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Introduction: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is the most potent post-remission treatment for Acute Myeloid Leukemia (AML) to reduce relapse rates. However, achieving Complete Remission (CR) and Minimal Residual Disease (MRD) before transplant are crucial predictors of relapse and mortality post-consolidation therapy. This study aims to describe the characteristics and outcomes of AML patients who underwent HSCT without achieving CR. Methods: We conducted a retrospective analysis of AML patients with active refractory disease who underwent HSCT between 2010 and 2024 at two Brazilian centers. Active AML was defined as having more than 5% blasts in the Bone Marrow (BM) before starting conditioning or a sequential conditioning regimen. Results: A total of 28 AML patients with refractory disease after multiple lines of therapy (including a prior HSCT in 5 patients) were included. The median age was 47 years (range, 19‒83), 39% were male, and the median percentage of blasts in BM at the start of HSCT was 11% (range: 5%‒50%). Nine out of 19 assessed patients (47%) were high-risk based on the HCT-CI score. Donors were haploidentical in 15 patients (53.6%), matched unrelated in 7 patients (25%), and matched related in 6 patients (21.4%). Reduced-Intensity Conditioning (RIC) was performed in 22 patients (79%), with FluCyTBI 2 or 4 Gy in 16 patients (73%), FluBu6.4 in 5 patients (23%), and FluMel140 in 1 patient (4%). Myeloablative Conditioning (MAC) was used in 6 patients (21%), with FluBu9.6 in 3 patients (50%), BuCy in 2 patients (33%), and FluTBI12Gy in 1 patient (17%). Mobilized peripheral blood stem cells were the most common stem cell source (21 patients, 75%), while bone marrow was used in 7 patients (25%). The cumulative incidence (CI) of relapse/progression at 3-months, and 3-years was 18%, and 36%, respectively. The CI of non-relapse mortality (NRM) at 3-months, and 3-years was 14% and 26%, respectively. The CI of acute grade II‒IV GVHD at 100-days was 21%, and the CI of chronic GVHD at 3-years was 29%, with only patients requiring prolonged systemic therapy. After a median follow-up of 42-months, Overall Survival (OS) and Progression-Free Survival (PFS) at 3-years were 42% and 44%, respectively. The blast count in BM immediately before HSCT was a strong predictor of survival: OS at 3-years was 22% compared to 76% for patients with 10% or fewer blasts (p = 0.015), and PFS was 22% vs. 65% (p = 0.035). Conclusion: HSCT is a feasible and safe alternative for patients with refractory or relapsed AML after multiple lines of therapy, particularly for those with 10% or fewer blasts in BM before transplant. However, prospective studies with larger cohorts are needed to further define the role of HSCT in this challenging context.

Objetivo: Descrição de casos de Transplante de Sangue de Cordão Umbilical (TSCU) para neoplasias hematológicas. Material e método: Estudo descritivo, observacional e retrospectivo dos últimos 5 anos de um serviço público de referência em Hematologia e Transplante de Medula Óssea de São Paulo com o objetivo de analisar os casos consecutivos de TSCU realizados entre fevereiro de 2019 e junho de 2024. Resultados: Foi realizado TSCU em 5 pacientes, dos quais 4 apresentavam Leucemia Linfoblástica Aguda (LLA), e um apresentava Leucemia Mieloide Aguda (LMA). Dentro da população estudada, 3 pacientes encontravam-se na faixa dos 20 aos 35 anos e 2 tinham mais do que 65 anos; a mediana do tempo entre diagnóstico e realização do transplante alogênico foi de 8 meses e com exceção do paciente com LMA, todos os demais apresentavam Doença Residual Mínima (DRM) indetectável. Todos receberam condicionamento de intensidade reduzida com a associação de fludarabina, ciclofosfamida e irradiação corporal total 4 Gray, e utilizaram Micofenolato de Mofetila (MMF) associado a Ciclosporina (CsA) como profilaxia da Doença do Enxerto Contra o Hospedeiro (DECH). Todos apresentavam incompatibilidades no sistema HLA (Human Leukocyte Antigen) mas dentro das recomendações internacionais e todos apresentavam incompatibilidade ABO. Em todos os casos ou não haviam doadores idênticos ou haploidênticos ou haviam anticorpos anti-HLA que inviabilizavam o transplante com esses doadores. Todos apresentaram enxertia com quimera completa e a mediana de tempo para a enxertia neutrofílica foi de 20 dias. Todos apresentaram algum grau de DECH aguda com necessidade de corticoterapia sistêmica com excelente controle e nenhum paciente apresenta DECH crônica ou necessidade de tratamento imunossupressor. A mediana de seguimento foi de 46 meses. Destes casos, houve apenas 1 óbito, que ocorreu 4 meses após o transplante por infecção de provável foco respiratório. E houve apenas 1 recaída em sistema nervoso central em uma paciente de 66 anos mas que segue em remissão 5 meses após segundo transplante alogênico. Discussão: O transplante de células tronco hematopoiéticas representa uma terapia padrão para leucemias agudas. Entretanto, apesar da pesquisa familiar e do banco de registros internacionais e nacionais, em muitos casos não há doador compatível disponível, fazendo com que o uso do cordão umbilical seja uma opção. O TSCU apresenta tempo mais prolongado para enxertia quando comparado às demais terapias (fonte de medula óssea ou de sangue periférico) além de estar associada a lenta reconstituição imune. E com o maior desenvolvimento do transplante haploidêntico para pacientes sem doadores idênticos, seu uso tem sido cada vez mais restrito. Ainda assim, em pacientes em que há dificuldade de encontrar doador e haploidêntico, o TSCU passa a ser a única alternativa viável. Conclusão: O TSCU é alternativa mais adequada para pacientes com leucemias agudas sem outras opções de doador permitindo acesso ao transplante a esses pacientes que, sem essa alternativa, não teria outra opção de tratamento com intenção curativa.

