RESUMO
The aim of the present study was to determine the associations between the MICB genetic variability and the expression and the risk of development of post-transplant complications after allogeneic hematopoietic stem cell transplantation (HSCT). HSCT recipients and their donors were genotyped for two MICB polymorphisms (rs1065075, rs3828903). Moreover, the expression of a soluble form of MICB was determined in the recipients' serum samples after transplantation using the Luminex assay. Our results revealed a favorable role of the MICB rs1065075 G allele. Recipients with donors carrying this genetic variant were less prone to developing chronic graft-versus-host disease (cGvHD) when compared to recipients without any symptoms of this disease (41.41% vs. 65.38%, p = 0.046). Moreover, the MICB rs1065075 G allele was associated with a lower incidence of cytomegalovirus (CMV) reactivation, both as a donor (p = 0.015) and as a recipient allele (p = 0.039). The MICB rs1065075 G variant was also found to be associated with decreased serum soluble MICB (sMICB) levels, whereas serum sMICB levels were significantly higher in recipients diagnosed with CMV infection (p = 0.0386) and cGvHD (p = 0.0008) compared to recipients without those complications. A protective role of the G allele was also observed for the rs3828903 polymorphism, as it was more frequently detected among donors of recipients without cGvHD (89.90% vs. 69.23%; p = 0.013). MICB genetic variants, as well as serum levels of sMICB, may serve as prognostic factors for the risk of developing cGvHD and CMV infection after allogeneic HSCT.
Assuntos
Infecções por Citomegalovirus , Predisposição Genética para Doença , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Menor , Transplante Homólogo , Humanos , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/etiologia , Infecções por Citomegalovirus/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , Feminino , Transplante Homólogo/efeitos adversos , Adulto , Pessoa de Meia-Idade , Doença Crônica , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Classe I/genética , Polimorfismo de Nucleotídeo Único , Alelos , Genótipo , Adulto Jovem , Citomegalovirus/fisiologia , Adolescente , Risco , Fatores de RiscoRESUMO
Cyclosporine A (CSA) is a commonly used immunosuppressive agent for the prophylaxis of graft-versus-host disease following allogeneic hematopoietic stem cell transplantation (alloHSCT). While tachycardia is a known adverse effect of CSA, bradycardia remains a phenomenon rarely described in the literature. We conducted a retrospective evaluation of the incidence of bradycardia in patients after alloHSCT treated with CSA between January 2020 and February 2023 at our center. Out of 206 patients, sinus bradycardia following the administration of CSA was observed in 6 (2.9%), comprising 3 women and 3 men, with the median age of 55 years (range: 20-65). The underlying diseases were myeloid malignancies in 4 and aggressive lymphoma in 2 patients. The patients received grafts from a matched unrelated (n=5) or a haploidentical family donor (n=1) following various conditioning regimens. Coexisting cardiovascular disorders were found in 5 of the 6 patients. All patients experienced symptomatic bradycardia within 1-4 days (median 2 days) after CSA introduction, which persisted until CSA withdrawal. One patient required treatment with atropine. All patients continued their immunosuppressive therapy with tacrolimus, which was well-tolerated Our study indicates CSA as a causative factor of sinus bradycardia in a small percentage of alloHSCT patients receiving CSA as graft-versus host disease (GvHD) prophylaxis. Importantly, these patients did not experience any cardiac complications when switched to tacrolimus. Although further research on the effects of CSA on heart automatation is needed, our single-center experience can help prompt diagnosis and therapeutic intervention in daily clinical practice.
RESUMO
Transplantation of hematopoietic stem cells (HSCT) is a procedure commonly used in treatment of various haematological disorders which is associated with significantly improved survival rates. However, one of its drawbacks is the possibility of development of post-transplant complications, including acute and chronic graft-versus-host disease (GvHD) or CMV infection. Various studies suggested that NK cells and their receptors may affect the transplant outcome. In the present study, patients and donors were found to significantly differ in the distribution of the NKG2A rs7301582 genetic variants - recipients carried the C allele more often than their donors (0.975 vs 0.865, p<0.0001). Increased soluble HLA-E (sHLA-E) levels detected in recipients' serum 30 days after transplantation seemed to play a prognostic and protective role. It was observed that recipients with higher sHLA-E levels were less prone to chronic GvHD (11.65 vs 6.33 pg/mL, p=0.033) or more severe acute GvHD grades II-IV (11.07 vs 8.04 pg/mL, p=0.081). Our results also showed an unfavourable role of HLA-E donor-recipient genetic incompatibility in CMV infection development after transplantation (OR=5.92, p=0.014). Frequencies of NK cells (both CD56dim and CD56bright) expressing NKG2C were elevated in recipients who developed CMV, especially 30 and 90 days post-transplantation (p<0.03). Percentages of NKG2C+ NK cells lacking NKG2A expression were also increased in these patients. Moreover, recipients carrying a NKG2C deletion characterized with decreased frequency of NKG2C+ NK cells (p<0.05). Our study confirms the importance of NK cells in the development of post-transplant complications and highlights the effect of HLA-E and NKG2C genetic variants, sHLA-E serum concentration, as well as NKG2C surface expression on transplant outcome.
