Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study.

BACKGROUND: PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximab vedotin for relapsed or refractory classical Hodgkin lymphoma. METHODS: In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximab vedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed. FINDINGS: Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4-33·0), median progression-free survival was 13·2 months (95% CI 10·9-19·4) for pembrolizumab versus 8·3 months (5·7-8·8) for brentuximab vedotin (hazard ratio 0·65 [95% CI 0·48-0·88]; p=0·0027). The most common grade 3-5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximab vedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receiving pembrolizumab and 16 (11%) of 152 patients receiving brentuximab vedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group. INTERPRETATION: Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post-autologous HSCT or are ineligible for autologous HSCT. FUNDING: Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA).

The diagnostic and prognostic significance of flow cytometric bone marrow assessment in myelodysplastic syndromes according to the European LeukemiaNet recommendations in single-centre real-life experience.

INTRODUCTION: This analysis attempts to determine the diagnostic and prognostic value of bone marrow (BM) evaluation by multiparameter flow cytometry in patients with myelodysplastic syndrome (MDS). MATERIALS AND METHODS: The study group consisted of patients who underwent diagnostic process in the years 2008-2017 due to cytopenia and finally were diagnosed with MDS (n = 71). The comparative group included patients with cytopenia diagnosed in the same period, whose definitive diagnosis was other than MDS (n = 39). Flow cytometric evaluation of BM was performed following the recommendations of the European LeukemiaNet (ELN) in all patients. RESULTS: The median number of immunophenotypic abnormalities found on granulocytes in the MDS group was significantly higher compared to the comparative group [2 (range 0-5) vs 0 (range 0-2); P < .0001]. Similarly, the median Ogata score was significantly higher in the MDS group [2 (range 0-4) vs 1 (range 0-3); P < .0001]. Since the disturbances of the CD11b/HLA-DR and CD11b/CD13 on granulocytes were significantly more common in MDS patients, the Ogata score was extended by these abnormalities, what resulted in its higher diagnostic sensitivity (82%) while preserving high specificity (87%). The positive correlation was found between risk score determined by the Revised International Prognostic Scoring System and the number of the BM immunophenotypic abnormalities (P = .017). CONCLUSIONS: Our results indicate that the diagnostic usefulness of the Ogata score may be increased by including the abnormal expression of CD11b/HLA-DR and CD11b/CD13 on granulocytes. Moreover, our findings suggest the prognostic significance of the number of BM cytometric abnormalities in MDS.

Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. RESULTS: At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2. CONCLUSIONS: The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).

Autologous hematopoietic stem cell transplant for progressive diffuse systemic sclerosis: procedural success and clinical outcome in 5-year follow-up.

Systemic sclerosis is an autoimmune connective tissue disease affecting both skin and internal organs. Progressive disease with multiple organ involvement is considered to have a poor prognosis. Treatment possibilities are limited, but certain patients may benefit from autologous hematopoietic stem cell transplantation (auto-HSCT). We report a case of a 30-year-old woman with progressive diffuse systemic sclerosis treated with parenteral cyclophosphamide with unsatisfactory results. Due to progression of the disease and lack of alternative therapies auto-HSCT was performed. After instituting treatment with autologous hematopoietic stem cell transplantation no immunosuppressive therapy has been required during 5-year follow-up. Improvement in exertion tolerance, partial regression of skin lesions and stabilization of pulmonary and cardiovascular changes were observed. Currently therapeutic options in patients with progressive systemic sclerosis are limited. Hematopoietic stem cell transplantation might become an alternative therapeutic solution not only in the early phase of the disease but also among selected patients with progressive systemic sclerosis resistant to standard therapy.

NPM1 alternative transcripts are upregulated in acute myeloid and lymphoblastic leukemia and their expression level affects patient outcome.

