Bortezomib retreatment is effective in relapsed multiple myeloma patients - real-life clinical practice data.

Nowadays, bortezomib, a proteasome inhibitor, is widely used in treatment of newly diagnosed or relapsed multiple myeloma. The aim of this study was to analyze efficiency of bortezomib retreatment in patients with relapsed or refractory multiple myeloma. From 2004 to 2016, 283 patients were retrospectively evaluated at all hematological centers in the Czech Republic. Bortezomib was administered at the standard dosing and in combined therapy with corticosteroids, chemotherapy or thalidomide. Before bortezomib retreatment, 61% of patients received previous lenalidomide treatment, 40.6% autologous transplantation, and median number of prior lines of therapy was three. In total, 21% of patients were refractory to the first bortezomib treatment. In bortezomib retreatment, overall response rate was 34.5%, median progression-free survival was 7.8 months (95% CI: 6.7-8.9), median duration of response was 10.5 months (95% CI: 8.0-13.0) and median overall survival was 20.3 months (95% CI: 17.9-22.7). Grade 3-4 adverse events included thrombocytopenia, neutropenia, anemia and infection. Neuropathy grade 2 or higher occurred in 19.4% of patients. We conclude that bortezomib retreatment is an effective and safe therapeutic alternative for relapsed or refractory multiple myeloma patients.

Lenalidomide and dexamethasone in treatment of patients with relapsed and refractory multiple myeloma - analysis of data from the Czech Myeloma Group Registry of Monoclonal Gammopathies.

Lenalidomide (LEN) is an immunomodulator with clinical activity against myeloma cells. Based on the pivotal phase 3 trials MM-009 and MM010, the combination of lenalidomide and dexamethasone(DEX) was approved for patients with multiple myeloma who received at least one prior therapy. Here, we evaluated LEN/DEX therapy in unselected population and subsequently in selected sub-groups of patients with relapsed/refractory multiple myeloma followed in the Registry of Monoclonal Gammopathies of the Czech Myeloma Group. Altogether 858 patients were treated with LEN/DEX in the Czech Republic and Slovakia until end of 2017. The analyzed sub-groups were defined as patients with high risk cytogenetic aberrations and patients with relapsed and refractory MM. The overall response rate (ORR; partial remission or better response, PR) in the whole group of patients was 46.3% for all lines of therapy, 26.4% for high-risk group and 32.1% for relapsed and refractory group. Medians of overall survival (OS) in the same cohorts were as follows: 25.6, 15.7 and 18.5 months, progression free survival (PFS) was: 11.2, 6.4 and 9.0 months respectively. The most common adverse events were hematologic and infectious. In conclusion we found that our results correlated with those found in other studies in terms of response rates, survival measures, and also of treatment toxicity.

Simplified novel prognostic score for real-life older adults with multiple myeloma-registry-based analysis.

The main goal was to find a simple prognostic to evaluate overall survival of patients older than 65 years of age with myeloma. Retrospective registry-based analysis from the Registry of Monoclonal Gammopathies was conducted. Patients over 65 years with symptomatic myeloma were included. The four major parameters with impact on survival were identified: male gender, age > 75, creatinine > 152 µmol/L, and ECOG performance status 2-4. The patients were scored as good (0 points), intermediate good (1 point), intermediate poor (2 points), poor (3-4 points). Patients (1410 MM) were included. Median OS (months) was 65.7 (95% CI 49.8-81.7) for good, 51.0 (44.1-57.8) for intermediate good, 32.2 (26.2-38.2) for intermediate poor, and 18.9 (15.1-22.7) for poor. The differences in OS were statistically significant (p < 0.0001). Good score was used as reference for hazard ratios, which for each other score were 1.43 (1.09-1.84) for intermediate good, 2.58 (2.00-3.33) for intermediate poor, and 3.88 (2.94-5.10) for poor. Time to progression showed medians (months) 20.5 (17.4-62.4) for good, 19.3 (17.0-21.7) for intermediate good, 19.6 (16.2-23.0) for intermediate poor, and 13.0 (10.8-15.2) for poor. The suggested scoring system provides readily available information about the prognosis of MM patients above 65 years.

