Ferritinemia and serum inflammatory cytokines in Swedish adults with Gaucher disease type 1.

BACKGROUND: The storage of glucosylceramide in macrophages produces an inflammatory response in Gaucher disease type 1 (GD1) resulting in iron metabolism dysregulation and cytokine release. PATIENTS AND METHODS: The study included 16 adults with GD1 aged 20-86years. All but one patient carried at least one allele with the c.1226A>G (N370S) mutation in the GBA1 gene. Ferritinemia, iron metabolism profiles including hepcidin, and inflammatory cytokine concentrations were assessed in GD1 patients in Sweden. RESULTS: Hyperferritinemia was present in 81% of patients. There was no correlation between hyperferritinemia and patient's gender, spleen status, or clinical status. Hepcidin was discrepantly low in relation to ferritin levels. TNF-α was moderately increased in 5 of 11 patients; 2 patients with the highest TNF-α concentrations showed mildly elevated IL-6 levels. The concentrations of IL-1ß, IL-8, and IL-10 were normal in all patients. Upon treatment, ferritinemia ameliorated but S-ferritin levels did not normalize. The increased TNF-α level however, normalized in all treated patients, reaching the lowest values after 2years of therapy and continued to be stable during the remaining 2years of follow-up. CONCLUSIONS: Hyperferritinemia is a frequent finding in GD1 in Sweden. The relatively low hepcidin levels reveal a distorted relationship between hepcidin and ferritin in GD1. Therapy has the potential to not only ameliorate hyperferritinemia but to also normalize the serum TNF-α concentration in GD1.

Primary Cardioprotection Reduces Mortality in Lymphoma Patients with Increased Risk of Anthracycline Cardiotoxicity, Treated by R-CHOP Regimen.

BACKGROUND: Advances in anti-lymphoma therapy prolong overall survival, making late adverse effects, like doxorubicin-related cardiotoxicity, an even more important clinical issue. The effectiveness of cardioprotective strategies with close monitoring, angiotensin-converting enzyme inhibitors and/or ß-blockers as well as liposomal doxorubicin are still unconfirmed in clinical practice. METHODS: This study evaluated the role of a primary cardioprotection strategy in preventing cardiovascular mortality and heart failure occurrence in non-Hodgkin lymphoma (NHL) patients with a high risk of anthracycline cardiotoxicity. Thirty-five NHL patients were subjected prospectively to ramipril and/or bisoprolol at NHL diagnosis, before implementing doxorubicin-containing regimens. Additionally, patients with a diagnosis of asymptomatic/mild heart failure received the liposomal form of doxorubicin. The clinical outcome and frequency of all serious cardiac events were compared with the results in a historical cohort of 62 high-risk cases treated without primary cardioprotection. RESULTS: NHL patients with a primary cardioprotection strategy did not experience cardiovascular deaths in contrast to the retrospective control group where cardiovascular mortality was 14.5% at 3 years (p < 0.05). Primary cardioprotection also decreased the frequency of new cardiotoxicity-related clinical symptoms (2.8 vs. 24.1%; p < 0.05) and prevented the occurrence of cardiac systolic dysfunction (0 vs. 8.5%, respectively; p < 0.05). Although the study was not planned to detect any survival benefit, it demonstrated a trend towards increased response rates (complete response 82 vs. 67%; p not significant) and prolonged survival (projected 5-year overall survival 74 vs. 60%; p < 0.05) for patients treated with primary cardioprotection. CONCLUSIONS: A primary personalized cardioprotection strategy decreases the number of cardiac deaths and may potentially prolong overall survival in NHL patients with increased risk of anthracycline cardiotoxicity.

[Psychological health's predictors of patients after bone marrow transplantation (BMT) 40 years of psychological researches of patients with blood cancers].

