Applicability of the acute leukemia (AL) - EBMT score as a prognostic model for allogeneic hematopoietic stem cell transplantation: a single-center, prospective, cohort study at a reference transplant center in Brazil

Abstract Introduction The Acute Leukemia-European Society for Blood and Marrow Transplantation (AL-EBMT) risk score was recently developed and validated by Shouval et al. Objective To assess the ability of this score in predicting the 2-year overall survival (OS-2), leukemia-free survival (LFS-2) and transplant-related mortality (TRM) in acute leukemia (AL) adult patients undergoing a first allogeneic hematopoietic stem cell transplant (HSCT) at a transplant center in Brazil. Methods In this prospective, cohort study, we used the formula published by Shouval et al. to calculate the AL-EBMT score and stratify patients into three risk categories. Results A total of 79 patients transplanted between 2008 and 2018 were analyzed. The median age was 38 years. Acute myeloid leukemia was the most common diagnosis (68%). Almost a quarter of the cases were at an advanced stage. All hematopoietic stem cell transplantations (HSCTs) were human leukocyte antigen-matched (HLA-matched) and the majority used familial donors (77%). Myeloablative conditioning was used in 92% of the cases. Stratification according to the AL-EBMT score into low-, intermediate- and high-risk groups yielded the following results: 40%, 12% and 47% of the cases, respectively. The high scoring group was associated with a hazard ratio of 2.1 (p= 0.007), 2.1 (p= 0.009) and 2.47 (p= 0.01) for the 2-year OS, LFS and TRM, respectively. Conclusion This study supports the ability of the AL-EBMT score to reasonably predict the 2-year post-transplant OS, LFS and TRM and to discriminate between risk categories in adult patients with AL, thus confirming its usefulness in clinical decision-making in this setting. Larger, multicenter studies may further help confirm these findings.

Applicability of the acute leukemia (AL) - EBMT score as a prognostic model for allogeneic hematopoietic stem cell transplantation: a single-center, prospective, cohort study at a reference transplant center in Brazil.

INTRODUCTION: The Acute Leukemia-European Society for Blood and Marrow Transplantation (AL-EBMT) risk score was recently developed and validated by Shouval et al. OBJECTIVE: To assess the ability of this score in predicting the 2-year overall survival (OS-2), leukemia-free survival (LFS-2) and transplant-related mortality (TRM) in acute leukemia (AL) adult patients undergoing a first allogeneic hematopoietic stem cell transplant (HSCT) at a transplant center in Brazil. METHODS: In this prospective, cohort study, we used the formula published by Shouval et al. to calculate the AL-EBMT score and stratify patients into three risk categories. RESULTS: A total of 79 patients transplanted between 2008 and 2018 were analyzed. The median age was 38 years. Acute myeloid leukemia was the most common diagnosis (68%). Almost a quarter of the cases were at an advanced stage. All hematopoietic stem cell transplantations (HSCTs) were human leukocyte antigen-matched (HLA-matched) and the majority used familial donors (77%). Myeloablative conditioning was used in 92% of the cases. Stratification according to the AL-EBMT score into low-, intermediate- and high-risk groups yielded the following results: 40%, 12% and 47% of the cases, respectively. The high scoring group was associated with a hazard ratio of 2.1 (p = 0.007), 2.1 (p = 0.009) and 2.47 (p = 0.01) for the 2-year OS, LFS and TRM, respectively. CONCLUSION: This study supports the ability of the AL-EBMT score to reasonably predict the 2-year post-transplant OS, LFS and TRM and to discriminate between risk categories in adult patients with AL, thus confirming its usefulness in clinical decision-making in this setting. Larger, multicenter studies may further help confirm these findings.

Efficacy and Safety of Innovative Experimental Chimeric Antigen Receptor (CAR) T-cells versus Axicabtagene ciloleucel (Yescarta) for the Treatment of Relapsed/Refractory Large B-Cell Lymphoma (LBCL): Matching Adjusted Indirect Comparisons (MAICs) and Systematic Review.

