Diagnostic relevance of 18F-FDG PET/CT in newly diagnosed patients with monoclonal gammopathy of undetermined significance (MGUS): Single-center experience.

Monoclonal gammopathy of undetermined significance (MGUS) is a known precursor of more serious cancers, such as multiple myeloma (MM), Waldenström macroglobulinemia (MW) and other lymphoproliferative disorders. Using 18F-FDG PET/CT, we aimed to evaluate its benefit in early detection of various accompanying disorders and illnesses in MGUS patients. We prospectively analyzed the diagnostic relevance of 18F-FDG PET/CT in 390 newly diagnosed MGUS patients. On 18F-FDG PET/CT scans, the presence of focal or diffuse areas of detectable increased tracer uptake was recorded in 37 (9.5%) MGUS patients. The most frequent pathology was lymphadenopathy (3.8%), followed by thyroid diseases (2.1%), rheumatic diseases (1.8%), and other solid malignancies (1.5%). These results have major implications for confirmed associations of MGUS with numerous malignant and non-malignant disorders. We believe that 18F-FDG PET/CT imaging in newly diagnosed MGUS patients may be useful in early detection of other serious pathologies, not only in predicting progression of MGUS to active MM, and should be strongly recommended if available.

Plasma Cell Leukemia ­â€Š the Forgotten Dis­ease

BACKGROUND: Plasma cell leukemia (PCL) is a rare dis-ease and possibly the most aggressive form of monoclonal gammopathy. It is classified into two forms -  primary PCL that occurs without a previously identifiable multiple myeloma stage, and secondary PCL that develops from previously dia-gnosed multiple myeloma. These two forms have different cytogenetic and molecular profiles, but both forms have an aggressive clinical course. Combinations of different therapeutic approaches includ-ing autologous stem cell transplantation and currently proteasome inhibitors and immunomodulatory drugs are used to treat PCL. Current dia-gnostic criteria, developed in the 1970s, may underestimate PCL prevalence; thus, prospective re-evaluation is be-ing considered. PURPOSE: The aim of this study is to review all available information about PCL with an emphasis on dia-gnostics, treatment, and circulat-ing plasma cells features. CONCLUSION: Although PCL is rare, it is quite a severe dis-ease. Current treatments us-ing the latest therapeutics have prolonged patient survival. However, due to the low incidence of PCL, information about the dis-ease is very limited and comes mostly from small retrospective studies. Further studies of PCL are needed, because new information could increase in patient survival and our understand-ing of its pathogenesis. Key words plasma cell leukemia -  multiple myeloma -  plasma cells -  cytogenetics -  treatment This work was supported by grant NV18-03-00203. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submited: 2. 11. 2018 Accepted: 18. 11. 2018.

Retreatment with lenalidomide is an effective option in heavily pretreated refractory multiple myeloma patients.

The combination of lenalidomide and dexamethasone is the current gold standard for treatment of relapsed multiple myeloma. This study analyzes the efficiency of repeated lenalidomide treatment in patients with relapsed and refractory multiple myeloma. A total of 41 patients were prospectively evaluated at the University Hospital Brno. Lenalidomide was administered at standard dosing and in combination with corticosteroids and/or chemotherapy. The maximum cumulative dose of lenalidomide was limited to 4,200 mg because of Czech health insurance rules. Before the second lenalidomide treatment, all patients were refractory to the last treatment; previously, 95% of patients had bortezomib treatment, 48% had autologous transplantation and the median number of prior therapy lines was three. A partial 14.2% or better response was achieved with the second lenalidomide treatment. The median progression-free survival was 4.8 months, and median overall survival was 11.9 months. Unfortunately, predicting risk factors in lenalidomide retreatment proved unsuccessful. Although our treatment results were significantly affected by limited Czech health care system coverage for lenalidomide, we established that its repeated treatment is an effective therapeutic alternative for heavily pretreated patients with relapsed and refractory multiple myeloma.

Minimal Residual Disease Assessment in Multiple Myeloma by Multiparametric Flow Cytometry.

BACKGROUND: Progress in treatment of multiple myeloma extensively increased patient remission rates, so minimal residual disease (MRD) detection becomes essential to assess the effectivity of treatment and depth of complete response. Nowadays, multiparametric flow cytometry (MFC) is the most used method for monitoring of MRD presence in the bone marrow of multiple myeloma patients; however, detection on molecular level can be used as well. It is evident that choice of protocol used for MFC-MRD assessment can significantly affect required results; nevertheless, standardized and highly sensitive approach of "next generation flow" is already available. Although benefit of MRD assessment as an independent predictor of progression-free survival and overall survival is known, very recent research showed that MRD-negative status surpasses the prognostic value of complete response achievement for progression-free survival and overall survival. AIM: This review is focused on use MFC in MRD assessment in multiple myeloma. The technical aspects and clinical benefits of this approach are mentioned as well. CONCLUSION: The information about MRD level detected by highly sensitive and reproducible MFC can be potentially used as a biomarker to evaluate the efficacy of different treatment strategies, help on treatment decisions and act as a surrogate for overall survival in multiple myeloma patients.Key words: multiple myeloma - minimal residual disease - flow cytometry - plasma cells.

Biobanking - the First Step to Successful Liquid Biopsy Experiments.