Assuntos
Infecções por Citomegalovirus , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe I , Subfamília C de Receptores Semelhantes a Lectina de Células NK , Humanos , Infecções por Citomegalovirus/metabolismo , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/metabolismo , Transplante Homólogo/efeitos adversos , Antígenos de Histocompatibilidade Classe I/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Antígenos HLA-ERESUMO
Previous studies suggest that postautologous stem cell transplant (ASCT) recovery of polyclonal immunoglobulin from immunoparesis in patients with multiple myeloma is a positive prognostic marker. We performed a longitudinal analysis of polyclonal immunoglobulin concentrations and unique B-cell sequences in patients enrolled in the phase 3 ATLAS trial that randomized 180 subjects to either carfilzomib, lenalidomide, dexamethasone (KRd) or lenalidomide (R) maintenance. In the KRd arm, standard-risk patients with minimal residual disease negativity after six cycles de-escalated to R alone after cycle 8. One year from the initiation of maintenance at least partial recovery of polyclonal immunoglobulin was observed in more patients on the R arm (58/66, p < 0.001) and in those who de-escalated from KRd to R (27/38, p < 0.001) compared to the KRd arm (9/36). In patients who switched from KRd to R, the concentrations of uninvolved immunoglobulin and the number of B-cell unique sequences increased over time, approaching values observed in the R arm. There were no differences in progression-free survival between the patients with at least partial immunoglobulin recovery and the remaining population. Our analysis indicates that patients receiving continuous therapy after ASCT experience prolonged immunoparesis, limiting prognostic significance of polyclonal immunoglobulin recovery in this setting.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Lenalidomida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Dexametasona/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante AutólogoRESUMO
BACKGROUND: Lenalidomide is a cornerstone of maintenance therapy in patients with newly diagnosed multiple myeloma after autologous stem-cell transplantation. We aimed to compare the efficacy and safety of maintenance therapy with carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone in this patient population. METHODS: This study is an interim analysis of ATLAS, which is an investigator-initiated, multicentre, open-label, randomised, phase 3 trial in 12 academic and clinical centres in the USA and Poland. Participants were aged 18 years or older with newly diagnosed multiple myeloma, completed any type of induction and had stable disease or better, autologous stem-cell transplantation within 100 days, initiated induction 12 months before enrolment, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) using permuted blocks of sizes 4 and 6 and a web-based system to receive up to 36 cycles of carfilzomib, lenalidomide, and dexamethasone (28-day cycles of carfilzomib 20 mg/m2 administered intravenously in cycle one on days 1 and 2 then 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 in cycles one to four and 36 mg/m2 on days 1, 2, 15, and 16 from cycle five up to 36 [per protocol]; lenalidomide 25 mg administered orally on days 1-21; and dexamethasone 20 mg administered orally on days 1, 8, 15, and 22) or lenalidomide alone (10 mg administered orally for the first three cycles and then at the best tolerated dose [≤15 mg for 28 days in 28-day cycles]) until disease progression or unacceptable toxicity as maintenance therapy. After 36 cycles, patients in both treatment groups received lenalidomide maintenance. Randomisation was stratified by response to previous treatment, cytogenetic risk factors, and country. Investigators and patients were not masked to treatment allocation. Patients in the carfilzomib, lenalidomide, and dexamethasone group with no detectable minimal residual disease after cycle six (as per International Myeloma Working Group criteria) and standard-risk cytogenetics were switched to lenalidomide maintenance as of cycle nine. The primary endpoint was progression-free survival in the intention-to-treat population (defined as all randomly assigned patients). Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. This unplanned interim analysis was triggered by the occurrence of 59 (61%) of the expected 96 events for the primary analysis and the results are considered preliminary. This trial is registered with ClinicalTrials.gov, NCT02659293 (active, not recruiting) and EudraCT, 2015-002380-42. FINDINGS: Between June 10, 2016, and Oct 21, 2020, 180 patients were randomly assigned to receive either carfilzomib, lenalidomide, and dexamethasone (n=93) or lenalidomide alone (n=87; intention-to-treat population). The median age of patients was 59·0 years (IQR 49·0-63·0); 84 (47%) patients were female and 96 (53%) were male. With a median follow-up of 33·8 months (IQR 20·9-42·9), median progression-free survival was 59·1 months (95% CI 54·8-not estimable) in the carfilzomib, lenalidomide, and dexamethasone group versus 41·4 months (33·2-65·4) in the lenalidomide group (hazard ratio 0·51 [95% CI 0·31-0·86]; p=0·012). The most common grade 3 and 4 adverse events were neutropenia (44 [48%] in the carfilzomib, lenalidomide, and dexamethasone group vs 52 [60%] in the lenalidomide group), thrombocytopenia (12 [13%] vs six [7%]), and lower respiratory tract infections (seven [8%] vs one [1%]). Serious adverse events were reported in 28 (30%) patients in the carfilzomib, lenalidomide, and dexamethasone group and 19 (22%) in the lenalidomide group. One treatment-related adverse event led to death (respiratory failure due to severe pneumonia) in the carfilzomib, lenalidomide, and dexamethasone group. INTERPRETATION: This interim analysis provides support for considering carfilzomib, lenalidomide, and dexamethasone therapy in patients with newly diagnosed multiple myeloma who completed any induction regimen followed by autologous stem-cell transplantation, which requires confirmation after longer follow-up of this ongoing phase 3 trial. FUNDING: Amgen and Celgene (Bristol Myers Squibb).
