Impact of the insertion of the clinical pharmacist in the Allogeneic Hematopoietic Stem Cells Transplantation team.

INTRODUCTION: Allogeneic Hematopoietic Stem Cells Transplantation (allo-HSCT) is capable of curing patients with neoplastic or non-neoplastic hematologic disorders or of prolonging their survival. This study assessed if the insertion of the clinical pharmacist in the allo-HSCT team modified the outcomes: transplantation-related mortality, grafting failure, incidence of Graft versus Host Disease, hospitalization time, time for grafting, number of readmissions, number of drug-related problems (DRPs), adherence and knowledge about pharmacotherapy. METHODS: Interventional study with historical control carried out in an allo-HSCT unit, in which the intervention group (IG) included 33 individuals who received pharmacotherapy follow-up. Control Group (CG) consisted of 28 individuals. RESULTS: A total of 250 DRPs were identified, 59 team's doubts were clarified, and 309 interventions were conducted in the IG. The DRPs mainly arose from safety (51.60%) and effectiveness (38.40%) problems. A mean of 9.36 (SD = 6.97) interventions per patient was obtained, mainly including dose reductions (19.09%), adjustments in administration time (18.12%), educational activities (15.21%) and drug removal (10.68%). Clinical significance of the interventions was considered high (75.7% extremely significant, very significant or significant), as well as their acceptability (89.7% accepted). Each patient attended a mean of 4.68 pharmaceutical consultations (SD = 1.91) after hospital discharge, presenting increase in knowledge (p = 0.0001) and in adherence (p = 0.0115). There was no evidence of differences between the groups in the other outcomes analyzed. CONCLUSIONS: The pharmacotherapy follow-up allowed detecting several DRPs and performing interventions of high clinical relevance and acceptability, in addition to improving adherence and individualizing the pharmacotherapy.

Can pharmacotherapeutic follow-up after allogeneic hematopoietic stem cell transplantation improve medication compliance?

BACKGROUND: Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is currently one of the most effective therapies in onco-hematology. For the treatment of the disease and prevention of such complications, a complex pharmacotherapeutic regimen is employed. Non-compliance is prevalent among adolescents and young adults with chronic hematological diseases, being reported by up to 50% of the patients. OBJECTIVE: To evaluate the results of pharmacotherapeutic follow-up on medication compliance and on the knowledge about pharmacotherapy of patients who underwent allo-HSCT. METHODS: A single-arm, open-label and non-randomized intervention study developed in an allo-HSCT outpatient clinic. The participants attended pharmaceutical consultations and had their knowledge about pharmacotherapy and medication compliance measured by MedTake and Brief Medication Questionnaire (BMQ), respectively. RESULTS: A total of 27 patients attended pharmaceutical consultations (4.81 consultations/patient; SD = 1.80). There was an improvement in medication compliance and in knowledge between the first and last consultations (p < 0.05). In the final consultation, 70.37% of the patients showed compliance, with a knowledge rate of 98.35% (SD = 3.63). Non-compliant individuals presented a greater tendency to hospital readmissions. There was no relationship between medication compliance and sociodemographic variables, graft-versus-host disease, and knowledge about pharmacotherapy. CONCLUSIONS: Pharmacotherapeutic follow-up contributed to improving medication compliance. Knowledge about pharmacotherapy alone does not translate into behaviors, which corroborates the complexity of the biopsychosocial factors associated with medication compliance.

