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1.
Klin Onkol ; 36(3): 177-191, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37353346

RESUMO

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.


Assuntos
Antineoplásicos , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/diagnóstico , Rituximab/uso terapêutico , Inibidores de Proteassoma/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Antineoplásicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Ciclofosfamida/uso terapêutico
2.
Klin Onkol ; 35(4): 315-322, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35989089

RESUMO

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.


Assuntos
Doença de Gilbert , Mieloma Múltiplo , Xantogranuloma Necrobiótico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bilirrubina , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Doença de Gilbert/tratamento farmacológico , Humanos , Hiperbilirrubinemia/tratamento farmacológico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Xantogranuloma Necrobiótico/diagnóstico , Xantogranuloma Necrobiótico/tratamento farmacológico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
3.
Neoplasma ; 67(4): 939-945, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32567936

RESUMO

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.


Assuntos
Gamopatia Monoclonal de Significância Indeterminada , Mieloma Múltiplo , Adulto , Fluordesoxiglucose F18 , Humanos , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico por imagem , Mieloma Múltiplo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons
4.
Klin Onkol ; 32(6): 445-452, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31842563

RESUMO

BACKGROUND: Thalidomide-and bortezomib-containing regimens are widely used for transplant-ineligible newly diagnosed multiple myeloma patients. The aim of this study was to analyse the efficiency of thalidomide-or bortezomib-based regimens in long-term follow-up. MATERIALS AND METHODS: From 2008 to 2012, 142 transplant-ineligible newly diagnosed multiple myeloma patients were analysed retrospectively. Bortezomib was administered at the standard dosing of 1.3mg/m2 weekly, and thalidomide was administered at a daily dose of 100mg. Both drugs were combined with cyclophosphamide and dexamethasone. A total of 95 patients were treated with thalidomide and 47 with bortezomib. A median four cycles of treatment were administered in both groups. RESULTS: In the thalidomide group, the overall response rate was 60.6%, the median progression-free survival (PFS) was 10.3 months (95% CI 7.4-13.2) and the median overall survival (OS) was 35.1 months (95% CI 23.9-46.3). In the bortezomib group, the overall response rate was 51.1%, the median PFS was 11.9 months (95% CI 8.8-15) and the median OS was 25.4 months (95% CI 9.3-41.6). There was a statistically significant difference in OS (p = 0.027), favouring the cyclophosphamide/thalidomide/dexamethasone group, but the response rates and PFS intervals were not significantly different between both groups. The median follow-up in the thalidomide group was 35.1 months (95% CI 0.2-95.9) compared to 25.1 months (95% CI 0.4-60.6) in the bortezomib group (p = 0.004). The incidence of serious adverse events was comparable in both groups. CONCLUSION: In conclusion, the results of bortezomib treatment are comparable to thalidomide treatment under conditions of short administration. According to other clinical trials, long-term bortezomib treatment provides an additional advantage for PFS and OS.


Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Ciclofosfamida/uso terapêutico , Dexametasona/uso terapêutico , Imunossupressores/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Talidomida/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Bortezomib/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Transplante de Células-Tronco , Análise de Sobrevida , Talidomida/efeitos adversos , Resultado do Tratamento
5.
Neoplasma ; 65(4): 585-591, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29940759

RESUMO

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.


Assuntos
Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , República Tcheca , Humanos , Retratamento , Resultado do Tratamento
6.
Klin Onkol ; 30(Supplementum2): 13-20, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28903565

RESUMO

Unlike bone marrow biopsies, liquid biopsies represent a gentler, more accessible, less painful, repeatable and more comprehensive approach to get biologically relevant information about the entire tumor but also about treatment response and level of minimal residual disease. This is all possible since peripheral blood contains not only circulating tumor cells but also many circulating molecules of nucleic acids (microRNA, cell-free DNA, long non-coding RNA etc.). Multiple myeloma is a genetically heterogeneous disease characterized by multifocal tumor deposits in the bone marrow but also focal lesions elsewhere. Single-site biopsy of the bone marrow creates a sampling bias that provides a limited molecular profile as the biopsy cannot capture all subclones. Moreover, during disease progression and treatment, molecular profile is changed and subclones of multiple myeloma cells resistant to treatment are formed. Likewise, various clones found in extramedullary sites that are not present in the bone marrow respond differently to treatment directly influencing survival of patients. Thus, liquid biopsies seem to be a relevant and necessary next step for diseases such as multiple myeloma.Key words: multiple myeloma - minimal residual disease - prognosis - liquid biopsies - cell-free DNA - non-coding RNA.


Assuntos
Biópsia Líquida/métodos , Mieloma Múltiplo/sangue , Medula Óssea/patologia , Ácidos Nucleicos Livres/sangue , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Neoplasia Residual , RNA não Traduzido/sangue
7.
Neoplasma ; 62(5): 827-32, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26278155

