Genotyping results were compared regarding progression, risk of disease and response to treatment. RESULTS Patients in stage I-II disease (Durie-Salmon criteria) more frequently carried the bFGF -921G allele compared to patients in stage III (p=0.053) and healthy controls (OR=2.010, p=0.040). Progression after first-line chemotherapy was more frequent among patients carrying this variant (p=0.022). CONCLUSION Our results imply that the course of disease in MM patients is associated with a polymorphism within the bFGF gene.

B-cell chronic lymphocytic leukemia (B-CLL) presents with progressive accumulation of monoclonal B cells in the peripheral blood, bone marrow and lymphoid organs. B-CLL is characterized by heterogeneous clinical outcome. The expression of Toll-like receptors (TLRs) and their association with other prognostic factors in B-CLL patients remain unclear. The aim of our study was to evaluate the expression of TLR2, TLR4 and TLR9 genes and their significance as biological markers in patients with B-CLL. Sixty patients with newly diagnosed B-CLL were evaluated. The healthy control group included 20 age-matched individuals. Using quantitative reverse transcriptase PCR, the mRNA expression of genes TLR2, TLR4 and TLR9 was measured. TLR4 gene expression was lower in B-CLL patients as compared to the control group and TLR2 gene expression was higher in B-CLL patients than in healthy individuals. TLR9 gene expression was higher in the control group than in patients with B-CLL. TLR4 mRNA expression was lower in patients with advanced-stage CLL (Rai stages III and IV) than in patients with early stage disease (Rai stages 0–II). TLR2 gene expression was higher in patients with advanced-stage CLL (Rai stages III and IV) than in patients with early stage disease (Rai stages 0–II; p

Organic cation transporter 1 (OCT1) is one of the membrane proteins in the large solute carrier (SLC) family. It participates in the transport of organic cations, i.e. nutrients, neurotransmitters, metabolites or drugs in an electrogenic manner and translocate various cationic cytostatics. Knowledge concerning the expression of drug transporters in tumor cells may help to develop cytotoxic agents that are targeted to specific tumors. OCT1 expression and its relationship to the proliferation of cancer cells, development of metastases and resistance to chemotherapy has been observed in solid tumors. There is no data concerning the significance of OCT1 expression in the clinical course and treatment results in acute myeloid leukemia (AML). The objective of the study was firstly to evaluate OCT1 mRNA expression in patients with newly diagnosed de novo AML, and secondly to compare the obtained results to the healthy control group as well as analyze them according to leukemia subtypes, CD34 expression, cytogenetic and molecular factors and treatment results. 101 patients with AML, excluding the subtype classified as M3 by French-American-British (FAB) criteria, were analyzed. The control group consisted of 26 healthy individuals. The evaluated material was bone marrow (BM). Real-time quantitative polymerase chain reaction (RQ-PCR) was used in the study as a method of evaluating OCT1 mRNA expression. The study showed a statistically significant lower expression of OCT1 mRNA in patients with AML in comparison to the control group. The level of OCT1 mRNA expression was lowest for CD34+ leukemia. No significant correlation between OCT1 mRNA expression and cytogenetic and molecular factors was observed. A significant influence of OCT1 mRNA expression on the clinical outcome of the disease was observed: patients with lower expression had higher chances of achieving complete remission (CR) and longer overall survival (OS).

BACKGROUND There are several regimens used in hematopoietic stem cell (HSC) mobilization in multiple myeloma (MM). Cyclophosphamide (Cy) is one of the most commonly used agents, although it does not always result in collecting adequate number of CD34+ cells. Recently, cytarabine (Ara-C) has been proposed as potentially efficient and safe option. AIMS Since the data regarding Ara-C in HSC mobilization is limited, the aim of our study was to compare retrospectively the efficiency and toxicity of G-CSF combined with either Ara-C or Cy in MM patients. MATERIALS & METHODS Of a total of 89 patients, 43 received low or intermediate doses of Cy, and 46 were treated with 800 mg/m2 /day of Ara-C administered for two days. RESULTS The mean peak of CD34+ cells/ul in peripheral blood was 132 (range, 84-202) in Ara-C and 51 (range, 29-69) in Cy cohort (p < 0.001). The median number of collected CD34+ cells (×106/kg) was 10.3 (range, 4.2-17.9) vs 4.5 (range, 2.7-8.9), respectively (p < 0.001). Mobilization failure was observed in one patient in Ara-C cohort (2%) and in 8 patients treated with Cy (19%) (p = 0.013). In the Ara-C group 98% of patients obtained more than 4×106 CD34+ cells/kg required for tandem transplantation. Moreover, we observed a trend toward increased paraprotein levels measured at transplant compared to before HSC mobilization in Ara-C cohort and significantly higher transfusion rates in that group. CONCLUSION Our findings confirm higher HSC mobilization efficacy of Ara-C compared to Cy in MM patients. However, lower transfusions rate and better disease control of Cy may justify its use in some cases.