A study on the psychological health`s predictors of patents after BMT is presented. The theoretical base of researches is Helena Wrona- Polanska's Functional Model of Health (FMH Wrona-Polanska 2003), in which health is a function of creative coping with stress. 110 patients after BMT - 64 males and 46 females ­ at the Hematology Clinic of Jagiellonian University of Collegium Medicum, were studied clinically. Examined methods were the questionnaires: Spielberger`s STAI, Endler`s, Parker`s CISS and CHIP, Antonovsky`s SOC-29, Rosenberg`s self-esteem scale, 10-point rating scales: of sense of health, sense of calm and sense of anxiety. Objective health was examined by physician on the 10-point rating scale. Cluster analysis to show psychological health`s predictors of patients after BMT: level of stress, styles and effective coping strategies with stress, personal resources, temporal factor since transplantation and gender. The psychological predictors of health are the base of health promotion of patients after BMT.

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.

[The role of the bone marrow microenvironment in the pathogenesis of multiple myeloma]. / Rola mikrosrodowiska szpiku kostnego w patogenezie szpiczaka plazmocytowego.

Multiple myeloma (MM) is one of the most common hematologic malignancies. It remains an incurable disease, so far. The mainstay of treatment for decades was pointless therapy with cytostatic agents and immunosuppressant's. Because myeloma is most common in the elderly population, vulnerable to aggressive therapy, non-specific treatment approaches led to poor patient survival. Intensive study of MM, allowed identification of the molecular interactions between myeloma cells and bone marrow tumour microenvironment, responsible for the development of the disease and associated complications, such as osteolytic bone lesions. Understanding the molecular mechanisms of action of adhesion molecules, cytokines and signalling pathways involved in the development of myeloma, has led to develop of novel, targeted therapies to improve the quality of patients life and significantly prolong the median survival time. This paper discusses the current state of knowledge of signalling pathways involved in the progression of cancer and the destruction of bone tissue, with particular emphasis on interactions with the bone marrow microenvironment of the tumour.

[Cutaneous involvement in multiple myeloma--case report and literature review]. / Zajecie skóry w przebiegu szpiczaka plazmocytowego--opis przypadku i przeglad literatury.

Cutaneous involvement in multiple myeloma is a very rare clinical problem. It occurs in less than 1% myeloma patients. Skin manifestation may be primary or secondary to MM. Primary involvement (PCP) according to the current WHO classification is one of the marginal zone lymphomas of the skin. PCP are characterized by significantly better prognosis than infiltrations secondary to MM. Skin manifestations require a thorough diagnosis to differentiate between myeloma-specific changes, MM-associated and non-specific skin disorders. Isolated primary infiltration can usually be successfully treated with radiation therapy or surgery. So far treatment of multiple and secondary to MM involvement are not satisfactory.

[Significant changes in diagnostic and therapeutic procedures in smoldering multiple myeloma]. / Znaczace zmiany w postepowaniu diagnostyczno-terapeutycznym w tlacej postaci szpiczaka plazmocytowego.

Smoldering multiple myeloma (SMM) is a precursor disease of multiple myeloma (MM) with an average annual risk of progression to MM of 10%. Several prognostic factors have been identified and combined in models to discriminate patient groups with different outcomes. These factors include size of the M-protein, plasma cell (PC) infiltration in the bone marrow (BM), serum free light-chain ratio, immunoparesis and percentage of aberrant BMPCs on flow cytometry or the presence of focal lesions on magnetic resonance imaging. The current standard of care has been to initiate treatment with progression to symptomatic MM. Current approaches aim at identifying patients with an ultra-high risk of progression (≥ 80% within the first 2 years) who are considered as 'early myeloma' patients requiring therapy. A recent trial on high-risk SMM patients, comparing early treatment with lenalidomide plus dexamethasone (Rd) versus observation, reported a benefit with respect to time to progression and survival for Rd-treated patients. Therefore, in 2014, the International Myeloma Working Group (IMWG) revised the diagnostic criteria and proposed to treat patients with ultra-high risk SMM as symptomatic MM. Promising markers for further studies may be high levels of circulating and high proliferative rate of PCs, abnormal PC phenotype with > 95% plus immunoparesis, evolving SMM, specific cytogenetic subtypes, genomic and additional biomarkers; all being acknowledged by the IMWG be added to the diagnostic criteria in the future, if any proves to be associated with a risk of progression of SMM to MM of at least 80% within 2 years.