BACKGROUND: Expression of the NPM1 gene, encoding nucleophosmin, is upregulated in cancers. Although more than ten NPM1 transcripts are known, the reports were usually limited to one predominant transcript. In leukemia, the NPM1 expression has not been widely studied so far. In acute myeloid leukemia (AML), the mutational status of the gene seems to play a pivotal role in carcinogenesis. Therefore, the aim of the study was to quantify alternative NPM1 transcripts in two types of acute leukemia, AML and ALL (acute lymphoblastic leukemia). METHODS: Using droplet digital PCR, we analyzed the levels of three protein-coding NPM1 transcripts in 66 samples collected from AML and ALL patients and 16 control samples. Using RNA-seq, we detected 8 additional NPM1 transcripts, including non-coding splice variants with retained introns. For data analysis, Welch two sample t-test, Pearson's correlation and Kaplan-Meier analysis were applied. RESULTS: The levels of the particular NPM1 transcripts were significantly different but highly correlated with each other in both leukemia and control samples. Transcript NPM1.1, encoding the longest protein (294 aa), had the highest level of accumulation and was one of the most abundant transcripts in the cell. Comparing to NPM1.1, the levels of the NPM1.2 and NPM1.3 transcripts, encoding a 265-aa and 259-aa proteins, were 30 and 3 times lower, respectively. All three NPM1 transcripts were proportionally upregulated in both types of leukemia compared to control samples. In AML, the levels of NPM1 transcripts decreased in complete remission and increased again with relapse of the disease. Low levels of NPM1.1 and NPM1.3 were associated with better prognosis. The contribution of non-coding transcripts to the total level of NPM1 gene seemed to be marginal, except for one short 5-end transcript accumulated at high levels in AML and control cells. Aberrant proportions of particular NPM1 splice variants could be linked to abnormal expression of genes encoding alternative splicing factors. CONCLUSIONS: The levels of the studied NPM1 transcripts were different but highly correlated with each other. Their upregulation in AML and ALL, decrease after therapy and association with patient outcome suggests the involvement of elevated NPM1 expression in the acute leukemia pathogenesis.

Mean platelet volume as a predictive marker for venous thromboembolism and mortality in patients treated for diffuse large B-cell lymphoma.

It has been suggested that mean platelet volume (MPV) is associated with the risk of venous thromboembolism (VTE) and increased mortality in patients with cancer. We evaluated the association of MPV with VTE and mortality in patients treated for diffuse large B-cell lymphoma (DLBCL). Retrospective analyses were performed on 184 adult patients (median age 59, 55% men), of whom 141 were newly diagnosed, and 43 had relapse/refractory DLBCL. During the observation period (median 499 days), 39 (21.2%) patients developed VTE. Thirty-nine patients died of various causes. In univariate analysis, only the MPV and the treatment line were associated with the occurrence of VTE. In multivariate analysis, MPV ≤10th percentile (odd ratio 1.81; 95% confidence interval 1.06-3.11, p = 0.03) and salvage therapy (odd ratio 2.46; 95% confidence interval 1.66-3.65, p < 0.001) remained significant factors for developing VTE. Other patient-related factors-age, gender, disease-related factors-stage, the International Prognostic Index score, DLBCL subclassification (the germinal centre type and the activated B-cell type), Ki-67 index and VTE risk assessment model failed to be prognostic for VTE. In a Kaplan-Meier analysis, patients with MPV >10th percentile had statistically significantly longer VTE-free survival than patients with lower MPV. In multivariable Cox regression analysis, MPV ≤10th percentile (hazard ratio 5.56, p < 0.001), male gender, age, Ki-67 index, high or high-intermediate International Prognostic Index and VTE development (hazard ratio 7.81, p = 0.029) all significantly correlated with the risk of mortality. The probability of survival was higher in patients with MPV >10th percentile. In conclusion, our results suggest that the pre-chemotherapy MPV value is a cheap and available parameter that may be a useful prognostic marker for a significant risk of VTE and inferior survival rates in patients with DLBCL.

Clinical usefulness of serum free light chains measurement in patients with multiple myeloma: comparative analysis of two different tests.

