Overview of histiocytic and dendritic disorders by the 5th version of WHO Classifi cation of Hematolymphoid Tumours from 2022.

BACKGROUND: Histiocytoses are rare disorders characterized by the accumulation of macrophages, dendritic cells, or monocyte-derived cells in various tissues and organs of children and adults, with a wide range of clinical manifestations, presentations, and histology. The histiocytoses are classified according to the WHO Classification, the last version of which was published in 2022, or according to the Histiocyte Society Classification, with the last version published in 2016. PURPOSE: This text provides an overview of histiocytoses as described in the WHO Classification 2022.

Monoclonal gammopathy of clinical signifi cance with osteosclerotic lesions - a case report and a literature review.

INTRODUCTION: Multiple myeloma is a common plasma cell neoplasia usually accompanied by the formation of osteolytic foci, whereas osteosclerotic myeloma is a very rare form of plasma cell dyscrasia. When osteosclerotic myeloma is detected, osteosclerotic foci are usually part of the POEMS syndrome. Osteosclerotic myeloma without other manifestations of the POEMS syndrome is an unusual finding. CASE DESCRIPTION: In a 46-year-old woman, osteosclerotic changes of the temporoparietal region caused soft tissue induration over this lesion, which initiated further investigation. Imaging studies subsequently showed multiple osteosclerotic foci in the skull. Examination of blood proteins revealed 8 g/L of IgG-lambda monoclonal immunoglobulin, subclass IgG1. In search of the cause of the osteosclerotic changes, FDG-PET/CT was performed, which revealed no FDG accumulation, i.e., no other tumor (breast or stomach cancer). Low-dose CT showed irregular bone structure, but not significant osteolytic or osteosclerotic foci. To map the extent of osteosclerotic changes, NaF-PET/CT imagination followed, which revealed multiple spots with high fluoride accumulation. A parietal bone biopsy showed osteosclerosis with minor clonal plasma cell infiltration. Trepanobioptic bone marrow sampling revealed an infiltration of bone marrow with atypical plasma cells in 8%. Flow-cytometric examination of bone marrow showed 0,37% of plasma cells, however predominantly (91%) clonal with lambda expression. MRI of the brain identified asymptomatic meningeal thickening. There was no evidence of POEMS syndrome in the patient; thus, we concluded the diagnosis as monoclonal gammopathy of clinical significance with osteosclerosis which was previously termed osteosclerotic multiple myeloma. CONCLUSION: Monoclonal gammopathy of clinical significance (MGCS) with osteosclerotic skeletal changes, documented on CT and multiple foci with intensive osteoneogenesis, documented on NaF-PET/CT without evidence of POEMS syndrome, is an extremely rare form of plasma cell dyscrasia. This publication documents the unique clinical manifestations of IgG-lambda type plasma cell proliferation without signs of POEMS syndrome and the role of NaF-PET/CT imaging. Classification of this disease as MGSC with osteosclerotic manifestations is more consistent with the indolent nature of the disease with a significantly better prognosis, compared with multiple myeloma.

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.

Rosai-Dorfman-Destombes disease - histiocytic disorder with inflammatory manifestation.

BACKGROUND: Rosai-Dorfman-Destombes disease (RDD) is a rare histiocytosis characterized by accumulation of activated histiocytes within affected tissues. Although the immunophenotype of this disease was described, the pathophysiology of this disease is still not sufficiently understood. Recent studies have found NRAS, KRAS, MAP2K1, and ARAF mutations in RDD lesions, raising the possibility of a clonal origin in some forms of RDD while in other cases reactive origin or association with other malignant and autoimmune disease is supposed. RDD is a widely heterogeneous entity with a range of clinical phenotypes occurring in some patients in association with autoimmune or malignant diseases. Its therapy should reflect the localization of the disease. Monotherapy with glucocorticoids is sufficient only in limited disease. In patients with advanced disease, combined nodal and extranodal forms of RDD need more intensive therapy. In older publications, antimetabolites, vinca alkaloids and prednisone were used; in recent publications, remissions after cladribine, rituximab, sirolimus, thalidomide, lenalidomide and cobimetinib were described. PURPOSE: This text summarizes current knowledge about this rare disease and reviews the therapeutic options.

Slow increase of bilirubin concentration during administration of lenalidomide, bortezomib and dexamethasone for multiple myeloma (unmasking previously undiagnosed Gilbert syndrome) and disappearance of necrobiotic xanthogranuloma after complete remission of multiple myeloma.