BACKGROUND: Archiving of biological materials in biobanks is considered to be the initial crucial part of research activities. Most often, biobanks are founded for research purposes since they allow collection of sufficient material for analysis of new or testing of previously identified biomarkers. Biobanking needs to quickly react to current needs of researchers as well as clinicians, it is not a rigid system. Laboratory analyses of monoclonal gammopathies are based on separation of plasma cells from bone marrow of patients. A specific problem is usually a lack of tumor cell fraction, which is due to location of tumor cell in bone marrow in combination with low infiltration. One of the challenges in clinical research is the necessity of changes in biobanking for samples allowing detection of minimal residual disease in the bone marrow but also from peripheral blood by the so-called liquid biopsies. AIM: The aim of this review is to show the importance of archiving biological material in the Czech Republic and to show concrete examples of its usage in hematooncology. CONCLUSION: A general problem in solving many research questions is the availability of a critical amount of specimens for statistical analysis. Obtaining critical amount of specimens of biological material can be quickly archived by cooperation of biobanks sharing both methodological standards and informations about the availability of samples for research projects.Key words: archiving - biological material - informed consent - multiple myeloma - plasma cells.

The quality of life following allogeneic hematopoietic stem cell transplantation - a multicenter retrospective study.

UNLABELLED: Although allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers a unique curative potential, it may be connected with high treatment-related morbidity and mortality. Besides many organ complications, allo-HSCT may significantly affect quality of life (QOL). PATIENTS AND METHODS: Between January 2011 and December 2012, five hundred and ninety patients (pts) from 6 transplant centers in the Czech Republic filled in the questionnaire for the quantitative measurement of QOL using Functional Assessment of Cancer Therapy-General (FACT-G) version 4. Study cohort characteristics were as follows: 325 males, 340 pts received myeloablative conditioning, 383 pts received PBPC, representation of diagnoses; acute leukemia (n=270), bone marrow failure (n=36), chronic myeloid leukemia (n=74), myelodysplastic/myeloproliferative syndrom (n=110), lymphoproliferative disease (n=93). The median age at allo-HSCT was 43 years (range: 1.7 - 71.0), the median time from allo-HSCT to questionnaire completing was 3.8 years (range: - 0.2 - 21.6). The earliest allo-HSCT was performed in November 1989, the last in September 2012. In this retrospective study, we investigated the impact of various factors on the QOL after allo-HSCT: age, gender, diagnosis, type of conditioning, time from diagnosis to allo-HSCT, disease stage, graft type, donor type, time from allo-HSCT to questionnaire completing, GVHD, relapse. Only data from patients who were more than 3 months after allo-HSCT were used for the multivariate analysis. The overall results of the total FACT-G score (median=85.0; range: 29-108) as well as the results of each specific dimension - PWB (median=23.0; range: 5-28), SWB (median=24.0; range: 7-28), EWB (median= 19.0; range: 4-24), FWB (mean=21.0; range: 2-28) showed a value in the highest quartile of the possible evaluation. In multivariate analysis, an inferior QOL score was reported for patients with aGVHD (p=0.002), cGVHD (p<0.001), QOL decreased with increasing age (p=0.048) and increased with time elapsed since allo-HSCT (p<0.001).Allogeneic HSCT represents an important intervention into the overall integrity of the organism. In particular, the development of GVHD can cause very serious organ, but also mental problems which can significantly reduce the QOL. The QOL is steadily increasing with increasing interval from allo-HSCT but improvement and disappearance of these complications may take many years, and sometimes these effects may probably persist permanently.

Outcomes of 167 healthy sibling donors after peripheral blood stem cell mobilization with G-CSF 16µg/kg/day: efficacy and safety.

Mobilization of peripheral blood stem cells (PBSC) using the granulocyte colony-stimulating factor (G-CSF) has enabled the collection even from older donors and those with comorbidities. Several clinical parameters have been reported to predict the success of PBSC mobilization. The aim of our study was to evaluate the safety of PBSC donation in a cohort of 167 sibling donors after mobilization with G-CSF 16 µg/kg/day for 5 days during short- and long term follow-up and to analyse the efficacy, toxicity and factors influencing CD34+ mobilization capacity. All 167 sibling donors completed the established mobilization protocol. The median yield was 7.9x106 CD34 cells/kg per recipient weight. The optimal target dose of CD34 cells ≥ 4.0x106/kg was achieved in 140 donors (84%). Only in 4 donors (2%) was the CD34+ yield < 2x106/kg. No major toxicities occured.Factors associated with higher PBSC yields included age 51/µL (p 45.5 x 109/L (p = 0.003). Comorbidity score, performance status and donor weight did not significantly influence PBSC yields. Long-term follow-up was possible in 60% (101/167) of the donors. The median length of follow-up from PBSC donation was 11.9 years. Most of these donors reported good or very good general health (91%), and no hematological malignancies were observed.The mobilization of PBSC in sibling donors with G-CSF 16 µg/kg/day is an effective and safe procedure with no significant short- and long-term toxicities.

Mycotic Aneurysm in the Aortoiliac Area - Current Options for Treatment.