INTRODUCTION: There are two commercially available tests for measurement of serum free light chains (sFLC) in multiple myeloma (MM) patients - Freelite and N Latex FLC. The aim of this study was to perform an assessment and direct comparison of the usefulness of the methods in routine clinical practice. METHODS: 40 refractory/relapsed MM patients underwent routine disease activity assessment studies, along with sFLC analysis using both assays. Correlation and concordance between the tests and sensitivity of studied methods of sFLC assessment were established. Special attention was focused on sFLC results in patients finally evaluated after completing the treatment. RESULTS: A weak correlation for the measurement of both κ [Passing-Bablok slope (PB) = 0.7681] and λ chains [(PB) = 1.542] was found. Using Bland-Altman plots, a bias of 0.0467 (κ) and -0.2133 (λ) between the measurements was documented. The concordance coefficient equaled 0.87 for κ, 0.62 for λ and 0.52 for κ/λ ratio. Ten patients had an abnormal Freelite assay κ/λ ratio and normal N Latex FLC κ/λ ratio. Three of these patients had negative serum protein electrophoresis results and fulfilled diagnostic criteria of stringent complete remission (sCR) according to N Latex FLC (but not according to Freelite). When the κ/λ ratio obtained by both methods was compared to patients' serum/urine protein electrophoresis and immunofixation results, sensitivity of Freelite and N Latex FLC was established to be 62.5% and 41%, respectively. CONCLUSIONS: There was no strong correlation or concordance between the two assays, and the sensitivity in terms of sFLC detection was different. This may cause problems when diagnosis of sCR is considered.

Successful treatment of pulmonary candidiasis and aspergillosis in patient with refractory Hodgkin lymphoma using micafungin - case study and brief literature review.

The number of patients with hematological malignancies who develop invasive fungal disease (IFD) has increased dramatically in recent decades. This increase is attributed to impairment of the host immune system due to intensive cytotoxic chemotherapies, use of corticosteroids and profound immunosuppression after hematopoietic stem cell transplantation (HSCT). Additionally, the increasing prevalence of fungal infections caused by emerging and rare pathogens, IFD of mixed etiology or of atypical localization is observed. There are also much more patients with IFD who do not belong to a well-described risk group, like patient with lymphoproliferative disorders. Within this heterogeneous group of patients, IFD epidemiology is not well defined and antifungal prophylaxis practices vary. The aim of this paper is to present the case of a 58-year-old patient with refractory Hodgkin disease, focusing on infectious complication after subsequent lines of chemotherapy. During deep and prolonged neutropaenia the patient developed symptoms of pneumonia. Despite antifungal prophylaxis with fluconazole, IFD of mixed etiology with the presence of Candida glabrata and Aspergillus fumigatus was diagnosed. The infection showed a poor response to monotherapy with liposomal amphotericin B, but was successfully treated with therapy involving micafungin. Analysis of the presented case demonstrated the necessity of new approaches to the prevention of IFD in patients with lymphoproliferative disorders heavily pretreated with numerous chemotherapy protocols. Prolonged neutropenia and high corticosteroid exposure put these patients in high risk of IFD like patients with acute myeloid leukemia/myelodysplastic syndrome or after allogeneic HSCT.

Mild chronic graft-versus-host disease may alleviate poor prognosis associated with FLT3 internal tandem duplication for adult acute myeloid leukemia following allogeneic stem cell transplantation with myeloablative conditioning in first complete remission: a retrospective study.

Internal tandem duplication (ITD) of the FLT3 gene (Fms-like tyrosine kinase 3) is the most commonly found mutation in acute myeloid leukemia (AML). The significance of FLT3-ITD at diagnosis was retrospectively estimated for allo-HSCT (allogeneic hematopoietic stem cell transplantation) outcomes in 140 patients, median age of 38, undergoing allo-HSCT after myeloablative conditioning in first complete remission of AML. FLT3-ITD was detected at AML diagnosis in 42/140 (30%) of included into this study patients. At 3 years, relapse incidence (RI) following allo-HSCT in AML patients with intermediate or normal karyotype was significantly higher in those FLT3-ITD positive than FLT3-ITD negative [52.9 vs. 20.4%, P = 0.002]. Additionally, patients with mild chronic graft-versus-host disease (cGvHD) had significantly lower RI compared to patients with moderate or severe grade cGvHD or those not experiencing cGvHD, respectively, 4.8 vs. 36.0 vs. 27.8%, P = 0.032. FLT3-ITD was harboring a poor prognosis in AML with intermediate or normal karyotype and significantly increased risk of relapse following allo-HSCT. It appears that allo-HSCT does not cure patients with FLT3-ITD, unless they develop symptoms of mild cGvHD and graft versus leukemia, which may decrease RI.