Long-Term Effects of Allogeneic Hematopoietic Stem Cell Transplantation on Systemic Inflammation in Sickle Cell Disease Patients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only currently available curative treatment for sickle cell disease (SCD). However, the effects of HSCT on SCD pathophysiology are poorly elucidated. Here, we assessed red blood cell (RBC) adhesiveness, intensity of hemolysis, vascular tone markers and systemic inflammation, in SCD patients treated with allogeneic HSCT. Thirty-two SCD patients were evaluated before and on long-term follow-up after HSCT. Overall survival was 94% with no severe (grade III-IV) graft-vs-host disease and a 22% rejection rate (graft failure). Hematological parameters, reticulocyte counts, and levels of lactate dehydrogenase (LDH), endothelin-1 and VCAM-1 normalized in SCD patients post-HSCT. Expression of adhesion molecules on reticulocytes and RBC was lower in patients with sustained engraftment. Levels of IL-18, IL-15 and LDH were higher in patients that developed graft failure. Increased levels of plasma pro-inflammatory cytokines, mainly TNF-α, were found in SCD patients long-term after transplantation. SCD patients with sustained engraftment after allo-HSCT showed decreased reticulocyte counts and adhesiveness, diminished hemolysis, and lower levels of vascular tonus markers. Nevertheless, systemic inflammation persists for at least five years after transplantation, indicating that allo-HSCT does not equally affect all aspects of SCD pathophysiology.

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. II: CAR-T cell therapy for patients with CD19+ acute lymphoblastic leukemia.

Chimeric antigen receptor T (CAR-T) cell therapy is a novel therapeutic modality for acute lymphoblastic leukemia (ALL) with robust outcomes in patients with refractory or relapsed disease. At the same time, CAR-T cell therapy is associated with unique and potentially fatal toxicities, such as cytokine release syndrome (CRS) and neurological toxicities (ICANS). This manuscript aims to provide a consensus of specialists in the fields of Hematology Oncology and Cellular Therapy to make recommendations on the current scenario of the use of CAR-T cells in patients with ALL.

Hematopoietic stem cell transplantation reverses white matter injury measured by diffusion-tensor imaging (DTI) in sickle cell disease patients.

Brain injury in sickle cell disease (SCD) comprises a wide spectrum of neurological damage. Neurocognitive deficits have been described even without established neurological lesions. DTI is a rapid, noninvasive, and non-contrast method that enables detection of normal-appearing white matter lesions not detected by conventional magnetic resonance imaging (MRI). The aim of the study was to evaluate if stem cell transplantation can revert white matter lesions in patients with SCD. Twenty-eight SCD patients were evaluated with MRI and DTI before and after allogeneic hematopoietic stem cell transplantation (HSCT), compared with 26 healthy controls (HC). DTI metrics included fractional anisotropy (FA), mean diffusivity (MD), radial (RD), and axial (AD) diffusivity maps, global efficiency, path length, and clustering coefficients. Compared to HC, SCD patients had a lower FA (p = 0.0086) before HSCT. After HSCT, FA increased and was not different from healthy controls (p = 0.1769). Mean MD, RD, and AD decreased after HSCT (p = 0.0049; p = 0.0029; p = 0.0408, respectively). We confirm previous data of white matter lesions in SCD and present evidence that HSCT promotes recovery of brain injury with potential improvement of brain structural connectivity.

The paradox of haematopoietic cell transplant in Latin America.

Hematopoietic cells transplants are technically complex and expensive imposing a huge burden on health care systems, especially those in developing countries and regions. In 2017 > 4500 transplants were done in 13 Latin American countries with established transplant programmes. We interrogated data on transplant rate, cost, funding source, hospital type, Gini coefficient and the United Nations Development Programme Inequality-Adjusted Human Development Index to determine co-variates associated with transplant development. Transplant rates varied almost 30-fold between the 13 countries from 345 in Uruguay to 12 in Venezuela with a regional transplant rate 7-8-fold lower compared with the US and EU. We found significant correlations between higher transplant cost, public funding, transplants in private hospitals with transplant rate. Low cost per transplant regardless of payor and transplants done in public hospitals were associated with low transplant rates. In contrast, high cost per transplant funded by the government and transplants done in private hospitals were associated with high transplant rates. Surprisingly, we found transplant rates were higher when transplants cost more, when they were done in private for-profit hospitals and payed for with public funds. These data give insights how to increase transplant rates in Latin America and other developing regions.