Asymptomatic and Treatment-requiring Multiple Myeloma - Data from the Czech Registry of Monoclonal Gammopathies.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) are premalignant stages of multiple myeloma (MM). MM is a malignancy of plasma cells, which is associated with a median overall survival of 5 to 7 years. MM accounts for approximately 10% of hematological malignancies. PATIENTS AND METHODS: Descriptive analysis of data from 19 Czech centres collected in the Registry of Monoclonal Gammopathies (RMG) was performed. RESULTS: Over the last 10 years of prospective collection of data, together with retrospectively recorded data on patients diagnosed before the registry establishment, data on 7,467 patients with either asymptomatic or symptomatic form of MM have been gathered. Validation criteria for the analysis were met by 2,506 MGUS patients, 400 SMM patients and 4,738 MM patients. The median duration of follow-up was 4.3 years in MGUS patients and 2.4 years in SMM patients. The overall risk of progression from MGUS to malignancy was 1.7% per year. The risk of progression from SMM to MM was highest in the 1st years after diagnosis: overall, this risk was 16.6% per year. The median duration of follow-up was 2.8 years in MM patients. The median overall survival from the diagnosis was 5.7 years. The median OS from treatment initiation/progression-free survival decreased from 60.5/21.0 months in the 1st line therapy to 34.3/12.4 months in the 2nd line therapy, 22.6/8.9 months in the 3rd line therapy and 13.8/5.8 months in the 4th or higher line therapies. Thanks to the availability of novel drugs for MM treatment in the Czech Republic, treatment strategies have changed dramatically over the last decade. CONCLUSION: RMG is a registry designated for the collection of data on diagnosis, treatment, treatment results and survival of patients with monoclonal gammopathies in the long-term follow-up. RMG is a valuable source of data from real clinical practice.Key words: registries - monoclonal gammopathy of undetermined significance - smouldering multiple myeloma - multiple myeloma - progression - treatment - survival.

Low molecular weight heparins for thromboprophylaxis during induction chemotherapy in patients with multiple myeloma.

BACKGROUNDS: Patients with multiple myeloma have a high risk of venous thromboembolism (VTE), especially during the induction chemotherapy. The aim of our observational study was to determine the impact of prophylaxis with low molecular weight heparin (LMWH) on the incidence of thromboembolic complications. PATIENTS AND METHODS: We analyzed the incidence of thromboembolic events in 258 patients treated with induction chemotherapy containing vincristin, doxorubicin or idarubicin, and dexamethasone, followed by stimulation chemotherapy with cyclophosphamide and G-CSF, and high-dose chemotherapy with melphalan. Two groups of these patients were compared based on the practice of thromboprophylaxis. Patients in the first group (Control, n = 140) were either not treated or treated with a short duration of anticoagulation therapy while the patients in the second group (Prophylactic, n = 118) underwent standard prophylaxis with LMWH throughout the entire period of induction chemotherapy. A total of 102 patients were selected for a close monitoring of the prophylactic effect of different LMWH doses and to be compared to patients without treatment. RESULTS: Standard prophylaxis with LMWH significantly (p < 0.007) lowered a risk of VTE when compared to patients without such prophylaxis (3.4% versus 12.9%, respectively). Furthermore, analysis of the subgroup of 102 patients revealed that higher LMWH doses (> 70 IU/kg per day) achieved full prophylaxis in 28 patients while lower doses were less effective leading to DVT in 3 (7.7%) out of 39 patients. In contrast, VTE was diagnosed in 5 (14.3%) out of 35 patients without any LMWH prophylaxis. CONCLUSION: Prophylaxis with LMWH leads to a significant reduction of the risk of thromboembolic complications during the induction chemotherapy in patients suffering from MM. The prophylactic effect of LMWH is dose-dependent.

Low-dose thalidomide regimens in therapy of relapsed or refractory multiple myeloma.