Quality of life in chronic myeloid leukaemia patients after haematopoietic cell transplantation pretreated with second-generation tyrosine kinase inhibitors.

AIM OF THE STUDY: The majority of patients with chronic myeloid leukaemia (CML) respond to tyrosine kinase inhibitors (TKI), while allogeneic haematopoietic cell transplantation (HCT) is indicated in selected clinical situations. HCT carries the risk of severe complications, while the toxicity profile of dasatinib and nilotinib may lead to adverse reactions affecting the quality of life (QoL). We present the results of observational analysis of CML patients who underwent HCT after exposure to second-generation TKI (TKI2), with respect to their quality of life assessed comparatively after transplantation. MATERIAL AND METHODS: Eligible subjects included 19 patients. The quality of life and global health assessment were performed with a questionnaire comparing the signs and symptoms present during the TKI2-therapy with those related to post-transplant complications, including psychosocial problems. RESULTS AND CONCLUSIONS: Most patients had no/few problems with exhausting activities, no/few difficulties during long-distance walks, and do not/rarely rest in the daytime. Seventeen (89.5%) patients reported at least one symptom related to TKI2-therapy and most of them disappeared after HCT. Thirteen (68.4%) patients noted no serious complication after HCT. Most patients claimed to have a very good QoL and general health compared to the period prior to HCT. We found statistically significant improvement in global health (p = 0.016) and QoL (p = 0.043) after HCT. From the survivors perspective, HCT influence positively general health and QoL comparing to TKI2-therapy period. Further studies on larger group of patients will more precisely define the QoL level and possible predictors of changes in QoL, to assess which group of patients needs psychological support.

Role of Donor Activating KIR-HLA Ligand-Mediated NK Cell Education Status in Control of Malignancy in Hematopoietic Cell Transplant Recipients.

Some cancers treated with allogeneic hematopoietic stem cell transplantation (HSCT) are sensitive to natural killer cell (NK) reactivity. NK function depends on activating and inhibitory receptors and is modified by NK education/licensing effect and mediated by coexpression of inhibitory killer-cell immunoglobulin-like receptor (KIR) and its corresponding HLA I ligand. We assessed activating KIR (aKIR)-based HLA I-dependent education capacity in donor NKs in 285 patients with hematological malignancies after HSCT from unrelated donors. We found significantly adverse progression-free survival (PFS) and time to progression (TTP) in patients who received transplant from donors with NKs educated by C1:KIR2DS2/3, C2:KIR2DS1, or Bw4:KIR3DS1 pairs (for PFS: hazard ratio [HR], 1.70; P = .0020, Pcorr = .0039; HR, 1.54; P = .020, Pcorr = .039; HR, 1.51; P = .020, Pcorr = .040; and for TTP: HR, 1.82; P = .049, Pcorr = .096; HR, 1.72; P = .096, Pcorr = .18; and HR, 1.65; P = .11, Pcorr = .20, respectively). Reduced PFS and TTP were significantly dependent on the number of aKIR-based education systems in donors (HR, 1.36; P = .00031, Pcorr = .00062; and HR, 1.43; P = .019, Pcorr = .038). Furthermore, the PFS and TTP were strongly adverse in patients with missing HLA ligand cognate with educating aKIR-HLA pair in donor (HR, 3.25; P = .00022, Pcorr = .00045; and HR, 3.82; P = .027, Pcorr = .054). Together, these data suggest important qualitative and quantitative role of donor NK education via aKIR-cognate HLA ligand pairs in the outcome of HSCT. Avoiding the selection of transplant donors with high numbers of aKIR-HLA-based education systems, especially for recipients with missing cognate ligand, is advisable.

