Recommendations for the management of cardiovascular risk in patients with chronic myeloid leukemia on tyrosine kinase inhibitors: risk assessment, stratification, treatment and monitoring

ABSTRACT This manuscript summarizes the results of the consensus meeting composed of hematologists and cardiologists to establish recommendations for the prevention and follow-up of cardiovascular (CV) risk in patients with chronic myeloid leukemia (CML) treated with BCR-ABL tyrosine kinase inhibitors (TKIs) from the point of view of clinical practice and from the perspective of hematology consultation.In the first medical appointment, the CV risk factors should be identified to perform the baseline risk stratification, based on the Brazilian Guideline of Dyslipidemia and Atherosclerosis Prevention Update (risk levels: very high, high, intermediate and low).Once stratified, the treatment of the CV risk factors should be administered. If the patient presents risk factors, such as hypertension, diabetes, renal disease, smoking and hypercholesterolemia, the evaluation and initial treatment may be done by the hematologist, being an option the request for evaluation by a specialist. If the patient has a history of previous CV disease, we recommend referral to a specialist. As the CV risk score is dynamic and the control of risk factors can reduce the patient risk, this expert consensus recommends that the re-evaluation of the CV risk after the baseline should be performed at 3 months, 6 months and 12 months. After this period, it should be done annually and, for specific patients, at the clinician's discretion.The evaluation of the baseline CV risk and the safe administration of a TKI allow the patient to benefit from the maximum treatment, avoiding unwanted effects.

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.

What happens to intolerant, relapsed or refractory chronic myeloid leukemia patients without access to clinical trials?

ABSTRACT Objective: To assess clinical outcomes of intolerant, relapsed or refractory patients who could not be treated with new tyrosine kinase inhibitors or experimental therapies. Methods: A retrospective cohort of 90 chronic myeloid leukemia patients in all phases of the disease treated with imatinib mesylate as their first TKI therapy, and with dasatinib or nilotinib as the next line of therapy. We evaluated clinical outcomes of these patients, with special focus on the group that needed more than two therapy lines. Results: Thirty-nine percent of patients were refractory or intolerant to imatinib. An 8-year overall survival rate of the patients who went through three or more lines of treatment was significantly lower, compared to those who were able to maintain imatinib as their first-line therapy (83% and 22%, respectively p < 0.01). Decreased overall survival was associated with advanced-phase disease (p < 0.01), failure to achieve major molecular response in first-line treatment (p < 0.01) and interruption of first-line treatment due to any reason (p = 0.023). Failure in achieving complete cytogenetic response and major molecular response and treatment interruption were associated with the progression to the third-line treatment. Conclusion: The critical outcome observed in relapsed, intolerant or refractory chronic phase CML patients reflects the unmet need for this group of patients without an alternative therapy, such as new drugs or experimental therapies in clinical trials. Broader access to newer treatment possibilities is a crucial asset to improve survival among CML patients, especially those refractory or intolerant to first-line therapies.

Prognostic impact of MYD88 mutation, proliferative index and cell origin in diffuse large B cell lymphoma

Abstract Background Diffuse large B-cell lymphoma, among non-Hodgkin lymphomas, is one of the most frequent subtypes. Clinical laboratory data and post-treatment outcomes are scarce in the Brazilian population. Objective The main objective of this retrospective study was to assess the impact of tumor markers, including the Myeloid differentiation primary response 88 (MYD88) mutation. Method Eighty-three patients were included and treated with R-CHOP or R-CHOP-like regimens. Results Median age was 64-years old and 58% were female patients. The median follow-up was 42 months. The progression free survival (PFS) at this time was 63% and overall survival (OS), 66%. In the patients with tumors expressing Myc proto-oncogene protein (MYC) and B-cell lymphoma 2 (BCL2), assessed by immunohistochemistry (IHC), known as dual protein expressers, median post-progression survival was 31 (15-45) months. An increased proliferative index were associated with a high rate of progression (hazard ratio 2.31 [95% confidence interval [1.05-5.12]; p = 0.04). The cell of origin (COO), identified by IHC, was not able to predict PFS (p = 0.76). The MYD88 L265P mutation was present in 10.8% (9/83) of patients and did not show a prognostic correlation. Conclusion In conclusion, the MYD88 mutation, although an important tool for diagnosis and a possible target drug, presented at a low frequency and was not a prognostic marker in this population.