Thalidomide has been estimated as a useful drug in therapy of refractory or relapsed multiple myeloma. Recently, several studies have shown very good results in therapy combination of thalidomide, cyclophosphamide and dexamethasone, but still high doses of thalidomide associated with serious adverse events have been used. In our study, we performed low-dose thalidomide regimens; the aim of this study was to verify the effect and to assess their toxicity. For younger patients up to 65 years we used a "CTD-junior" regimen, consisting of oral thalidomide 200 mg daily, pulsed intravenous cyclophosphamide 800 mg on day 1 and pulsed oral dexamethasone 40 mg on days 1-4 and 12-15, for every three weeks. For patients over 65 years, the "CTDsenior" regimen was used, with oral thalidomide 50-100 mg daily (according to tolerability), oral cyclophosphamide 50 mg daily and pulsed dexamethasone 20 mg on days 1-4 and 15-18, for every four weeks. From the group of 97 patients with progressive form of multiple myeloma or with resistance to conventional chemotherapy, 85 patients were evaluated. According to the EBMT criteria, we observed in 8% complete remission (CR), in 50% partial response (PR) and in 22% minimal response (MR). Ten patients (12%) were stabilized and seven patients (8%) progressed. Toxicity of both regimens was mild and well manageable, when weakness, obstipation, neuropathy of lower extremities, glycoregulation worsening and mild leucopenia occurred most often. These results showed that low doses of thalidomide are still effective, when combined with other drugs. Both CTD regimens are safe also for patients with advanced and heavily pretreated multiple myeloma.

High-dose chemotherapy followed by autologous stem cell transplantation changes prognosis of IgD multiple myeloma.

Immunoglobulin D (IgD) multiple myeloma (MM) is a rare plasma cell disorder constituting less than 2% of all MM cases. Survival of patients with IgD MM is generally shorter than that of patients with other types of monoclonal (M-) protein. We have retrospectively analyzed patients with IgD MM participating in clinical trials of the Czech Myeloma Group. Twenty-six IgD MM patients treated between 1996 and 2006 were identified, 14 (54%) men and 12 (46%) women. The median age was 61 years (range: 37-79 years). Ten of 26 patients (39%) were treated with first-line high-dose chemotherapy (HDCT) using melphalan 200 mg/m(2) followed by autologous stem cell transplantation (ASCT). Thirteen of 26 patients (50%) received conventional chemotherapy (CHT), mostly melphalan and prednisone or a vincristine/doxorubicin/dexamethasone (VAD) regimen. Treatment responses were evaluable for 23 of 26 (89%) patients. All HDCT patients had treatment responses, including seven patients (70%) with complete responses and three patients (30%) with partial responses. The median progression-free survival was 18 months for HDCT patients and 20 months for CHT patients. The median overall survival (OS) for all patients was 34 months. The median OS for the HDCT group has not yet been reached (70% of the patients are still alive). In contrast, the median OS for CHT patients was only 16 months. The difference in OS between the two groups was statistically significant (P=0.005). In conclusion, the overall response rate for patients with IgD MM aged 65 years or less treated with HDCT and ASCT is similar to that seen in other MM types.

International Staging System required standardization of biochemical laboratory testing in multiple myeloma.

The standardization of biochemical measurement procedures in multiple myeloma is necessary for reliable prognostic stratification of patients in multicentric trials. The new prognostic index International Staging System for multiple myeloma uses only two laboratory markers, albumin and beta-2 microglobulin. Our study compared results of albumin, beta-2 microglobulin and monoclonal immunoglobulin measurements from six centers which provide treatment for multiple myeloma in the Czech Republic and attempted to standardize the analytic procedures. We have found that the measurement of albumin is well standardized and the results from all laboratories were comparable. The measurement of beta-2 microglobulin achieved comparability only after a partial unification of analytical methods. The determination of monoclonal immunoglobulin concentration provided comparable results for concentrations higher than 20 g/l with higher variability for lower values.

[Recommendations for early identification of damage to the skeleton by malignant processes, and for early diagnosis of multiple myeloma]. / Doporucení pro casné rozpoznání postizení skeletu maligním procesem a pro casnou diagnostiku mnohocetného myelomu.

