Clinical efficacy, safety and pharmacokinetic properties of the plasma-derived factor IX concentrate Haemonine in previously treated patients with severe haemophilia B.

Plasma-derived factor IX (FIX) concentrate remains an important choice for replacement therapy in haemophilia B patients. Haemonine is a high purity double-virus inactivated human plasma-derived coagulation FIX concentrate (pdFIX). Aim was to evaluate the clinical efficacy, safety and pharmacokinetic properties of Haemonine in three prospective, open-label uncontrolled studies and a compassionate use program in previously treated patients with severe haemophilia B. Long-term efficacy and safety were investigated in 29 patients treated prophylactically and, in addition, treatment on-demand (TOD) in the case of acute haemorrhage. Pharmacokinetic properties were assessed in 14 patients at baseline and after 3 months of regular treatment. Pharmacokinetic parameters were in accordance with published data and remained nearly unchanged over time, notably recovery and half-life. Mean terminal elimination half-life was 27.6 h and 25.0 h, mean incremental recovery (IU dL(-1) /IU kg(-1)) was 1.55 and 1.60, at baseline and 3 months, respectively. Haemonine was shown to be effective in preventing and controlling bleeds. 55.2% (16/29) of patients were free of bleeds under prophylaxis. 38 haemorrhages occurred, 42% (16/38) required treatment and 87.5% (14/16) resolved after a single infusion, 12.5% after 2 infusions. All responses reported on haemorrhages were rated as 'excellent' or 'good'. Moreover, 'excellent' haemostatic efficacy was demonstrated in 12 surgeries with no complications. Few adverse events (AEs) and no thrombogenic complication, nor induction of FIX inhibitory antibodies were observed. Haemonine is effective, safe and well tolerated in long-term prophylaxis, TOD and when applied after minor and major surgeries.

Hospital outbreak of vancomycin-resistant enterococci caused by a single clone of Enterococcus raffinosus and several clones of Enterococcus faecium.

A mixed outbreak caused by vancomycin-resistant Enterococcus raffinosus and Enterococcus faecium carrying the vanA gene was analysed. The outbreak occurred in a large hospital in Poland and affected 27 patients, most of whom were colonised, in three wards, including the haematology unit. The E. raffinosus isolates had a high-level multiresistant phenotype and were initially misidentified as Enterococcus avium; their unambiguous identification was provided by multilocus sequence analysis. The molecular investigation demonstrated the clonal character of the E. raffinosus outbreak and the polyclonal structure of the E. faecium isolates. All of the isolates carried the same Tn1546-like element containing an IS1251-like insertion sequence, located on a c. 50-kb conjugative plasmid. One of the E. faecium clones, found previously to be endemic in the hospital, was probably the source of the plasmid. The results of the study suggest that difficulties in identification may have led to an underestimate of the importance of E. raffinosus in vancomycin-resistant enterococci (VRE) control strategies.

2-Chlorodeoxyadenosine (Cladribine) in the treatment of patients with chronic lymphocytic leukemia 55 years old and younger.

The aim of the study was to determine the effectiveness of 2-chlorodeoxyadenosine (2-CdA) administered in 2-h i.v. infusions in the treatment of B cell chronic lymphocytic leukemia (B-CLL) in patients 55 years old and younger. One hundred and thirteen patients received three to 10 courses of 2-CdA administered at a dose of 0.12 mg/kg daily for 5 consecutive days. Sixty-seven patients were previously treated with chlorambucil and prednisone, COP and some of them also with CHOP, and 46 were untreated. Complete remission (CR) was achieved in 21 (18.6%) (19 in untreated and two in previously treated) patients and partial response (PR) in 38 (33.6%) (23 and 15, respectively) giving an overall response rate in 52.2%. The differences in CR and overall response rate between previously treated and untreated patients were statistically significant (P = 0.001). Surface immunophenotyping by flow cytometry using dual-color staining on the peripheral blood and/or bone marrow was performed in 38 patients who responded to 2-CdA therapy. Residual disease had been demonstrated in five out of 17 (29.4%) patients who were in CR and in all 21 investigated PR patients. 2-CdA-induced thrombocytopenia occurred in 24 (35.8%) of previously treated and in 13 (28.3%) previously untreated patients (P = NS). Neutropenia was observed in eight (11.9%) and in five (10.9%) patients, respectively (P = NS). Severe infections, including pneumonia and sepsis, occurred more often in previously treated (44.8%) than untreated patients (26.1%) (P < 0.05). Twenty-seven (23.9%) patients died, 11 because of infections, five because of drug-related thrombocytopenia and hemorrhage, one because of second malignancy and eight because of disease progression. In conclusion, our results indicate that 2-CdA is an effective agent in younger patients with B-CLL, especially used as a first line therapy.