Biosimilar Filgrastim for Progenitor-Cell Mobilization prior to Autologous Transplantation: Retrospective Analysis of Patients with Multiple Myeloma and Lymphomas / Filgrastim Biossimilar para Mobilização de Células Progenitoras antes do Transplante Autólogo: Análise Retrospectiva de Pacientes com Mieloma Múltiplo e Linfomas / Filgrastim Biosimilar para la Movilización de Células Progenitoras antes del Trasplante Autólogo: Análisis Retrospectivo de Pacientes con Mieloma Múltiple y Linfomas

Introduction: Filgrastim, which plays a key role in peripheral blood progenitor cell (PBPC) harvesting, has been available for nearly 25 years, and several filgrastim biosimilars are available. Objective: We assessed whether a biosimilar filgrastim (Filgrastine®) was associated with effective mobilization in patients undergoing PBPC collection for autologous transplantation. Method: We reviewed the charts of patients with multiple myeloma and lymphomas treated at three institutions in Brazil. The primary outcome (mobilization success rate, MSR) was the proportion of patients in the intention-to-treat (ITT) group in whom at least 2 x 106 CD34+cells/Kg were harvested by leukapheresis on days 5 and/or 6. The per-protocol (PP) group comprised patients who received at least 4 days of Filgrastine and had at least one CD34+ count on days 5 or 6. Results: The daily dose of Filgrastine (on D1, with few changes thereafter) ranged from 8.5 to 28.9 mcg/Kg in the 52 patients in the ITT group, with a median of 13.8 mcg/Kg; 51 patients received at least four doses. A mean of 2.84±1.97 x 106 CD34+cells/Kg were harvested. MSR was 53.9% (95%CI, 39.5%-67.8%) in the ITT group and 62.2% (95%CI, 46.5%-76.2%) in the 45 patients in the PP group. Mobilization was considered effective by investigators in 80.8% of patients in the ITT group and 88.9% of those in the PP group. Conclusion: Despite the study's observational design, the results suggest that Filgrastine® is associated with the expected success rates in PBPC collection for autologous transplantation.

Introdução: O filgrastim, que desempenha um papel fundamental na coleta de células progenitoras de sangue periférico (CPSP), está disponível há quase 25 anos, e existem vários biossimilares de filgrastim sendo comercializados. Objetivo: Avaliar se um filgrastim biossimilar (Filgrastine®) foi associado com mobilização efetiva em pacientes submetidos à coleta de CPSP para transplante autólogo de medula óssea. Método: Foram revisados os prontuários de pacientes com mieloma múltiplo e linfomas tratados em três instituições no Brasil. O desfecho primário (taxa de sucesso de mobilização) foi a proporção de pacientes na população intenção de tratar (ITT), em que pelo menos 2 x 106 células CD34+/kg foram coletadas por leucaférese nos dias 5 e/ou 6. A população per protocolo (PP) foi composta por pacientes que receberam pelo menos quatro dias de Filgrastine e tiveram pelo menos uma contagem de CD34+ nos dias 5 ou 6. Resultados: A dose diária de Filgrastine (no D1, com pequenas alterações subsequentes) variou de 8,5 a 28,9 mcg/Kg nos 52pacientes na população ITT, com uma mediana de 13,8 mcg/Kg; 51 pacientes receberam pelo menos quatro doses. Uma média de 2,84±1,97 x 106 células CD34+/kg foram coletadas. A taxa de sucesso de mobilização foi de 53,9% (IC 95%, 39,5% a 67,8%) na população ITT e 62,2% (IC 95%, 46,5% a 76,2%) nos 45 pacientes da população PP. A mobilização foi considerada efetiva pelos pesquisadores em 80,8% dos pacientes da população ITT e 88,9% daqueles na população PP. Conclusão: Apesar de sua natureza observacional, este estudo sugere que Filgrastine esteja associado com as taxas de sucesso esperadas na coleta de CPSP para transplante autólogo de medula óssea.