The number of newly diagnosed cases of multiple myeloma in the Czech Republic is about 3-4 per 100 000 persons per year. In the higher age groups, the incidence increases. Multiple myeloma is an illness that reacts well to treatment which can result in periods of remission lasting for years. Some of the patients are even able to return to work. A pre-requisite for successful treatment is early diagnosis and this is usually in the hands of first line physicians. This is the reason why the Czech Myeloma Group, in conjunction with neurologists, orthopedicians and radio diagnosticians has issued the following recommendations for first line physicians containing a more detailed description of the symptoms and the diagnostic pitfalls of the disease. This disease reminds a chameleon for the variety of its symptoms. For the sake of clarification, we shall divide multiple myeloma symptoms into five points, each of which is reason enough to warrant an examination to confirm or rule out a malignant cause of health problems (a negative result does not automatically mean exclusion). If any of the recommended examinations results positive, the diagnostic process must be continued, in which case a general practitioner refers the patient to a specialist health centre. Observing these recommendations should minimize the number of cases of late diagnosis. 1. Bone destruction symptoms. - Unexplained backache for more than one month in any part of spine even without nerve root irritability or without pain in other part of skeleton (ribs, hips, or long bones). - Pain at the beginning of myeloma disease is very similar to benigne common discopathy, however the intensity of backache is decreasing within one months in benigne disease. In the case of malignant process the intensity of bone pain is steadily increasing. - Immediate imaging and laboratory investigation are indicated by resting and night pain in spinal column or in any part of skeleton. - Backache with the sign of spinal cord or nerve compression should be sent for immediate X Ray, and focussed CT/MRI followed by acute surgery if needed. - Osteoporosis especially in men and premenopausal women. 2. Features of changed immunity or bone marrow function. Persistent and recurrent infection, typical is normochromic anaemia, with leucopenia and trombocytopenia. 3. Raised erythrocyte sedimentation rate even increase concentration of total plasma protein. 4. Impaired renal function. Increased level of creatinin or proteinuria, nephrotic syndrome with bilateral legs oedema. 5. Hypercalcemia with typical clinical symptoms (polyuria with dehydratation, constipation, nausea, low level conscience, coma). Every one from these points has to be reason for general medical doctor to start battery of tests: -X-ray of bones focused to painful area (mandatory before physiotherapy, local anaesthesia or other empiric therapy). If plain X-ray does not elucidate pain and symptoms are lasting more than one month, please consider all circumstances and results from laboratory investigation. This patient needs referral to the centre with MRI/CT facilities (CT or MRI is necessary investigation in case of nerve root or spine compression). -Investigation of erythrocyte sedimantion rate (high level of sedimentation of erythrocyte can indicate multiple myeloma). -Full blood count. -Basic biochemical investigation serum and urine: serum urea, creatinin, ionts including calcium, total protein, and albumin CRP (high concentration of total protein indicates myeloma, low level of albumin indicates general pathological process, similary increased concentration of fibrinogen, impaired renal function indicates myeloma kidney, however hypercalcemia is typical for highly aggressive myeloma). -Quantitative screening for IgG, IgM and IgA in serum (isolated raised level one of immunoglobulin with decreased level of the others indicates myeloma). -Common electrophoresis of serum is able to detect monoclonal immunoglobulin level at few gramm concentration. If all the laboratory investigation are in normal level the possibility that the current problems are multiple myeloma origine is smaller, but it does not exclude one of rare variant--non secretory myeloma (undifferentiated plasmocyt lost characteristic feature to produce monoclonal immunoglobulin). If any of tests indicate the possibility of myeloma, patient require urgent specialist referral to department with possibility to make diagnosis of malignant myeloma.

[Bortezomib (Velcade) in relapsed/refractory multiple myeloma--the first experience in the Czech Republic]. / Inhibitor proteazomu--bortezomib (Velcade)--v lécbe refrakterního mnohocetného myelomu První zkusenosti v Ceské republice.