BACKGROUND: Infection represents a less frequent cause for the development of an abdominal aortic aneurysm. The diagnosis is associated with a high risk of rapir progression and rupture. CASE REPORTS: Case 1 is a female operated on urgently for a ruptured mycotic aneurysm of the abdominal aorta. After resection of the aneurysm, we performed in situ replacement using a rifampicin-soaked vascular prosthesis. In case 2, an asymptomatic aneurysm of the right iliac artery was treated by endovascular implantation of a stent-graft. Both patients were treated with antibiotics concurrently and are still alive. DISCUSSION: The discussion deals with the up-to-date treatment modalities for mycotic aneurysms in the aorto-iliac region. The indication criteria must be adjusted individually. CONCLUSION: The prognosis of patients with a mycotic aneurysm depends particularly on an early diagnosis.

[Management of groin wound infection after arterial surgery using negative-pressure wound therapy]. / Lécba infekce v trísle po tepenné rekonstrukci pomocí podtlakové terapie.

INTRODUCTION: Infection is a serious complication in vascular reconstructive surgery. When the entire graft is infected, its excision and subsequent replacement is the only option of treatment. In case of localised graft infection in the groin, the vascular reconstruction can be saved using negative-pressure wound therapy (NPWT). METHODS: Retrospective study design was used to evaluate the efficiency of NPWT in the treatment of infected inguinal wounds following arterial reconstructive surgery. The assessments included demographic patient characteristics, causative agents, type of reconstruction and NPWT outcome. Wound infection was graded based on the Szilagyi classification. Patients were followed-up for 12 months after the therapy. Complete wound healing, retained graft patency, and no clinical signs or laboratory evidence of infection were regarded as successful results of treatment. RESULTS: Between 2009 and 2012, 20 patients with deep groin infection (Szilagyi II and III) following arterial reconstructive surgery were treated by NPWT. The patient group included 12 men and 8 women; mean age was 68.1 years. Nine patients underwent aorto-femoral arterial reconstructions (with vascular prosthesis in 8 cases), and surgery below the inguinal ligament was done in 11 patients (with vascular prosthesis in 7 cases). Of the 20 patients, early infection within 30 days of surgery was recorded in 17 (85%) patients; Szilagyi grade III groin infection with exposed prosthetic graft was found in 5 (25 %) patients (infection: early, 4; late, 1). The causative agents isolated from the wound included Staphylococcus aureus (n=8), Pseudomonas aeruginosa (n=5) and Escherichia coli (n=5). Mean NPWT duration was 12.7 days. Wound healing was achieved in 17 patients (success rate, 85 %). Patients with early Szilagyi II infection showed the best outcomes (92.3%). CONCLUSION: Localised wound infection in the groin after arterial surgery is a serious complication of arterial reconstruction procedures. In eligible patients, such an infection can be treated conservatively using NPWT. The method is most efficient in the management of early infections. Wounds infected with P. aeruginosa or those with suture line exposure require special treatment. Long-term follow-up is necessary due to the risk of recurrent infection.

[Treatment of AL amyloidosis in 2012; the benefit of new drugs (bortezomib, thalidomide, and lenalidomide). Summary of published clinical trials]. / Lécba AL-amyloidózy v roce 2012, prínos nových léku (bortezomibu, thalidomidu a lenalidomidu). Prehled publikovaných klinických studií

Until 2011, the gold standard of treatment for patients with AL amyloidosis was the combination of alkylating cytostatics (melphalan or cyclophosphamide) and dexamethasone. For a selected group of patients under 65 years of age with only moderate damage to their body caused by amyloid and with good cardiac function (EF> 40%), high-dose chemotherapy with autologous hematopoietic cell transplantation seems to be optimal. Patients with AL amyloidosis and low bone marrow plasma cell count generally undergo the harvest of hematopoietic cells from peripheral blood, followed by high-dose chemotherapy immediately after they are diagnosed. In contrast to multiple myeloma, high-dose chemotherapy is not preceded by several months of conventional treatment. The year 2012 witnessed a release of reports about extensive experience with new drugs that were used in Phase I and Phase II clinical trials, and in isolated cases also in Phase III, for the treatment of patients with AL amyloidosis. Based on these studies it can be concluded that among the new available drugs (bortezomib, thalidomide and lenalidomide) bortezomib is the drug with the greatest curative effect in patients with AL amyloidosis; it achieved 24-37% of complete remissions in monotherapy. The greatest number of treatment responses was reported during the treatment that combined bortezomib, alkylating cytostatics and dexamethasone. This treatment showed significantly more treatment responses during the first-line drug therapy than during therapies that followed. Clinical trials with lenalidomide combined with other drugs saw a lower number of treatment responses than the number described in treatment with bortezomib combined with other drugs. That is the reason why lenalidomide combinations are not considered the optimal first-line therapy, with the exception of AL amyloidosis with bortezomib contraindication (severe neuropathy caused by AL amyloidosis). It was confirmed that lenalidomide combined with other drugs could cause remission in patients whose disease was resistant to the initial bortezomib therapy. Lenalidomide (or alternatively also thalidomide) can therefore be used as second-line therapy if bortezomib therapy proves unsuccessful, with the possibility of achieving a complete remission. The increase in the number of complete remissions brought about by bortezomib therapies in patients with AL amyloidosis poses a question about which treatment should be used for younger patients with only moderate damage to their body, i.e. high-dose chemotherapy with autologous hematopoietic cell transplantation or combined treatment with bortezomib. Additional comparative studies are required to be able to answer that question and determine which of the aforesaid therapy modalities is optimal. A question still remains whether the increase in the number of complete remissions due to bortezomib will also bring about longer survival comparable to the results of high-dose chemotherapy treatment with autologous hematopoietic cell transplantation.