Pretransplantation use of the second-generation tyrosine kinase inhibitors has no negative impact on the HCT outcome.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (HCT) was a standard therapy in chronic phase (CP) chronic myeloid leukemia (CML). As a result of the effective therapy with tyrosine kinase inhibitors (TKI), HCT was shifted to defined clinical situations. We present the results of observational prospective analysis of 28 CML patients undergoing HCT after exposure to, at least, two lines of TKI (including dasatinib and/or nilotinib), with respect to response, overall survival (OS), treatment toxicity, graft versus host disease (GVHD), and progression/relapse incidence. RESULTS: All the patients but one engrafted with median time 19 days. OS for patients in CP1 and CP2/accelerated phase (AcP) were 92.9 and 85.7 %, respectively. Six patients allotransplanted in blast crisis (BC) CML died early after HCT. Eighteen patients achieved deep molecular remission (MR(4.5) or MR(4.0)). Relapse incidence was 29.6 %. Median time to progression (TTP) differs significantly depending on the CML phase prior to HCT, the best response achieved after HCT and development of chronic GvHD. NRM yielded the values 7.1, 12.5, and 50 % in CP1, CP2/AcP, and BC, respectively. Fatal outcome, due to veno-occlusive disease (VOD), was observed in two (7 %) patients. In five (17.9 %) patients, mild or moderate VOD was observed with no negative impact of preceding therapy with TKI2. Acute GvHD was diagnosed in 25.9 % of patients, while chronic GvHD developed in 42.9 % of individuals. CONCLUSION: Pretransplantation therapy with TKI2 in CP CML is safe and reasonable. In BC, the optimal approach before HCT is to reduce the leukemic burden and achieve subsequent CP.

The roles of consolidation and maintenance therapy with novel agents after autologous stem cell transplantation in patients with multiple myeloma.

Novel agents including immunomodulatory drugs and proteasome inhibitors incorporated into induction regimens and subsequently followed by autologous stem cell transplantation in cases of multiple myeloma have resulted in enhancement of response rate and its depth. Maintaining or even improving the response is an important treatment goal. Most clinical trials have revealed increased progression-free survival after consolidation and maintenance therapy. Some of them have also shown prolongation of overall survival. However, continuous therapy may be associated with significant side effects and costs, and therefore remains controversial. Treatment decisions should be individualized and based upon projected benefits and risks.

Assessing the efficacy of allogeneic hematopoietic stem cells transplantation (allo-HSCT) by analyzing survival end points in defined groups of acute myeloid leukemia patients: a retrospective, multicenter Polish Adult Leukemia Group study.

The importance of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for survival outcomes in patients with acute myeloid leukemia (AML) currently remains unclear. The study aimed to compare measures of clinical treatment for patients with AML in CR1 (the first complete remission) with or without being subjected to allo-HSCT. These consisted of leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality disease (NRM). Subjects were 622 patients, median age of 44, forming part of the prospective, randomized, and multicenter clinical Polish Adult Leukemia Group trials during 1999-2008. The Mantel-Byar approach was used to assess allo-HSCT on survival endpoints, accounting for a changing transplant status. Undergoing allo-HSCT significantly improved the LFS and OS for the entire group of patients with AML in CR1, along with the DAC induction subgroup and for the group with unfavorable cytogenetics aged 41-60. The CIR demonstrated that allo-HSCT reduced the risk of relapse for patients with AML in CR1 and those with an unfavorable cytogenetic risk. In addition, the NRM analysis showed that allo-HSCT significantly reduced the risk of death unrelated to relapse for the entire group of AML patients in CR1 and aged 41-60. The allo-HSCT treatment particularly benefitted survival for the AML in CR1 group having an unfavorable cytogenetic prognosis.

[Point mutations of genes encoding proteins involvedin RNA splicing in patients with myelodysplastic syndromes]. / Mutacje punktowe genów kodujacych bialka biorace udzial w splicingu RNA u chorych z zespolami mielodysplastycznymi.