Efficacy and safety of stem cell mobilization with cyclophosphamide plus etoposide versus cyclophosphamide alone.

The use of the combination of two cytostatics cyclophosphamide (CTX) and etoposide (VEP) and G-CSF is a reasonable alternative, especially for stem mobilization in multiple myeloma (MM) patients from countries in which newer treatments are limited due to financial constraints. The aim of this study was to compare the efficacy and safety of CTX-VEP versus CTX alone for mobilization of hematopoietic stem cells in MM patients. The analysis included 48 consecutive MM patients mobilized with CTX-VEP compared to 43 consecutive historical controls mobilized with CTX alone. The two groups of MM patients did not differ in terms of the median number of apheresis procedures, median yield the first day, median numbers of harvested CD34+ cells, proportion of patients with at least 5 x 106/kg yield and incidence of non-hematological complications. The median cumulative dose of G-CSF given to individuals in the CTX-VEP group was significantly lower than in the CTX group (p < 0.001). The incidence of post-mobilization thrombocytopenia was higher in the CTX group (p<0.001). The median time to platelet count > 20 x 109/l (10 vs. 11 days, p = 0.004) and the median time to neutrophil count > 50 x 109/l (11 vs. 13 days, p < 0.001) were significantly shorter among the patients mobilized with CTX-VEP than in those treated with CTX alone. These findings suggest that CTX-VEP is as efficacious and possibly safer than CTX alone.

[Daratumumab--breakthrough drug in multiple myeloma therapy]. / Daratumumab--przelomowy lek w terapii szpiczaka plazmocytowego.

Multiple myeloma (MM) remains incurable despite important recent advances in treatment. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.

[The importance of imaging techniques in the modern treatment of multiple myeloma]. / Znaczenie technik obrazowych w nowoczesnym leczeniu szpiczaka plazmocytowego.

The main symptom of multiple myeloma (MM) are pathological changes in bone. Imaging techniques are useful in determining the proper stage of the disease, follow-up after treatment and, as highlighted in recent times, in predicting prognosis and prediction. In the near future, radiographic examination of the whole body can be replaced by more sensitive techniques, such as low-dose computed tomography (CT) of the whole body. Magnetic resonance imaging (MRI) is a standard in the evaluation of bone marrow infiltration of the spine, allowing the prediction of the risk of vertebral fractures. Positron emission tomography (PET) coupled with CT (PET/CT) provides relevant information on the extent of lesions throughout the body, including soft tissues and is the best tool to distinguish active from inactive disease after treatment. Diagnostic imaging technique of PETIMR has the potential for precisely diagnosing in this condition. Prospective use of new imaging techniques in clinical practice in the near future will help to optimize the therapeutic management in individual cases of MM.

[Atypical BCR-ABL transcripts in patients with chronic myeloid leukemia--the scheme for the diagnosis and monitoring of minimal residual disease]. / Nietypowe odmiany transkryptu BCR-ABL u chorych na przewlekla bialaczke szpikowa--schemat postepowania diagnostycznego w monitorowaniu minimalnej choroby resztkowej.