[Atypical fracture of metatarsal bone in a patient with multiple myeloma who was treated long-term with bisphosphonates]. / Atypická fraktura metatarzální kosti u pacienta s mnohocetným myelomem, který byl dlouhodobe lécen bisfosfonáty.

The first reports found in professional literature on the use of bisphosphonates as a treatment date back to 1972. We found the first report on the use of a bisphosphonate comprising nitrogen in its molecule in a publication from 1990. Some of the adverse effects of the particular types of bisphosphonates were described in the registration studies. At least two serious adverse effects of this group of medicines had not been described until 2000. We found the first description of jaw osteonecrosis in relation to the longterm application of bisphosphonates in a publication from 2002 and we found the first description of an atypical bone fracture originating without a corresponding traumatic event in a location with no presence of an osteolytic focus in an article from 2006. These so  called atypical fractures, which are also called fractures without a corresponding traumatic event (low energy fractures), have been described to have occurred in femurs, in the pelvis and less frequently in the metatarsal area. "Atypical fractures" are linked to longterm administration of bisphosphonates, which significantly increases the bone density and impedes osteolysis but it simultaneously increases the fragility of bones and decreases their flexibility. The definition of an atypical fracture of the skeleton emphasises the fact that such fractures occur with an inadequately minimal force (energy) in the aforementioned predilection locations. In the following text we are describing a patient who has been treated for a multiple myeloma with an atypical fracture of the Metatarsal bone 2. This fracture occurred during a regular walk without any excessive load and the patient could not recall any corresponding injury or longer walking. The patient had been administered bisphosphonates for 34 months before the atypical metatarsal fracture occurred. The metatarsal bone fracture was treated through a nonweight  bearing regime for the sole and the pain diminished within a single month. In comparison with the published data of atypical fractures, our case concerns a short interval between initiation of the bisphosphonate administration and the occurrence of the atypical fracture. In the available literature these fractures are described after more than a five year application of a bisphosphonate. New pain in the bearing skeleton in patients treated with bisphosphonates are therefore always subject to an imaging examination among others to exclude an atypical fracture due to an increased fragility of the bone.

[Cold agglutinin disease -  no response to glucocorticoids and rituximab, what treatment is best for the 3rd line of therapy? Case report and review of the literature]. / Nemoc chladových aglutininu nereagující na lécbu glukokortikoidy a na lécbu rituximabem. Jaký postup zvolit pro III. linii lécby? Popis prípadu a prehled literatury.

Acquired autoimmune haemolytic anaemia is divided according to the characteristics of immunoglobulin causing haemolysis. The most frequent are haemolytic anaemia with thermal antibodies. They bind to erythrocytes and initiate their destruction in the reticuloendothelial system cells, leading to extravascular haemolysis. Cold agglutinin disease differs significantly from haemolytic anaemia with thermal antibodies. Agglutination is caused by monoclonal antibodies, in most cases class IgM and very rarely class IgG. Under cold conditions they bind to erythrocytes and cause their agglutination and subsequent disorder of blood circulation in body parts with a lower temperature. Agglutinins binding initiate the binding of the complement to the erythrocytes. Under warm conditions the binding becomes loose but the parts of the complement, which are already bound, cause haemolysis, which is mainly of an intravascular nature. The loose haemoglobin causes haemoglobinuria. Description of a patient with the disease. The 1st symptoms of the disease, i.e. anaemia + circulatory disorders in the acral parts of the body, disappearing under warm conditions followed with haemoglobinuria, led to the dia-gnosis of cold agglutinin disease. The 1st line treatment, prednison, did not show any response. The 2nd line treatment used was rituximab and dexametazon. Rituximab was administered in doses of 500 mg/ m2 to 4 times in a row in weekly intervals. Dexametazon was administered in doses of 40 mg from 1st to 4th day and from 15th to 18th day of the cycle. This treatment, however, did not show any response either. Therefore this article brings an overview of all publications regarding the disease treatment with the aim of choosing the most effective treatment options in the case of failure of the monotherapy using rituximab. The 1st line treatment for cold agglutinin disease is rituximab in monotherapy, usually administered once per week at least for 4 weeks. This treatment shows a response in about one  half of treated patients and the remission duration median after rituximab administration is 11 months. A combination of rituximab with fludarabin was more effective, though more toxic; this combination, in a clinical study, led to 75% of patients responding to treatment, including 20% experiencing complete remission. The treatment response median reached over 66 months. In a small study (10 patients) an increase in the amount of rituximab administrations from 4 to 8 led to a treatment response in 6 patients in whom administration of 4 doses of rituximab had no response. When treating Waldenström macroglobulinemia, effectiveness of the following drugs and their combinations was proven: rituximab, chlorambucil, cyclophosphamide, fludarabin, bortezomib, lenalidomid, bendamustin and alemtuzumab. The same drugs and treatment procedures are used for the treatment of the cold agglutinin disease as for Waldenström macroglobulinemia. Successful treatment with vortezomibem, combinations of rituximab + bendamustin, rituximab + cyclophosphamide or rituximab + fludarabin + cyclophosphamide, were recorded in the form of a description as regards the cold agglutinin disease treatment. An important benefit is also shown through treatment with the monoclonal antibody antiC5, eculizumab, which is otherwise used for the treatment of paroxysmal nocturnal haemoglobinuria. Eculizumab blocks the C5 element of the component and thus stops haemolysis in a patient with cold agglutinin disease. As cold agglutinin disease is very rare, there are only a few clinical studies and when treating this rare disease we have no other option than to take into account the information contained in the descriptions of the particular cases of cold agglutinin disease and the experience of Waldenström macroglobulinemia disease treatment. The discussion seeks to solve the issue regarding what 3rd line treatment option to use in the described patient.

