How to set up a clinical research center in Brazil, as an example of a middle-income country.

In health care, innovation is a core part of the process that pushes advances forward. Drug and device development follow a step-by-step process from the discovery of a molecule to the final product. While patent filing and preclinical studies are usually performed by academic centers or start-ups, the clinical development is usually performed by pharmaceutical companies. To assess safety, efficacy and fulfil regulatory demands, clinical trials must be performed in sequential Phase I, II, and III stages prior to market access. In this context, clinical research centers have been established around the globe, also outside traditional academic centers, aiming to increase the access for patients to participate in clinical trials and the capacity for clinical development. The increasing number of clinical trial sites across the world, gives pharmaceutical companies, investigators and developers an improved access to properly test the exponentially increasing number of potential medicinal products and treatment approaches in trials in different parts of the world. Historically, Low- and Middle-Income Countries (LMIC) did not significantly take part in clinical trial development. As participation in all steps of clinical research provides earlier access to novel treatment options in LMIC along with creating data on efficacy and toxicity within more diverse populations, it is warranted to improve clinical trial access in LMIC. With the goal to provide input on how to tackle the challenges during the built of a clinical research center, we here describe the experience from setting up a clinical trial unit within a private hospital network in Brasília, Brazil, a Middle-Income country, to provide inspiration, "how to" knowledge and a recipe for those with a similar road ahead in LMIC.

Brazilian experience with caplacizumab in acquired thrombotic thrombocytopenic purpura: outcomes of the expanded access program.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare disease with an acute and severe clinical presentation. The anti-von Willebrand factor caplacizumab was licensed for adults with aTTP based on prospective controlled trials. However, until now, there was no Brazilian experience with this new treatment modality. This retrospective, multicenter, single-arm, expanded access program (EAP) with caplacizumab, plasma exchange (PEX), and immunosuppression was conducted between 02/24/21 and 04/14/21, and enrolled 5 Brazilian patients with aTTP. EAP allowed access to caplacizumab in Brazil and real-world data was collected, at a time when the medication was not commercially available in Brazil. The median age was 31 years old, most patients were women (80%), and neurological manifestation was observed in 80% of cases. The median of laboratory tests was hemoglobin (Hb) of 11 g/dL, platelets (16.1 × 109/L), lactic dehydrogenase (LDH) of 1471 U/L, creatinine (0.7 mg/dL), ADAMTS13 activity lower than 0.71%, and PLASMIC score of 6. All patients received immunosuppression, PEX, and caplacizumab. Until clinical response was achieved, the median was 3 sessions of PEX and 3 days of treatment. The median time of caplacizumab use was 35 days, with platelet normalization in 2 days after starting the drug. The median total length of stay was 8 days. All patients achieved clinical response and clinical remission, with a good safety profile. There was rapid clinical response, few PEX sessions were necessary, and there were short hospital stay, absence of refractoriness, little exacerbation, no death, and resolution of signs and symptoms at diagnosis.

SOHO State of the Art Updates and Next Questions | Infections in Chronic Lymphocytic Leukemia Patients: Risks and Management.

Although chronic lymphocytic leukemia (CLL) is a malignancy characterized by accumulation of tumor cells in the blood, bone marrow, lymph nodes and secondary lymphoid tissues, the hallmark of the disease and the major cause of death for patients with CLL is actually immune dysfunction and associated infections. Despite improvement in treatment based on combination chemoimmunotherapy and targeted treatment with BTK and BCL-2 inhibitors leading to longer overall survival for patients with CLL, the mortality due to infections have not improved over the last 4 decades. Thus, infections are now the main cause of death for patients with CLL, posing threats to the patient whether during the premalignant state of monoclonal B lymphocytosis (MBL), during the watch & wait phase for treatment naïve patients, or upon treatment in terms of chemoimmunotherapy or targeted treatment. To test whether the natural history of immune dysfunction and infections in CLL can be changed, we have developed the machine learning based algorithm CLL-TIM.org to identify these patients. The CLL-TIM algorithm is currently being used for selection of patients for the clinical trial PreVent-ACaLL (NCT03868722), testing whether short-term treatment with the BTK inhibitor acalabrutinib and the BCL-2 inhibitor venetoclax can improve immune function and decrease the risk of infections for this high-risk patient population. We here review the background for and management of infectious risks in CLL.

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.

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

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.

A 61-year-old woman with adult T-cell leukemia÷lymphoma.

Adult T-cell leukemia÷lymphoma (ATL) is caused by human T-cell lymphotropic virus type-1 (HTLV-1) infection. Classification of ATL includes acute, chronic, lymphomatous and smoldering, and main features are hypercalcemia, organomegaly, bone, brain, lung, and skin changes. Elevated mortality rates of ATL may be due to the advanced age at diagnosis, because this malignancy can evolve unsuspected for decades before the first clinical manifestations. Palliative therapy, chemotherapy and stem cell transplantation are often utilized, but response to treatment is poor. The patient herein reported presented diffuse abdominal pain with duration of eight months in addition to ascites. The diagnosis of the acute leukemia type of ATL was done with base on clinical, laboratory and imaging findings. Gastrointestinal symptoms and ascites are uncommon first manifestations of ATL, and pose challenging diagnosis.

Mucormycosis in a patient with acute myeloid leukemia successfully treated with liposomal amphotericin B associated with deferasirox and hyperbaric oxygen.

We report a 38-year-old woman presenting with febrile neutropenia, acute myeloid leukemia (AML) and invasive mucormycosis. Bone marrow aspirate was characteristic of AML minimally differentiated (WHO classification 2008). Flow cytometric immunophenotyping analysis showed blasts positive for CD7, CD33, CD34, CD71, CD117, HLA-DR, MPO, and TdT, with normal karyotype (46, XX), and the absence of the FLT3-ITD and NPM1 mutations. The patient's management included chemotherapy with cytarabine and idarubicin, and treatment with liposomal amphotericin B, deferasirox, hyperbaric oxygen therapy, and antibiotics. Nowadays, she is in complete hematological remission, and CT images of control are normal. Invasive mucormycosis is an uncommon and severe condition, which involves diagnosis and treatment challenges. Clinical features and predisposing factors should be highlighted in order to enhance the suspicion index, contributing to early diagnosis and disease control. Our aim is to report classical features of this uncommon condition and to emphasize usual management challenges.