RESUMO

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic, potentially malignant condition. It has been established that annually approximately 1-2% of MGUS cases transforms into one of the malignant forms of monoclonal gammopathies. Progression risk factors include the quantity and type of M-protein, and namely the ratio of free light immunoglobulin chains (FLC). These factors, enable purposeful stratification of MGUS individuals. Some authors consider suppression of polyclonal immunoglobulin levels to be another progression factor. The aim of the study was to compare polyclonal immunoglobulin (PIg) levels with uninvolved heavy/light chain pair (HLC) levels in order to verify the degree of immunoparesis depending on MGUS risk category (0-3). The analyzed set consisted of 159 serum samples from MGUS patients (102 IgG, 57 IgA), who were stratified into 4 risk groups (0 - low, 1 - low-intermediate, 2 - high-intermediate and 3 - high risk of transformation). The results of analysis showed that with increasing degree of MGUS increases risk of immune paresis defined by decreasing levels of polyclonal immunoglobulins, ie. IgA and IgM in the case of IgG MGUS, respectively, IgG and IgM in case of IgA MGUS. Significant differences were also found when analyzing the levels of uninvolved HLC pairs IgG kappa (resp. IgG lambda) in IgG lambda (IgG kappa) dominant secretion. In the case of MGUS with IgA isotype, the results were similar. Discovery of the connection between the degree of immunosuppression and the level of MGUS risk contributes to our understanding of the relationship between biology, development and potential malignant transformation of MGUS. It is apparent that uninvolved HLC pair assay enables more reliable identification of at-risk MGUS patients than a simple quantitative assay for polyclonal immunoglobulins alone.

8.
Neoplasma ; 59(4): 440-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22489700

RESUMO

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.


Assuntos
Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Imunoterapia , Proteínas Inibidoras de Diferenciação/imunologia , Proteínas Inibidoras de Diferenciação/metabolismo , Mieloma Múltiplo/terapia , Adjuvantes Imunológicos , Idoso , Estudos de Casos e Controles , Células Dendríticas/transplante , Ensaio de Imunoadsorção Enzimática , Feminino , Hemocianinas/imunologia , Humanos , Hipersensibilidade Tardia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Vacinação
9.
Vnitr Lek ; 58(12): 896-903, 2012 Dec.
Artigo em Tcheco | MEDLINE | ID: mdl-23427947

RESUMO

UNLABELLED: According to the criteria for multiple myeloma, systemic AL-amyloidosis may be divided into primary systemic AL-amyloidosis, where monoclonal gametopathy is present but the criteria for multiple myeloma are not satisfied, and systemic AL-amyloidosis with underlying multiple myeloma. There is a continuous transition between the two units. The present paper describes treatment of patients with established systemic AL-amyloidosis who satisfy the 2003 International Myeloma Working Groups criteria for symptomatic multiple myeloma (confirmed monoclonal immunoglobulin, clonal plasmocytes confirmed in the bone marrow and at least one clinical symptom of myeloma - confirmed amyloid). From 2009, a total of 10 patients with AL-amyloidosis and underlying multiple myeloma have been treated at our centre with combined bortezomib-containing regimens. The cohort includes 5 women and 5 men. Median age of these AL-amyloidosis patients at the diagnosis was 65.5 years. All 10 patients were treated with a combination of 3 drugs, bortezomib, cyclophosphamide and dexamethasone or bortezomib, doxorubicin a dexamethasone. Two of the 10 patients died during the first month of treatment. Treatment response cannot be evaluated in these patients. Haematological treatment response was evaluable in 8 patients only. Monoclonal immunoglobulin disappearance with negative urine and serum immunofixation and normalization of free light chain immunoglobulins was observed in six of the 8 patients. Treatment response according to the current IMWG was evaluated as very good partial remission (VGPR) as we did not perform bone marrow testing after the treatment to confirm complete remission according to the current criteria. One of the 8 evaluated patients died due to disease progression in the third month of treatment and there was no haematological treatment response in one who was considered to have a stable disease. Organ treatment response was evaluated in patients who were followed up for longer than 3 months of treatment only. Organ treatment response (reduced cardiac impairment) was not evaluable in a patient who had heart transplantation and then received chemotherapy. A total of 5 (83%) of the 6 evaluated patients fulfilled the criteria of organ treatment response. CONCLUSION: Our small cohort showed a high number of haematological treatment responses (VGPR in 75% of patients) as well as organ treatment response in patients with systemic AL-amyloidosis who were treated with bortezomib-containing treatment regimens.


Assuntos
Amiloidose/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/complicações , Idoso , Amiloidose/complicações , Ácidos Borônicos/administração & dosagem , Bortezomib , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Masculino , Pirazinas/administração & dosagem
10.
Klin Onkol ; 24 Suppl: S14-7, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21923058

RESUMO

Monoclonal gammopathy of undetermined significance (MGUS) is a precancerosis comprising two different kinds of cancer: lymphoid/lymphoplasmocytoid MGUS and plasma cell MGUS that represents about 85% of all MGUS cases. This type of MGUS has low but persistent tendency to transform to malignant disease, mainly multiple myeloma (MM), with frequency of about 1% per year. Using known risk stratification models based on clinical parameters, it is possible to identify patients' groups with average rates of progression as low as 0.26% and as high as 12% per year. However, due to the lack of clear genetic and/or phenotypic markers distinguishing MGUS from MM, we are not able to predict if and when MGUS will progress to MM in individual patients. There are partially overlapping molecular pathogenic events shared by MGUS and MM. Better understanding of pathogenesis of MGUS and MM using molecular-genetic approaches will help disclose the mechanisms of myeloma genesis; it can be also useful for identification of novel molecular targets. The ultimate goal for the near future is to develop better markers for definition of high-risk MGUS patients who will be candidates for early treatment intervention.


Assuntos
Gamopatia Monoclonal de Significância Indeterminada , Progressão da Doença , Humanos , Imunoglobulina M , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Mieloma Múltiplo/etiologia , Lesões Pré-Cancerosas
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