Introducción: El filgrastim, que desempeña un papel fundamental en la colecta de células progenitoras de sangre periférica (CPSP), está disponible desde hace casi 25 años y existen varios biosimilares de filgrastim siendo comercializados. Objetivo: Se evaluó si un filgrastim biosimilar (Filgrastine®) se asoció con una movilización efectiva en pacientes sometidos a la colecta de CPSP para el trasplante autólogo de médula ósea. Método: Se revisaron los prontuarios de pacientes con mieloma múltiple y linfomas tratados en tres instituciones en Brasil. El resultado primario (tasa de éxito de movilización) fue la proporción de pacientes en la población intención de tratar (ITT) en que al menos 2 x 106 células CD34+/kg fueron obtenidas por leucoféresis en los días 5 y/o 6. La población por protocolo (PP) fue compuesta por pacientes que recibieron por lo menos 4 días de Filgrastine y tuvieron al menos un recuento de CD34 + en los días 5 o 6. Resultados: La dosis diaria de Filgrastine (en el D1, con pequeños cambios subsiguientes) varió de 8, 5 a 28,9 mcg/Kg en los 52 pacientes en la población ITT, con una mediana de 13,8 mcg / Kg; 51 pacientes recibieron al menos cuatro dosis. Se obtuvo una media de 2,84±1,97 x 106 células CD34+/kg. La tasa de éxito de movilización fue del 53,9% (IC 95%, 39,5% a 67,8%) en la población ITT y el 62,2% (IC 95%, 46,5% a 76,2%), en los 45 pacientes de la población PP. La movilización fue considerada efectiva por los investigadores en el 80,8% de los pacientes de la población ITT y el 88,9% de aquellos en la población PP. Conclusión: A pesar de su naturaleza observacional, este estudio sugiere que Filgrastine está asociado con las tasas de éxito esperadas en la recolección de CPSP para trasplante autólogo de médula ósea.

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.

Obinutuzumabe no tratamento de pacientes com leucemia linfoide crônica, não elegíveis à dose completa de fludarabina: análise de impacto orçamentário baseado no tempo para a próxima terapia / Obinutuzumab for the treatment of unfit patients with chronic lymphocytic leukemia: budget impact analysis based on time to next treatment

Objetivo: Comparar o impacto orçamentário de obinutuzumabe + clorambucila (GClb), rituximabe + clorambucila (RClb), ofatumumabe + clorambucila (OClb) ou clorambucila (Clb) na primeira linha de tratamento (1L) e suas respectivas opções de segunda linha (2L) recomendadas por consenso brasileiro e internacional para adultos com leucemia linfoide crônica (LLC) não tratados previamente e inelegíveis à dose completa de fludarabina (slow-go). Métodos: A análise foi conduzida a partir do desfecho de tempo para próxima terapia (TPPT) na perspectiva do Sistema de Saúde Suplementar (SSS). Apenas custos de aquisição de medicamentos foram considerados, incluindo posologia de bulas registradas. Regimes de tratamento de 2L considerados foram RClb ou ibrutinibe. As curvas de TPPT foram obtidas do estudo CLL11 e COMPLEMENT 1. Resultados: Em horizonte temporal de cinco anos, GClb demonstrou benefício econômico, quando comparado com RClb, OClb e Clb, sendo o potencial de savings por paciente de R$ 80 mil, R$ 149 mil e R$ 284 mil, respectivamente. Adicionalmente, em cinco anos, verificou-se que a adoção de GClb na 1L para pacientes com LLC pode promover economia de R$32 milhões para SSS quando comparado com RClb e Clb, uma vez que seu intervalo livre de tratamento é mais longo do que o das tecnologias comparadas, o que posterga o início do tratamento de 2L. Conclusões: Apesar de o preço unitário de obinutuzumabe e o custo de tratamento inicial de GClb serem superiores aos de RClb, OClb e Clb, o tratamento de 1L com GClb pode promover benefícios econômicos em longo prazo, consequentes dos resultados clínicos favoráveis da associação de GClb no tratamento da LLC.