[PET-CT documented fast onset of treatment response to cyclophosphamide, thalidomide and dexamethasone in patients with multicentric Castlemans disease. Case description and treatment information overview]. / PET-CT dokumentovaný rychlý nástup lécebné odpovedi cyklofosfamidu, thalidomidu a dexametazonu u multicentrické formy Castlemanovy nemoci. Popis prípadu a prehled informací o lécbe

Castlemans disease (also called angiofollicular lymph node hyperplasia) can take two forms with different prognosis: the localized form can usually be treated by a surgical intervention and has therefore a favourable prognosis. On the other hand, the multicentric form has an unfavourable prognosis and requires systemic treatment. Classic manifestations of multicentric Castlemans disease are multiple sites of lymphadenopathy, sometimes hepatomegaly and also splenomegaly or serous cavity effusions. Typical pathological laboratory levels measured in patients with this disease include an increased CRP level, anaemia of chronic diseases, and many patients have an increased total protein concentration, in some cases exceeding even 100g/ l. It is caused by a high concentration of polyclonal immunoglobulins. Typical clinical symptoms include fluctuating subfebrile or febrile temperatures, increased night sweats and fatigue usually related to anaemia. In some patients, the disease is manifested as vasculitis, frequently also affecting cerebral arteries, i.e. leading to cerebrovascular accidents. The aetiology of this disease is unclear; it is a polyclonal lymphocyte proliferation, often with differentiation into plasma cells. It is not a clonal malign disease; however, it can transform into a clonal lymphoproliferative disease. Even though it is not a malign disease in the histomorphological sense, the disease symptoms are so acute that systemic treatment is required. In the past, the treatment method of this disease used to be based on corticoids and cytostatics; however, such treatment was not always successful in achieving its objective, i.e. complete remission. In the past few years, an improvement of treatment results was accomplished by adding a new drug to the basic medication, i.e. to cytostatics and dexamethasone. Many publications describe the benefi t of adding a third drug from the IMiDs group (immunomodulatory drugs), such as thalidomide or lenalidomide. These drugs affect the formation of cytokines and block the angiogenesis, which in turn positively influences the speed of the treatment response. The second new drug that has helped in combination with classical treatment is the anti-CD20 antibody, rituximab. The third new drug to add this list is the monoclonal antibody against the interleukin-6 receptor, tocilizumab. This paper describes a rapid treatment response after combined treatment with cyclophosphamide 500mg/ m2 i.v. infusion 1st and 15th day in a 28- day cycle, dexamethasone 20mg p.o. cycle day 1- 4 and cycle day 15- 18, and thalidomide 100mg daily. In the course of the two-month treatment, the accumulation of fl uorodeoxyglucose during the PET-CT imaging has normalized; the originally pathologically enlarged nodes have become smaller, the originally elevated CRP level has normalized and the originally signifi cantly lower haemoglobin level has risen. This is the second patient with multicentric Castlemans disease in the last three years who showed a rapid response to treatment with thalidomide combined with cyclophosphamide and dexamethasone. Therefore, we consider such treatment suitable for newly diagnosed patients with multicentric Castlemans disease.

[Heart transplantation and the subsequent treatment of AL amyloidosis]. / Transplantace srdce a následná lécba AL-amyloidózy.