We retrospectively analyzed long-term disease outcome of 350 elderly Hodgkin Lymphoma (eHL) patients treated with ABVD/ABVD-like regimen enrolled in the PLRG-R9 study between 2001 and 2013 in Poland. Complete remission was reported for 73% of early (ES) and 61% advanced stage (AS) patients. Nine (10%) ES and 56 (20%) AS patients have died. With the median follow-up of 36 (1-190) months, 3-year EFS and OS was 0.74 (95%CI: 0.63-0.85) and 0.90 (95%CI: 0.82-0.98) for ES; 0.51 (95%CI: 0.44-0.57), and 0.81 (95%CI: 0.75-0.86) for AS patients, respectively. For ES patients, Cox regression revealed ECOG2 and age70 as predictive for inferior OS and EFS. For AS patients, the most predictive for OS was the presence of cardiovascular disorders (CVD) (p = .00044), while for EFS four factors were significantly associated with a poor outcome: ECOG 2, age70 years, CVD and extranodal disease. In conclusion, CVD significantly impacts outcomes of ABVD-treated advanced eHL patients.

Idelalisib is a selective inhibitor of phosphoinositide 3-kinase d , approved in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), first line CLL with del17p/TP53 mutation in patients unsuitable for immunochemotherapy and RR follicular lymphoma (FL) in whom at least two lines of therapy have failed. Despite good clinical efficacy, the development of this drug has been hampered due to its adverse events (i.e. autoimmune reactions and life-threatening opportunistic infections). In this retrospective study, we summarise the tolerability of idelalisib therapy in a Polish population, analysing 61 patients treated with idelalisib in monotherapy or idelalisib-based combination regimens. Idelalisib treatment was feasible for the majority of patients, with upper respiratory tract infections (N = 13.21%) being the most common adverse event (AE), and pneumonia (N = 11.18%) — the most prevalent grade 3 or higher non-hematological AE. We observed two cases of pneumonitis, one case of gastroenteritis, and no cases of liver transaminases elevation (all regarded as the AEs characteristic of idelalisib). Most of the patients were treated in haematology reference centres where physicians are more accustomed to dealing with opportunistic infections. Cotrimoxazole prophylaxis was given to 20 (32.8%) patients, whereas acyclovir prophylaxis was administered in 33 (54.1%) cases. This could explain the less frequent life-threatening infections and decreased mortality rate compared to the published registration studies. Our study confirms the high clinical efficacy of idelalisib in CLL and RR FL.

Monosomal karyotype (MK) and complex karyotype (CK) are poor prognostic factors in acute myeloid leukemia (AML). A comprehensive analysis of cytogenetic and clinical factors influencing an outcome of AML-CK+ was performed. The impact of cladribine containing induction on treatment results was also evaluated. We analyzed 125 patients with AML-CK+ treated within PALG protocols. MK was found in 75 (60%) individuals. The overall complete remission (CR) rate of 66 intensively treated patients was 62% vs. 28% in CK+ MK− and CK+ MK+ group (p = .01). No difference in CR rate was observed between DA and DAC arms. The overall survival (OS) in intensively treated patients was negatively influenced by MK, karyotype complexity (≥5 abnormalities), and WBC >20 G/L in multivariate analysis. The addition of cladribine to DA regimen improved OS only in MK− but not in MK+ group. In conclusion, concomitance of MK with ≥5 chromosomal abnormalities is associated with dismal treatment outcome in AMK-CK+.

MicroRNAs (miRs) are small non-coding RNAs that play important roles in cell differentiation and survival. Abnormal expression of miRs has been demonstrated in numerous types of cancer, including acute myeloid leukaemia (AML). The aim of the present study was to evaluate miR-181 expression at diagnosis and following the completion of chemotherapy in AML patients, with regard to clinical response and outcome, particularly in patients treated with azacitidine. miR-181 expression was analysed using reverse transcription-quantitative polymerase chain reaction in 95 bone marrow specimens from newly diagnosed AML patients and in 20 healthy subjects for comparison. The results revealed upregulated miR-181 expression in the total cohort of AML patients, which was correlated with longer survival. However, in a subset of older AML patients treated with azacitidine, low miR-181 expression at diagnosis was a predictor for complete remission and prolonged survival. The findings indicated that miR-181 has an important role in AML and determines response to azacitidine treatment in older AML patients.