More than 95% of patients with detected translocation t(9;22), is characterized by the fusion between exons e13 or e14 of BCR gene, which are located in major breakpoint cluster region (M-bcr) and exon a2 of ABL gene. These fusions are described as b2a2 (e13a2) and b3a2 (e14a2). Other fusions of exons e1, e6, e8, e12, e19, e20 of BCR gene with exons a2 or a3 of ABL gene occur very rarely and lead to formation of so called unusual fusion BCR-ABL genes. The aim of this study is to describe long-term observations of the occurrence and routine procedure in the diagnosis of atypical variants of the fusion gene BCR-ABL in a population of patients with chronic myeloid leukemia (CML). It was found that the vast majority of patients with detected BCR-ABL transcripts were b3a2 and b2a2. Other detected variants, which are described as rare were: e1a2, b2a3, b3a3, c3a2, e6a2, e6a3. At the stage of diagnosis as well as during monitoring of the effects of treatment, molecular methods which are based on polymerase chain reaction were used (multiplex RT-PCR, nested RT-PCR, RQ-PCR). Multiplex RT-PCR reaction gave possibility to detect variants of the fusion BCR-ABL gene in one reaction and was crucial in the selection of appropriate test used for further monitoring of the disease and the effectiveness of treatment. This paper proposes a scheme for dealing with the diagnosis and monitoring of minimal residual disease (MRD) in patients with CML treated with tyrosine kinase inhibitors (TKIs) in the presence of rare fusion of the BCR and ABL genes.

New drugs in multiple myeloma - role of carfilzomib and pomalidomide.

Carfilzomib (CFZ), an epoxyketone with specific chymotrypsin-like activity, is a second-generation proteasome inhibitor with significant activity in patients with relapsed and refractory multiple myeloma. On July 20, 2012, the US Food and Drug Administration approved CFZ to treat patients with multiple myeloma who have received at least two prior therapies including bortezomib (BORT) and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Cytogenetic abnormalities did not appear to have a significant impact on the CFZ activity. Carfilzomib was well tolerated and demonstrated promising efficacy in patients with renal insufficiency. Pomalidomide (POM) (CC-4047) is a novel immunomodulatory derivative (IMID) with a stronger in vitro anti-myeloma effect compared with "older" IMIDs - thalidomide and lenalidomide (LEN). On February 8, 2013, the US Food and Drug Administration approved POM (Pomalyst, Celgene) for the treatment of MM patients who have received at least two prior therapies including LEN and BORT and have demonstrated progression on or within 60 days of completion of the last therapy. Pomalidomide is a novel IMID with significant anti-myeloma activity and manageable toxicity. This compound has shown high efficacy in MM patients who were resistant to prior use of LEN/BORT as well as in patients with a high-risk cytogenetic profile. Carfilzomib and POM have very high efficacy and will be used also in first line therapy in future.

[Health of patients after bone marrow transplantation and coping with stress -- psychological and medical perspective]. / Zdrowie pacjentów leczonych metoda transplantacji szpiku kostnego a radzenie sobie ze stresem -- perspektywa psychologiczna i medyczna.

A study on the relationship between level of subjective and objective health by patients after bone marrow transplantation (BMT) and their coping with stress is presented. The theoretical basis of researches is Helena Wrona-Polanska's Functional Model of Health (2003), in which health is a function of creative coping with stress.141 patients after BMT -- 80 males and 61 females -- at the Hematology Clinic of University Hospital were studied clinically. Objective health was examined doctor on the scales. Examined methods were -- the questionnaires examining stress, coping strategies, and grading scales of health and anxiety. There is a clear difference between subjective and objective level of health. Subjective health depend on coping strategies with stress and objective health depend on patient's collaboration with terapeutic team. The basis of health promotion by persons after BMT is development effective strategies of coping with stress and increase patent's activity.

[Liposomal cytarabine in prophylaxis of the central nervous system involvement in rare aggresive lymphomas]. / Liposomalna cytarabina w profilaktyce zajEcia centralnego systemu nerwowego w rzadkich chloniakach agresywnych.