UNLABELLED: Severe damage to the heart caused by AL amyloid deposits is a contraindication of high-dose chemotherapy with autologous haematopoietic stem cell transplantation. Severe heart damage caused by AL amyloid results in frequent life-threatening complications, even during the course of the classical chemotherapy treatment and it often makes keeping to the treatment schedule impossible. Scheduling heart transplantation before the treatment of AL amyloidosis will significantly improve the patients overall condition and enable them to undergo the intensive AL amyloidosis treatment with the hope that a long-term complete remission may be achieved. CASE DESCRIPTIONS: Transplantations of heart damaged by AL amyloid deposits were conducted in three patients; two men, age 48 and 54, and one woman, age 63. In the interval of 3-6 months from the heart transplantation before the scheduled AL amyloidosis treatment was initiated, an examination of bone marrow, the concentration of monoclonal immunoglobulin and free light chains was carried out. Both men had more than 10% of plasma cells in the bone marrow after the heart transplantation and the concentrations of the λ free light chains were pathologically increased. During the first-line therapy, autologous haematopoietic stem cells were harvested from peripheral blood after mobilizaton with granulocyte growth factor (filgrastim) at the dose of 5 µg/kg twice a day. During the administration of filgrastim until the end of the haematopoietic stem cell harvest, the combined immunosuppressive treatment was reduced and a corticosteroid dose was compensatory increased. The prophylactic antiviral drug valganciclovir was discontinued during the haematopoietic stem cell harvest. High-dose chemotherapy (melphalan 100 mg/m2) with autologous haematopoietic stem cell transplantation followed. In the interval from administering melphalan until the rise in neutrophil count over 2 x 109/l, antiviral prophylaxis was discontinued again, the immunosuppressive drug doses were reduced and corticoid doses were slightly increased. High-dose chemotherapy with melphalan at the of 100 mg/m2 was tolerated without major complications and without mucositis; however, in neither of the male patients did it lead to a complete haematological remission. Consequently, the second-line therapy followed using bortezomib combined with dexamethasone and also with cyclophosphamide or doxorubicin. One of these two patients reached a complete haematological remission after the bortezomib therapy; the values of free light chains were normal, immunofixation was negative, and clonal plasma cells were absent in the bone marrow. In the case of the other patient, the bortezomib therapy only induced partial remission. In this case, the third-line therapy followed, applying a combination of lenalidomide, dexamethasone and cyclophosphamide. This therapy significantly reduced the values of free light chains; however, their ratio remained pathological. To conclude, the latter response can be described as a very good partial remission. Both men currently show no signs of disease activity and are in a good clinical condition 28 and 30 months after the heart transplantation. The third heart transplantation, due to severe heart damage by AL amyloid deposits, was conducted in a woman aged 63. An examination of this woman three months after the heart transplantation showed that the original pathological values of free light chains became normal. The woman had approx. 8% of clonal plasma cells before the heart transplantation. Three months after the heart transplantation the bone marrow contained only 3% of polyclonal plasma cells. In this case, the immunosuppressive treatment with corticosteroids after the heart transplantation probably induced a complete haematologic remission. The woman is in a complete AL amyloidosis remission seven months after the heart transplantation. CONCLUSION: It was beneficial to perform the heart transplantation first and to initiate the AL amyloidosis treatment no sooner than three months after the heart transplantation in patients with severe heart damage caused by AL amyloid deposits. If the patients are in a good clinical conditions, autologous haematopoietic stem cells can be harvested after the heart transplantation and high-dose chemotherapy can be offered to the patients. If this intensive treatment does not induce remission, it is necessary to apply additional alternative treatments.

Waldenström's macroglobulinemia - clinical symptoms and review of therapy yesterday, today and tomorrow.

BACKGROUND: Waldenström macroglobulinemia (WM) is a lymphoplasmocytic lymphoma with immunoglobulin M monoclonal protein. The incidence of this disease is very low (0.4/100,000), so that this disease can be regarded as an orphan's disease. It means that new drugs are often tested and registered for more frequent diseases. PURPOSE: In this review we will focus on the efficacy of the new drugs for WM. RESULTS: The current treatment options for symptomatic WM patients include alkylating agent cyclophosphamide and anti-CD20 monoclonal antibodies. Therapy with rituximab and bendamustin resulted in longer therapeutic response then therapy with rituximab, cyclophosphamide and dexamethasone. Many drugs, used in multiple myeloma (MM), shoved promising results in WM patients. Bortezomib is effective in WM, but its neurotoxicity is higher in WM than in MM patients. Therefore, new proteasome inhibitors, carfilzomib and ixazomib, are better tolerated as documented in several studies. New types of antiCD20 antibody (obinutuzumab) can be used in patients with rituximab intolerance. in five of our patients with WM, obinutuzumab and bendamustin reached deeper responses than therapies administered in previous lines of therapy. Oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib alone and in combination with rituximab have extended the treatment options for WM patients. New BTK inhibitors (e. g. acalabrutinib, zanubrutinib, and vecabrutinib) were tested and their lower toxicity (atrial fibrillation) was documented. Moreover, the BCL2 inhibitor venetoclax is newly tested. CONCLUSION: New antiCD20 antibody (obinutuzumab) is of advantage in patients with WM with rituximab intolerance as well as bendamustin and new proteasome inhibitors (ixazomib and carfilzomib) or new BTK inhibitors with lower cardiotoxicity. Many of the abovementioned drugs do not have official registration for WM and can be administrated with the consent of the health care provider only. Thus, this work brings evidence of their efficacy.

Therapy of Castleman's disease with siltuximab - case report and review of literature.

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is characterized by constitutional symptoms, enlarged lymph nodes and laboratory test abnormalities, which are primarily related to the overproduction of interleukin-6 (IL-6). This form (iMCD) was treated earlier with cytostatics used for lymphoma, later with bio-logic therapy as rituximab, immunodulatory drugs and proteasome inhibitors, and in the last years with an anti-IL-6 antibody, siltuximab. Siltuximab is a human-mouse chimeric immunoglobulin G1k monoclonal antibody against human IL-6 approved in the European Union for the treatment of iMCD. In view of the limited treatment options for iMCD, this case report aimed to evaluate the efficacy and safety of siltuximab in the management of this condition. CASE: We describe a young woman with iMCD diagnosed at the age of 25 years. For first line treatment, rituximab and dexamethasone were used without any cytostatic because the patient wished to give birth to a healthy child in the future. However, the response after this first line therapy was short. In addition, after 3 years from the start of rituximab + dexamethasone therapy, it was necessary to administer treatment for the relapse of iMCD. We decided for siltuximab in this young woman, still aged < 30 years, and started administration of siltuximab in 3-week intervals. RESULTS: After administration of first two infusions of siltuximab, all inflammatory markers returned to normal value. Moreover, serum hemoglobin and albumin levels as well as C-reactive protein normalized after the first two administrations of siltuximab. The clinical response continue, siltuximab is still administered in 3-week intervals. PET/CT with fluorodeoxyglucose confirmed a very good anatomic and metabolic response to the treatment. Siltuximab demonstrated a favorable safety profile, and the prolonged treatment was well tolerated. CONCLUSION: This result is encouraging and demonstrates the potential of siltuximab as treatment of CD. As earlier published, this case confirms that significantly elevated inflammatory markers in a patient with CD predict a good response to siltuximab.

