Outcomes of allogeneic stem cell transplantation among patients with acute myeloid leukemia presenting active disease: Experience of a single European Comprehensive Cancer Center / Resultados do transplante alogênico de células-tronco em doentes com leucemia mieloide aguda com doença ativa: experiência de um único Centro Oncológico Europeu

Summary Introduction: Allogeneic hematopoietic stem cell transplantation (ASCT) representes a potentially curative approach for patients with relapsed or refractory acute myeloid leukemia (AML). We report the outcome of relapsed/refractory AML patients treated with ASCT. Method: A retrospective cohort from 1994 to 2013 that included 61 patients with diagnosis of relapsed/refractory AML. Outcomes of interest were transplant-related mortality (TRM), incidence of acute and chronic graft-versus-host disease (GVHD), relapse incidence, progression-free survival (PFS) and overall survival (OS). Statistical significance was set at p<0.05. Results: The median age was 61 years (range 1 to 65). The cumulative incidence of 90 days, 1 year, and 3 years TRM were 60%, 26.7%, and 13.3%, respectively (p<0.001). The incidence of relapse was 21.7% at 1 year, 13% at 3 years, and 8.7% at 5 years. Median OS was estimated to be 8 months (95CI 3.266-12.734) and median PFS, 3 months (95CI 1.835-4.165). Conclusion: In our cohort, TRM in first years after ASCT remains considerable, but ASCT in this setting seems to be a good choice for AML patients with active disease. However, novel approaches are needed to reduce TRM and relapse in this set of patients.

Resumo Introdução: o transplante alogênico de células-tronco hematopoiéticas (TCTH-alo) representa uma abordagem potencialmente curativa para pacientes com leucemia mieloide aguda (LMA) recorrente ou refratária. Nosso trabalho apresenta o resultado de pacientes com recaída ou doença refratária tratados com TCTH-alo. Método: coorte retrospectiva incluindo 61 pacientes de 1994 a 2013 com diagnóstico de recidiva/LMA refratária. Os desfechos de interesse foram mortalidade relacionada ao transplante (MRT), incidência da doença aguda e crônica do enxerto contra hospedeiro (DECH), incidência de recaídas, sobrevida livre de progressão (PFS - progression-free survival) e sobrevida global (SG). A significância estatística foi considerada para p<0,05. Resultados: a média de idade foi de 61 anos (variação de 1 a 65). A incidência cumulativa de 90 dias, 1 ano e 3 anos de MRT foram de 60%, 26,7% e 13,3%, respectivamente (p<0,001). A incidência de recaída foi de 21,7% em 1 ano, 13% em 3 anos e 8,7% em 5 anos. A SG mediana foi estimada em 8 meses (IC 95% 3,266-12,734) e a mediana de PFS, em 3 meses (IC 95% 1,835-4,165). Conclusão: em nossa coorte, MRT no primeiro ano após o transplante permanece considerável, mas TCTH-alo nesse cenário parece ser uma boa opção para pacientes com LMA ativa. No entanto, novas abordagens são necessárias para reduzir MRT e recaída nesse conjunto de pacientes.

Hemorrhagic Cystitis Requiring Bladder Irrigation is Associated with Poor Mortality in Hospitalized Stem Cell Transplant Patients

Purpose: To evaluate the overall prognosis of post-stem cell transplant inpatients who required continuous bladder irrigation (CBI) for hematuria. Materials and Methods: We performed a retrospective analysis of adult stem cell transplant recipients who received CBI for de novo hemorrhagic cystitis as inpatients on the bone marrow transplant service at Washington University from 2011-2013. Patients who had a history of genitourinary malignancy and/or recent surgical urologic intervention were excluded. Multiple variables were examined for association with death. Results: Thirty-three patients met our inclusion criteria, with a mean age of 48 years (23-65). Common malignancies included acute myelogenous leukemia (17/33, 57%), acute lymphocytic leukemia (3/33, 10%), and peripheral T cell lymphoma (3/33, 10%). Median time from stem cell transplant to need for CBI was 2.5 months (0 days-6.6 years). All patients had previously undergone chemotherapy (33/33, 100%) and 14 had undergone prior radiation therapy (14/33, 42%). Twenty-eight patients had an infectious disease (28/33, 85%), most commonly BK viremia (19/33, 58%), cytomegalovirus viremia (17/33, 51%), and bacterial urinary tract infection (8/33, 24%). Twenty-two patients expired during the same admission as CBI treatment (22/33 or 67% of total patients, 22/28 or 79% of deaths), with a 30-day mortality of 52% and a 90-day mortality of 73% from the start of CBI. Conclusions: Hemorrhagic cystitis requiring CBI is a symptom of severe systemic disease in stem cell transplant patients. The need for CBI administration may be a marker for mortality risk from a variety of systemic insults, rather than directly attributable to the hematuria.