BACKGROUND: Multiple myeloma is the second most prevalent and mostly fatal hematologic cancer. Further advances have been made in understanding the mechanisms involved in the myeloma pathogenesis and elucidation of critical signalling pathways as therapeutical targets. Proteasome inhibitors are the example of this new approach and bortezomib is the first agent in this class to enter clinical trials. METHODS AND RESULTS: In 6 hematological centers in Czech Republic 29 patients with refractory/relapsed myeloma had been treated with bortezomib (Velcade, Millennium Pharmaceuticals) in 2004. The initial dose 1.3 mg/m2 of Velcade was given, in 1 case the dose was adjusted due to pre-existing renal failure to 1 mg/m2. The response was achieved in 17 patients (59%). Four patients had complete, 11 partial and two minor responses. In 5 cases stabilization of disease was observed and 6 patients progressed during the therapy. CONCLUSIONS: Unfortunately, one patient died immediately after the start of therapy due to sepsis. The most common adverse events were thrombocytopenia, anaemia, neuropathy, gastrointestinal complication, renal failure and fatigue. Grade 4 adverse events occurred in 37.9% of patients (4x thrombocytopenia, 2x gastrointestinal, 2x renal failure, 1x sepsis, leucopenia, hepatopathy and anaemia, respectively). Peripheral neuropathic pain of grade 3 was reported in 4 cases, in one patient therapy had to be interrupted due to this complication. We confirmed promising results of phase II trials.

Standardized parenteral alanyl-glutamine dipeptide supplementation is not beneficial in autologous transplant patients: a randomized, double-blind, placebo controlled study.

We conducted a controlled, double-blind study of parenteral glutamine supplementation in an unselected group of consecutive autologous transplant patients. Patients received 30 g of alanyl-glutamine dipeptide (Dipeptiven; Fresenius-Kabi, Bad Homburg, Germany) or glutamine-free amino acid solution i.v. from day +1 to day +14 or to discharge. All patients were assessed for clinical status, mucositis, blood counts, oral intake and immune reconstitution. Parenteral nutrition was administered according to predefined guidelines. Forty patients were randomized; 21 into the glutamine and 19 into the placebo arm. Glutamine patients had less days with diarrhoea (3.3 +/- 4.0 vs 4.3 +/- 3.0, P = 0.03), but they had more severe oral mucositis (mean 4 +/- 4.7 vs 1.4 +/- 2.3 days of mucositis score >13, P = 0.04), spent more days on opioids (mean 3.5 +/- 4.2 vs 1.2 +/- 2.2 days, P = 0.03) and left hospital later than placebo patients (mean 13.5 +/- 3.1 vs 11.7 +/- 2.4 days after transplant, P = 0.06). There were more relapses (P = 0.02) and deaths (P = 0.05) in the glutamine group. The cost of supportive care (mean 2960 +/- 1694 vs 1534 +/- 513 Euro, P = 0.002) was also greater for glutamine patients, mainly due to the cost of glutamine dipeptide itself. The described mode and dosage of glutamine administration did not produce meaningful benefit in our autologous transplant patients and it was certainly not cost-effective.

Rare presentation of non-Hodgkin lymphoma of the thoracolumbar spine in pregnancy with 7 years' survival.

A rare, so far unpublished, case of non-Hodgkin lymphoma in 26-year-old pregnant woman is presented. As X ray examination and other investigations were avoided during her pregnancy, the discrete signs of spinal cord compression led to sudden severe neurological deterioration after delivery. This necessitated emergency decompression and stabilization of the spine. Acute surgical treatment resulted in complete functional recovery. It was followed by chemotherapy and radiotherapy, which led to disease-free survival 7 years after the surgery. Magnetic resonance imaging is the examination of choice when long-lasting back pain during pregnancy does not resolve with bed rest.

[Parenteral glutamine does not improve the nutritional status in patients during high-dose chemotherapy and autologous peripheral stem cell transplantation]. / Parenterální glutamin nezlepsuje nutricní stav nemocných v prubehu vysokodávkové chemoterapie s autologní transplantací periferních kmenových bunek.