A review of hematopoietic stem cell transplantation for autoimmune diseases: multiple sclerosis, systemic sclerosis and Crohn's disease. Position paper of the Brazilian Society of Bone Marrow Transplantation

ABSTRACT Autoimmune diseases are an important field for the development of bone marrow transplantation, or hematopoietic stem cell transplantation. In Europe alone, almost 3000 procedures have been registered so far. The Brazilian Society for Bone Marrow Transplantation (Sociedade Brasileira de Transplantes de Medula Óssea) organized consensus meetings for the Autoimmune Diseases Group, to review the available literature on hematopoietic stem cell transplantation for autoimmune diseases, aiming to gather data that support the procedure for these patients. Three autoimmune diseases for which there are evidence-based indications for hematopoietic stem cell transplantation are multiple sclerosis, systemic sclerosis and Crohn's disease. The professional stem cell transplant societies in America, Europe and Brazil (Sociedade Brasileira de Transplantes de Medula Óssea) currently consider hematopoietic stem cell transplantation as a therapeutic modality for these three autoimmune diseases. This article reviews the evidence available.

NT157, an IGF1R-IRS1/2 inhibitor, exhibits antineoplastic effects in pre-clinical models of chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is successfully treated with BCR-ABL1 tyrosine kinase inhibitors, but a significant percentage of patients develop resistance. Insulin receptor substrate 1 (IRS1) has been shown to constitutively associate with BCR-ABL1, and IRS1-specific silencing leads to antineoplastic effects in CML cell lines. Here, we characterized the efficacy of NT157, a pharmacological inhibitor of IGF1R-IRS1/2, in CML cells and observed significantly reduced cell viability and proliferation, accompanied by induction of apoptosis. In human K562 cells and in murine Ba/F3 cells, engineered to express either wild-type BCR-ABL1 or the imatinib-resistant BCR-ABL1T315I mutant, NT157 inhibited BCR-ABL1, IGF1R, IRS1/2, PI3K/AKT/mTOR, and STAT3/5 signaling, increased CDKN1A, FOS and JUN tumor suppressor gene expression, and reduced MYC and BCL2 oncogenes. NT157 significantly reduced colony formation of human primary CML cells with minimal effect on normal hematopoietic cells. Exposure of primary CML cells harboring BCR-ABL1T315I to NT157 resulted in increased apoptosis, reduced cell proliferation and decreased phospho-CRKL levels. In conclusion, NT157 has antineoplastic effects on BCR-ABL1 leukemogenesis, independent of T315I mutational status.

A review of hematopoietic stem cell transplantation for autoimmune diseases: multiple sclerosis, systemic sclerosis and Crohn's disease. Position paper of the Brazilian Society of Bone Marrow Transplantation.

Autoimmune diseases are an important field for the development of bone marrow transplantation, or hematopoietic stem cell transplantation. In Europe alone, almost 3000 procedures have been registered so far. The Brazilian Society for Bone Marrow Transplantation (Sociedade Brasileira de Transplantes de Medula Óssea) organized consensus meetings for the Autoimmune Diseases Group, to review the available literature on hematopoietic stem cell transplantation for autoimmune diseases, aiming to gather data that support the procedure for these patients. Three autoimmune diseases for which there are evidence-based indications for hematopoietic stem cell transplantation are multiple sclerosis, systemic sclerosis and Crohn's disease. The professional stem cell transplant societies in America, Europe and Brazil (Sociedade Brasileira de Transplantes de Medula Óssea) currently consider hematopoietic stem cell transplantation as a therapeutic modality for these three autoimmune diseases. This article reviews the evidence available.

Epidemiology of invasive fungal disease in haematologic patients.