BACKGROUND: Lenalidomid ranks among immunomodulatory drugs. There are a few of the more common side effects, like a higher risk of venous trombembolism or diarrhea. Other side effects are rare. The hyperbilirubinemia described in this article can be assigned to them. In our case, the increase of bilirubin was associated with unrecognized Gilbert syndrome. CASE DESCRIPTION: We report a patient with multiple myeloma and necrobio-tic xanthogranuloma (NXG) of the skin and liver. After the treatment with bortezomib, lenalidomid and dexamethasone, complete remission was attained after 4 cycles with decrease of monoclonal immunoglobulin to an unmeasurable concentration. At the same time, the dis-appearance of cutaneous and hepatic lesions of NXG on FDG-PET/CT was evident. The administration of bortezomib was stopped after 8 cycles and only continued with lenalidomide as a maintenance therapy. However, after four cycles of this therapy, bilirubin increased above the upper limit and the increase continued till the 11th month of lenadomide administration, when bilirubin reached the highest concentration of 75 μmol/l (more than the three-fold of the upper limit, grade III toxicity). The patient had asymptomatic hyperbilirubinemia with no underlying liver disease or renal impairment while being on lenalidomide therapy. Genetic studies proved mutation; insertion in the promotor gene UGT1A1 typical for Gilbert syndrome. Hyperbilirubinemia may be attributed to the unmasking of previously undia-gnosed Gilbert syndrome. Therefore, the therapy with lenalidomide was interrupted after 11 months. The bilirubin level decreased after the discontinuation of the drug. CONCLUSION: NXG disappeared after fulfilling complete remission of multiple myeloma with disappearance of monoclonal immunoglobulin. This observation supports the hypothesis that monoclonal immunoglobulin has a crucial role in the ethiopathogenesis of NXG and suggests the treatment of monoclonal gammopathy if present in a patient with NXG, hoping that this will result in xantogranuloma disappearance.

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.

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.

[Treatment of Relapsed and Refractory Hodgkin Lymphoma - Recommendations of the Czech Hodgkin Lymphoma Study Group]. / Lécba relabovaného a refrakterního Hodgkinova lymfomu - doporucení ceské studijní skupiny Hodgkinuv lymfom.

High-dose chemotherapy with autologous stem cell transplantation remains the current standard of treatment for young patients with Hodgkin lymphoma in first relapse or in those who are refractory to first-line treatment. The most important prognostic factors in relapses are clinical stage IV, poor performance status, bulky mass, and less than partial remission after salvage chemotherapy. Standard salvage chemotherapy in relapse before autologous transplantation has not been defined; however, DHAP and ICE are most frequently used in this setting. A standard conditioning regimen before autologous transplantation is BEAM. Tandem autologous transplantation has been investigated in high-risk patients. Brentuximab vedotin is recommended as a consolidation treatment in patients with a high risk of relapse after autologous transplantation. Brentuximab vedotin is the standard of treatment for relapse after autologous transplantation, and subsequent allogeneic stem cell transplantation should be considered in young patients. Bretuximab vedotin in combination with bendamustine, nivolumab, and pembrolizumab, and combinations thereof with other drugs, were investigated in clinical trials in relapsed or refractory patients with Hodgkin lymphoma.Key words: Hodgkin lymphoma - autologous stem cell transplantation - brentuximab vedotin - nivolumabThis work was supported by grant awarded by AZV 16-29857, Ministry of Health in Czech Republic, Research project P 27/2012 awarded by Charles University in Prague, 3rd Faculty of Medicine, Prague.The authors declare they have no potential confl icts 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.Submitted: 7. 6. 2016Accepted: 24. 8. 2016.

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.

[Treatment and prognosis of relapsed or refractory Hodgkin lymphoma patients ineligible for stem cell transplantation]. / Lécba a prognóza pacientu s relabovaným nebo refrakterním Hodgkinovým lymfomem nevhodných k transplantaci kmenových bunek.

BACKGROUND: Relapses occur in 20-30% of patients with Hodgkin lymphoma (HL). Currently, there is no widely accepted standard treatment strategy in relapsed/refractory HL patients ineligible for autologous stem cell transplantation (ASCT). This article retrospectively evaluates survival and prognosis of patients with relapsed/refractory HL who were not suitable for high-dose chemotherapy and ASCT. New drugs and their efficacy in this indication are also disscussed. PATIENTS AND METHODS: A total of 17 patients treated with at least three lines of standard chemotherapy ± radiotherapy were analysed. High-dose chemotherapy and ASCT was not indicated due to advanced age (seven patients), chemorefractory disease (seven patients), cardiotoxicity (two patients) and insufficient stem cell collection of CD34+ cells (one patient). RESULTS: Median follow-up of the whole group after establishing the diagnosis was 3.48 years. Overall response to the second-line treatment was achieved in eight patients (47.0%). Four patients (23,5%) were classified as primary refractory after the first-line treatment and three more chemorefractory patients (17,6%) were detected after the second-line treatment. Out of 17 patients four are still alive (23,5%) in remission and 13 have died (eight due to HL progressions, four due to toxicity of the treatment and one patient with unknown cause of death). The estimated 5-year overall survival from the time of initial diagnosis was 46.3% and 30.8% when counted from the diagnosis of the first relapse. The estimated 5-year overall survival of four primary chemorefractory patients was significantly worse when compared to the group of 13 relapsed patients: 0 vs. 60.6%, p < 0,001. CONCLUSION: Prognosis of relapsed/refractory HL patients ineligible for ASCT and treated with several lines of standard chemotherapy ± radiotherapy is poor. Brentuximab vedotin is indicated in primary refractory patients in the second-line settings and in other relapsed patients in the third-line treatment. This strategy would help to increase the number of remissions, hence achieving a higher survival rate.

[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.

[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.

[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).