Cladribine combined with cyclophosphamide and mitoxantrone as front-line therapy in chronic lymphocytic leukemia.

The objective of the study was to determine the effectiveness and the toxicity of a combined chemotherapy consisting of cladribine (2-CdA), mitoxantrone and cyclophosphamide (CMC regimen) in the treatment of previously untreated B cell chronic lymphocytic leukemia (B-CLL). From August 1998 to December 2000 2-CdA was administered at a dosage of 0.12 mg/kg for 3 (CMC3) or 5 (CMC5) consecutive days, mitoxantrone at 10 mg/m2 on day 1 and cyclophosphamide at 650 mg/m2 on day 1 to 62 patients with advanced or progressive B-CLL. The cycles were repeated at 4 week intervals or longer if severe myelosuppression occurred. Twenty patients received CMC5 and 42 patients CMC3. Within the analyzed group an overall response (OR) rate (CR+PR) of 64.5% (95% CI: 52.7-76.3%) was reported, including 29.0% CR. There was no difference in the CR rate between the patients treated with CMC5 (30%) and CMC3 (28.6%) (P = 0.9), nor in the OR rate (55.0% and 69.0%, respectively, P = 0.3). Residual disease was identified in seven out of 18 (38.9%) patients who were in CR, including two treated with CMC5 and five treated with CMC3 protocols. CMC-induced grade III or IV thrombocytopenia occurred in 12 (19.4%) of patients, including four (20%) CMC5-treated and eight (19%) CMC3-treated patients (P= 0.8). Neutropenia grade III or IV was observed in seven (35%) and 11 (26.2%) patients, respectively (P = 0.8). Severe infections, including pneumonia and sepsis, occurred more frequently after CMC5 (11 patients, 55.0%) than CMC3 (10 patients, 28.6%) (P = 0.03) Fourteen patients died, including six treated with CMC5 and eight treated with CMC3 (30% and 19%, respectively). Infections were the cause of death in nine patients, including four in the CMC5 group and five in the CMC3 group. In conclusion, our results indicate that the CMC programme is an active combined regimen in previously untreated B-CLL patients; its efficiency seems to be similar to that observed earlier in B-CLL patients treated with 2-CdA as a single agent. However, toxicity, especially after CMC5 administration, is significant. Therefore, we recommend the CMC3 but not the CMC5 programme for further evaluation.

Importance of parenteral nutrition in patients undergoing hemopoietic stem cell transplantation procedures in the autologous system.

