How to manage lymphoid malignancies during novel 2019 coronavirus (CoVid-19) outbreak: a Brazilian task force recommendation

ABSTRACT: The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.

Fluorodeoxyglucose-positron emission tomography staging can replace bone marrow biopsy in Hodgkin's lymphoma. Results from Brazilian Hodgkin's Lymphoma Study Group

ABSTRACT Objective: To investigate, in a large prospective multicenter study, whether 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography is sufficiently accurate to identify clinically important bone marrow involvement by Hodgkin's lymphoma to replace routine bone marrow biopsy in a developing tropical country. Methods: Patients newly diagnosed with Hodgkin's lymphoma were recruited from six cancer centers in Brazil. All were staged by the results of positron emission tomography/computed tomography that were centrally reviewed and by iliac crest bone marrow biopsy. Patients were classified as having marrow disease if they had lymphoma identified by marrow biopsy histology or had focal 2-[18F]-fluoro-2-deoxy-D-glucose marrow uptake that resolved following chemotherapy. Results: A total of 246 participants were recruited from six different centers and 62 (25.2%) were judged to have Hodgkin's lymphoma in the bone marrow. Positron emission tomography and biopsies were concordant in 206 patients (83%). Positron emission tomography correctly identified marrow disease in 59/62 patients (95.1%) and marrow biopsy in 25/62 patients (40.3%). In 22/62 (35.4%) patients, the two techniques were concordant in the diagnosis of marrow involvement. Of the forty discordant results, positron emission tomography found bone marrow involvement in 37 patients, upstaging 22 to stage IV and having an impact on therapeutic decision in nine cases given their reallocation from early to advanced stage. Three false negative positron emission tomography results were obtained with bone marrow biopsy giving positive findings. All three cases were classified as stage IV regardless of bone marrow findings implying no modification in the clinical management. The sensitivity, specificity and accuracy of positron emission tomography for detecting bone marrow disease were 95%, 100% and 98% and for bone marrow biopsy they were 40%, 100% and 84%, respectively. Conclusion: We conclude that positron emission tomography can replace marrow biopsy in Brazilian patients with Hodgkin's lymphoma without compromising clinical management.

For survival, the emergence of oligoclonal bands after multiple myeloma treatment is less important than achieving complete remission

Abstract Background: The emergence of oligoclonal bands, proteins differing from those originally identified at diagnosis, has been reported in multiple myeloma patients after high-dose chemotherapy followed by autologous stem cell transplantation and after successful conventional chemotherapy. The clinical relevance of oligoclonal bands remains unclear, but their emergence has been associated with better prognosis. The aim of the present study was to determine the prevalence, clinical characteristics and prognostic impact of the presence of oligoclonal bands in multiple myeloma patients. Methods: A retrospective cohort study was conducted. The study included newly diagnosed multiple myeloma patients with at least very good partial response after conventional dose or high-dose chemotherapy followed by autologous stem cell transplantation. The emergence of oligoclonal bands was identified using serum protein electrophoresis as well as serum and urine immunofixation techniques. Results: A total of 101 patients were included with a median follow-up of 42 months. In total, 55% were male, and the median age was 58 years (29-87 years). Fifty-one (50.5%) patients developed oligoclonal bands. They comprised 60% (45/75) of patients treated with autologous stem cell transplantation and 23% (6/26) of those who were not transplanted. Patients with oligoclonal bands showed better progression-free survival than those without the emergence of oligoclonal bands (p-value = 0.0075). Conclusion: The prevalence of oligoclonal bands in this study population was 50.5% with its frequency being greater in cases treated with autologous stem cell transplantation and in those attaining complete remission. Complete remission was more important than the emergence of oligoclonal bands on progression-free survival.

Everolimus as a single agent in refractory or relapsed Hodgkin's lymphoma: the Brazilian Named Patient Program Experience

Abstract Background Despite all the scientific progress that has been made on understanding the disease, prognosis for patients with relapsed and refractory Hodgkin's lymphoma remains poor and the treatment is palliative in the majority of the cases. Thus, the aim of this study was to present the results on the compassionate use of everolimus in a group of patients who were monitored at nine different centers in Brazil. Methods A 10-mg oral dose of everolimus was given to each patient daily. Response time was evaluated from the beginning of medication use until loss of response, toxicity or medical decision to cease treatment. Results Thirty-three patients were evaluated. The median age at the beginning of medication administration was 29 years. Patients had received a median of five prior therapies. Overall response rate was 45.4%, with 13 patients achieving partial response, two achieved clinical response, 14 remained with stable disease, two had disease progression, and two were not evaluated. Patients received a median of 14 cycles. Progression-free survival was nine months, and overall survival was estimated to be 36 months. Three patients used the medication for more than four years. The most frequently reported adverse events were thrombocytopenia and hypercholesterolemia. Three patients had pulmonary toxicity. Grade III and IV adverse events occurred in 39% of the patients. Conclusion Everolimus was found to provide a response in a group of patients with refractory or relapsed Hodgkin's lymphoma who had adequate tolerability to the drug.