Objective: To compare the budget impact of obinutuzumab + chlorambucil (GClb), rituximab + chlorambucil (RClb), ofatumumabe + chlorambucil (OClb) or chlorambucil (Clb) in first line treatment (1L) and their respective therapeutic options in second line (2L), recommended by a Brazilian and international consensus for adults with chronic lymphocytic leukemia (CLL), with no previous treatment and classified as ineligible to full dose fludarabine treatment (slow-go). Methods: The analysis was conducted based on the outcome time to next treatment (TPPT) under the perspective of the Brazilian Private Healthcare System (SSS). Only drug acquisition costs were considered, including dosage from registered labels. RClb and ibrutinib were considered as 2L treatment regimens. The TPPT curves were obtained from the CLL11 and COMPLEMENT 1 studies. Results: Considering a five-year time horizon, GClb demonstrated economic benefit when compared to RClb, OClb and Clb, with potential savings per patient of R$ 80 thousand, R$ 149 thousand and R$ 284 thousand, respectively. Additionally, in five years, the adoption of GClb as 1L for patients with CLL can promote an economy of R$ 32 million to the SSS when compared to RClb and Clb, since the GClb treatment free interval is longer than the compared technologies, which delays the beginning of the more costly 2L treatment. Conclusions: Although the unitary obinutuzumab price and the cost of initial GClb treatment are greater than RClb, OClb and Clb, 1L treatment with GClb can promote economic benefits in the long term, resulting from the favorable clinical results of GClb association in CLL treatment.

Doença de Erdheim-Chester / Erdheim-Chester Disease

A Doença de Erdheim-Chester é uma histiocitose não Langerhans rara e de incidência ainda desconhecida. Caracteriza-se por lesões osteoescleróticas de ossos longos podendo, também, infiltrar tecidos extraesqueléticos como coração, pulmões, olhos e retroperitônio. É relatado o caso de uma paciente portadora de Doença de Erdheim-Chester tratada no Hospital de Clínicas de Porto Alegre (AU)

Erdheim-Chester disease is a rare form of non-Langerhans histiocytosis whose incidence remains unknown. Characterized by osteosclerotic lesions in long bones, it can also penetrate such extraskeletal tissues as heart, lungs, eyes and retroperitoneum. Here we report the case of a female patient with Erdheim-Chester disease treated at the Hospital de Clínicas of Porto Alegre (AU)

Importance of adherence to BCR-ABL tyrosine-kinase inhibitors in the treatment of chronic myeloid leukemia

Treatment of chronic myeloid leukemia with BCR-ABL tyrosine kinase inhibitors requires full adherence in order to maximize the likelihood of achieving optimal responses, and to minimize healthcare costs. In this article, we review some of the methods available for assessing compliance, the main consequences of nonadherence on treatment outcomes, major factors commonly associated with poor compliance, a few successful measures for improving adherence and the most accepted recommendations for proactively managing adverse events.

Leucemia mielóide aguda: o olhar dos anos 2000 no Serviço de Hematologia do Hospital de Clínicas de Porto Alegre-RS / Acute myeloid leukemia from the year 2000 point of view Hematology Service - Hospital de Clínicas de Porto Alegre-RS

A leucemia mielóide aguda (LMA) representa uma preocupação para os especialistas, porque perfaz um percentual alto das leucemias no adulto e o sucesso terapêutico ainda é insatisfatório. A partir do ano 2000, o Serviço de Hematologia do Hospital de Clínicas de Porto Alegre definiu estratégias para diagnóstico, tratamento e seguimento das LMAs, de acordo com o subtipo FAB, idade, citogenética e performance status (ECOG). Todos os casos de LMA "de novo"não promielocítica, em adultos (15 a 65 anos) foram acompanhados prospectivamente, desde outubro de 2001, data da implantação do protocolo c,ompreendendo três fases de tratamento: indução com o tradicional "7+3", citarabina 100 mg/m²/dia em infusão contínua em 7d, e daunorrubicina 60 mg/m²/dia em 3d e citarabina intratecal no D1 nas LMA M4 e M5. Após a recuperação medular, segue a consolidação idêntica à indução e posteriormente a intensificação com dois ou três ciclos de altas doses de citarabina 6 g/m²/dia por três dias. Foram diagnosticados, entre outubro/01 e dezembro/05, 69 pacientes portadores de LMA e destes, 39 com LMA "de novo"e idade entre 15 e 65 anos. Neste grupo foram analisadas a taxa de remissão, a taxa de recaída, a refratariedade e o tempo de sobrevida global. No final da observação foram encontrados: a taxa de indução de remissão 75 por cento; aconteceram 12 (40 por cento) recaídas, 7 (19 por cento) foram refratários ao tratamento. A sobrevida global foi 37 por cento em 56 meses, representando um incremento aos resultados obtidos no Serviço na década passada.