OBJECTIVE: The aim of this study was to assess the frequency of parenteral nutrition and to compare the impact of parenteral and oral feeding on the nutrition and clinical status of adults undergoing autologous hemopoietic stem cell transplantation. METHODS: The study involved 35 patients with neoplasm of the hemopoietic system who underwent hemopoietic cell autotransplantation at the Hematology Clinic (Jagiellonian University, Krakow, Poland). The patients' nutrition status was assessed using body mass index (BMI) values, body mass components, concentration of albumin, and total protein in blood serum. The clinical status evaluation included duration of hematologic reconstruction, concentration of bilirubin, enzyme activity (alanine aminotransferase and aspartate aminotransferase), severity of infections, and duration of hospitalization. RESULTS: Parenteral nutrition was required in 19 patients. Oral feeding was used in 16 patients. Symptoms of malnutrition on the day preceding the introduction of conditioning treatment were recorded only in patients requiring parenteral nutrition (31.6%). In the posttransplantation period, a statistically significant decrease in body mass was observed in both groups, whereas the share of fatty tissue in total body mass was significantly less in patients (men and women) fed parenterally. CONCLUSION: A supply of 25-30 kcal/kg and 1-1.5 g protein/kg/day as an element of parenteral nutrition (where 20%-30% of the energy requirement was covered by fats, 15%-20% by amino acids, and 50%-55% by glucose) helped prevent the development of malnutrition and restore the functions of the hemopoietic system at a level comparable to that for patients fed naturally.

Addition of cladribine to induction/consolidation regimen does not impair peripheral blood stem cell mobilization and bone marrow harvest for autotransplantation in acute myeloid leukemia patients.

BACKGROUND: The previous study by the Polish Adult Leukemia Group has demonstrated that addition of cladribine to standard DNR+AraC induction potentiates the antileukemic activity. The goal of this study was to compare the efficacy of bone marrow or peripheral blood hematopoietic cell collection in patients who obtained remission after daunorubicine plus cytarabine induction with cladribine (DAC-7) or without addition of cladribine (DA-7) in preparation for autotransplantation. PATIENTS AND METHODS: Sixty-six patients aged 41 years (range, 17-58 years) were included in this study: 33 cases in the DAC-7 and 33 in the DA-7 arm. Hematopoietic cells were collected from the bone marrow (ABMT, n = 29) or from the peripheral blood (ABCT, n = 37) using cytopheresis after administration of AraC (2 x 2 g/m2) on days 1, 3, 5 and subsequent G-CSF (10 microg/kg) from day 7 as mobilization therapy. RESULTS: The numbers of harvested CD34+ cells were similar in the DAC-7 and DA-7 pretreated patients both after harvesting from peripheral blood (2.55 x 10(6)/kg vs 2.5 x 10(6)/kg) and from bone marrow (1.62 x 10(6)/kg vs 1.55 x 10(6)/kg), respectively. The proportion of patients with sufficient material for autologous bone marrow transplantation was higher in the DAC-7 compared with the DA-7 arm. All patients engrafted; hematopoietic recovery was similar in both subgroups. CONCLUSION: Addition of cladribine to a standard DA induction does not impair the harvesting of hematopoietic cells and their engraftment after autotransplantation.

The effect of 2-h infusion of 2-chlorodeoxyadenosine (cladribine) with prednisone in previously untreated B-cell chronic lymphocytic leukaemia.

2-Chlorodeoxyadenosine (2-CdA) is a new antimetabolite chemotherapeutic agent active in indolent lymphoid malignancies. In this retrospective study, 69 previously untreated patients with B-cell chronic lymphocytic leukaemia (B-CLL) were treated with 2-CdA administered at a dose of 0.12 mg/kg daily in 2-h intravenous infusion for 5 consecutive days. 45 patients also received prednisone 30 mg/m2 orally each day for 5 days starting with 2-CdA courses. Patients were given 2-6 courses (mean 4.6) of 2-CdA repeated usually at monthly intervals. If a complete response was achieved, no further 2-CdA courses were administered. Guidelines for response were those developed by the NCI Sponsored Working Group. Complete response (CR) was achieved in 26 (38%) and partial response (PR) in 27 (39%) cases, giving an overall response rate of 77%. 16 patients (23%) did not respond to 2-CdA. In the subgroup of 45 patients receiving 2-CdA with prednisone, CR was obtained in 15 (33%) and PR in 20 (44%) patients giving an overall response rate of 78%. CR was achieved in 11 (46%) out of 24 patients treated only with 2-CdA and in 7 cases (29%) PR was observed, giving an objective response rate of 75%. The differences between both subgroups were not statistically significant. However, we observed a relationship between the response and the number of courses of 2-CdA given in patients receiving and those not receiving prednisone. In the subgroup receiving 2-CdA with prednisone, an earlier response to 2-CdA was observed. In this group a response was achieved in 9 (20%) patients after two courses of 2-CdA and in 18 (40%) after four courses. In the subgroup receiving only 2-CdA, 17 (71%) responses were obtained after six cycles.