Objectives: Second allogeneic Hematopoietic Stem Cell Transplant (HSCT) is the only curative treatment option for patients who relapse after a first transplant for malignant diseases. Previously reported outcomes for this intervention are often dismal, with high Relapse Incidence (RI), Non-Relapse Mortality (NRM), and low Overall Survival (OS). Here, we present encouraging results from two centers in São Paulo performing second HSCT for acute leukemias and Myelodysplastic Syndromes (MDS). Material and methods: This retrospective observational study included 17 patients, aged 18 years or older, who underwent a second allogeneic HSCT for relapsed acute leukemia (AML, n = 9, ALL, n = 7) or MDS (n = 2) at two Brazilian centers in São Paulo between November 2012 and March 2024. Clinical data were collected using standardized forms based on information obtained from medical records. Results: The median age was 37-years (range: 18‒65), with a majority of male patients (n = 11, 61%). The majority of donors were haploidentical (n = 14, 78%), followed by matched sibling donors (n = 3, 17%) and matched unrelated donors (n = 1, 5%). Most patients (n = 16, 89%) received Reduced-Intensity Conditioning (RIC) regimens, with mobilized peripheral blood as the stem cell source in 15 patients (83%) and bone marrow in 3 patients (17%). All but one patient had different donors from the first HSCT. Among the patients, 10 (55%) were not in remission before the transplant. The median follow-up was 19-months (range: 9‒19). The Cumulative Incidence (CI) of acute GVHD grade II‒IV was 36%, and grade III‒IV was 16% at 100-days. The CI of chronic GVHD at 2-years was 20%. The CI of relapse/progression was 12% at 100-days and 20% at two years, and CI of NRM was 13% at 100-days and remained 13% at two years. OS and Progression-Free Survival (PFS) at two years were 72% and 62%, respectively. When stratified by diagnosis, the 2-year OS rates were 27% for acute lymphoblastic leukemia (ALL), and 100% for AML or MDS. Discussion: A second HSCT is a feasible and safe curative option for malignant hematologic diseases in the challenging setting of relapse or failure after a first allogeneic HSCT, especially in AML. These findings may reflect improvements in supportive therapies, the growing use of RIC regimens, and personalized immunosuppressive therapy timing. The superior 2-year OS observed in myeloid malignancies may reflect the superior graft-versus-leukemia effect elicited by HSCT in these diseases, even in the setting of a previous relapse/failure. Conclusion: Although previous data have reported low rates of survival and high TRM, here we present encouraging results supporting that second HSCT can elicit positive outcomes when performed with judicious choices of patients, donors, conditioning regimens and imunossupressive therapy modulation.