The myelodysplastic syndromes (MDS) constitute heterogeneous group of clonal disorders, characterized by ineffective hematopoiesis, peripheral cytopenia and increased risk of acute myeloid leukemia development. Molecular mechanisms behind MDS have not been fully explained, however recent studies based on new technologies confirmed that epigenetic abnormalities and somatic mutation in the spliceasome machinery are crucial in pathogenesis of these diseases. Abnormal mRNA splicing (excision of intronic sequences from mRNA) has been found in over half of all MDS patients and resulted in accumulation of cytogenetical and molecular changes. The biological impact of splicing factor genes mutations has been evaluated only in a limited extend and current studies concentrate on analysis of MDS transcriptome. Molecular characteristic of classical and alternative splicing is presented in the paper, according to current knowledge. We review the most prominent findings from recent years concerning mutation in the spliceasome machinery with respect to MDS phenotype and disease prognosis. Perspectives in applying of novel diagnostic and therapeutic possibilities for myelodysplasia, based on spliceosome mutations identification are also presented.

Successful treatment of Epstein-Barr virus-related post-transplant lymphoproliferative disease with central nervous system involvement following allogeneic haematopoietic stem cell transplantation - a case study.

Post-transplant lymphoproliferative disease (PTLD) is a rare but severe form of Epstein-Barr virus (EBV)-driven complication that develops in patients after haematopoietic stem cell transplantation. In rare cases it manifests as primary central nervous system (CNS) involvement, which is thought to be the most unfavourable localisation with respect to outcome. Disease confined to the CNS is much more challenging than systemic PTLD, and one of the contributing factors is the limited drug penetration across the blood-brain barrier. We describe the case of a 29-year-old woman who was successfully treated for PTLD with CNS involvement. The patient was diagnosed with T-cell lymphoblastic lymphoma and underwent the procedure of haematopoietic stem cell transplantation from an unrelated donor. Two months after transplantation she manifested severe headache and progressive mental deterioration accompanied by enlargement of the lymph nodes. Magnetic resonance imaging (MRI) scan revealed segmental, asymmetrical thickening of the meninges. Based on the clinical picture and the laboratory findings diagnosis of PTLD was made. The patient was effectively treated with reduction of immunosuppressive therapy and intravenous rituximab. Initially started intrathecal chemotherapy was stopped due to iatrogenic complications. We conclude that in this case the involvement of meninges in the course of the lymphoproliferative process might have compromised the blood-brain barrier. This factor probably improved rituximab's penetration to CNS, contributing to our patient's recovery.

Donor NK cell licensing in control of malignancy in hematopoietic stem cell transplant recipients.

Among cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), some are sensitive to natural killer (NK) cell reactivity, described as the "missing self" recognition effect. However, this model disregarded the NK cell licensing effect, which highly increases the NK cell reactivity against tumor and is dependent on the coexpression of inhibitory killer cell immunoglobulin-like receptor (iKIR) and its corresponding HLA Class I ligand. We assessed clinical data, HLA and donor iKIR genotyping in 283 patients with myelo- and lymphoproliferative malignancies who underwent HSCT from unrelated donors. We found dramatically reduced overall survival (OS), progression free survival (PFS), and time to progression (TTP) among patients with malignant diseases with the lack of HLA ligand cognate with this iKIR involved in NK cell licensing in corresponding donor (events 83.3% vs. 39.8%, P = 0.0010; 91.6% vs. 47.7%, P = 0.00010; and 30.0% vs. 17.3%, P = 0.013, for OS, PFS, and TTP, respectively). The extremely adverse PFS have withstand the correction when patient group was restricted to HLA mismatched donor-recipient pairs. The incidence of aGvHD was comparable in two groups of patients. In malignant patients after HSCT the missing HLA ligand for iKIR involved in NK cell licensing in corresponding donor ("missing licensing proof") induced extremely adverse survival of the patients due to the progression of malignancy and not to the aGvHD. Avoiding the selection of HSCT donors with the "missing licensing proof" in the malignant patient is strongly advisable.

The relationship between mean platelet volume and thrombosis recurrence in patients diagnosed with antiphospholipid syndrome.