Efficacy and safety of fludarabine and cyclophosphamide combined therapy in patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL)-Polish multicentre study.

The aim of this study was to investigate the efficacy of a combination of fludarabine (F) and cyclophosphamide (C) in the treatment of patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL). Between November 1999 and December 2001, 63 patients with B-CLL (median age 60 years) received a regimen that consisted of F 25 mg/m2 and C 250 mg/m2, days 1-3, intravenously, every 4 weeks, for a maximum of 6 courses, Response and toxicity were assessed according to current criteria (NCI-WG and WHO). Complete and partial remissions were achieved in 17.5% and 55.6% of patients, respectively; 19% of patients had stable disease and 7.9% of patients showed disease progression. The median follow-up was 16.5 (range 1.5-32) months. The median duration of progression-free survival (PFS) has not been reached among patients treated with FC regimen as second-line therapy. The median PFS was 13 (range 8-26) months in the 19 responding patients treated with FC regimen as third-line therapy. The most frequent side-effects were neutropenia (45%), thrombocytopenia (42%) and infections (57%). We conclude that the combination of fludarabine and cyclophosphamide demonstrated significant efficacy in pretreated, advanced B-CLL patients, with tolerable toxicity.

Intermittent 2-hour intravenous infusions of 2-chlorodeoxyadenosine in the treatment of 110 patients with refractory or previously untreated B-cell chronic lymphocytic leukemia.

The purpose of our study was to determine the effectiveness of 2-CdA in 2-hour intravenous infusions in the treatment of B-CLL. One hundred and ten patients with B-CLL received 1 to 10 courses of 2-CdA (median 2.5) at a dosage of 0.12 mg/kg daily for 5 consecutive days. Eighteen of them were untreated and 92 relapsed or became refractory to previous therapeutic modalities. Complete remission (CR) was achieved in 8 (7.3%) and partial remission (PR) in 35 patients (31.8%) giving an overall response rate of 39.1%. In 3 patients, cross-resistance to fludarabine was noticed. Toxic effects of 2-CdA were more frequently observed in previously treated patients. Hemorrhagic complications due to drug-induced thrombocytopenia were noticed in 25 (22.7%) and severe infections including sepsis in 14 (12.7%) patients.

Visceral leishmaniasis diagnosed by trephine biopsy. A case report.

A case of visceral leishmaniasis has been reported in a 41-year-old man. The diagnosis was made on the basis of trephine biopsy and fine needle aspiration biopsy of the spleen.

[History of Kraków hematology]. / Historia krakowskiej hematologii.

The development of the studies of the blood diseases at the IIIrd Department of Internal Medicine and later at the Department of Hematology of the Medical Academy and subsequently the Collegium Medicum at the Jagiellonian University in the years 1950 to 2000 are presented here. The Cracow Hematological Center, headed by professor Julian Aleksandrowicz from 1950 to 1979, by professor Julian Blicharski from 1979 to 1989, by ass. professor Jerzy Lisiewicz from 1990 to 1993, and presently by Aleksander B. Skotnicki--has drawn many brilliant hematologists who have initiated, developed and verified new concepts of pathogenesis as well as new methods of diagnosis and therapy of haematological diseases. The Polish Haematological Society was founded in 1949 in Cracow where the first Conference took place in May 1950. The first specialistic haematological journal--Haematologica Cracoviensia later retitled as Haematologica Polonica was first published in Cracow in 1957. Finally here, in Cracow, one of the first syngeneic bone marrow transplantation was performed in 1958. Presently the Chair and Department of Haematology of the Collegium Medicum at the Jagiellonian University is a modern and well facilitated center of research and didactics (both pre and post graduate studies); the modern cytological, immunophenotype, cytogenetic and molecular diagnostic methods are used in haematological patients from the Macroregion of South-Eastern Poland (inhabited by approximately 8 million people). The offered treatment includes chemo- and radiotherapy, immunotherapy and autologous and allogeneic bone marrow transplantation.