Kinetics of bilirubin and liver enzymes is useful for predicting of liver graft-versus-host disease.

Graft-versus-host disease (GVHD) is the most frequent complication after allogeneic hematopoietic cell transplantation. We analyzed the kinetics of bilirubin and liver enzymes in 47 cases with liver GVHD and in 47 cases without GVHD after allogeneic transplantation for various hematological malignancies. The duration of an liver GVHD episode (LGVHD) was defined as the interval from the point when the criteria of LGVHD were met to the decrease to < 2 upper normal limit (UNL) for aminotransferases or bilirubin < 34 µmol/l for bilirubin. The imminent LGVHD episode was defined as the interval from the start of continuous increase (≥ 3 consecutive rising values) of bilirubin and liver enzymes above UNL to the point of LGVHD diagnosis.The number of imminent LGVHD episodes, and median length in days were as follows: bilirubin (39;5), ALT(28;12), AST(9;12), GGTP(34;9), and ALP(13;14). Statisticallly significant associations between asymptomatic continuous increase of bilirubin, ALT, and GGTP and later liver GVHD manifestation were found (p=0.004, p=0.008, p=0.005, respectively). The asymptomatic continuous increase in bilirubin, ALT, and GGTP occurred at a median of 5, 12, and 9 days before liver GVHD episode, respectively. In the control group without GVHD, median levels of bilirubin and liver enzymes were within normal limits and no continuous increase was observed.Kinetics of bilirubin and liver enzymes is useful for predicting of liver GVHD. A continuous increase of bilirubin and/or ALT, GGTP before the standard liver GVHD criteria are met can be a sign of coming liver GVHD.

Efficacy and safety of Id-protein-loaded dendritic cell vaccine in patients with multiple myeloma--phase II study results.

UNLABELLED: In a phase II clinical study, pretreated multiple myeloma patients with relapsing or stable disease received autologous anticancer vaccine containing dendritic cells loaded with Id-protein. Patients received a total of 6 vaccine doses intradermally in monthly intervals. No clinical responses were observed. During the follow-up with a median of 33.1 months (range: 11-43 months), the disease remained stable in 7/11 (64%) of patients. Immune responses measured by ELISpot were noted in 3/11 (27%) and DTH skin test for Id-protein was positive in 8/11 (73%) of patients; out of those, 1/11 (9%) and 5/11 (46%), respectively, had preexisting immune response to Id-protein before the vaccination began. Outcomes were compared to those of a control group of 13 patients. A trend to lower cumulative incidence of progression in the vaccinated group was observed at 12 months from the first vaccination (p= 0.099). More patients from the control group compared to vaccinated patients required active anticancer therapy [4/11 (36%) vs. 8/13 (62%)]. Vaccines based on dendritic cells loaded with Id-protein are safe and induce specific immune response in multiple myeloma patients. Our results suggest that the vaccination could stabilize the disease in approximately two-thirds of patients. KEYWORDS: dendritic cells, immunotherapy, anticancer vaccines, Id-protein, multiple myeloma.

[The effect of lenalidomide on rare blood disorders: Langerhans cell histiocytosis, multicentric Castleman disease, POEMS syndrome, Erdheim-Chester disease and angiomatosis]. / Úcinnost lenalidomidu u vzácných krevních chorob: u histiocytózy z Langerhansových bunek, multicentrické Castlemanovy choroby, POEMS syndromu, Erdheimovy-Chesterovy choroby a angiomatózy. Popis prípadu a prehled literatury.