[Teleangiectasia hereditaria haemorrhagica--Osler-Weber-Rendu syndrome. Case study and treatment experience]. / Teleangiectasia hereditaria haemorrhagica - syndrom Osler-Weber-Rendu. Popis prípadu a zkuseností s lécbou.

Hereditary haemorrhagic telangiectasy is an inborn disease with autosomal dominant transmission. Nose bleeding usually occurs during the 2nd decade of life as the first sign of the disease. Later, during the 3rd or 4th decade of life, typical subtle, pinhead-sized (1-2 mm in diameter) vascular arteriovenous malformations occur. These are usually found on the oral mucosa and in the stomach and small intestine. During later stages of the disease, nose as well as gastrointestinal bleeding causes severe anaemia requiring transfusions. Advanced stages of hereditary hemorrhagic telangiectasy are associated with a development of ateriovenous vascular malformations in the liver, lungs and possibly the brain. Vascular ateriovenous malformations in the liver cause hyperkinetic circulation that may lead to heart failure. Blood within the pulmonary ateriovenous malformations bypasses filtration in the pulmonary capillary circulation and thus infected microtrombi may pass from the inferior vena cava to, for example, the brain. At first, local treatment - stopping epistaxis - is used. Symptomatic embolisation treatment and, sometimes, liver transplantation are used in advanced forms of the disease with anaemisation, despite iron substitution, and clinically significant ateriovenous malformations. Angiogenesis-inhibiting substances have been shown effective in patients with an advanced disease. Older clinical studies confirmed benefits of combined oestrogen-progesterone treatment, later also treatment with raloxifene or antioestrogens. Many post-2000 publications showed thalidomide and bevacizumab to be effective in this indication. Treatment with bevacizumab has led not only to increased haemoglobin concentrations but, through regression of ateriovenous malformations, provided control of hyperkinetic circulation. Discussion section provides an overview of treatment modalities. The main text describes a case of a 56 years old female patient with hypochromic anaemia despite maximum oral iron substitution. The patient lost blood through repeated epistaxes as well as continuous mild bleeding into gastrointestinal tract. The patient also had confirmed large ateriovenous malformations in the liver. Interferon alpha was used as the first line of treatment. The patient unexpectedly developed fast and pronounced myelosuppression. The number of neutrophils fell down from 1.15 x 109/l to 0.6 × 109/l as soon as after 3 injections of interferon alpha at a starting dose of 1.5 million units 3 times a week. Therefore, interferon alpha was discontinued. Blood count returned to normal following interferon discontinuation. The patient was started on thalidomide in December 2011. The patient reported lower incidence of epistaxes and smaller blood loss than before treatment as soon as during the first month of therapy. Regular administration of thalidomide reduced intensity and frequency of epistaxes in this patient.

[Treatment of Langerhans cells histiocytosis by cladribin reached long-term complete remission in 9 out of 10 adult patients]. / Lécba histiocytózy z Langerhansových bunek kladribinem dosáhla u 9 z 10 dospelých pacientu dlouhodobé kompletní remise.

BACKGROUND: The effectiveness of cladribine depends on the ratio of activating (deoxycytidine kinase) and inactivating (5-nucleotidase) enzymes. Not only is this ratio high in resting lymphocytes but also in Langerhans cells as well in some other histiocytic cells. Therefore, cladribine shows high effectiveness in patients with Langerhans cell histiocytosis (LCH). In 2003, the first report on excellent results with cladribine in first line treatment of patients with multisystem or multifocal LCH was published. That is why we use cladribine for adult patients with relapsing form of LCH and also for first line treatment of multifocal and multisystem LCH at our department. PATIENTS AND METHODS: Since 2001, we have treated altogether 10 adults (9 male and 1 female) with cladribine. The median age at diagnosis was 31.5 years (range: 5-45). The multiorgan form of the disease was present in 8 patients, and 2 patients had the multifocal skeletal form with aggressive disease course. Cladribine at a dose of 5 mg/m2 SC per day was given as a 5-day course at 28-day intervals. In cases of insufficient effectiveness, in two patients after the 3rd cycle with cladribine monotherapy, we proceeded to combination therapy with cladribine of 5 mg/m2 per day, cyclophosphamide 150 mg/m2 per day and dexamethasone 20 mg per day, all on days 1-5. We planned 6 cycles at the most. RESULTS: The median of cladribine cycles was 5 (range: 4-6). Altogether, 10 patients finished therapy; out of them 9 are in complete remission with the follow-up median of 26 months (range: 16-94). Treatment failure was noted only in 1 patient - in 60 days after therapy cessation the disease progressed and required further treatment (CHOEP, high-dose BEAM chemotherapy with autologous transplantation followed by Revlimid treatment and allogeneic transplantation). Treatment response - disappearance of infiltrate in the pituitary infundibulum - was observed in 2 patients with LCH affecting the pituitary infundibulum. CONCLUSION: Cladribine is a suitable medication for multiorgan and multifocal forms of LCH. In our group of ten evaluated patients, cladribine therapy resulted in 90% of long-term complete remissions. Three patients had CNS involvement and in all three patients, treatment responses have been achieved.