Cardiovascular Management of Patients Undergoing Hematopoietic Stem Cell Transplantation: From Pretransplantation to Survivorship: A Scientific Statement From the American Heart Association

Hematopoietic stem cell transplantation can cure various disorders but poses cardiovascular risks, especially for elderly patients and those with cardiovascular diseases. Cardiovascular evaluations are crucial in pretransplantation assessments, but guidelines are lacking. This American Heart Association scientific statement summarizes the data on transplantation-related complications and provides guidance for the cardiovascular management throughout transplantation. Hematopoietic stem cell transplantation consists of 4 phases: pretransplantation workup, conditioning therapy and infusion, immediate posttransplantation period, and long-term survivorship. Complications can occur during each phase, with long-term survivors facing increased risks for late effects such as cardiovascular disease, secondary malignancies, and endocrinopathies. In adults, arrhythmias such as atrial fibrillation and flutter are the most frequent acute cardiovascular complication. Acute heart failure has an incidence ranging from 0.4% to 2.2%. In pediatric patients, left ventricular systolic dysfunction and pericardial effusion are the most common cardiovascular complications. Factors influencing the incidence and risk of complications include pretransplantation therapies, transplantation type (autologous versus allogeneic), conditioning regimen, comorbid conditions, and patient age. The pretransplantation cardiovascular evaluation consists of 4 steps: (1) initial risk stratification, (2) exclusion of high-risk cardiovascular disease, (3) assessment of cardiac reserve, and (4) optimization of cardiovascular reserve. Clinical risk scores could be useful tools for the risk stratification of adult patients. Long-term cardiovascular management of hematopoietic stem cell transplantation survivors includes optimizing risk factors, monitoring, and maintaining a low threshold for evaluating cardiovascular causes of symptoms. Future research should prioritize refining risk stratification and creating evidence-based guidelines and strategies to optimize outcomes in this growing patient population

BendaEAM versus BEAM as conditioning regimen for ASCT in patients with relapsed lymphoma (BEB): a multicentre, randomised, phase 2 trial.

BACKGROUND Replacement of carmustine (BCNU) in the BEAM regimen (BCNU, etoposide, cytarabine, melphalan) with bendamustine (BendaEAM) before autologous stem cell transplantation (ASCT) is feasible in lymphoma. However, randomised trials are lacking. Here, we present the first trial addressing this topic. METHODS This multicentre, randomised, phase 2 study (BEB-trial) conducted at four haematological centres in Austria and Switzerland compares BEAM with BendaEAM in patients with relapsed lymphoma. Both regimens were administered intravenously before ASCT, in BEAM according to the standard protocol (300 mg/m2 BCNU on day -6), in BendaEAM, BCNU was replaced by 200 mg/m2 bendamustine given on days -7 and -6. Eligible patients were aged 18-75 years and had mantle cell lymphoma, diffuse large B-cell lymphoma, or follicular lymphoma in first or second remission or chemosensitive relapse. The primary endpoint of the study was to evaluate whether replacement of BCNU by bendamustine reduces lung toxicity, defined as a decrease of the diffusion capacity of the lung for carbon monoxide by at least 20% at three months after ASCT. Data analyses were performed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02278796, and is complete. FINDINGS Between April 20, 2015, and November 28, 2018, 108 patients were enrolled; of whom 53 were randomly assigned to receive BendaEAM (36 male, 17 female) and 55 to receive BEAM (39 male, 16 female). All patients engrafted rapidly. Lung toxicity did not differ between groups (BendaEAM: n = 8, 19.5%; BEAM: n = 11, 25.6%; risk difference = -6.1%: 95% confidence interval: -23.9% to 11.7%). Acute toxicities of at least grade 3 were comparable in both groups (BendaEAM: 35.8%, BEAM: 30.9%). Overall survival (BendaEAM: 92.5%, BEAM: 89.1%) and complete remission (BendaEAM: 76.7%, BEAM: 74.3%) after 1 year (median follow-up: 369 days) were similar. No difference in quality of life was observed. INTERPRETATION Results were similar for both regimens in terms of survival and response rates. A phase 3 non-inferiority study is required to investigate whether BendaEAM can be considered as an alternative to BEAM. FUNDING Mundipharma