Invasive fungal disease (IFD) is frequent in patients with haematologic malignancies and in recipients of haematopoietic cell transplantation (HCT). An epidemiologic study conducted in Brazil reported a high incidence of IFD in haematologic patients, and invasive fusariosis was the leading IFD. A limitation of that study was that galactomannan was not available for at least half of the study period. In order to characterise the epidemiology and burden of IFD in three cohorts, HCT, acute myeloid leukaemia (AML) or myelodysplasia (MDS), and acute lymphoid leukaemia (ALL), we conducted a prospective multicentre cohort study in four haematologic Brazilian centres. From August 2015 to July 2016, all patients receiving induction chemotherapy for newly diagnosed or relapsed AML, MDS or ALL, and all HCT recipients receiving conditioning regimen were followed during the period of neutropenia following chemotherapy or the conditioning regimen. During a 1-year period, 192 patients were enrolled: 122 HCT recipients (71 allogeneic, 51 autologous), 46 with AML, and 24 with ALL. The global incidence of IFD was 13.0% (25 cases, 11 proven and 14 probable). Invasive aspergillosis (14 cases) was the leading IFD, followed by candidemia (6 cases) and fusariosis (3 cases). The incidence of IFD was 26.1% in AML/MDS, 16.7% in ALL, 11.3% in allogeneic HCT, and 2.0% in autologous HCT. The burden of IFD in haematologic patients in Brazil is high, with a higher frequency in AML and ALL. Invasive aspergillosis is the leading IFD, followed by invasive candidiasis and fusariosis.

A multicenter comparative acute myeloid leukemia study: can we explain the differences in the outcomes in resource-constrained settings?

Outcomes in acute myeloid leukemia (AML) are dependent on patient- and disease-characteristics, treatment, and socioeconomic factors. AML outcomes between resource-constrained and developed countries have not been compared directly. We analyzed two cohorts: from São Paulo state, Brazil (USP, n = 312) and Oxford, United Kingdom (OUH, n = 158). USP cohort had inferior 5-year overall survival compared with OUH (29% vs. 49%, adjusted-p=.027). USP patients have higher early-mortality (23% vs. 6% p<.001) primarily due to multi-resistant Gram-negative bacterial and fungal infections. USP had higher 5-year cumulative incidence of relapse (60% vs. 50%, p=.0022), were less likely to undergo hematopoietic stem cell transplant (HSCT) (28% vs. 75%, p<.001) and waited longer for HSCT (median, 23.8 vs. 7.2 months, p<.001). Three-year survival in relapsed patients was worse in USP than OUH (10% vs. 39%, p<.001). Our study indicates that efforts to improve AML outcomes in Brazil should focus on infection prevention and control, and access to HSCT.

Autologous Hematopoietic Stem Cell Therapy of the Subjects with Systemic Sclerosis: Electromyographic Results of the Masticatory Muscles.

Musculoskeletal system impairment is a major cause of functional alterations in subjects with systemic sclerosis. Autologous hematopoietic stem cell therapy (AHSCT) may have an important role in the treatment functional of systemic sclerosis patients. The aim of this pilot study was to assess whether AHSCT interferes with the electromyographic activity of the masseter and temporalis muscles of subjects with systemic sclerosis. Before transplantation, seven subjects with systemic sclerosis (mean age [± SD], 40.1 ± 9.6 years) underwent electromyographic analysis of the masseter and temporalis muscles in mandibular tasks at rest, right and left laterality, protrusion and maximum voluntary contraction. Two months after AHSCT, the subjects re-evaluated using the same methods. Data were analyzed using the repeated-measure test, with p<0.05 considered to be statistically significant. Two months after AHSCT, there was reduction in normalized electromyographic activity in the dental clenching in maximal voluntary contraction, with significant differences, for the left temporal muscle (p=0.04). AHSCT in subjects with systemic sclerosis promotes alterations in stomatognathic system function, especially those related to electromyographic activity of masticatory muscles.

Analysis of daunorubicin and its metabolite daunorubicinol in plasma and urine with application in the evaluation of total, renal and metabolic formation clearances in patients with acute myeloid leukemia.