Allogeneic hematopoietic stem cell transplantation in the elderly: Predicting the risk for non relapse mortality

We have retrospectively reviewed 137 medical records of patients older than 50 years receiving an allogeneic hematopoietic stem cell transplantation (HSCT) between January 1997 and July 2013. Median follow up was 1.3 years. Sex, age, diagnosis, disease stage, comorbidities (according to HCT-CI score), type of donor, histocompatibility, conditioning regimen and graft-versus-host disease (GVHD) prophylaxis were evaluated. The incidence and severity of acute and chronic GVHD, overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM) and relapse were investigated according those variables. Acute GVHD incidence was 41% (7.3% GIII-IV). Patients with acute myeloid leukemia had lesser aGVH GII-IV (14% vs. 35%, p < 0.01) comparing to the entire population. Extensive cGVHD incidence was 9.4%. Global OS 1-3 years was 44-20%, DFS 33-20%, relapse 35-41% and NRM 36-43% respectively. The presence of comorbidities showed a significant increase in NRM (CT-CI 0 vs. 1 vs ≥ 2: 1-3 years 17-24% vs. 40-46% vs. 45-67%, p = 0.001, MA HR 2.03, CI 95% 1.02-5.29), as well as cyclosporine vs. tacrolimus (1-3 years 47-53% vs. 25-36%, p = 0.01). Tacrolimus patients had higher 1-3 years OS (49-25% vs. 31-13%, p = 0.01) and DFS (41-26% vs. 20-11%, p < 0.01). Age, type of donor and myeloablative conditioning showed no significant differences in any outcome. Allogeneic HSCT is a valid therapeutic option for older patients in Argentina. The main risk factor for a significantly increased NRM and a trend to inferior OS was the number of comorbidities. Age was not a factor for a worse result. The other factor having a significant effect in better outcome was tacrolimus administration.

Se efectuó un análisis retrospectivo de 137 historias clínicas de pacientes mayores de 50 años que recibieron un trasplante alogénico de precursores hematopoyéticos (TAPH). Se evaluaron las siguientes características: sexo, edad, enfermedad, estadio, comorbilidades (según el HCT-CI), donante, acondicionamiento e inmunosupresión. Se analizó la incidencia de enfermedad injerto vs. huésped aguda (aEICH) y crónica (cEICH), supervivencia global (SG), supervivencia libre de enfermedad (SLE), recaída y mortalidad libre de enfermedad (MLE). Los trasplantes fueron realizados entre 1997-2013, mediana de seguimiento 1.3 años. La incidencia de aEICH fue de 41% (7.3% GIII-IV). Los pacientes con leucemia mieloide aguda presentaron menor incidencia de EICHa GII-IV (14% vs. 34%, p < 0.01). La incidencia de EICHc extenso fue de 9.4%. La SG a 1-3 años fue 44-20%, SLE 33-20%, recaída 35-41% y la MLE 36-43%. Los pacientes con comorbilidades tuvieron un aumento significativo de la MLE (HCT-CI 0 vs. 1 vs. ≥2: 1-3 años 17-24% vs. 40-46% vs. 45-67%, p = 0.001, AMV HR 2.03, IC 95% 1.02-5.29), al igual que el uso de ciclosporina vs. tacrolimus (1-3 años 47-53% vs. 25-36%, p = 0.01). Los pacientes que recibieron tacrolimus tuvieron una mayor SG (1-3 años 49-25% vs. 31-13%, p = 0.01) y SLE (1-3 años 41-26% vs. 20-11%, p < 0.01). La edad, tipo de donante y acondicionamiento no resultaron significativos para ningún evento. El TAPH es una herramienta terapéutica válida en pacientes mayores. Los factores pronósticos que inciden mayormente en el trasplante son las comorbilidades y no la edad. El otro factor que demostró un efecto significativo fue el uso de tacrolimus.

