Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. METHODS: We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety. RESULTS: Overall, 879 patients underwent randomization: 440 were assigned to the pola-R-CHP group and 439 to the R-CHOP group. After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P = 0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94; 95% CI, 0.65 to 1.37; P = 0.75). The safety profile was similar in the two groups. CONCLUSIONS: Among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP. (Funded by F. Hoffmann-La Roche/Genentech; POLARIX ClinicalTrials.gov number, NCT03274492.).

The Screening of microRNAs in Chronic Myeloid Leukemia: A Clinical Evaluation.

Chronic myeloid leukemia (CML) is a type of leukemia whose main genetic marker is the reciprocal translocation that leads to the production of the BCR::ABL1 oncoprotein. The expression of some genes may interfere with the progression and development of leukemias. MicroRNAs are small non-coding RNAs that have the potential to alter the expression of some genes and may be correlated with some types of leukemia and could be used as biomarkers in the diagnosis and prognosis of patients. Therefore, this project carried out an analysis of microRNA-type plasma biomarkers in patients with chronic myeloid leukemia at unique points, including follow-up analysis of patients from the Erasto Gaertner Hospital. 35 microRNAs were analyzed in different cohorts. Inside those groups, 70 samples were analyzed at unique points and 11 patients in a follow-up analysis. Statistically different results were found for microRNA-7-5p, which was found to be upregulated in patients with high expression of the BCR::ABL1 transcript when compared to healthy controls. This microRNA also had evidence of behavior related to BCR::ABL1 when analyzed in follow-up, but strong evidence was not found. In this way, this work obtained results that may lead to manifestations of a relationship between miR-7-5p and chronic myeloid leukemia, and evaluations of possible microRNAs that are not related to this pathology.

Molecular BCR::ABL1 Quantification and ABL1 Mutation Detection as Essential Tools for the Clinical Management of Chronic Myeloid Leukemia Patients: Results from a Brazilian Single-Center Study.

Chronic myeloid leukemia (CML) is a well-characterized oncological disease in which virtually all patients possess a translocation (9;22) that generates the tyrosine kinase BCR::ABL1 protein. This translocation represents one of the milestones in molecular oncology in terms of both diagnostic and prognostic evaluations. The molecular detection of the BCR::ABL1 transcription is a required factor for CML diagnosis, and its molecular quantification is essential for assessing treatment options and clinical approaches. In the CML molecular context, point mutations on the ABL1 gene are also a challenge for clinical guidelines because several mutations are responsible for tyrosine kinase inhibitor resistance, indicating that a change may be necessary in the treatment protocol. So far, the European LeukemiaNet and the National Comprehensive Cancer Network (NCCN) have presented international guidelines on CML molecular approaches, especially those related to BCR::ABL1 expression. In this study, we show almost three years' worth of data regarding the clinical treatment of CML patients at the Erasto Gaertner Hospital, Curitiba, Brazil. These data primarily comprise 155 patients and 532 clinical samples. BCR::ABL1 quantification by a duplex-one-step RT-qPCR and ABL1 mutations detection were conducted. Furthermore, digital PCR for both BCR::ABL1 expression and ABL1 mutations were conducted in a sub-cohort. This manuscript describes and discusses the clinical importance and relevance of molecular biology testing in Brazilian CML patients, demonstrating its cost-effectiveness.

Fluorescent and colorimetric RT-LAMP as a rapid and specific qualitative method for chronic myeloid leukemia diagnosis.

The detection of BCR-ABL1 mRNA transcripts is essential to molecular chronic myeloid leukemia (CML) diagnosis. In most cases, the RT-qPCR technique is performed as the gold standard diagnosis tool for clinical cases. However, this method requires expensive reagents and equipment, such as a real-time thermal cycler, probes and master mix. Consequently, the development and validation of simple and low-cost methods are essential for a rapid CML diagnosis in less specialized and equipped centers. In this study, we develop and demonstrate an accessible, rapid, and low-cost method using RT-LAMP for BCR-ABL1 detection in both cell lines and CML clinical samples, using fluorescent and colorimetric assays. Both methods demonstrated diagnostic specificity of 100% and while diagnostic sensitivity reaches more than 90% in samples with RT-qPCR cycle threshold above 31. The obtained data indicates that the proposed method here described is robust, specific and rapid approach for CML diagnosis with outstanding performance, especially for CML diagnostic procedure where present high BCR-ABL1 expression.

Nilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd.

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose-optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re-escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2-75·1%) achieved major molecular response (BCR-ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re-escalation). The safety profile of nilotinib was consistent with prior studies. The most common non-haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).

Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML.