Is it feasible to use granulocyte-colony stimulating factor alone to mobilize progenitor cells in multiple myeloma patients induced with a cyclophosphamide, thalidomide and dexamethasone regimen?

ABSTRACT Background: Cyclophosphamide plus thalidomide as induction for multiple myeloma patients eligible for autologous stem cell transplantation may be a limiting factor for cell mobilization. The minimum acceptable mobilized peripheral blood stem cell count to prevent deleterious effects during transplantation is 2.0 × 106 CD34+ cells/kg. Combining other treatments to granulocyte-colony stimulating factor, such as cyclophosphamide, could overcome the mobilization limitation. The objective of this study was to assess the number of CD34+ cells mobilized using granulocyte-colony stimulating factor with and without cyclophosphamide after induction with cyclophosphamide, thalidomide and dexamethasone. Methods: A retrospective study was performed of a cohort of multiple myeloma patients submitted to autologous stem cell transplantations at two Brazilian centers between May 2009 and July 2013. The oral cyclophosphamide and thalidomide induction doses used were 1500 mg/month and 100-200 mg/day, respectively. Mobilization doses were 10-15 mcg/kg granulocyte-colony stimulating factor with 2-4 g/m2 cyclophosphamide, or 15-20 mcg/kg granulocyte-colony stimulating factor alone for 5 days. Collection of >2.0 × 106 CD34+ cells/kg was considered sufficient. Results: Eighty-eight patients were analyzed; only 18 received cyclophosphamide. The median age was 58 years old (range: 51-62) for the granulocyte-colony stimulating factor group and 56.5 years old (range: 54-60) for granulocyte-colony stimulating factor plus cyclophosphamide group. Fifty-two patients were male. Eighty cases (90.9%) were Durie-Salmon Staging System III-A/B and 38 (44.7%) and 20 cases (23.5%) were International Staging System 2 and 3, respectively. The group that received cyclophosphamide collected a higher median number of progenitor cells [3.8 (range: 3.1-4.4) vs. 3.2 (range: 2.3-3.8)] (p-value = 0.008). No correlation was observed between better responses or number of induction cycles and the number of cells collected. Conclusion: The number of cells mobilized with granulocyte-colony stimulating factor plus cyclophosphamide was higher. However, in both groups, the median number of CD34+ cells was sufficient to perform a single autologous stem cell transplantation; no deleterious effects were reported during harvesting.

Diagnosis and treatment of chronic lymphocytic leukemia: recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia

ABSTRACT Chronic lymphocytic leukemia is characterized by clonal proliferation and progressive accumulation of B-cell lymphocytes that typically express CD19+, CD5+ and CD23+. The lymphocytes usually infiltrate the bone marrow, peripheral blood, lymph nodes, and spleen. The diagnosis is established by immunophenotyping circulating B-lymphocytes, and prognosis is defined by two staging systems (Rai and Binet) established by physical examination and blood counts, as well as by several biological and genetic markers. In this update, we present the recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia for the diagnosis and treatment of chronic lymphocytic leukemia. The following recommendations are based on an extensive literature review with the aim of contributing to more uniform patient care in Brazil and possibly in other countries with a similar social-economic profile.

Modern techniques of magnetic resonance in the evaluation of primary central nervous system lymphoma: contributions to the diagnosis and differential diagnosis

Abstract In addition to findings from conventional magnetic resonance imaging, modern magnetic resonance imaging techniques have provided important information about tumor metabolism, in vivo metabolite formation, water molecule diffusion, microvascular density, and blood-brain barrier permeability, all of which have improved the in vivo diagnostic accuracy of this method in the evaluation of primary central nervous system lymphoma. These nonconventional magnetic resonance techniques are useful in the clinical practice because they enhance conventional magnetic resonance imaging by reinforcing the possibility of a diagnosis and by allowing the early detection of disease recurrence. This report is a review of the most relevant contributions of nonconventional magnetic resonance techniques to the imaging diagnosis of primary central nervous system lymphoma, the differential diagnosis of this disease, and the prognosis of patients. This paper aims to describe a wide range of presentations of primary central nervous system lymphoma, their appearance in imaging, and the differential diagnoses of this disease.