Acute myeloid leukemia (AML) is still a concern for hematologists as it represents a significant percentage of adult leukemias and the therapeutic success rates are unsatisfactory. In 2000, the Hematology Department of Hospital de Clínicas de Porto Alegre defined strategies for the diagnosis, treatment and follow up of AML patients according to the FAB subtype classification, age, cytogenetic tests and performance status (ECOG). Patients with promyelocytic leukemia are treated using the AIDA (GIMEMA) protocol with those older than 65 years receiving palliative therapy using hydroxyurea, oral etoposide, thalidomide, subcutaneous cytarabine or an association of drugs. Since October 2001 all our "de novo"AML patients aged 15 to 65 years with non-promyelocytic acute leukemia were prospectively followed up. At diagnosis we start a three phase treatment protocol: induction with a classical "7+3"therapy regimen, that is continuous infusion of 100 mg/m²/day cytarabine for 7 days, 60 mg/m²/day daunorubicin for 3 days and on day 1 an intrathecal cytarabine in AML M4 and M5 cases. After bone marrow recovery, if complete remission is achieved, follow ups involve an identical "7+3"consolidation phase followed by two or three high dose cycles of 6 g/m²/day cytarabine for 3 days. A group of 39 patients diagnosed between October 2001 and December 2005 was followed up until June 2006. Our objectives were to evaluate the effectiveness of the protocol for remission, relapse rates and overall survival. The rate of complete remission was 75 percent. Relapse occurred in 12/29 (40 percent) patients and the overall survival rate at 56 months was 37 percent, showing an improvement on our results of previous decades.

Leucemia aguda e gestaçäo: relato de 4 casos e revisäo da literatura / Acute leukemia and pregnancy: report of 4 cases and literature review

O diagnóstico de leucemia aguda na gestäo é pouco comum e possui particularidades próprias relacionadas, principalmente, ao manejo. A gestäo em si parece näo alterar a história natural da doença, nem a resposta ao tratamento. Sua maior implicaçäo reside nos riscos da exposiçäo fetal aos agentes quimioterápicos, bem como as complicaçöes maternas relacionadas à própria doença e tratamento. Os efeitos tóxicos do quimioterápicos säo potencialmente prejudiciais ao feto durante o período da embriogênese. Complicaçöes maternas relacionadas ao tratamento podem alterar o desenvolvimento fetal. Este trabalho realiza uma revisäo da literatura existente sobre leucemia e gestaçäo e relata a evoluçäo de 4 pacientes gestantes com diagnóstcio de leucemia aguda, atendidas no Serviço de Hematologia do Hospital de Clínicas de Porto Alegre (HCPA), entre 1990 - 1994. Em três casos o diagnóstico foi de leucemia linfocítica aguda (LLA) e em um de leucemia mielocitica aguda (LMA). O tratamento de induçäo foi realizado com quimioterapia intensiva, obtendo-se a remissäo em todos os casos. Três gestaçöes evoluíram com morte fetal e uma foi interrompida com cesareana. Todas as pacientes apresentaram algum tipo de complicaçäo (anemia, infecçäo) relacionada ao tratamento. A série apresentada é restrita pelo pequeno número de pacientes, assim, seus resultados näo säo conclusivos. A criaçäo de um registro geral destes casos poderia aumentar a casuística e as informaçöes referentes ao tratamento, evoluçäo e efeitos dos quimioterápicos sobre o feto