This report presents improved analysis methods of daunorubicin (DAUN) and its metabolite daunorubicinol (DAUNOL) in small volumes of plasma, as total and unbound concentrations, as well as in urine. This study also presents the pharmacokinetics of DAUN and DAUNOL in patients (n = 12) diagnosed with acute myeloid leukemia treated with intravenous DAUN (60 mg/m2/day, for three days). Serial blood and urine samples were collected up to 144 h after the beginning of the first infusion. The analytical methods presented no significant matrix effect. The linear ranges were 0.1-1000 ng/mL in plasma, 0.05-40 ng/mL in ultrafiltrate and 0.5-3000 ng/ml in urine. The precision and accuracy presented coefficients of variation and standard errors lower than 15 % in the three matrices. The methods allowed for the quantification of samples up to 144 h after the beginning of the first infusion. Unbound fractions for DAUN and DAUNOL were 23.91 % (17.33-32.99) and 29.23 % (25.84-33.07), respectively. The fraction recovered in urine was 4.40 % (3.87-5.03) for DAUN and 7.91 % (6.86-9.19) for DAUNOL. Total 292.96 L/h (261.74-327.90), renal 13.01 L/h (11.44-14.88), and hepatic 280.26 L/h (248.40-317.91) clearances of DAUN, as well as the DAUNOL formation clearance 23.41 L/h (19.09-28.97), were evaluated.

A proteomic study of myeloproliferative neoplasms using reverse-phase protein arrays.

Myeloproliferative neoplasms polycythemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis constitute a group of haematological diseases. The comprehensive assessment of signaling pathway activation in blood cells may aid the understanding of MPN pathophysiology. Thus, levels of post-translational protein modifications and total protein expression were determined in MPN patients and control leukocytes by using reverse-phase protein arrays (RPPA). Compared to control samples, p-SRC, p-CTNNB1, c-MYC, MCL-1, p-MDM2, BAX and CCNB1 showed higher expression in PV samples than controls. P-JAK2/JAK2 and pro-apoptotic BIM showed differential expression between JAK2V617F-positive and -negative ET patients. Apoptosis, cancer and PI3K/AKT pathways proteins showed differential expression among the studied groups. For most of the proteins analyzed using Western-Blot and RPPA, RPPA showed higher sensitivity to detect subtle differences. Taken together, our data indicate deregulated protein expression in MPN patients compared to controls. Thus, RPPA may be a useful method for broad proteome analysis in MPN patients´ leukocytes.

HLA-Matched Unrelated Donors for Patients with Sickle Cell Disease: Results of International Donor Searches.

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy. Hematopoietic stem cell transplantation (HCT) is the sole curative therapy for SCD, but few patients will have a matched sibling donor. Patients with SCD are mostly of African origin and thus are less likely to find a matched unrelated donor in international registries. Using HaploStats, we estimated HLA haplotypes for 185 patients with SCD (116 from a Brazilian center and 69 from European Society for Blood and Marrow Transplantation [EBMT] centers) and classified the ethnic origin of haplotypes. Then we assessed the probability of finding an HLA-matched unrelated adult donor (MUD), considering loci A, B, and DRB1 (6/6), in international registries. Most haplotypes were African, but Brazilians showed a greater ethnic admixture than EBMT patients. Nevertheless, the chance of finding at least one 6/6 potential allelic donor was 47% for both groups. Most potential allelic donors were from the US National Marrow Donor Program registry and from the Brazilian REDOME donor registry. Although the probability of finding a donor is higher than previously reported, strategies are needed to improve ethnic diversity in registries. Moreover, predicting the likelihood of having an MUD might influence SCD management.

Differential cytokine network profile in polycythemia vera and secondary polycythemia.

Polycythemia vera (PV) is a clonal disorder resulting from neoplastic transformation of hematopoietic stem cells, while secondary polycythemia (SP) is a disease characterized by increased absolute red blood cell mass caused by stimulation of red blood cell production. Although the physiopathology of SP and PV is distinct, patients with these diseases share similar symptoms. The early differential diagnosis may improve the quality of life and decrease the disease burden in PV patients, as well as enable curative treatment for SP patients. PV is considered an oncoinflammatory disease because PV patients exhibit augmented levels of several pro-inflammatory cytokines. In this sense, we examined whether analysis of the cytokine production profile of SP and PV patients would help to distinguish them, despite their clinical similarities. Here we reported that SP patients exhibited decreased plasma levels of, IL-17A, IFN-γ, IL-12p70 and TNF-α when compared with PV patients, suggesting that analysis of the cytokine production profile may be an useful diagnostic biomarker to distinguish PV from SP patients.