Introdução: A LLA B com fusão BCR::ABL1 (LLA B Ph+) é mais prevalente entre pacientes mais idosos e historicamente associada a alto risco de recaída. O uso de Inibidores de Tirosina Quinase (ITK) é essencial para atingir a Doença Mínima Mensurável (DRM) indetectável, tendo modificado a história natural da doença. A terapia com Células com Receptor Antigênico quimérico (CAR-T) anti-CD19 é associada a boa resposta e baixa toxicidade. Há poucos dados sobre o tratamento de recaídas de LLA após células CAR-T. Objetivo: Descrever o tratamento com segundo transplante alogênico em paciente adulto com LLA B Ph+ com múltiplas recaídas isoladas em SNC após primeiro transplante alogênico e células CAR-T. Paciente e método: Caso descrito com informações de prontuário eletrônico de serviço público de referência em Hematologia e Transplante de Medula Óssea de São Paulo. Relato de caso: Paciente feminina, 62 anos, diagnosticada com LLA B Ph+, realizou indução com protocolo GRAAPH e Imatinibe. Encaminhada para TCTH alogênico não aparentado com duplo cordão umbilical, uma vez que não tinha doadores idênticos e apresentava altos títulos de anticorpos anti-HLA contra os potenciais doadores haploidênticos. Teve enxertia neutrofílica no D+16. No D+100 foi reintroduzido imatinibe e evoluiu com doença do enxerto contra o hospedeiro (DECH) crônica leve ocular após 8 meses, a qual foi bem controlada com tratamento tópico. Apresentou recaída em SNC e trocado ITK para ponatinibe e realizadas aplicações de Quimioterapia Intratecal (QT IT). Apresentou trombose de artéria retiniana, tendo sido trocado novamente o ITK para dasatinibe. Após tratamento e atingir DRM indetectável, apresentou nova infiltração em SNC. Na 3ª recaída, foram reiniciados ponatinibe, QT IT e corticoide sistêmico. Após negativação do LCR, foi encaminhada para infusão de CAR-T acadêmico, com reintrodução de ponatinibe no D+45. Teve nova recaída no SNC 5 meses após procedimento. Realizados 2 ciclos de altas doses de metotrexato e encaminhada para o segundo TCTH alogênico, dessa vez haploidêntico a partir do filho. O condicionamento foi de intensidade reduzida e consistiu na associação de fludarabina, ciclofosfamida e TBI 4 Gray, e como profilaxia de DECH realizou Ciclofosfamida Pós-Transplante (PTCy), micofenolato de mofetila e ciclosporina. Não houve complicações significativas. Atualmente está há 5 meses do transplante e segue em remissão com quimera completa de 100% doador e Doença Residual Mínima (DRM) indetectável na medula óssea e no LCR por citometria. Conclusão: Descrevemos a viabilidade de realizar um segundo transplante alogênico em paciente com recaída após primeiro transplante e células CAR-T, com troca do doador, oferecendo ainda possibilidade de cura para essa paciente com múltiplas recaídas.

Objectives: Many hematological diseases, such as Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) commonly affect individuals diagnosed in their seventh decade of life or later. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) can cure these conditions. However, elderly patients are often considered ineligible due to high morbimortality rates. Recent advances in supportive care and new conditioning regimens have made HSCT more feasible and safer for elderly patients. However, there are few reports regarding HSCT in patients aged 70-years or older in Brazil. Material and methods: This retrospective observational study analyzed 44 patients aged 65-years or older who underwent their first allogeneic HSCT for myeloproliferative neoplasms: acute myelogenous leukemia (AML, n = 27), myelodysplastic syndrome (MDS, n = 12), or myelofibrosis (MF, n = 5), at two Brazilian centers in São Paulo between December 2013 and March 2024. Clinical data were collected using standardized forms based on information from electronic medical records. Results: The median age was 70-years (range: 65‒81), with most patients being male (64%). The majority of donors were haploidentical (59%), followed by matched unrelated donors (30%) and matched sibling donors (11%). All patients received Reduced-Intensity Conditioning (RIC) regimens, with the vast majority receiving mobilized peripheral blood as the stem cell source (n = 40, 91%), and only four (9%) bone marrow. Among the 27 patients with AML, seven (26%) were not in complete remission before transplant. The main Graft-Versus-Host Disease (GVHD) prophylaxis was the combination of mycophenolate mofetil and cyclosporine or sirolimus. T-cell depletion was used in most cases with either post-transplant cyclophosphamide in 26 patients (59%) or Antithymocyte Globulin (ATG) in 15 patients (34%). Median follow-up was 18-months (range: 4‒138). The Cumulative Incidence (CI) of acute GVHD grade II‒IV was 28% but only 9% for grade III‒IV. The CI of chronic GVHD at 2-years was 39%, but only 4 patients (9%) required prolonged immunosuppression. Median Progression-Free Survival (PFS) and Overall Survival (OS) were not reached within two years of follow-up. PFS and OS at two years were 54% and 64%, respectively. The CI of Non-Relapse Mortality (NRM) was 11% at 100 days and 19% at two years. The main causes of death were infections (33%), followed by relapse or progression (29%). Discussion: This retrospective study demonstrates that allogeneic HSCT is an effective and safe curative option for myeloproliferative neoplasms in patients aged 65-years or older. Despite the use of RIC regimens and the inclusion of patients not in remission before transplantation, we observed a low relapse rate. Additionally, the rates of NRM and chronic extensive GVHD were relatively low. Conclusions: Although the study has limitations, including its retrospective nature and lack of comparison with other specific therapies, the findings suggest HSCT is a viable treatment option for elderly patients.