UNLABELLED: The involvement of central nervous system in the course of lymphoma is an adverse prognostic factor, therefore primary prevention is a standard of care of aggressive lymphoma subtypes. The aim of the paper is the safety and efficiency, retrospective analysis of liposomal cytarabine used profilactically in patients with rare aggressive lymphomas. MATERIALS AND METHODS: In the analysis we included 19 patients with aggressive lymphomas: LBL (lymphoblastic lymphoma), BL (Burkitt lymphoma) and PTCL (peripheral T- cell lymphoma) from three PLRG (Polish Lymphoma Research Group) centers, who received liposomal cytarabine as primary prevention of central nervous system involvement. All the included patients had a high risk of CNS due to histological subtype (10 patients with LBL, 4 patients with BL), the specific location of the disease (N=3) or the presence of at least 2 risk factors for CNS involvement (elevated LDH, IPI 3-5 or involvement of at least 2 extranodal sites, N = 16). In this group, 18 patients were subjected to prophylaxis during the 1-st line therapy and one after relapse. None of the patients had symptoms of central nervous system involvement at the time of diagnosis. The median age was 43 years (the range of 20-60 years). In this group there were 14 males (73.68%) and 5 females (26.32%). The patients were treated with liposomal cytarabine every 2 to 4 weeks during the systemic chemotherapy. The median number of cytarabine doses was 2 (the range of 1-5). RESULTS: Liposomal cytarabine was well-tolerated. 63.1% of patients had transient side effects (nausea, vomiting, fever, dizziness) in grade 1-2, 5.2% of patients experienced a more severe headache (grade 3). During the average follow-up of 18 months, 50% of patients died and 27.7% of systemic recurrences were noted. Only one patient had a relapse in the CSN con comitant with a systemic recurrence. CONCLUSIONS: Lipo somal cytarabine is well-tolerated and effective medicine used in the prevention of CNS relapse in patients with ag gressive lymphoma subtypes.

[Management of multiple myeloma-related bone disease]. / Postepowanie w chorobie kostnej zwiazanej ze szpiczakiem mnogim.

Multiple myeloma is still incurable malignant neoplasm of plasma cells, which is characterized by the presence of osteolytic bone disease, the latter resulting from increased osteoclast function accompanied by decreased osteoblast activity. Myeloma bone disease is associated with the risk of skeletal events, such as pathologic fractures, spinal cord compression, or a need of palliative bone treatment or surgery, and may be related to decreased survival. In this review article, the results of the studies analyzing treatment options for myeloma bone disease and its complications are summarized. In addition, up-to-date guidelines based on those results are presented. Indications for therapy with bisphosphonates, the route of their administration and the optimal treatment duration are presented. Moreover, methods used for management of myeloma bone disease complications are discussed, including local radiotherapy, kyphoplasty and vertebroplasty.

[Necessary diagnostic requirements and therapeutic recommendations in multiple myeloma]. / Niezbedne wymogi diagnostyczne i zalecenia terapeutyczne w szpiczaku plazmocytowym.

Recent years have brought new diagnostic and therapeutic tools for the patients with multiple myeloma. New methods have become available to assess the biology and the extent of multiple myeloma, such as testing for cytogenetic and precise evaluation of extramedullar and minimal residual disease. New drugs have entered the clinical practice leading to significant outcome improvements but also resulting in the need of prevention and treatment for their side effects. In this review, novel diagnostic and therapeutic methods are discussed in the context of their practical utilization in a real-life clinical practice.

Safety of AFM11 in the treatment of patients with B-cell malignancies: findings from two phase 1 studies.