UNLABELLED: Lenalidomide has been licenced for the treatment of multiple myeloma and, in 2012, it is used as a standard treatment of relapses of the disease. Literature contains a number of publications on the effects of lenalidomide in myelodysplastic syndrome, in malignant lymphomas and chronic B lymphocytic leukaemia. The effects of the drug in rare diseases, however, have not been investigated so far. In this paper, we summarize our experience with lenalidomide in rare blood disorders. We observed an excellent effect of lenalidomide in multifocal aggressive, repeatedly relapsing Langerhans cell histiocytosis where it led to complete remission. This patient was treated with 2-chlorodeoxyadenosine and with CHOEP (cyclophosphamide, etoposide, doxorubicin, vincristine and prednisone) chemotherapy and high dose BEAM chemotherapy with autologous transplantation of haematopoietic tissue for an early disease relapse. Following another early relapse, the patient was treated with lenalidomide (25 mg). Treatment with lenalidomide induced complete remission on PET-CT. The patient was consolidated during the remission with a reduced intensity conditioning regimen and allogeneic transplantation of haematopoietic tissue. Following allogeneic transplantation, the patient has been in full remission for 10 months. We further showed an excellent effect of lenalidomide in multicentric Castleman disease with generalized involvement of lymphatic nodes, B symptoms and vasculitis. The patient was first treated R-CHOP chemotherapy (rituximab, cyclophosphamide, adriamycin, vincristine and prednisone). Due to a lack of efficacy, this was changed to the CVD combination (cyclophosphamide, thalidomide, dexamethazone). This treatment delivered complete remission but was complicated by thalidomide-associated neuropathy. Due to persistent neuropathy, thalidomide could not be used to manage further relapse and thus lenalidomide (25 mg, 11 cycles) was used. The patient has been in complete PET-CT remission for 7 months following this treatment. We observed partial efficacy in Erdheim-Chester disease. We used 2-chlorodeoxyadenosine as part of initial treatment that delivered partial regression of brain infiltrates only; fluorodeoxyglucose accumulation in the bones has not changed. Lenalidomide 25 mg was used as second line treatment. This led to complete regression of CNS infiltrates on MRI but fluorodeoxyglucose accumulation in bone lesions did not change. Regression of clinical signs and regression of fibrosis of retroperitoneum was achieved with an ongoing treatment with anakinra. A patient with multiple angiomatosis affecting the abdominal cavity, mediastinum and vertebrae and digestive tract had been stabilized with zoledronate (4 mg once every 2 months) and thalidomide (100 - 200 mg/den) for several years. However, several years of this treatment led to severe neuropathy. Consequently, we attempted to substitute thalidomide for lenalidomide. However, 10 mg of lenalidomide alone was not sufficiently effective and thus low dose of 50 mg of thalidomide was added. Combined treatment with zoledronate, lenalidomide 10 mg/day and thalidomide 50 mg/day stabilized the condition for 9 months. Due to relapsed gastrointestinal bleeding the treatment had to be changed after 9 months to thalidomide 100 mg/day and Sandostatin 0.1 mg twice daily s.c. A patient with osteosclerotic myeloma and POEMS syndrome was initially treated with CAD chemotherapy (cyclophosphamide, adriamycine and dexamethazone) that was followed by tandem high dose chemotherapy (melphalan 100 mg/m2) and autologous transplantation. Treatment with thalidomide was given due to insufficient efficacy but was not tolerated. Lenalidomide was administered as the fourth line treatment. Even though literature describes remission of POEMS syndrome following lenalidomide, four cycles did not lead to remission in our patient. CONCLUSION: We showed an effect of lenalidomide in Langerhans cell histiocytosis and in Castleman disease. The treatment led to regression of brain infiltrates in a patient with Erdheim-Chester disease. A dose of 10 mg of lenalidomide daily in combination with 50 mg of thalidomide stabilized a course of angiomatosis. Lenalidomide did not deliver the required treatment response in a patient with POEMS syndrome and multiple previous therapies.

[Cladribine is highly effective in the treatment of Langerhans cell histiocytosis and rare histiocytic disorders of the juvenile xanthogranuloma group]. / Kladribin je velmi úcinným lékem pro lécbu histiocytózy z Langerhansových bunek a vzácných histiocytárních nemocí ze skupiny juvenilního xantogranulomu.

UNLABELLED: Cladribine (2-chlorodeoxyadenosine) is metabolised and phosphorylated in a cell up to 2-chloroadenosine triphosphate which is the actual effective form of the drug. The greatest accumulation of 2-chloroadenosine triphosphate is in the most active cells, where activating (phosphorylation) enzyme, deoxycytidine kinase, has the highest activity, whereas inactivating enzyme (dephosphorylation), cytoplasmic 5-nucleotidase, has the lowest activity. A very good ratio of the both enzymes for high effectiveness of cladribine is in resting and proliferating lymphocytes. Therefore, cladribine is an effective medication for hairy cell leukemia, Waldenström macroglo-bulinemia but also for chronic -B-lymphocytic leukemia. However, such high concentrations of 2-chloroadenosine triphosphate are reached in some cells of histiocytic lines, in monocytes and also in Langerhans dendritic cells. That's why cladribine is highly effective medication in treating Langerhans cell histiocytosis and also in treating diseases of the juvenile xanthogranuloma group. In the paper we present a survey of published experience with cladribine in patients with Langerhans cell histiocytosis. The effectiveness of cladribine in the childhood form of Langerhans cell histiocytosis is investigated only in 1 multicentric clinical study, other data are taken from single case reports or small series studies. Cladribine was used in 60 adult patients altogether and in 51 of them (85%) treatment response (CR + PR) was achieved. In the group of childhood patients cladribine was used in 182 cases and treatment response (CR + PR) was reached in 110 (60.4%) thereof. One possible explanation for a higher number of therapy responses in adults is lower Langerhans cell histiocytosis aggressiveness in adults than in children. Another explanation is the fact that therapy responses in adults are summarized only from case reports and smaller cohorts, whereas in children, case reports and also results of a prospective randomized clinical study are included. Diseases of the juvenile xanthogranuloma group are much more rare than Langerhans cell histiocytosis and so the number of publications is smaller. In total, 7 publications describe therapy response of cladribine in some of the juvenile xanthogranuloma forms (Erdheim-Chester disease, disseminated juvenile xanthogranuloma and localized form of plane xanthoma type). Cladribine was also effective in CNS infiltration by Langerhans cell histiocytosis cells or juvenile xanthogranuloma cells. CONCLUSIONS: Cladribine is a highly effective medication used in treating Langerhans cell histiocytosis. It is very good tolerated in monotherapy. Therefore, it is suitable for initial therapy of adults with multifocal or multisystem form of Langerhans cell histiocytosis. Furthermore, it has the use in treating relapses after some other initial therapy. According to published experience, it is an effective drug for diseases of the juvenile xanthogranuloma group (Erdheim-Chester disease, diffuse juvenile xanthogranuloma and also Rosai-Dorfman disease).