Despite favorable results of CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), several challenges remain, including incomplete response, immune-mediated toxicity, and antigen-loss relapse. We delineated the relative clinical benefit of the novel approaches compared to the currently approved CAR T-cell therapies. In the absence of head-to-head comparisons and randomized controlled trials, we performed Matching Adjusted Indirect Comparisons to quantify the relative efficacy and safety of experimental CARs against Axicabtagene ciloleucel (Yescarta), the first FDA-approved CAR. A total of 182 R/R LBCL patients from 15 clinical trials with individual patient data (IPD) were pooled into eight populations by their CAR T-cell constructs and +/- ASCT status. The study endpoints were Progression-Free Survival (PFS), grade ≥ 3 cytokine release syndrome (CRS), and grade ≥ 3 neurotoxicity (NT). Tandem CD19.CD20.4-1BBζ CARs indicated favorable efficacy and safety, whereas the co-infusion of CD19 & CD20 with 4-1BBζ showed no clinical benefit compared to Yescarta. Third generation CD19. CD28. 4-1BBζ, and sequential administration of autologous stem cell transplantation (ASCT) and CD19. CARs presented statistically insignificant yet improved PFS and safety except for ASCT combined intervention which had suggestively higher NT risk than Yescarta. CARs with modified co-stimulatory domains to reduce toxicity (Hu19. CD8.28Zζ and CD19. BBz.86ζ) presented remarkable safety with no severe adverse events; however, both presented worse PFS than Yescarta. Third-generation CARs demonstrated statistically significantly lower NT than Yescarta. CD20. 4-1BBζ data suggested targeting CD20 antigen alone lacks clinical or safety benefit compared to Yescarta. Further comparisons with other FDA-approved CARs are needed.

Allogeneic Bone Marrow Transplants for Pediatric Severe Aplastic Anemia: Real-world Data comparing Matched Related and Unrelated Donors in a Developing Country. Retrospective study on behalf of the Pediatric Hematopoietic Stem Cell Transplant Working Group of the Brazilian Bone Marrow Transplantation Society (SBTMO) and the Brazil-Seattle Consortium (Gedeco).

In this study, we report on major MRD or URD BMT outcomes in pediatric patients with SAA in Brazil. This was a retrospective study, which included 106 patients ≤18 years old who received a first BMT for SAA. All patients received bone marrow as graft source from an MRD (n = 69) or a URD (n = 37). Conditioning regimen was non-myeloablative in 73.6% of cases, and GVHD prophylaxis comprised a calcineurin inhibitor plus methotrexate in 89.6% of patients. After a median follow-up of 4.5 years after BMT, 81 patients are alive, with a 4-year OS of 77% and no statistically significant difference between the MRD and URD groups (82% vs. 69%, respectively; P = .08). Grade III-IV aGVHD at 6 months and cGVHD at 2 years were observed in 8% and 14% of cases, respectively, and were not statistically different between the groups. Twenty-five (23%) patients died at a median of 2.9 months after BMT. Our study showed that 4-year OS after BMT was not statistically different between MRD and URD recipients. This study shows that the outcomes of pediatric patients transplanted for SAA with a URD in Brazil are approaching those of MRD transplants. In contrast, OS after MRD BMT was lower than we would expect based on previous reports. The wide range of preparatory regimens used by the study centers highlights the need for standardized protocols for these children. Our findings provide a benchmark for future studies focused on improving BMT outcomes in this setting in Brazil.