BACKGROUND: The prognosis for patients with relapsed and/or refractory (R/R) non-Hodgkin's lymphoma (NHL) or acute lymphoblastic leukaemia (ALL) remains poor, with existing treatments having significant side effects. Developed for the treatment of these cancers, AFM11 is a tetravalent, bispecific humanised recombinant antibody construct (TandAb®) designed to bind to human CD19 and CD3 and lead to the activation of T cells inducing apoptosis and killing of malignant B cells. METHODS: Two open-label, multicentre, dose-escalation phase 1 studies evaluated the safety, pharmacokinetics and activity of AFM11 in patients with R/R CD19-positive B cell NHL (AFM11-101) and in patients with CD19 + B-precursor Philadelphia-chromosome negative ALL (AFM11-102). Adverse events (AEs) were assessed and recorded; imaging (NHL) or bone marrow assessment (ALL) were used to evaluate response. Additional pharmacodynamic assays undertaken included cytokine release analysis and B-cell and T-cell depletion. RESULTS: In AFM11-101, 16 patients with R/R NHL received AFM11 in five different dose cohorts. Of which, 14 experienced drug-related treatment-emergent AEs (TEAEs) [including five serious AEs (SAEs)], five patients experienced dose-limiting toxicity (DLT) and ten patients discontinued the study. The high number of neurological events led to a decrease in infusion frequency during the study. No objective response to treatment was observed. In AFM11-102, 17 patients with R/R ALL received AFM11 in six different dose cohorts. Thirteen patients experienced drug-related TEAEs (including four SAEs), DLTs occurred in two patients and five patients discontinued the study. An objective response was recorded in three patients. The maximum tolerated dose could not be determined in either study due to early termination. CONCLUSIONS: AFM11 treatment was associated with frequent neurological adverse reactions that were severe in some patients. In ALL, some signs of activity, albeit short-lived, were observed whereas no activity was observed in patients with NHL; therefore, further clinical development was terminated. TRIAL REGISTRATION: NCT02106091 . Safety Study to Assess AFM11 in Patients With Relapsed and/or Refractory CD19 Positive B-cell NHL. Registered April 2014. NCT02848911 . Safety Study to Assess AFM11 in Patients With Relapsed or Refractory Adult B-precursor ALL. Registered July 2016.

[Escalated BEACOPP as an alternative in high risk Hodgkin lymphoma]. / Eskalowany BEACOPP jako alternatywa dla ABVD w chorobie Hodgkina o wysokim ryzyku.

Hodgkin Disease is one of the common lymphoma subtypes: every year over 750 new cases are diagnosed in Poland. It is most frequent in young adults between 25 - 30 years of age. In a low risk cases prognosis is excellent, and the treatment may be limited to short chemotherapy consolidated by involved field radiotherapy. In high risk cases with a large tumor burden prognosis depends from the choice of the initial therapy. Results of 8 years experience with escalated BEACOPP in UJ CM Department of Hematology are summarized in the paper. Monitoring the early response in imaging studies, particularly in positron emission tomography, allows in the majority of cases to decrease the duration of intensive therapy, without loosing it's efficacy.

[Hematological toxicity of radioimmunotherpy with 90Y Ibritumomab]. / Toksycznosc hematologiczna radioimmunoterapii z zastosowaniem 90Y Ibritumomabu.

Radioimmunotherapy with 90Y Ibritumomabu (Zevalin, BSP) is a new method of systemic radiotherapy applicable to B-cell lymphoma patients. It may be delivered as a short outpatient procedure, with few adverse effects other than hematological toxicity. In the paper, we present length and depth of cytopenias, together with the results of additional tests performed to reveal the possible pathomechanisms, based on 102 patients treated at the University Hospital in Krakow.

The early reduction of leukemic blasts in bone marrow on day 6 of induction treatment is predictive for complete remission rate and survival in adult acute myeloid leukemia; the results of multicenter, prospective Polish Adult Leukemia Group study.

The aim of this study was to prospectively evaluate the impact of early bone marrow response on complete remission (CR) rate and long-term outcome in adults with acute myeloid leukemia. Bone marrow cytology was assessed on day 6 of induction treatment in 164 patients, revealing the presence of ≥5% blasts in 61 cases. In this subgroup the CR rate was significantly lower compared to the remaining patients (P < 0.00001) resulting in decrease of the overall survival (P = 0.002). Persistence of ≥5% blasts in bone marrow on day 6 of induction is an easily available surrogate marker to be used for treatment decisions.