Age-adjusted international prognostic index is a predictor of survival in gastric diffuse B-cell non-Hodgkin lymphoma patients

Background The clinical course of gastric lymphoma is heterogeneous and clinical symptoms and some factors have been related to prognosis. Objective The present study aims to identify prognostic factors in gastric diffuse B-cell non-Hodgkin lymphoma diagnosed and treated in different countries. Methods A consecutive series of gastric diffuse B-cell non-Hodgkin lymphoma patients diagnosed and treated in Brazil, Portugal and Italy, between February 2008 and December 2014 was evaluated. Results Of 104 patients, 57 were female and the median age was 69 years (range: 28­88). The distribution of the age-adjusted international prognostic index was 12/95 (13%) high risk, 20/95 (21%) high-intermediate risk and 63/95 (66%) low/low-intermediate risk. Symptoms included abdominal pain (63/74), weight loss (57/73), dysphagia (37/72) and nausea/vomiting (37/72). Bulky disease was found in 24% of the cases, anemia in 33 of 76 patients and bleeding in 22 of 72 patients. The median follow-up time was 25 months (range: 1­77 months), with 1- and 5-year survival rates of 79% and 76%, respectively. The multivariate Cox Regression identified the age-adjusted international prognostic index as a predictor of death (hazard risk: 3.62; 95% confidence interval: 2.21­5.93; p-value <0.0001). Conclusions This series identified the age-adjusted international prognostic index as predictive of mortality in patients treated with conventional immunochemotherapy.

Evaluation correlates C-reactive protein with advanced stage Hodgkin's lymphoma and response to treatment in a tertiary university hospital in Brazil

To demonstrate a correlation of C-reactive protein levels with disease stage and response to treatment in Hodgkin's lymphoma patients of the Hematology Service of Santa Casa de São Paulo.METHODS: A retrospective study based on review of medical records was carried out of 38 patients diagnosed with Hodgkin's lymphoma between October 2010 and December 2012. Three patients met the exclusion criteria, giving a final sample of 35 patients for analysis. C-reactive protein levels >1 mg/dL were considered positive.RESULTS: Among the patients analyzed, median age was 29 years, 65% were male and 85% had the classical nodular sclerosis subtype. Twenty-nine (82%) were in the advanced stage and 28% had bulky mass at diagnosis. Seventeen percent had bone marrow invasion by lymphoma. Baseline C-reactive protein levels were associated with both stage (p-value = 0.0035) and presence or absence of B symptoms (p-value = 0.008). The highest C-reactive protein levels were detected in patients with advanced disease while no patients with localized disease had C-reactive protein >5 mg/dL (p-value = 0.02). After the first treatment cycle, C-reactive protein fell to near-normal levels and no direct association with response pattern was found. As the mean follow-up was only 14 months, it was not possible to determine whether relapse was accompanied by a further increase in C-reactive protein.CONCLUSION: Baseline C-reactive protein levels directly correlated with stage and presence or absence of B symptoms, but the degree of improvement with treatment did not correlate with response pattern. After a longer follow-up, it may be possible to assess whether relapse correlates with a further increase in C-reactive protein levels...

Outcomes of autologous transplantation for multiple myeloma according to different induction regimens

Background: Induction therapy followed by high-dose chemotherapy and autologous transplantation is the standard treatment for suitable patients with multiple myeloma. Objective: The aim of this study was to assess whether induction therapy with thalidomidecontaining regimens was associated with improved results compared to vincristine, doxorubicin, and dexamethasone, and whether cyclophosphamide, thalidomide, and dexamethasone were associated with better results than thalidomide and dexamethasone. Methods: The records of 152 patients who underwent autologous transplantation at this institution from August of 2004 to January of 2012 were reviewed, selecting those with at least partial response to a maximum of eight cycles of induction therapy and sufficient follow-up information for analysis. Results: This study included 89 patients; 44 were female, with a mean age of 55 years (there was a significant trend for increasing age over the years of the study).The median number of induction therapy cycles was four, again with a trend of increase over the years.At least a very good partial response to induction therapy was achieved more often in the cyclophosphamide, thalidomide, and dexamethasone group (61.1%) and in the thalidomide and dexamethasone group (59.2%) than in the vincristine, doxorubicin, and dexamethasone group (16.2%). The overall median progression-free survival was 34 months, with no statistically significant difference between the three groups. The overall median survival was not reached, and there was no significant difference between the three groups; the estimated five-year overall survival was 55%. Conclusion: Although the quality of responses appeared to be better with thalidomidecontaining regimens, these improvements did not translate into improved long-term outcomes. Given its track record, cyclophosphamide, thalidomide, and dexamethasone is currently considered the preferred regimen for first-line ...