Assessing the impact of ABO incompatibility on major allogeneic hematopoietic stem cell transplant outcomes: a prospective, single-center, cohort study

Abstract Background ABO blood group incompatibility between donor and recipient is associated with a number of immunohematological complications, but is not considered a major contraindication to allogeneic hematopoietic stem cell transplantation. However, available evidence from the literature seems to be conflicting as to the impact of incompatibility on overall survival, event-free survival, transplant-related mortality, graft-versus-host disease, and time to neutrophil and platelet engraftment. Methods This single-center, prospective, cohort study included patients with hematological malignancies who underwent a first allogeneic hematopoietic stem cell transplantation between 2008 and 2014. Patients receiving umbilical cord blood as the stem cell source were excluded from this analysis. The impact of ABO incompatibility was evaluated in respect to overall survival, event-free survival, transplant-related mortality, acute graft-versus-host disease and engraftment. Results A total of 130 patients were included of whom 78 (60%) were males. The median age at transplant was 36 (range: 2-65) years, 44 (33%) presented ABO incompatibility, 75 (58%) had acute leukemia, 111 (85%) had a related donor, 100 (77%) received peripheral blood hematopoietic stem cells as graft source and 99 (76%) underwent a myeloablative conditioning regimen. There was no statistically significant association between ABO incompatibility and overall survival, event-free survival, transplant-related mortality, grade II-IV acute graft-versus-host disease, neutrophil or platelet engraftment in multivariate analysis. Conclusion These results show that ABO incompatibility does not seem to influence these parameters in patients undergoing allogeneic hematopoietic stem cell transplantation.

Assessing the impact of ABO incompatibility on major allogeneic hematopoietic stem cell transplant outcomes: a prospective, single-center, cohort study.

BACKGROUND: ABO blood group incompatibility between donor and recipient is associated with a number of immunohematological complications, but is not considered a major contraindication to allogeneic hematopoietic stem cell transplantation. However, available evidence from the literature seems to be conflicting as to the impact of incompatibility on overall survival, event-free survival, transplant-related mortality, graft-versus-host disease, and time to neutrophil and platelet engraftment. METHODS: This single-center, prospective, cohort study included patients with hematological malignancies who underwent a first allogeneic hematopoietic stem cell transplantation between 2008 and 2014. Patients receiving umbilical cord blood as the stem cell source were excluded from this analysis. The impact of ABO incompatibility was evaluated in respect to overall survival, event-free survival, transplant-related mortality, acute graft-versus-host disease and engraftment. RESULTS: A total of 130 patients were included of whom 78 (60%) were males. The median age at transplant was 36 (range: 2-65) years, 44 (33%) presented ABO incompatibility, 75 (58%) had acute leukemia, 111 (85%) had a related donor, 100 (77%) received peripheral blood hematopoietic stem cells as graft source and 99 (76%) underwent a myeloablative conditioning regimen. There was no statistically significant association between ABO incompatibility and overall survival, event-free survival, transplant-related mortality, grade II-IV acute graft-versus-host disease, neutrophil or platelet engraftment in multivariate analysis. CONCLUSION: These results show that ABO incompatibility does not seem to influence these parameters in patients undergoing allogeneic hematopoietic stem cell transplantation.

Immunophenotyping of the cerebrospinal fluid as a prognostic factor at diagnosis of acute lymphoblastic leukemia in children and adolescents.

This study aimed at evaluating the use of immunophenotyping (IMP) in the identification of blast cells in the cerebrospinal fluid (CSF) of children and adolescents with acute lymphoblastic leukemia (ALL). Sixty-seven patients aged 18 years or younger were included. Fifty-five CSF samples were analyzed at initial diagnosis and 17 at the time of relapse. A cytological analysis (CA) was performed in all 72 samples, while IMP was done in 63. Blasts were identified in only three samples by CA, whereas all three samples were found negative by IMP, one of which had no isolation of nucleated cells after centrifugation. Among the samples analyzed by IMP, 11 showed a positive blast count, two of which had been inconclusive using CA. No equivalence was found between CA and IMP results (p = 0.55). CSF IMP positivity was not associated with other risk factors for ALL relapse. Among the 55 patients included at the time of diagnosis of ALL, eight relapsed during follow-up. Considering the cases of central nervous system (CNS) relapse, one of the patients belonged to the CSF IMP-positive group (11%) at diagnosis, and the other two cases, to the IMP-negative (5%) group. Detection of CSF blast cells using IMP was associated with a worse overall (p < 0.0001) and event-free survival (p < 0.0001). These results show that CSF IMP may be a useful additional method to conventional CA in the diagnosis of CNS involvement in ALL, and for the identification of high-risk subgroups that would benefit from an intensified therapy.