Predicting mortality and cost of hematopoeitic stem-cell transplantation / Preditores de mortalidade e custo de transplante de célula-tronco hematopoéticas

Objective: To evaluate whether the Pretransplantion Assesment of Mortality risk score is associated to transplant costs and can be used not only to predict mortality but also as a cost management tool. Methods: We evaluated consecutively patients submitted to allogeneic (n = 27) and autologous (n = 89) hematopoietic stem cell-transplantation from 2004 to 2006 at Hospital Israelita Albert Einstein (SP), Brazil. Participants mean age at hematopoietic stem cell-transplantation was 42 (range 1 to 72) years; there were 69 males and 47 females; 30 patients had multiple myeloma; 41 had non-Hodgkin and Hodgkin?s lymphomas; 22 had acute leukemia; 6 had chronic leukemia; and 17 had non-malignant disease. The Pretransplantion Assesment of Mortality risk score was applied in all patients using the available web site (http://cdsweb.fhcrc.org/pam/). Results: Patients could be classified in three risk categories: high, intermediate and low, having significant difference in survival (p = 0.0162). The median cost in US dollars for each group was $ 281.000, $ 73.300 and $ 54.400 for high, intermediate and low risk, respectively. The cost of hematopoietic stem cell-transplantation significantly differed for each Pretransplantin Assesment of Mortality risk group (p = 0.008). Conclusion: The validation of the Pretransplantion Assesment of Mortality risk score in our patients confirmed that this system is an important tool to be used in transplantation units, being easy to apply and fully reproducible.

Objetivo: Avaliar se o escore de risco Avaliação de Mortalidade Pré-Transplante está associado aos custos de transplante e pode ser usado não apenas para predizer a mortalidade, mas também como ferramenta de gerenciamento de custos. Métodos: Foram avaliados consecutivamente 27 pacientes submetidos a transplante alogênico e 89 a transplante autólogo de células tronco hematopoéticas no período de 2004 a 2006 no Hospital Israelita Albert Einstein (SP). A média de idade dos pacientes por ocasião do transplante foi de 42 anos (variação de 1 a 72 anos); 69 eram do gênero masculino e 47 feminino; 30 pacientes tinham mieloma múltiplo, 41 linfoma não Hodgkin e linfoma de Hodgkin; 22 tinham leucemia aguda; 6 tinham leucemia crônica; e 17 doença não maligna. O escore de risco Avaliação de Mortalidade Pré-Transplante foi aplicado a todos os pacientes usando um web site fornecido pelos autores (http://cdsweb.fhcrc.org/pam/). Resultados: Classificaram-se os pacientes em três categorias de risco: alto, intermediário e baixo, apresentando diferença significativa de sobrevivência (p = 0,0162). O custo médio, em dólares, foi de U$ 281.000, U$ 73.300 e U$ 54.400 para risco alto, intermediário e baixo, respectivamente. O custo do transplante de células tronco hematopoéticas diferiu significantemente para cada grupo de risco segundo o escore Avaliação de Mortalidade Pré-Transplante (p = 0,008). Conclusão: A validação do escore de risco Avaliação de Mortalidade Pré-transplante em nossos pacientes confirmou que esse sistema é uma importante ferramenta a ser usada em unidades de transplante, sendo facilmente aplicável e inteiramente reprodutível.

Infection profile of patients undergoing autologous bone marrow transplantation in a Brazilian institution / Perfil de infecção em pacientes submetidos a transplante autólogo de medula óssea em uma instituição brasileira