PANTHER is a global, randomized phase 3 trial of pevonedistat+azacitidine (n = 227) vs azacitidine monotherapy (n = 227) in patients with newly diagnosed higher-risk myelodysplastic syndromes (MDS; n = 324), higher-risk chronic myelomonocytic leukemia (n = 27), or acute myeloid leukemia (AML) with 20% to 30% blasts (n = 103). The primary end point was event-free survival (EFS). In the intent-to-treat population, the median EFS was 17.7 months with pevonedistat+azacitidine vs 15.7 months with azacitidine (hazard ratio [HR], 0.968; 95% confidence interval [CI], 0.757-1.238; P = .557) and in the higher-risk MDS cohort, median EFS was 19.2 vs 15.6 months (HR, 0.887; 95% CI, 0.659-1.193; P = .431). Median overall survival (OS) in the higher-risk MDS cohort was 21.6 vs 17.5 months (HR, 0.785; P = .092), and in patients with AML with 20% to 30% blasts was 14.5 vs 14.7 months (HR, 1.107; P = .664). In a post hoc analysis, median OS in the higher-risk MDS cohort for patients receiving >3 cycles was 23.8 vs 20.6 months (P = .021) and for >6 cycles was 27.1 vs 22.5 months (P = .008). No new safety signals were identified, and the azacitidine dose intensity was maintained. Common hematologic grade ≥3 treatment emergent adverse events were anemia (33% vs 34%), neutropenia (31% vs 33%), and thrombocytopenia (30% vs 30%). These results underscore the importance of large, randomized controlled trials in these heterogeneous myeloid diseases and the value of continuing therapy for >3 cycles. The trial was registered on clinicaltrials.gov as #NCT03268954.

Rituximab biosimilar and reference rituximab in patients with previously untreated advanced follicular lymphoma (ASSIST-FL): primary results from a confirmatory phase 3, double-blind, randomised, controlled study.

BACKGROUND: GP2013 is a rituximab biosimilar developed to stringent development guidelines, including non-clinical and preclinical investigations and clinical trials in rheumatoid arthritis and follicular lymphoma. We aimed to compare the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of GP2013 plus cyclophosphamide, vincristine, and prednisone (GP2013-CVP) with rituximab-CVP (R-CVP) in patients with follicular lymphoma. METHODS: In this phase 3, multinational, double-blind, randomised, controlled trial, adults (aged 18 years or older) with previously untreated, advanced stage (Ann Arbor stage III or IV) follicular lymphoma of WHO histological grades 1, 2, or 3a were randomly assigned (1:1) using interactive response technology to eight cycles of GP2013-CVP or R-CVP (combination phase), followed by monotherapy maintenance in responders for a 2-year period. Randomisation was stratified by Follicular Lymphoma International Prognostic Index risk group and geographic region. The primary endpoint was comparability in overall response, with equivalence concluded if the entire 95% CI was within a margin of -12% to 12%. The primary endpoint was analysed using the per-protocol set, which included all patients who received at least one (partial or complete) dose of investigational treatment and who did not have any major protocol deviations. The trial is registered with ClinicalTrials.gov, number NCT01419665, and is ongoing. FINDINGS: Between Dec 1, 2011, and Jan 15, 2015, 858 patients were screened for eligibility. 314 patients were randomly assigned to GP2013, of whom 312 were given GP2013, and 315 were assigned to reference rituximab. Median follow-up was 11·6 months (IQR 5·8-18·2) for the primary analysis. The primary endpoint, equivalence of overall response, was met (271 [87%] of 311 patients with GP2013 and 274 [88%] of 313 patients with reference rituximab achieved an overall response; difference -0·40% [95% CI -5·94 to 5·14]). Occurrence of adverse events and serious adverse events was similar between the treatment groups (289 [93%] of 312 patients in the GP2013-CVP group had an adverse event and 71 [23%] of 312 patients had a serious adverse event; 288 [91%] of 315 patients in the R-CVP group had an adverse event and 63 [20%] had a serious adverse event). The most common adverse event was neutropenia (80 [26%] of 312 patients in the GP2013-CVP group and 93 [30%] of 315 patients in the R-CVP group in the combination phase and 23 [10%] of 231 patients in the GP2013-CVP group and 13 [6%] of 231 patients in the R-CVP group in the maintenance phase). The most common grade 3 or 4 adverse event during the combination and maintenance phase was neutropenia (55 [18%] of 312 patients in the GP2013-CVP group and 65 [21%] of 315 patients in the R-CVP group in the combination phase and 17 [7%] of 231 patients in the GP2013-CVP group and nine [4%] of 231 patients in the R-CVP group in the maintenance phase). The occurrence of anti-drug antibodies was similar in the treatment groups (five [2%] of 268 patients in the GP2013-CVP; three [1%] in the R-CVP group). INTERPRETATION: Our results show that GP2013 represents a viable rituximab biosimilar candidate for patients with previously untreated advanced follicular lymphoma. The introduction of biosimilars provides additional therapeutic options with potential to increase access to effective and life-saving biological therapies such as rituximab. FUNDING: Hexal.