Increased mean platelet volume (MPV) is associated with platelet reactivity and is a predictor of cardiovascular risk and unprovoked venous thromboembolism. The aim of our study was to evaluate MPV in patients with confirmed antiphospholipid antibody syndrome (APS) and to identify the correlation between the value of MPV and the recurrence of thrombosis. The studied group consists of 247 patients with a history of thrombosis and/or pregnancy loss (median age 38, range 18-66 years) classified as APS group (n = 70) or APS negative patients (n = 177) according to the updated Sapporo criteria. The control group consisted of 98 healthy subjects. MPV was significantly higher in the group of patients with clinically and laboratory confirmed APS (median 7.85, range 4.73-12.2 fl) in comparison with the controls. It was also higher than in APS negative patients (7.61, range 5.21-12.3 fl). APS patients with triple positivity for antiphospholipid antibodies with respect to Miyakis classification categories had higher MPV values than other APS patients (9.69 ± 1.85 vs. 7.29 ± 1.3 fl, p = 0.001). Recurrent thrombotic episodes were observed in 83 patients, but among the triple positive high-risk patients with APS in 80 % cases (p = 0.0046). In receiver operating characteristic curve analysis, the value of MPV level for thrombosis recurrence prediction in the APS group with sensitivity of 86 % and specificity of 82 % was 7.4 fl. In the multivariate logistic regression model, MPV above 7.4 fl (OR 3.65; 95 % CI 1.38-9.64, p = 0.009) significantly predicts thrombosis recurrence. Our results identify the value of MPV as a prognostic factor of thrombosis recurrence in patients with APS.

Primary systemic amyloidosis as a real diagnostic challenge - case study.

Primary amyloidosis (AL) is a rare variety of plasma cell dyscrasia, the diagnosis of which is often difficult to establish. Pathogenesis of amyloidosis involves extracellular deposition of insoluble protein fibrils in tissues, leading to insufficiency of affected organs. According to various sources, mean survival rate of patients with primary amyloidosis ranges from 12 to 24 months, making primary amyloidosis a disease with a very poor prognosis. Survival rate is significantly lowered in case of cardiac manifestation of amyloidosis (about 6 months survival in untreated patients). In recent years a considerable progress in AL treatment has been observed. Nowadays we are able not only to delay progression of amyloidosis, but also to improve the function of the affected organs. Unfortunately as first signs and symptoms of AL are usually nonspecific, the diagnosis of AL is often delayed, resulting in late introduction of optimal therapy. There are many diagnostic tests which can be used in diagnostic process of amyloidosis, i.e. electrophoresis, serum and urine immunofixation or affected organs and bone marrow biopsy. On establishing the diagnosis in a patient with suspected amyloidosis it should be remembered that particular diagnostic methods vary considerably in sensitivity. The aim of this paper is to present a case report of a 27-year-old patient with primary amyloidosis focusing on diagnostic aspect of this condition. On the basis of this case, the authors would like to emphasize the value of precise diagnostic process, with immunological techniques playing undoubtedly a crucial role.

Spontaneous hematological remission of acute myeloid leukemia.

Spontaneous remission (SR) of acute myeloid leukemia (AML) in adults is observed very rarely. To date, about 100 cases have been presented in the literature. To our best knowledge, we describe the first adult Polish patient suffering from acute myelomonocytic leukemia (48, XY, +13, +21/46, XY), in whom after supportive therapy, including non-irradiated, non-leukocyte depleted red cell transfusions and low-dose corticosteroid, we observed resolution of the disease without cytogenetic remission. We suggest a potential transfusion-associated graft versus-host-diseases (TA-GVHD) and graft-versus leukemia (GVL) reaction which might lead to spontaneous hematological remission. However, we did not observe clinical symptoms of such reactions apart from a short episode of non-infectious diarrhea. Additionally, steroids were administered but their role in inducing SR, in our opinion, seems less probable. This 77-year-old man remained in SR for 7 months, when repeated analysis showed AML recurrence. He died due to septic shock 2.5 months later. Additionally, we present a review of the literature.