[Fungal infection in patients with granulocytopenia. Pathogenetic, diagnostic and therapeutic aspects]. / Infekcje grzybicze u chorych z granulocytopenia. Aspekty patogenetyczne, diagnostyczne i terapeutyczne.

The invasive diagnostic procedures, use of the broad-spectrum antibiotics, adrenal corticoids, immunosuppressive and cytostatic drugs have lead to the increase in the number of fungal infections in granulocytopenic patients. For the most part fungal infections in those patients consist of the opportunistic, systemic infections in granulocytopenic patients is exceptionally frustrating because more often than not, diagnosis is very difficult to establish. The article presents some problems regarding their pathogenesis, classification, diagnosis and management.

[Rationale and methods for high dose chemotherapy in oncology]. / Zalozenia i metody chemioterapii wysokodozowanej w onkologii.

Waiting for a new, highly effective cytotoxic drugs it is necessary to improve antineoplastic treatment using presently existing drugs and methods. Chemosensitive tumors should be treated with intensive, short-lasting courses of the induction as well as of the adjuvant chemotherapy. Chemotherapy delay, dose reduction, unproper therapy regimen increases risk of the development of drug-resistance and treatment failure. Autologous hemopoietic cell transplantation allows cytostatics dose escalation (high-dose chemotherapy, HDCT) with an acceptable non-hematological toxicity. HDCT with autologous peripheral blood stem cell transplantation (auto-PBSCT) is increasingly used. Auto-PBSCT has the same efficacy as autologous bone marrow transplantation (ABMT), but it is a safer procedure, allows more rapid hemopoietic recovery and shorter hospitalization.

[Autotransplantation for solid tumors]. / Autotransplantacja w guzach litych.

Over the last three decades, there have been a number of advances made in the treatment of haematological malignancies including an increasingly defined role in curative therapy programmes for high dose chemotherapy (HDC) with stem cell support. This has provided an impetus for similar approaches to be tested in solid tumours. Drug resistance is one of the most important reasons for treatment failure in these diseases, and therefore attempting to overcome it with HDC is an obvious strategy to investigate. This rationale is supported by laboratory data demonstrating that dose correlates with number of cells killed, and that increasing drug doses by 5-10 fold can overcome resistance. Clear evidence of a dose-response effect in patients is provided by numerous clinical trials of chemotherapy in solid tumours. A large number of studies have investigated HDC in solid tumours, particularly in those malignancies which demonstrate initial chemo-sensitivity, but later relapse. Except for breast cancer, for other solid tumours there are no randomised trials defining the role of HDC. Many of the trials are small pilot studies in heavily pretreated patients with large volume disease and therefore any conclusions must be guarded.

[The effect of magnesium on blood coagulation--state of the art literature review from 1959 to 1995]. / Wplyw magnezu na uklad krzepniecia krwi--obecny stan wiedzy--przeglad literatury od 1959 do 1995 roku.

The effect of magnesium on coagulation system is still an interesting subject for investigations. Shionoya in his publication (1927) reported for the first time possible inhibitory effect of magnesium on coagulation system. Since then, a large number of studies were undertaken to explain the mechanisms of influence of Mg++ on plasma coagulation, platelet function and fibrinolysis. In recent decades, the effect of magnesium on coagulation has led to controversy in a wide range of scientific publications. At present, series of experiments are undertaken in laboratories using modern methodology to evaluate the possible effect of magnesium on coagulation. The results of Anders's and Frisch's study reported here support the theory of the authors, who found no change in coagulation in the presence of physiological concentration of magnesium in blood serum. The influence on the final results, often contradictory, could have: different type of study (in vitro or in vivo), the object of the study (human being, animal), concentrations of magnesium (in most of cases non-physiologic and toxic) and out of date methodology. In majority of reported here studies there were no control groups, and clinical trials were not a double blind studies.