AIM OF THE STUDY Azacitidine is a hypomethylating agent which is used in the treatment of myelodysplastic syndromes, acute myeloid leukemia and chronic myelomonocytic leukemia. Because of good tolerance to the drug, azacitidine can be administered both during hospitalization and in an outpatient setting. The aim of our retrospective analysis was to assess the efficacy of azacitidine treatment in patients with a myelodysplastic syndrome and with acute myeloid leukemia who had received treatment in hospital and in an ambulatory care setting. Offsets in the course of azacitidine administration and discontinuations of treatment have a negative impact on patients' response to the therapy. MATERIAL AND METHODS The study included 31 patients. Sixteen patients received azacitidine in an ambulatory care setting, 15 patients within their hospitalization. RESULTS A hematologic response was achieved in 48% of the patients. Forty-one percent of the cycles were delayed. In an outpatient setting, 62% of the cycles were administered systematically, while during hospitalization the patients received 54% of cycles on time. Administrative problems caused the delay of 26% of the cycles. CONCLUSIONS Azacitidine has a high tolerance level and a high safety profile which allows for its use in an outpatient care setting. Outpatient administration of azacitidine is feasible and safe without compromising efficacy.

Recent studies have suggested that cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide, and that dysregulation of Wnt/β-catenin pathway may be one of possible reasons of lenalidomide resistance. This prompted us to analyze the effect of polymorphisms within the genes coding for cereblon (CRBN (rs121918368 C>T)) and β-catenin (CTNNB1 (rs4135385 A>G; rs4533622 A>C)). MM patients (n=142) and healthy individuals (n=123) were genotyped using the Light SNiP assays. The presence of the CTNNB1 (rs4533622) A allele was more frequently detected in patients presented with stage II-III disease according to International Staging System (63/82 vs. 26/44, p=0.043) and Durie-Salmon criteria (75/99 vs. 14/26, p=0.049). The CTNNB1 (rs4135385) AA homozygosity was more frequent among patients with better response to CTD, i.e., cyclophosphamide-thalidomide-dexamethasone (18/23 vs. 32/60, p=0.047). Patients carrying the CTNNB1 (rs4533622) AA genotype were better responders to the first line therapy with thalidomide containing regimens (p

// Wojciech Wojtowicz 1 , Angelika Chachaj 2 , Andrzej Olczak 3 , Adam Ząbek 1 , Elzbieta Piątkowska 4 , Justyna Rybka 5 , Aleksandra Butrym 6, 7 , Monika Biedron 5 , Grzegorz Mazur 6 , Tomasz Wrobel 5 , Andrzej Szuba 2 and Piotr Mlynarz 1 1 Wroclaw University of Technology, Department of Bioorganic Chemistry, Wroclaw, Poland 2 Wroclaw Medical University, Department of Angiology, Wroclaw, Poland 3 Opole University of Technology, Faculty of Electrical Engineering, Automatic Control and Informatics, Opole, Poland 4 Wroclaw Research Centre EIT+, Wroclaw, Poland 5 Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland 6 Department of Internal Medicine, Wroclaw Medical University, Wroclaw, Poland 7 Department of Physiology, Wroclaw Medical University, Wroclaw, Poland Correspondence to: Piotr Mlynarz, email: piotr.mlynarz@pwr.edu.pl Keywords: metabolomics; haematological malignancies; nHL; AML; CLL Received: January 24, 2018 Accepted: April 07, 2018 Published: May 11, 2018 ABSTRACT Haematological malignancies are a frequently diagnosed group of neoplasms and a significant cause of cancer deaths. The successful treatment of these diseases relies on early and accurate detection. Specific small molecular compounds released by malignant cells and the simultaneous response by the organism towards the pathological state may serve as diagnostic/prognostic biomarkers or as a tool with relevance for cancer therapy management. To identify the most important metabolites required for differentiation, an 1 H NMR metabolomics approach was applied to selected haematological malignancies. This study utilized 116 methanol serum extract samples from AML (n= 38), nHL (n= 26), CLL (n= 21) and HC (n= 31). Multivariate and univariate data analyses were performed to identify the most abundant changes among the studied groups. Complex and detailed VIP-PLS-DA models were calculated to highlight possible changes in terms of biochemical pathways and discrimination ability. Chemometric model prediction properties were validated by receiver operating characteristic (ROC) curves and statistical analysis. Two sets of eight important metabolites in HC/AML/CLL/nHL comparisons and five in AML/CLL/nHL comparisons were selected to form complex models to represent the most significant changes that occurred.