This multicenter international retrospective analysis aimed to evaluate the efficacy and safety of subcutaneous alemtuzumab (ALZ) as an alternative immunosuppressive therapy for aplastic anemia (AA). The study included 57 with AA patients who received ALZ treatment in four centers in Brazil and the United Kingdom. Most patients had severe aplastic anemia (SAA). The median age of the patients was 52 years, with 21% being older than 65 years. Out of the 60 ALZ treatments analyzed, 57% were first-line treatments, 26% were second-line, and 17% were administered after at least two lines of therapy. At 6 months, the overall response rate (ORR) was 54%. At 12 months, the ORR increased to 57%, with a complete response rate of 18% and a partial response rate of 39%. The cumulative incidence of response was significantly higher in patients younger than 65 years (68%) and in those who received a 103 mg subcutaneous ALZ dose (61%). The overall survival (OS) rates were 84% at 1 year and 71% at 4 years. OS at 4 years was significantly higher in patients who responded to ALZ treatment (hazard ratio: 9.88, 95% confidence interval 2.12 - 46.0, p = 0.004). Adverse events associated with ALZ were mostly of low grade, and infectious events were infrequent. In conclusion, subcutaneous ALZ appears to be a feasible, effective, and safe alternative to horse antithymocyte globulin (hATG) in patients with aplastic anemia who require immunosuppressive treatment. This is particularly relevant for centers and countries with limited access to hATG.

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by acquired abnormalities in the PIG-A gene, leading to hemolytic anemia, a hypercoagulable state, and cytopenias. Complement inhibitors targeting C5 have transformed PNH management. This study assessed clinical characteristics and outcomes of complement inhibition therapy in PNH. Methods: Multiparametric flow cytometry identified 151 PNH patients from 1987 to 2022, categorized as classic PNH (group 1), PNH with another hematologic disease (group 2), or subclinical PNH (group 3). Clinical and laboratory data were collected pre- and post-treatment. Informed consent was obtained from all patients. Results: Of the 151 patients, 53% were male, and the median age at diagnosis was 34 years. The hemolytic group (n = 90, 60%) exhibited common symptoms: fatigue (88%), hemoglobinuria (60%), abdominal pain (40%), headaches (19%), and dysphagia (17%). Venous thromboembolism occurred in 21 cases (24%), abdominal thrombosis in 11 cases (12%), and arterial thrombosis in eight patients (9%). Acute renal injury requiring dialysis affected five hemolytic patients (6%), with eventual recovery. Anti-complement treatment was administered to the majority of hemolytic patients (n = 62, 69%) after a median time of 22 months. It significantly reduced intravascular hemolysis, improved anemia, and alleviated symptoms. Within six months, 92% achieved transfusion independence, and within a year, 88% reached a good response or better, according to the Severe Aplastic Anemia Working Party (SAAWP/EBMT) hematological repsonse criteria. Overall survival at six years was 92% for classical PNH, 75% for PNH with another hematologic disease, and 67% for subclinical PNH. Notably, treated patients had significantly higher overall survival compared to untreated individuals (100% vs. 41%, p < 0.0001). Discussion: Groups 1 and 2, representing hemolytic PNH, exhibited a higher prevalence of symptoms such as fatigue, abdominal pain, and anemia requiring transfusion support, similar to previously reported. In this study, we observed a lower frequency of venous or arterial thrombosis in hemolytic patients, and the incidence of renal dysfunction was lower than previously reported, with only five patients (6%) in the hemolytic group experiencing acute renal failure, and demonstrated renal function recovery after resolving the crisis. Here we present the largest series of anti-complement treatment patients in Brazil. Although most patients treated with eculizumab demonstrate a good response, in previous series about 25-35% of patients continue to experience anemia and require transfusions, and here, we observed better results: 92% of patients achieved transfusion avoidance, with an 88% transfusion avoidance rate within one year, wich is classified as a hematological good response. The five-year overall survival rates were 92%, 75%, and 67% in groups 1, 2, and 3, respectively. Conclusions: This study corroborates clinical characteristics and PNH subtype distributions found in previous research. Anti-complement treatment effectively controlled hemolysis, improved symptoms, and reduced complications. Lower thrombosis and chronic kidney disease rates, and better hematological responses to anti-complement treatment warrant further investigation in this cohort.