[Telomeres and telomerase in leukemias]. / Telomeazy i telomeraza w bialaczkach.

There is increasing evidence that telomere shortening both in vitro and in vivo is the clock that counts cell divisions and determines the onset of cellular senescence. Cells overcome the normal senescence mechanism by stabilising telomere length; probably due to the activity of telomerase activity that specifically elongates telomeres. Most human primary tumors contain telomerase, while the cells of most normal tissues lack this activity. Normal haematopoietic cells express telomerase activity. This review is a discussion of utility of telomere length and telomerase activity measurements in the diagnostics and prognosis of leukaemia as well as the potential value of antitelomerase therapy. Results of telomere lengths measurements in young recipients of allogenic transplants are also reported.

[Aplastic anemia--contemporary procedures and therapeutic perspectives]. / Anemia aplastyczna--wspólczesna diagnostyka, mozliwosci oraz perspektywy terapeutyczne.

Severe aplastic anaemia (SAA) state of art is summarised. Currently there are two therapeutic possibilities: allogeneic bone marrow transplantation (BMT) and immunosuppressive therapy. Decision should be based on disease severity, patient performance status, age and the availability of the HLA identical donor. Allogeneic BMT is the treatment of choice for the young (less than 25 years) SAA patients. It's side effects including graft versus host disease markedly increase with age. Immunosuppressive therapy is an option for patients older than 45, or younger ones with no HLA compatible donor. Optimisation of the treatment protocols is the subject of various ongoing randomised multicentre studies.

[Thrombopoietic growth factor--thrombopoietin. Molecular and biological properties]. / Plytkotwórczy czynnik wzrostu--trombopoetyna. Wlasciwosci molekularne i biologiczne.

Thrombopoietin (TPO) is a newly identified hematopoietic growth factor, that stimulates both megakaryopoiesis and thrombopoiesis through its interaction with a specific cell surface receptor (c-Mpl), a member of hematopoietic receptor superfamily, encoded by the c-mpl proto-oncogene. Recently the Janus kinases and STAT proteins have emerged as important elements in signaling via this family of receptors. The complete gene for human thrombopoietin has been cloned and mapped. TPO is believed to be the major physiological regulator of circulating platelet levels and it is hoped that this hormone will be valuable in stimulating megakaryocyte and platelet recovery in patients with thrombocytopenia, just as erythropoietin and GM-CSF or G-CSF have been valuable in stimulating the production of red and white cells.

[Veno-occlusive disease--an important complication in hematopoietic cells transplantation]. / Choroba zylno-okluzyjna watroby--istotne powiklanie po transplantacji komórek macierzystych hematopoezy.

Hemopoietic stem cell transplantation is frequently used in clinical practice. However, many severe complications limit its usage. One of the most important is veno-occlusive disease of the liver (VOD). The key pathophysiologic event is a damage to epithelium during chemotherapy. Gradual development of intrahepatic portal hypertension leads to clinical manifestations (jaundice, liver enlargement, ascites). Many risk factors has been identified (pre-transplant liver disturbance, chemotherapy and conditioning, drugs). The diagnosis is based on clinical criteria and exclusion of other diseases. Laboratory, haemodynamic, ultrasound studies and histopathology are very important in diagnosis. In pharmacological prophylaxis heparin is widely used. Therapy requires strict fluid and electrolyte balance. Some patients can benefit from transjugular intrahepatic portosystemic shunt (TIPS) or liver transplantation. Defibrotide gives more hope for patients but further investigations are needed.