Clinical assessment of oral mucositis and candidiasis compare to chemotherapic nadir in transplanted patients.

Oral mucositis is a chief complication in patients undergoing hematopoietic stem cell transplantation (HSCT). It is considered a toxic inflammatory reaction that interferes with the patient's recuperation and quality of life. Oral candidiasis is a common fungal infection observed in dental practice, particularly in immunocompromised patients. The aim of this study was to evaluate the presence of oral mucositis and oral candidiasis in patients who underwent HSCT and their correlation with the chemotherapeutic nadir (lowest possible outcome). We evaluated patients with different diagnoses who underwent HSCT at the Hospital Erasto Gaertner. No chemotherapeutic nadir curves could be associated with mucositis, and patients had different presentations of mucositis. No patient developed oral candidiasis during hospitalization. Together with cell counts, we collected demographic data including age, oral hygiene, habits harmful to health, and the use of oral prostheses. It was observed that patients who smoked cigarettes before hospitalization showed less mucositis, resulting in no feeding problems or other comorbid conditions due to the effect of mucositis. However, the nadir of the chemotherapy curve, in isolation, is not a predictive tool for the appearance (or no appearance) of oral mucositis.

Pharmaconutrition: acute fatty acid modulation of circulating cytokines in elderly patients in the ICU.

BACKGROUND: Enteral supply of ω-3 polyunsaturated fatty acids has been used in an attempt to modulate inflammation and improve outcome in critically ill patients. However, enteral administration may be slow to change membrane composition and therefore may not be the best route to supply these fatty acids in patients with acute conditions. This study evaluated the effects of short-term intravenous (IV) administration of fish oil-based lipid emulsion (FLE) as pharmaconutrition on cytokine levels in critically ill elderly patients. METHODS: Enterally fed patients (n = 40; aged 60-80 years) were recruited in the first 48 hours of intensive care unit (ICU) admission. Fifteen patients received IV FLE (0.2 g/kg body weight) over 6 hours for 3 consecutive days, and 25 patients did not receive IV lipid (control). Samples were collected before and 24 hours and 72 hours after the third FLE infusion. Nutrient intakes, clinical parameters, and serum cytokine concentrations were measured. RESULTS: Compared with the control, FLE resulted in higher energy intake, lower serum tumor necrosis factor-α and interleukin (IL)-8 concentrations, and higher serum IL-10. These differences occurred around 7-9 days of ICU stay at the time of the patient's extubation. ICU stay, mortality, and markers of coagulation and liver function did not differ between groups. CONCLUSIONS: Short-term IV FLE modulates some inflammatory markers in critically ill elderly patients receiving enteral nutrition (EN), suggesting an anti-inflammatory effect. This may be a benefit and suggests a role for FLE administration as a supplement in elderly ICU patients receiving standard EN.

Supplemental intravenous n-3 fatty acids and n-3 fatty acid status and outcome in critically ill elderly patients in the ICU receiving enteral nutrition.

BACKGROUND & AIMS: N-3 fatty acids (FA) may have benefits in ICU patients. The aims were to identify whether FA status is altered in critical illness and to evaluate the effect of supplemental intravenous n-3 FA on plasma FA status and clinical outcome in ICU patients receiving enteral nutrition. METHODS: Enterally fed patients (n = 49; 60-80 years) were recruited in the first 48 h of ICU admission. Fifteen patients received n-3 FA emulsion (0.2 g/kg) over 6 h for 3 consecutive days, and 34 patients did not (control). Samples were collected before supplementation, and 24 and 72 h after the third infusion. Nineteen healthy elderly subjects were also studied; they gave a single blood sample. FA were measured in plasma phosphatidylcholine (PC). RESULTS: Critically ill patients had altered plasma PC FA compared with healthy elderly subjects. Surviving ICU patients had higher levels of docosahexaenoic acid and total n-3 FA and a lower ratio of n-6:n-3 FA in plasma PC than non-survivors. Infusion of n-3 FA increased eicosapentaenoic, docosahexaenoic and total n-3 FA, and decreased arachidonic and total n-6 FA and n-6:n-3 FA and arachidonic:eicosapentaenoic acid ratios. Gas exchange was enhanced 72 h after the third n-3 FA infusion (p = 0.001). CONCLUSIONS: Critically ill patients may have altered plasma FA profiles. A higher total n-3 FA and docosahexaenoic acid content in plasma PC is associated with survival and improved gas exchange.