OBJECTIVES PALG CLL4 is the first, randomized, phase IIIb study with rituximab, cladribine, and cyclophosphamide (RCC) induction and subsequent maintenance with rituximab in previously untreated chronic lymphocytic leukemia (CLL) patients. METHODS The induction treatment consisted of 6 RCC cycles regimen. Patients with complete response (CR) or partial response (PR) after an induction phase were randomized into a maintenance arm with rituximab or an observational arm. RESULTS In the intention-to-treat population, 97 patients completed the induction phase with an overall response rate (ORR) of 73.2% (CR 22.7%, PR 50.5%). Subsequently, 66 patients were randomized into the rituximab maintenance arm (n = 33) or the observational arm (n = 33). CR rates were 57.1% in the maintenance group vs 50% in the observational group. PFS was significantly longer in the rituximab maintenance vs the observational arm (P = .028). The multivariate Cox model indicated that del17p (P = .006) and elevated beta-2-microglobulin (P = .015) significantly increased the hazard ratio (HR) of progression, whereas the presence of CD38 (P = .013) significantly decreased it; maintenance therapy with rituximab (P

Background/aim There is limited amount of data available on the comparative efficacy of ibrutinib and idelalisib, the B-cell receptor inhibitors (BCRi) newly approved for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (r/r CLL/SLL) treatment. The aim of our study was to analyze and compare the outcomes of real-world r/r CLL/SLL patients treated with these two BCRi in outside clinical trials. Patients and methods A comparative case matched 1:2 analysis was performed on idelalisib combined with rituximab and ibrutinib efficacy in 102 patients with r/r CLL/SLL from two observational studies of the Polish Adult Leukemia Group (PALG). Results Both therapies produced similar overall response rates (idelalisib plus rituximab 76.4% and ibrutinib 72.1%). Median progression-free survival (PFS) and overall survival (OS) in both groups were not reached. Furthermore, no significant difference was observed between both BCRi regimens in regard to PFS (HR=0.75, 95% CI=0.30-1.86, p=0.55) and OS (HR=0.65, 95%CI=0.26-1.68, p=0.39). Conclusion In summary, the results of this retrospective analysis suggest that idelalisib combined with rituximab and ibrutinib therapies have comparable activity in r/r CLL/SLL in daily clinical practice.

Aim: Aberrant expression of microRNAs (miRs) has been proved to have a role in acute myeloid leukemias (AML), but there is no information on miR-331 in AML. Materials & methods: miR-331 expression has been analyzed using reverse-transcription polymerase chain reaction (RT-PCR) in 95 bone marrow specimens from newly diagnosed AML patients in comparison with 20 healthy subjects. Results: miR-331 was upregulated in AML patients and its expression seemed to influence remission achieving and death risk. The time of remission duration in patients with complete remission was longer in subjects with miR-331 downregulation after induction chemotherapy. Conclusion: we showed for the first time that miR-331 higher expression appears to be correlated with worse response to therapy and shorter survival of AML patients.

Toll-like receptors play an important role in the host defense against microorganisms. TLRs are mainly expressed in human immune-related cells, such as monocytes, neutrophils, macrophages, dendritic cells, T cells, B cells and NK cells. The expression or up-regulation of TLRs has been demonstrated in some tumors and tumor cell lines but the role of TLRs in pathogenesis and development of acute leukemias remains unclear. The aim of this study was to evaluate the expression of TLR2, TLR4 and TLR9 and their significance as prognostic factors in patients with acute leukemias treated with induction chemotherapy. 103 patients with newly diagnosed acute myeloid leukemia (AML) were evaluated (47 females and 56 males). The median age of patients was 51 years. Using quantitative reverse transcriptase PCR, the mRNA expression of genes TLR2, TLR4 and TLR9 was measured. The mRNA expression of TLR2 and TLR4 was significantly higher in patients with NR than in patients with CR and CRi. We especially observed that mRNA expression of TLR2 and TLR4 was significantly higher in patients with myelomonocytic and monoblastic acute leukemia than in patients with other types of AML. The mRNA expression of TLR2 and TLR4 was higher in AML patients than in healthy individuals, although there was no statistically significant difference. Patients with higher mRNA expression of TLR2 and TLR4 had significantly shorter OS than patients with lower mRNA expression of TLR2 and TLR4. Multivariate analysis showed that mRNA expression of TLR2 and the age of patients were independent factors associated with treatment response. Our results suggest that TLRs could be an independent prognostic factor for response rate after induction therapy in patients with acute myeloid leukemias.