BACKGROUND AND AIM: High-dose chemotherapy is aggressive treatment modality adversely affecting both energy/protein demands and oral intake/resorption of nutrients. Aminoacid glutamine is known for its' proteoanabolic effect and as an energy source for enterocytes and immune system. Nutritional parameters have been studied in a controlled, randomised, double-blinded trial of parenteral glutamine supplementation of autologous stem cell transplant patients. METHODS: Forty consecutive patients with haematological and solid cancer and multiple sclerosis were treated from 1999 to 2001 by high-dose chemotherapy with autologous stem cell transplantation. Patients were randomly assigned either for parenteral administration of 30 g of alanyl-glutamine dipeptide (Dipeptiven, Fresenius-Kabi) or isonitrogenous glutamine-free amino acid solution from day +1 to day +14 or to discharge from hospital. Patients were closely monitored from admission to day +100. Nutritional parameters included: oral dietary intake, body weight, body composition, energy expenditure, concentration of serum proteins and nitrogen balance. Parenteral nutrition in dose of 26.5 kcal/kg and 1 g of aminoacid/kg was given to patients who did not reach adequate oral intake for 5 days and withheld after three consecutive days of adequate intake. RESULTS: Nutritional assessment on admission differed according to the method used but no parameter of nutrition predicted the clinical course of treatment. Inadequate oral intake period lasted (mean +/- SD) 6.8 +/- 5.9 days, average length of stay being 17.5 +/- 3.9 days. Patients were unable to use sipping of enteral feed. Resting energy expenditure neither on admission nor in critical period differed from predicted value. Serum protein concentrations significantly decreased on discharge with normalisation as soon as to day +28, correlating inversely with changes in extracellular water content. Nitrogen urine loss was 10-16 g/day. Only 42.5% of patients were treated with parenteral nutrition. Cumulative nitrogen balance at day +9 was -30.7 +/- 24.1 g N. Body weight at day +28 significantly decreased (-2.94 +/- 4.4 kg), mostly consisting of loss of pure body cell mass. Glutamine supplementation did not improve any of the listed nutritional parameters. CONCLUSIONS: High-dose chemotherapy with autologous stem cell transplantation causes proteocatabolism of medium severity. Nutritional status of patients cannot be improved by the mode and dosage of parenteral glutamine used in our study. Optimal nutritional monitoring and treatment for this group of patients is suggested.

[Effect of parenteral glutamine on restoration of lymphocyte subpopulations after high-dose chemotherapy and autologous hematopoietic cell transplantation: data from a double-blind randomized study]. / Vliv parenterálního glutamínu na obnovu lymfocytárních subpopulací po vysokodávkované chemoterapii s autologní transplantací krvetvorných bunek: data z dvojite slepé randomizované studie.

Within the framework of a randomized double blind study focused on the effect of glutamine on the clinical course of autologous transplantation of peripheral cells the authors assessed lymphocyte sub-populations (CD3, CD4, CD8, CD19 and CD57+ cells) before transplantation and 14, 28 and 42 days after transplantation. A total of 36 patients were investigated (18 glutamine, 18 placebo). In the whole group of patients the authors found restoration of CD4 and CD19 cells to pretransplantation values one day +42 after transplantation, in CD8 and CD57 cells a statistically significant increase as compared with the pre-transplantation state occurred. In the glutamine group they observed on day +28 a more rapid restoration of CD8 and a marginally better restoration of CD19 positive cells, while patients who were given placebo restored CD57+ cells more rapidly. All these differences were balanced on day +42, only CD19+ cells were at that time marginally higher in the placebo group. With the exception of CD19+ lymphocytes the authors observed weak correlations between the number of lymphocytes on day +42 after transplantation and the number of transplanted CD34+ cells. It may thus be stated that the drop of lymphocyte sub-populations has a short-term character, the restoration correlates among others with the administered amount of haematopoietic cells. Significant importance of glutamine for the restoration of the lymphocyte sub-population was however not proved.

[GBV-C/HGV, a new virus as one possible cause of hepatitis of unknown etiology]. / Nový virus GBV-C/HGV jako jeden z mozných puvodcu etiologicky nevyjasnených hepatitid.