Tratamiento de rescate en linfomas agresivos: eficacia del trasplante autólogo de progenitores hematopoyéticos y evaluación de nuevos fármacos

[ES]Los linfomas no Hodgkin presentan una incidencia comprendida entre 3 y 6 casos por cada 100.000 habitantes y año y son la causa del 3% de mortalidad por procesos neoplásicos. Constituyen un grupo heterogéneo de neoplasias linfoides y esta diversidad determina que su tratamiento sea uno de los aspectos más complejos y controvertidos de la hematología. La presente tesis doctoral se centra, principalmente, en los linfomas difusos de células grandes B (LDCGB) que constituyen el grupo más frecuente en nuestro medio (casi un tercio de todos los linfomas no Hodgkin) y, más brevemente, en los linfomas B transformados y en los linfomas T periféricos. Actualmente, los regímenes terapéuticos de primera línea que combinan rituximab y quimioterapia son altamente efectivos en los pacientes con LDCGB, pero aquellos que son refractarios o recaen tienen muy mal pronóstico con las estrategias de rescate actuales. Por ello, estos grupos de pacientes son candidatos a ensayos clínicos con esquemas que incorporen nuevos fármacos, bien como parte del tratamiento de rescate o en el régimen de acondicionamiento del trasplante autólogo. La lenalidomida y la bendamustina han conseguido resultados prometedores en el tratamiento de los linfomas agresivos refractarios o en recaída, aunque ninguno ha demostrado suficiente eficacia como para ser utilizado como agente único. Como consecuencia, uno de los retos actuales de la investigación clínica en linfomas consiste en definir el papel de los nuevos fármacos combinados con los regímenes de quimioterapia habituales. En la presente tesis doctoral hemos realizado un estudio biológico para evaluar, in vitro, la eficacia de lenalidomida y bendamustina solas y en combinación con quimioterapia, en líneas celulares de linfoma. Por otro lado, hemos realizado varios estudios clínicos: en primer lugar, un estudio retrospectivo para analizar la influencia del tratamiento con rituximab previo al trasplante sobre los resultados del mismo; en segundo lugar, un ensayo clínico fase I donde combinamos quimioterapia convencional con lenalidomida como tratamiento de rescate de pacientes con LDCGB y por último, un ensayo clínico fase II donde introducimos bendamustina en el régimen de acondicionamiento previo al trasplante de pacientes con linfoma agresivo. Los dos últimos estudios tuvieron como objetivos principales analizar la toxicidad y eficacia de dos nuevos regímenes de tratamiento para pacientes con linfoma

Sex-Specific Cardiovascular Risks of Cancer and Its Therapies

In both cardiovascular disease and cancer, there are established sex-based differences in prevalence and outcomes. Males and females may also differ in terms of risk of cardiotoxicity following cancer therapy, including heart failure, cardiomyopathy, atherosclerosis, thromboembolism, arrhythmias, and myocarditis. Here, we describe sex-based differences in the epidemiology and pathophysiology of cardiotoxicity associated with anthracyclines, hematopoietic stem cell transplant (HCT), hormone therapy and immune therapy. Relative to males, the risk of anthracycline-induced cardiotoxicity is higher in prepubertal females, lower in premenopausal females, and similar in postmenopausal females. For autologous hematopoietic cell transplant, several studies suggest an increased risk of late heart failure in female lymphoma patients, but sex-based differences have not been shown for allogeneic hematopoietic cell transplant. Hormone therapies including GnRH (gonadotropin-releasing hormone) modulators, androgen receptor antagonists, selective estrogen receptor modulators, and aromatase inhibitors are associated with cardiotoxicity, including arrhythmia and venous thromboembolism. However, sex-based differences have not yet been elucidated. Evaluation of sex differences in cardiotoxicity related to immune therapy is limited, in part, due to low participation of females in relevant clinical trials. However, some studies suggest that females are at increased risk of immune checkpoint inhibitor myocarditis, although this has not been consistently demonstrated. For each of the aforementioned cancer therapies, we consider sex-based differences according to cardiotoxicity management. We identify knowledge gaps to guide future mechanistic and prospective clinical studies. Furthering our understanding of sex-based differences in cancer therapy cardiotoxicity can advance the development of targeted preventive and therapeutic cardioprotective strategies