Assessing the Influence of Different Comorbidities Indexes on the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in a Developing Country.

Although the application of Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) has enabled better prediction of transplant-related mortality (TRM) in allogeneic hematopoietic stem cell transplants (AHSCT), data from developing countries are scarce. This study prospectively evaluated the HCT-CI and the Adult Comorbidity Evaluation (ACE-27), in its original and in a modified version, as predictors of post-transplant complications in adults undergoing a first related or unrelated AHSCT in Brazil. Both bone marrow (BM) and peripheral blood stem cells (PBSC) as graft sources were included. We analyzed the cumulative incidence of granulocyte and platelet recovery, sinusoidal obstructive syndrome, acute and chronic graft-versus-host disease, relapse and transplant-related mortality, and rates of event-free survival and overall survival. Ninety-nine patients were assessed. Median age was 38 years (18-65 years); HCT-CI ≥ 3 accounted for only 8% of cases; hematologic malignancies comprised 75.8% of the indications for AHSCT. There was no association between the HCT-CI or the original or modified ACE-27 with TRM or any other studied outcomes after AHSCT. These results show that, in the population studied, none of the comorbidity indexes seem to be associated with AHSCT outcomes. A significantly low frequency of high-risk (HCT-CI ≥ 3) in this Brazilian population might justify these results.

Hemophagocytic lymphohistiocytosis associated with visceral leishmaniasis in late adulthood.

We describe a case of hemophagocytic lymphohistiocytosis related to visceral leishmaniasis in late adulthood. Because clinical features of visceral leishmaniasis can mimic those of hemophagocytic lymphohistiocytosis, diagnosing leishmaniasis as the underlying etiology can be quite challenging. In our case, treatment with amphotericin B resulted in a dramatic resolution of clinical abnormalities.

Cefepime encephalopathy and normal renal function / Encefalopatia induzida por cefepime em um paciente com função renal normal

BACKGROUND: Several cases of cefepime neurotoxicity have been reported. Herein reported is a case of cephalosporin-associated neurotoxicity in apatient with normal renal function. CASE REPORT: A 64-year-old woman with a history of post-transplantation chronic myeloid leukemia was admittedto hospital due to hyporexia, fever, productive cough and mild dyspnea. Initial blood screen revealed pancytopenia and a normal renal function.Intravenous cefepime was empirically started and after 40 hours the patient developed sudden mental confusion. Neurological examination was normal. Cranial computed tomography and brain magnetic resonance scans were normal. Electroencephalography showed triphasic waves of diffuse slowness without ongoing epileptic activity. Lumbar puncture was normal. Cefepime neurotoxicity was promptly considered and antibiotics were switched to piperacillin and tazobactam. After five days, the patient recovered completely with remission of myoclonus. CONCLUSIONS: Awareness should be given to possible central nervous system complications induced by cefepime, especially in the elderly, even without renal failure