For etiologically obscure (some 4%) viral hepatitis agents are sought and tested to make elucidation of their cause possible. One of the candidates is since 1995 the newly discovered virus GBV-C/HGV. Despite intense research its relationship to viral hepatitis of obscure origin (VHN) has not been elucidated so far. In the submitted paper the authors attempted to contribute to the elucidation of etiological associations of GBV-C/HGV infection and VHN by comparing the dynamics of markers of the infection in a group of 59 patients with VHN, two control groups exposed to a high risk of parenteral operations and a third comparative group. The first control group comprised 64 patients in a long-term haemodialyzation programme (HD), the second group was formed by 82 patients with haematooncological disease (BD). The third comparative group comprised 22 patients coinfected (CI) with virus of hepatitis C (VHC), or possibly hepatitis B (VHB). The patients with VHN were HBsAg, anti HCV and anti HEV negative. In the majority in the first blood sample transaminases were elevated which was one of the main reasons for examination of GBV-C/HGV RNA. Prevalence of GBV-C/HGV infection, proved by the presence of at least one of the two markers of current or past infection (GBV-C/HGV RNA, antiGBV-C/HGV) was in the compared VHN, HD and BD groups as follows: 88.1%, 59.4% and 43.9%. The frequency of GBV-C/HGV positivity was highest in VHN-76.3%. In control groups HD and BD GBV-C/HGV RNA positivity was substantially lower, 18.8% and 25.6% resp. Long-term continuous viraemia was recorded in patients with VHN in 18.6%. In groups HD and BD it was half that value: 9.3% and 9.18%. In patients with VHN surprisingly after 6.5 months a marked rise of negative findings occurred (5.6x) without the expected increase of antibodies. A similar finding was recorded also in the other groups (HD and BD), incl. CI patients. Disappearance of viraemia was observed most frequently in VHN (55.9%). In groups HD and BD GBV-C/HGV RNA disappeared only in 7.8% and 12.1% resp. In treated patients of the CI group viral RNA was present in 45.5% and it disappeared in 36.4%. On the other hand, seroconversion to antibodies was comparable in VHN, HD and BD (11.9%, 9.4%, 8.5%), only in group CI it was higher (18.2%), obviously in conjunction with treatment of concurrent HCV or HBV infection. Disappearance of viraemia without subsequent seroconversion occurs in GBV-C/HGV infection frequently, the highest rate was observed by the authors in patients with VHN. Disappearance of viraemia does not necessarily imply clearance of GBV-C/HGV but may be due to a change of GBV-C(HGV into a state of persistence without positive laboratory markers of the infection. Persistence of the virus could also be the reason of the assumed conditioned pathogenicity of the virus, and the effect of frequent disappearance of both markers could explain some controversial epidemiological observations when in studies only static data without dynamic associations were used.

Pharmacokinetics of viral antibodies after administration of intravenous immunoglobulin in patients with chronic lymphocytic leukaemia or multiple myeloma.

OBJECTIVE: Intravenous immunoglobulin (IVIG) preparations are derived from human pooled plasma and should fulfil high standards of purity and viral safety. Introduction of additional purification steps, however, may result in modulation of the biological properties of immunoglobulins. Since cleavage of the Fab-fragment leads to a significant decrease in half-life, the latter provides information about the integrity of the immunoglobulin G (IgG) molecules. Therefore, a pharmacokinetic study of a novel preparation is required to determine safety and disposition in the target population. METHODS: Twenty-seven patients with chronic lymphocytic leukaemia (CLL) and 12 with multiple myeloma received intravenous infusions of IVIG containing antibodies against hepatitis B virus (anti-HBs; n= 15; 8960 IU), cytomegalovirus (anti-CMV; n = 9; 14,250 U) or varizella-zoster-virus (anti-VZV; n = 15; 6000 IU), respectively. Serum concentrations of viral antibodies were determined for 71 days during and after infusion. RESULTS: Maximum serum concentrations of anti-HBs, anti-CMV and anti-VZV were observed at about 4 h (median) after start of the infusion. Total body clearances came to 0.14 +/- 0.08 ml/min (anti-HBs), 0.10 +/- 0.02 ml/ min (anti-CMV) and 0.14 +/- 0.07 ml/min (anti-VZV). The terminal elimination half-lives were determined to be 25.34 +/- 8.34 days (anti-HBs), 24.66 7.28 days (anti-CMV) and 31.79 +/- 12.47 days (anti-VZV). Clinical chemistry parameters including C3- and C4-complement serum concentrations revealed no pathological changes, seroconversion for hepatitis B and C and HIV did not occur. CONCLUSIONS: The pharmacokinetic parameters of the IgG antibodies calculated after administration of the novel IVIG preparations to patients with CLL and multiple myeloma are in close agreement with data obtained from healthy volunteers and with values of native IgG, suggesting that the production process did not impair clinically relevant characteristics of the viral antibodies.