Secondary infiltration of the central nervous system in patients with diffuse large B-cell lymphoma

OBJECTIVE: To investigate the incidence and risk factors of infiltration of the central nervous system after the initial treatment of diffuse large B-cell lymphoma in patients treated at Santa Casa de Misericórdia de São Paulo. METHODS: A total of 133 patients treated for diffuse large B-cell lymphoma from January 2001 to April 2008 were retrospectively analyzed in respect to the incidence and risk factors of secondary central nervous system involvement of lymphoma. Intrathecal prophylaxis was not a standard procedure for patients considered to be at risk. This analysis includes patients whether they received rituximab as first-line treatment or not. RESULTS: Nine of 133 (6.7%) patients developed central nervous system disease after a mean observation time of 29 months. The median time to relapse or progression was 7.9 months after diagnosis and all but one patient died despite the treatment administered. Twenty-six (19.5%) patients of this cohort received rituximab as first-line treatment and nine (7.1%) received intrathecal chemoprophylaxis. Of the nine patients that relapsed, seven (77.7%) had parenchymal central nervous system involvement; seven (77.7%) had stage III or IV disease; one (11.1%) had bone marrow involvement; two (22.2%) had received intrathecal chemoprophylaxis; and 3 (33.3%) had taken rituximab. In a multivariate analysis, the risk factors for this infiltration were being male, previous use of intrathecal chemotherapy and patients that were refractory to initial treatment. ...

Philadelphia-negative chronic myeloproliferative neoplasms

Chronic myeloproliferative diseases without the Philadelphia chromosome marker (Ph-), although first described 60 years ago, only became the subject of interest after the turn of the millennium. In 2001, the World Health Organization (WHO) defined the classification of this group of diseases and in 2008 they were renamed myeloproliferative neoplasms based on morphological, cytogenetic and molecular features. In 2005, the identification of a recurrent molecular abnormality characterized by a gain of function with a mutation in the gene encoding Janus kinase 2 (JAK2) paved the way for greater knowledge of the pathophysiology of myeloproliferative neoplasms. The JAK2 mutation is found in 90-98% of polycythemia vera and in about 50% essential thrombocytosis and primary myelofibrosis. In addition to the JAK2 mutation, other mutations involving TET2 (ten-eleven translocation), LNK (a membrane-bound adaptor protein); IDH1/2 (isocitrate dehydrogenase 1/2 enzyme); ASXL1 (additional sex combs-like 1) genes were found in myeloproliferative neoplasms thus showing the importance of identifying molecular genetic alterations to confirm diagnosis, guide treatment and improve our understanding of the biology of these diseases. Currently, polycythemia vera, essential thrombocytosis, myelofibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia and mastocytosis are included in this group of myeloproliferative neoplasms, but are considered different situations with individualized diagnostic methods and treatment. This review updates pathogenic aspects, molecular genetic alterations, the fundamental criteria for diagnosis and the best approach for each of these entities.

T-Cell Lymphomas in South America and Europe

Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cells, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneous. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in Asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year overall survival of about 30 percent. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promoting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies.

Mucosa-associated lymphoid tissue lymphoma of the trachea: case report / Linfoma do tecido linfoide associado à mucosa de traqueia: relato de caso

CONTEXT: Mucosa-associated lymphoid tissue (MALT) lymphomas are most commonly found in the stomach, lungs, orbital soft tissue, salivary glands and thyroid. Involvement of the trachea is extremely rare. CASE REPORT: This report describes a rare case of MALT lymphoma of the trachea in a 71-year-old woman who presented with a one-year history of coughing, dyspnea, hoarseness and weight loss. There was an infiltrative lesion in the mid-trachea. The anatomopathological diagnosis was only made from the fifth endoscopic biopsy attempt. Immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine and prednisone (R-COP) induced complete remission of the symptoms and endoscopic lesion. CONCLUSIONS: MALT lymphoma of the trachea is extremely rare and indolent disease. It has to be considered in the differential diagnosis of airway lesions. It is crucial to obtain an anatomopathological diagnosis from a specialized pathologist. Immunochemotherapy with R-COP induced complete remission of the disease.