INTRODUÇÃO: Existem vários relatos de casos de toxicidade do sistema nervoso central induzida pelo cefepime. Relata-se um caso de toxicidade do sistema nervoso central associada ao uso de uma cefalosporina em um paciente com função renal normal. RELATO DE CASO: Uma mulher de 64 anos com história de transplante de medula óssea devido a leucemia mielóide crônica foi admitida ao hospital devido a hiporexia, febre, tosse produtiva e dispnéia leve. Os exames laboratoriais de rotina demonstraram pancitopenia e função renal normal. O cefepime intravenoso foi empiricamente iniciado e, após 40 horas da administração, o paciente apresentou quadro súbito de confusão mental. Exame neurológico foi normal, assim como a tomografia computadorizada craniana e a ressonância magnética encefálica. O eletroencefalograma demonstrou ondas trifásicas de lentificação difusa sem evidência de atividade epileptiforme. O líquor estava normal. A toxicidade do sistema nervoso central pelo cefepime foi rapidamente considerada e o antibiótico foi trocado para piperacilina e tazobactan. Após cinco dias, o paciente apresentou recuperação completa com remissão da mioclonia. CONCLUSÃO: Deve-se dar atenção às possíveis complicações do sistema nervoso central induzidas pelo cefepime, especialmente em idosos, mesmo sem insuficiência renal.

Granulocytic sarcoma of the stomach: relapse after hematopoietic stem-cell transplantation for chronic myeloid leukemia.

An 18-year-old male underwent an allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myeloid leukemia (CML) in the first late chronic phase. On day 132, he was readmitted to the hospital with nausea, vomiting and nodular lesions on endoscopy. A diagnosis of granulocytic sarcoma of the stomach was made. Bone marrow cytogenetic analysis for the Philadelphia chromosome and nested polymerase chain reaction for BCR-ABL1 were both negative. Immunosuppression was abruptly discontinued, and by day 180, all gastric lesions had completely disappeared. However, there were histological signs of graft-versus-host disease. The patient developed progressive anorexia and elevated hepatic enzymes, which prompted the reintroduction of cyclosporine. Considering the risk of another relapse, imatinib mesylate (IM) 600 mg/day was started. The patient Is condition improved, and there was no evidence of disease recurrence at 36 months after relapse. Relapse of CML is the commonest cause of treatment failure after allo-HSCT. On rare occasions, a localized extramedullary presentation is seen. Unless properly treated, other extramedullary relapse sites and/or marrow infiltration usually occur. Withdrawal of immunosuppression, along with IM therapy seems to be an acceptable approach in this setting.

Avaliação e tratamento da perda de peso involuntária e significativa / Evaluation and treatment of significant and unintentionalweight loss

A queixa de perda de peso possui incidência de 13% em pacientes ambulatoriais e 65% em pacientes institucionalizados. Considera-se significativa a perda de 5% ou mais do peso corporal em seis a 12 meses. Associa-se a diversas condições clínicas agudas e crônicas, ao uso de medicamentos e a fatores psicossociais. Constitui fator de risco independente para aumento na morbidade e mortalidade, sendo de particular relevância em indivíduos acima de 40 anos. A familiaridade com o processo de investigação clínica e laboratorial de pacientes com essa queixa pode auxiliar na abordagem e cuidado aos mesmos. Faz-se, aqui, revisão detalhada sobre o tema, incluindo-se comentários sobre os seus principais estudos clínicos disponíveis.

The complaint of weight loss has an incidence of 13% in outpatients and 65% in institutionalized patients. It is considered significant the loss of 5% or more of the body weight within 6 to 12 months. It is associated with several acute or chronic clinical conditions, the use of medication and psychosocial factors. It is an independent risk factor for morbidity and mortality increase, particularly relevant in individuals over 40 years old. Familiarity with the process of clinical and laboratory investigation of patients with this complaint can assist in their evaluation and care. This is a detailed review on the subject, including comments on its main clinical studies available.

A retrospective comparison of allogeneic peripheral blood stem cell versus bone marrow transplantation.