Assuntos
Mieloma Múltiplo , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/diagnóstico , Lenalidomida , Resultado do Tratamento , Dexametasona , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Células , Transplante AutólogoRESUMO
Vaccination against SARS-CoV-2 is currently the best tool in the fight against the COVID-19 pandemic. However, there are limited data on its efficacy and safety after hematopoietic stem cell transplantation (HCT). We present the results of a prospective analysis of the humoral response to two doses of BNT162b2 mRNA vaccine in 93 adult patients, including 29 after autologous HCT (autoHCT) and 64 after allogeneic HCT (alloHCT). Positive anti-SARS-CoV-2 antibodies were detected before vaccination in 25% of patients despite a negative medical history of COVID-19. Seroconversion after vaccination was achieved in 89% of patients after alloHCT and in 96% after autoHCT, without grade 3/4 adverse events. Post-vaccination anti-SARS-CoV-2 antibody level correlated with the time from transplant and absolute B-cell count at the vaccination. In univariate analysis restricted to the alloHCT group, short time since transplantation, low B-cell count, low intensity conditioning, GvHD, and immunosuppressive treatment at the vaccination were associated with lack of seroconversion. In the multivariate model, the only negative predictor of seroconversion remained treatment with calcineurin inhibitor (CNI). In conclusion, the BNT162b2 mRNA vaccine is highly immunogenic in patients after HCT, but treatment with CNI at the time of vaccination has a strong negative impact on the humoral response.
RESUMO
BACKGROUND Constant stimulation of lymphocytes and histiocytes can result in hemophagocytic lymphohistiocytosis (HLH), which can be primary or secondary (sHLH). The main causes of sHLH are infections and hematological malignancies, especially non-Hodgkin lymphoma. Despite new insights into the pathogenesis of HLH, the diagnosis and treatment of this immune disorder remain a great challenge. CASE REPORT We present a case of a young adult without comorbidities whose clinical course was nonspecific for several months and resulted in late diagnosis of HLH secondary to peripheral T cell lymphoma (PTCL). The etiological factor of recurring fever, hepatosplenomegaly, and deteriorating condition was unidentified for a long time before fatal sHLH was finally diagnosed. The patient was treated according to the HLH-2004 protocol; however, he did not achieve any response. Unfortunately, due to nonspecific symptoms, lack of lymphadenopathy for a long time, and negative positron emission tomography results, the diagnosis of PTCL was established only after the patient's death. CONCLUSIONS It should be emphasized that early diagnosis is crucial for better prognosis of patients with sHLH. Bone marrow biopsy is worth considering in patients with prolonged fever of unknown origin, hyperferritinemia, splenomegaly, and unexplained cytopenia of 2 or more lineages. Despite the existence of diagnostic and therapeutic protocols available in the literature, the prompt diagnosis and treatment of HLH remains a great challenge. More precise and specific diagnostic tools for HLH are needed.