CONTEXTO: Linfomas de tecido linfoide associado à mucosa (TLAM) são mais comumente encontrados no estômago, pulmões, órbita, glandulas salivares e tireoide. O envolvimento da traqueia é extremamente raro. RELATO DE CASO: Relato de caso raro de linfoma TLAM de traqueia, em mulher de 71 anos com tosse, dispneia, rouquidão e emagrecimento há um ano. Detectou-se lesão infiltrativa na porção média da traquéia. O diagnóstico anatomopatológico só foi obtido na biópsia do quinto procedimento endoscópico. A imunoquimioterapia R-COP (rituximabe, ciclofosfamida, vincristina e prednisona) induziu remissão completa dos sintomas e da lesão endoscópica. CONCLUSÕES: Linfoma TLAM de traqueia é uma doença indolente e extremamente rara, que deve ser considerada no diagnóstico diferencial das lesões de vias aéreas. O diagnóstico anatomopatológico por um patologista experimentado é fundamental. Imunoquimioterapia com R-COP levou à remissão completa da doença.

Efficacy and safety of intravenous iron sucrose in treating adults with iron deficiency anemia

BACKGROUND: Iron deficiency is the most common disorder in the world, affecting approximately 25 percent of the world`s population and the most common cause of anemia. OBJECTIVE: To evaluate the efficacy and safety of intravenous iron sucrose (IS) in the treatment of adults with iron deficiency anemia METHODS: Eighty-six adult patients with iron deficiency anemia, who had intolerance or showed no effect with oral iron therapy, received a weekly dose of 200 mg of intravenous iron sucrose until the hemoglobin level was corrected or until receiving the total dose of intravenous iron calculated for each patient RESULTS: The mean hemoglobin and serum ferritin levels were 8.54 g/dL and 7.63 ng/mL (pre-treatment) and 12.1 g/dL and 99.0 ng/mL (post-treatment) (p-value < 0.0001), respectively. The average increases in hemoglobin levels were 3.29 g/dL for women and 4.58 g/dL for men; 94 percent of male and 84 percent of female patients responded (hemoglobin increased by at least 2 g/dL) to intravenous iron therapy. Correction of anemia was obtained in 47 of 69 (68.1 percent) female patients and in 12 of 17 male (70.6 percent) patients. A total of 515 intravenous infusions of iron sucrose were administered and iron sucrose was generally well tolerated with no moderate or serious adverse drug reactions recorded by the investigators. CONCLUSIONS: Our data confirm that the use of intravenous iron sucrose is a safe and effective option in the treatment of adult patients with iron deficiency anemia who lack satisfactory response to oral iron therapy. Intravenous iron sucrose is well tolerated and with a clinically manageable safety profile when using appropriate dosing and monitoring. The availability of intravenous iron sucrose would potentially improve compliance and thereby reduce morbidities from iron deficiency.

Classificação dos tumores hematopoéticos e linfoides de acordo com a OMS: padronização da nomenclatura em língua portuguesa, 4ª edição / Classification of haematopoietic and lymphoid tumors: WHO, standardization of nomenclature in Portuguese, 4th edition

INTRODUÇÃO: A classificação da Organização Mundial da Saúde (OMS) para os tumores do tecido hematopoético e linfoide (4ª edição, 2008) representa uma revisão atualização da 3ª edição publicada em 2001. A tradução da nomenclatura utilizada para identificar as entidades descritas deve ser clara, precisa e uniforme no sentido de reproduzir de forma correta as diversas entidades clinicopatológicas para clínicos, patologistas e pesquisadores envolvidos na área da onco-hematopatologia. OBJETIVO: Os autores apresentam uma proposta de atualização e padronização terminológica em língua portuguesa, com base na OMS/2008.

INTRODUCTION: The World Health Organization (WHO) classification of hematopoietic and lymphoid tissue (4th edition, 2008) tumors constitutes an updated review of the 3rd edition published in 2001. The translation of the nomenclature used to describe the entities should be clear, precise and uniform so that clinicians, pathologists and researchers involved in the onco-hematopathological area may identify them accurately. OBJECTIVE: With this purpose, the authors present an updated proposal and a terminological standardization in Portuguese based on WHO/2008.