BACKGROUND AND OBJECTIVES: Disease evolution depends in part on the source of transplanted cells. Therefore, we compared outcomes after allogeneic bone marrow (BM) and peripheral blood stem cell (PBSC) transplantation in patients who underwent transplant at Hospital das Clinicas of the Federal University of Minas Gerais, Brazil. PATIENTS AND METHODS: We studied 364 patients who received allogeneic BM (n = 142) or PBSC transplantation (n = 222) between July 1995 and May 2005. The median age of the patients was 31 years (range, 3.1-58 years). Chronic myeloid leukemia was the predominant diagnosis (41.2%). A conditioning regimen with cyclosphosphamide and busulfan was used in 79.4% (n = 289) and graft-versus-host disease (GVHD) prophylaxis was cyclosporine/methotrexate in 95.9% (n = 349) of cases. RESULTS: The patients in the PBSC group had faster neutrophil (P < .001) and platelet engraftment (P = .03) but increased rates of acute GVHD (P < .001) vs. those in the BM group. There was no significant difference between the groups in chronic GVHD, transplant-related mortality, relapse and survival rates. CONCLUSIONS: Although allogeneic PBSC transplant results in a faster hematopoietic engraftment, there was an increase in acute GVHD. There was no clear benefit in relapse rate and no evidence that transplantation with PBSC benefits patient survival in our institution.

Paracoccidioidomicose com acometimento da glândula supra-renal e do sistema nervoso central / Paracoccidioidomycosis with adrenal gland and central nervous system involvement

Descreveu-se um caso de paracoccidioidomicose em paciente com história de tosse seca, dispnéia, febre, sudorese noturna, hiporrexia e emagrecimento, com três meses de evolução. Apresentava lesão de pele ulcerada em região malar esquerda. A telerradiografia de tórax evidenciou imagem com padrão em "asa de borboleta". Biópsia de lesão na face foi compatível com paracoccidioidomicose. À tomografia computadorizada (TC) de encéfalo, verificou-se lesão expansiva em núcleos da base à direita. A ressonância nuclear magnética do encéfalo constatou lesão parenquimatosa no nível do tálamo direito. A TC abdominal revelou supra-renal esquerda aumentada, sugerindo acometimento pelo P.brasiliensis. A sorologia para o fungo, pelo método de imunodifusão radial dupla, foi reagente (1:4). A biópsia estereotáxica de lesão encefálica evidenciou numerosas formações fúngicas arredondadas, com cápsula birrefringente e esporulação em roda de leme. O paciente evoluiu com melhora do quadro geral com o uso de itraconazol.

Infecção pelo vírus epstein-barr e oncogênese: [revisão] / Epstein-Barr virus infection and oncogenesis: [review]

As infecções como um todo associam-se a 15% a 20% dos cânceres em geral. Entre os agentes etiológicos carcinogênicos, destacam-se os vírus oncogênicos. O vírus Epstein-Barr (VER) é o mais potente vírus indutor de transformação e crescimento celular conhecido, sendo capaz de imortalizar linfócitos B humanos. Está relacionado com o linfoma de Burkitt, o carcinoma nasofaríngeo e outros tipos de neoplasia. Porém, não se sabe ao certo se o VER seria apenas um componente inocente ou se contribui realmente para o desenvolvimento desses tumores. A compreensão da persistência do VEB no organismo e dos mecanismos pelos quais, na sua interação com a célula, ele contribui para o surgimento de uma neoplasia pode permitir novas abordagens para a prevenção e o tratamento dos tumores a ele associados.

Infections as a whole are associated with 15% to 20% of human cancers. Amongst a variery of infectious agents, oncogenic viruses are of especial importance, particularly the Epstein-Barr virus (EBV). It is the most efficient vírus known to induce transformation and cellular growth and induces immortality of B-cells. Its relation to Burkitt's lymphoma and nasopharyngeal carcinoma, as well as to other neoplasms, has long been emphazised. However, it is not clear whether it actually plays a causative role in these tumors or is simply an incidental finding. A better understanding of the means of EBV persistence and of the mechanisms by which this vírus leads to malignant transformation of the host-cell may shed light on new approaches to the prevention and treatment of EBV-associated tumors.