[Hematopoietic stem cell transplantation in autoimmune diseases in rheumatology practice]. / Transplantace krvetvorných bunek autoimunitních chorob v revmatologii.

Autoimmune diseases (AID) result from the impairment of the effector and/or recognition phase of the immune response. The autoimmune process plays a crucial role in the pathogenesis of the systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), and their treatment is therefore largely based on immunosuppression. However, some patients do not respond to its standard doses. The disease becomes intractable with the survival rate comparable to that of some haematological malignancies, or patients become soon handicapped with very poor quality of life, depending on continual administration of high doses of steroids. The new hope for those patients becomes therapy with high dose myelo- and immuno-ablative chemotherapy with autologous hematopoietic progenitor cell support (PBPC). Tens of patients with intractable forms of AID were transplanted in the pilot clinical studies with promising results. The most frequent indications included: SLE, SSc, and RA. Final conclusion of the therapeutic effects will be drawn from the analysis of larger trails.

[Immunoablation and hematopoietic stem cell transplantation in the treatment of multiple sclerosis]. / Imunoablace s transplantací krvetvorných bunek v lécbe roztrousené sklerózy.

High dose chemotherapy with autologous hematopoietic cell support is a standard approach in the management of selected hematological malignancies. Autoimmune diseases which do not respond to conventional immunosuppression might benefit from high dose immunoablative chemotherapy. The transplantation of hematopoietic cells is necessary after the high dose chemotherapy to restore bone marrow function. The immune system undergoes a new ontogeny which can result in the development of tolerance. Multiple sclerosis (MS) has so far been the most common indication for this kind of treatment. Experience with preclinical studies on murine experimental allergic encephalomyelitis (EAE), as well as the course of MS following bone marrow transplantation for coincidental malignancy in humans formed the basis of the first clinical studies involving high dose chemotherapy and autologous hematopoietic support. Results of the first studies confirm that the method is feasible in patients with MS, and that the effect is very promising. Nonetheless, more consistent results vis a vis the therapeutic effect should emanate from upcoming studies.

[Prognostic factors and markers of activity in multiple myeloma (results of the Cooperative Group for Diagnosis and Treatment of Multiple Myeloma)]. / Prognostické faktory a markery aktivity u mnohocetného myelomu (výsledky Kooperativní skupiny pro diagnostiku a lécbu mnohocetného myelomu).

BACKGROUND: Multiple myeloma (MM) is mostly fatal neoplastic disorder, however, the median survival of 30-40 months does not adequately express the wide spectrum courses of the disease. Therefore better prognostic factors are needed. METHODS AND RESULTS: We analyzed the value of both standard clinical features and cytokines for differential diagnosis, assessment of myeloma activity, prediction of overall survival and duration of remission in a group of 124 patients with MM and in 156 with various monoclonal gammapathies, respectively. The initial levels of Ca2+, LD, Hb, albumin, IL-6, PO4- and creatinine were useful for differentiation of monoclonal gammapathy of undetermined significance from MM. Serum IL-6 correlated with the stage and activity of MM, sIL-6R levels were significantly higher only in stage III and in newly diagnosed myeloma. We did not found the correlation between IL-6 and CRP levels. The usefulness of some standard features for prediction of survival was confirmed (Ca2+, Hb, clinical stage and subclassification A/B according to Durie-Salmon, SB2M > 4 mg/ml, creatinine, LD, ALP) as well as sIL-6R serum level determined both at time of diagnosis and during the course of disease. The prognosis of patients with reversible renal failure and those with intact renal function was not significantly different. Among other features, only serum sIL-6R, measured at time of diagnosis or during the course of disease, had significant predictive value for the assessment of duration of event-free survival in patients with MM. CONCLUSION: Due to short follow-up possible association of high levels of IFN-gamma with better prognosis of MM could not be stated.