Mechanical properties of biological structures play an important role in regulating cellular activities and are critical for understanding metabolic processes in cancerous cells and the effects of drugs. For some cancers, such as acute myeloid leukaemia, chemotherapy is one of preferential methods. However, due to the lack of selectivity to cancer cells, cytostatic agents cause toxicity to normal tissues. Here, we study the effect of doxorubicin (DOX) on the mechanical properties of DNA molecules, leukemic blast cells and erythrocytes, using optical tweezers. In addition, we controlled the subcellular distribution of the drug by confocal microscopy. Our results indicated that doxorubicin affects mechanical properties of cellular structures. In all cases the drug reduced mechanical strength of examined objects. For the leukemic cells the drug subcellular distribution was predominantly nuclear with some particulate cytoplasmic fluorescence. In erythrocytes, doxorubicin showed fluorescence mainly in cytoplasm and plasma membrane. The lowering of blast cells stiffness may be due to the interaction of doxorubicin with nuclear structures, especially with nucleic acids, as our studies with DNA confirmed. In addition, it is known that DOX inhibits the polymerization of actin and thus cytoskeletal modification may also be important in reducing of cell mechanical strength. In the case of erythrocytes - the non-nucleated cells, a significant effect on the decrease of cell stiffness, besides the cytoskeleton, may have the interaction of the drug with the cell membrane. Experiments with model phospholipid membranes confirmed that observed increase in cell elasticity originates, among other things, from the drug incorporation in the lipid membrane itself. The lowering of mechanical strength of leukemic cells may have an significant impact on the effectiveness of chemotherapy. However, the fact that doxorubicin interacts not only with proliferating cancer cells, but also with the health ones may explains the high toxicity of the drug at the therapeutic concentrations. Our observations also suggest that chemotherapy with doxorubicin may decrease the risk of vascular complications in acute leukemia, due to increasing the cell elasticity.

We present the case where immune thrombocytopenia (ITP) and essential thrombocythemia (ET) sequentially appeared in the space of twenty-one years of follow-up. Impaired platelet production is present in both diseases, but clinical presentation and treatment are different. On the basis of this case history a possible role of autoimmunity as a predisposing factor to myeloproliferation has been discussed.

Background Interim PET after two ABVD cycles (iPET2) predicts treatment outcome in classical Hodgkin’s lymphoma. To test whether an earlier assessment of chemosensitivity would improve the prediction accuracy, we launched a prospective, multicenter observational study aimed at assessing the predictive value of iPET after one ABVD (iPET1) and the kinetics of response assessed by sequential PET scanning. Patients and methods Consecutive patients with newly diagnosed classical Hodgkin’s lymphoma underwent interim PET scan after one ABVD course (iPET1). PETs were interpreted according to the Deauville score (DS) as negative (−) (DS 1–3) and positive (+) (DS 4, 5). Patients with iPET1 DS 3–5 underwent iPET2. Results About 106 early (I–IIA) and 204 advanced (IIB–IV) patients were enrolled between January 2008 and October 2014. iPET1 was (−) in 87/106 (82%) or (+) in 19/106 (18%) of early, and (−) in 133/204 (65%) or (+) in 71/204 (35%) of advanced stage patients, respectively. Twenty-four patients were excluded from response analysis due to treatment escalation. After a median follow-up of 38.2 (3.2–90.2) months, 9/102 (9%) early and 43/184 (23%) advanced patients experienced a progression-free survival event. At 36 months, negative and positive predictive value for iPET1 were 94% and 41% (early) and 84% and 43% (advanced), respectively. The kinetics of PET response was assessed in 198 patients with both iPETs. All 116 patients with iPET1(−) remained iPET2(−) (fast responders), 41/82 with IPET1(+) became iPET2(−) (slow responders), and the remaining 41 stayed iPET2(+) (non-responders); progression-free survival at 36 months for fast, slow and non-responders was 0.88, 0.79 and 0.34, respectively. Conclusion The optimal tool to predict ABVD outcome in HL remains iPET2 because it distinguishes responders, whatever their time to response, from non-responders. However, iPET1 identified fast responders with the best outcome and might guide early treatment de-escalation in both early and advanced-stage HL.