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Linfo-Histiocitose Hemofagocítica , Linfoma de Células T Periférico , Medula Óssea , Febre , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Linfoma de Células T Periférico/complicações , Linfoma de Células T Periférico/diagnóstico , Masculino , Recidiva Local de Neoplasia , Adulto JovemRESUMO
INTRODUCTION: This analysis attempts to determine the diagnostic and prognostic value of bone marrow (BM) evaluation by multiparameter flow cytometry in patients with myelodysplastic syndrome (MDS). MATERIALS AND METHODS: The study group consisted of patients who underwent diagnostic process in the years 2008-2017 due to cytopenia and finally were diagnosed with MDS (n = 71). The comparative group included patients with cytopenia diagnosed in the same period, whose definitive diagnosis was other than MDS (n = 39). Flow cytometric evaluation of BM was performed following the recommendations of the European LeukemiaNet (ELN) in all patients. RESULTS: The median number of immunophenotypic abnormalities found on granulocytes in the MDS group was significantly higher compared to the comparative group [2 (range 0-5) vs 0 (range 0-2); P < .0001]. Similarly, the median Ogata score was significantly higher in the MDS group [2 (range 0-4) vs 1 (range 0-3); P < .0001]. Since the disturbances of the CD11b/HLA-DR and CD11b/CD13 on granulocytes were significantly more common in MDS patients, the Ogata score was extended by these abnormalities, what resulted in its higher diagnostic sensitivity (82%) while preserving high specificity (87%). The positive correlation was found between risk score determined by the Revised International Prognostic Scoring System and the number of the BM immunophenotypic abnormalities (P = .017). CONCLUSIONS: Our results indicate that the diagnostic usefulness of the Ogata score may be increased by including the abnormal expression of CD11b/HLA-DR and CD11b/CD13 on granulocytes. Moreover, our findings suggest the prognostic significance of the number of BM cytometric abnormalities in MDS.
Assuntos
Medula Óssea/patologia , Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Antígeno CD11b/metabolismo , Antígenos CD13/metabolismo , Feminino , Citometria de Fluxo/métodos , Antígenos HLA-DR/metabolismo , Humanos , Imunofenotipagem/métodos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Prognóstico , Adulto JovemRESUMO
BACKGROUND: Acute promyelocytic leukemia (APL) has a favorable prognosis. However, results of randomized studies do not necessarily reflect the outcomes of a real-life population. PATIENTS AND METHODS: We analyzed 283 unselected APL patients treated in 20 Polish hospitals between 2005 and 2017. All patients were intended to be treated with PETHEMA (Programa Español para el Tratamiento de las Hemopatías Malignas) protocols based on all-trans retinoic acid plus chemotherapy. RESULTS: The probability of overall survival at 4 years was 67%, while event-free survival was 64%. The early death (ED) rate was 20.1% (n = 57), while 3.5% (n = 10) patients died before induction therapy was started. The main causes of ED included hemorrhage (45.6%), infections (17.5%), and differentiation syndrome (14.5%). Of 273 treated patients, 214 (78.4%) experienced hematologic morphologic remission, 2 (0.7%) were found to have resistant disease, 47 (17.2%) could not be evaluated for response because of ED, and in 6 (3.7%) no data concerning the response were available. Multivariate analyses showed that predictors of ED and overall survival were Eastern Cooperative Oncology Group performance status > 2, age > 60 years, and all types of bleeding episodes that occurred before starting therapy, while an additional predictor of event-free survival was high white blood cell count (> 10 109/L). CONCLUSION: ED remains a major problem in APL patients, especially in a real-life population. Shortening of the time between the initial contact with a health care professional, and all-trans retinoic acid administration and the use of appropriate supportive care could improve the outcome of unselected APL population, mainly by reducing the ED rate.
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Leucemia Promielocítica Aguda/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Promielocítica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Polônia , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Chronic lymphocytic leukemia is the most common cancer of the lymphatic tissue in adults. The peak incidence falls on the 65-70 year old. Therefore, the majority of patients with chronic lymphocytic leukemia (CLL) has at least one coexisting disease. Successful oncological and supportive treatment, that is common in recent years, significantly prolongs the survival. This paper presents ibrutinib - a new drug used to treat CLL. The aim of this paper is, to show an example of this drug, meaning and benefits of modern methods of pharmacotherapy in the treatment of oncology.
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Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Humanos , Piperidinas , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologiaRESUMO
PROBLEM: We tested the hypothesis that the number of both CECs and CEPCs as well as the vWf blood plasma concentration are altered in pregnant women with hypertensive disorders. METHOD OF STUDY: Seventy-five pregnant women were enrolled in our study. We used multicolor flow cytometry for CEC and CEPC analysis and the commercial human VWF ELISA kit to measure vWf blood plasma concentration. RESULTS: The highest number of CECs was found in the chronic hypertension group and the lowest number in the healthy pregnant control group. The highest number of CEPCs was found in the control group and the lowest number in the chronic hypertension group. The vWf blood plasma concentration was the highest in the pre-eclampsia group. The CEPC/CEC ratio reached its lowest value in the chronic hypertension group and its highest value in the control group. CONCLUSION: The number of both CECs and CEPCs as well as the vWf blood plasma concentration depends on the type of hypertension complicating the pregnancy.