Pancreatitis in adult with acute lymphoblastic leukemiausing L-asparaginase and simvastatin: case report and systematic review / Pancreatite em adulto com leucemia linfoblástica aguda usando L-asparaginase e sinvastatina: relato de caso e revisão sistemática

Context: Acute pancreatitis is a inflammatory process of the pancreas. It can be caused by gallstones, metabolic disorders, associated or not with alcohol abuse, or medication. Case Report: A 38-year-oldman was admitted to the hospital because of worsening of nausea, abdominal pain, dizziness and white stool. Patient was diagnosed with severe acute pancreatitis. After six days of hospitalization, patient progressed into hypotension and severe bradycardia, and died. The patient used simvastatin chronically, and was in treat with L-asparaginase, both drugs related to the occurence of acute pancreatitis separately. Naranjo´s probability scale of adverse drug reaction established the causality between these medications and acute pancreatitis as probable. However, due to the absence of reports of causality, the acute pancreatitis is associated with to the use of L-asparaginase with possible drug interactions with simvastatin. Conclusion: It is very important to monitor patients treated with L-asparaginase, throughcareful observation of clinical signs and laboratory follow-up, as well as verification of other medications in use. The AP may have different levels of severity, being indispensable the quick diagnosis and early treatment.

Contexto: Pancreatite aguda é um processo inflamatório do pâncreas. É causada por cálculos biliares, desordens metabólicas, associadas ou não ao uso abusivo de álcool, ou medicamentos. Relato do Caso: Homem de 38 anos foi admitido no hospital em razão do agravamento de náuseas, dor abdominal, tontura e fezes brancas. O paciente foi diagnosticado com pancreatite aguda. Após seis dias de internação, paciente progrediu com hipotensão e bradicardia severa, evoluindo à óbito. O paciente fazia uso crônico de sinvastatina, e estava em tratamento com L-asparaginase, ambos fármacos, de modo separado, são relacionados com a ocorrência de pancreatite aguda severa. O algoritmo de Naranjo para estabelecimento de reação adversa a medicação classificou a causalidade entre as medicações citadas e a pancreatite aguda como provável. Porém, em razão da ausência relatos dessa causalidade, associa-se a pancreatite aguda ao uso de L-asparaginase, com possível interação medicamentosa com sinvastatina. Conclusão: É de suma importância o acompanhamento clínico e laboratorial de pacientes em uso de Lasparaginas e para sinais de pancreatite aguda, sendo imprescindível o rápido diagnóstico e tratamento precoce.

Doenças hepatobiliares eosinofílicas: relato de dois casos e revisão de literatura / Eosinophilic hepatobiliary diseases: a report of two cases and literature review

As doenças hepatobiliares eosinofílicas são patologias raras de origem e de fatores etiológicos ainda não esclarecidos, sendo muitas vezes relacionadas à gastroenterite eosinofílica ou síndrome hipereosinofílica. Caracterizam-se por infiltração de eosinófilos em tecidos hepatobiliares e podem estar associadas à eosinofilia periférica na ausência de outras causas de eosinofilia. A raridade e conhecimento incompleto dessas doenças refletem na dificuldade de diagnóstico e de escolha terapêutica. O diagnóstico é feito através da exclusão de outras causas de eosinofilia periférica, tais como parasitoses, reações medicamentosas e doenças malignas, e também por análise histopatológica do tecido infiltrado. A maioria dos casos é responsiva ao tratamento com corticosteroides. Descrevemos dois casos clínicos, um de colecistite eosinofílica e outro de hepatite eosinofílica, avaliando, segundo revisão de literatura, a possibilidade de uma gastroenterite eosinofílica ou de uma síndrome hipereosinofílica em ambos os casos.

The eosinophilic hepatobiliary diseases are rare pathologies of origin and etiologic factors not yet clarified, being many times related to eosinophilic gastroenteritis or hipereosinophilic syndrome. They are characterized by an infiltration of eosinophils in hepatobiliary tissues and can be associated to peripheral eosinophilia, in the absence of other eosinophilia causes. The rareness and incomplete knowledge about these diseases reflect on the difficulty of diagnosis and choice of treatment. The diagnosis is made through exclusion of other causes of peripheral eosinofilia, such as parasitosis, drug reactions and malignant diseases, and also through histopathological analysis of the infiltrated tissue. Most cases respond to treatment with corticosteroids. We reported two cases, one of eosinophilic colecistitis and other of eosinophilic hepatitis, evaluating, according to literature review, the possibility of eosinophilic gastroenteritis or hipereosinophilic syndrome in both cases.

Novas doenças estreptocócicas de interesse reumatológico. Nossa experiência com a artrite reativa pós-estreptocócica / New streptococcal diseases of interest to rheumatology. Our experience with the arthritis reactivales powder-streptococci

Os autores realizaram uma revisão da clínica das doenças estreptocócicas no tocante ao interesse reumatológico, destacando-se a artrite reativa e outros quadros cutâneos/articulares.