CONTEXT AND OBJECTIVE: Hematopoietic stem cell transplantation (HSCT) has been widely used for treating oncological and hematological diseases. Although HSCT has helped to improve patient survival, the risk of developing infection during hospitalization is an important cause of morbidity and mortality. This study aimed to analyze the infection profile during hospitalization and the associated risk factors among patients undergoing autologous HSCT at the University Hospital, Universidade Federal de Juiz de Fora. DESIGN AND SETTING: This was a cross-sectional study on patients undergoing autologous HSCT at a public university hospital. METHODS: Patients with febrile neutropenia between 2004 and 2009 were retrospectively evaluated regarding their infection profile and associated risk factors. RESULTS: Infection occurred in 57.2 percent of 112 patients with febrile neutropenia. The main source of infection was the central venous catheter (25.9 percent). Infection was chiefly due to Gram-positive bacteria, although Gram-negative-related infections were more severe and caused a higher death rate. Sex, age, skin color, nutritional status and underlying disease were not associated with the development of infection. Patients with severe mucositis (Grades III and IV) had a higher infection rate (P < 0.001). Patients who developed pulmonary complications during hospitalization had higher infection rates (P = 0.002). Infection was the main cause of death (57.1 percent) in the study sample. CONCLUSION: Strategies aimed at reducing infection-related mortality rates among patients undergoing autologous HSCT are necessary.

CONTEXTO E OBJETIVO: O transplante de células-tronco hematopoiéticas (TCTH) vem sendo amplamente utilizado no tratamento das doenças onco-hematológicas. Embora o TCTH tenha colaborado para a melhora na sobrevida dos pacientes, o risco de desenvolver infecção no período de internação é uma importante causa de morbi-mortalidade. O presente estudo teve como objetivo analisar o perfil das infecções no período de internação e os fatores de risco associados entre os pacientes submetidos ao TCTH autólogo, no Hospital Universitário da Universidade Federal de Juiz de Fora. TIPO DE ESTUDO E LOCAL: Trata-se de um estudo transversal sobre pacientes submetidos a transplante autólogo, em um hospital público universitário. MÉTODOS: Foram analisados retrospectivamente os pacientes que apresentaram neutropenia febril no período de 2004 a 2009, com relação ao perfil infeccioso e os fatores de risco associados. RESULTADOS: A infecção foi determinada em 57,2 por cento dos 112 pacientes com neutropenia febril. A principal fonte de infecção foi o cateter venoso central (25,9 por cento). A infecção ocorreu principalmente devido a bactérias Gram-positivas, apesar de as infecções causadas por bactérias Gram-negativas terem sido mais graves e causado maior taxa de morte. Sexo, idade, cor da pele, estado nutricional e doença de base não estiveram associados com o desenvolvimento da infecção. Pacientes com mucosite grave (graus III e IV) apresentaram maior taxa de infecção (P < 0.001). Os pacientes que desenvolveram complicações pulmonares durante a internação apresentaram maiores taxas de infecção (P = 0,002). A infecção foi a principal causa do óbito (57,1 por cento) na amostra estudada. CONCLUSÃO: São necessárias estratégias voltadas para a redução da taxa de mortalidade relacionada com infecção entre pacientes submetidos ao TCTH autólogo.

Trasplante de células hematopoyéticas de sangre periférica utilizando quimioterapia inmunosupresora sin destrucción de la médula ósea: "minitrasplante" / Peripheral blood hematopoietic cell transplant using immunosuppressive chemotherapy without bone marrow destruction: minitransplant

Using a nonmyeloablative, immunosuppressive, fludarabine (FLU)-base conditioning regimen, we have performed allogeneic peripheral blood stem cell transplants in 17 patients (six with chronic granulocytic leukemia, four with acute myelogenous leukemia, five with acute lymphoblastic leukemia, one with myelodysplasia and one, with thalassemia major). Conditioning regimen consisted of FLU/busulfan/cyclophosphamide or FLU melphalan. To avoid graft vs. host disease (GVHD), cyclosporine and methotrexate were used. Median granulocyte recovery time to 0.5 x 10(9) was 11 days, whereas median platelet recovery time to 20 x 10(9) was 12 days. Seven patients did not need red blood cell transfusions and four did not need platelet transfusions. In thirteen individuals (76), the procedure could be completed fully on an outpatient basis. Follow-up times range between 1 and 14 months. Five of 17 patients developed acute GVHD whereas 4/10 developed chronic GVHD. The 14-month survival (SV) is 70 and median SV is not reached. Five patients (29) have died, three due to relapse of the disease and two due to GVHD. The transplant-related mortality was 5.8. This procedure is substantially less costly than its counterpart, using in-hospital myeloablative conditioning regimens, and may represent another approach in management of patients requiring allogeneic stem cell transplant.

Transplante hematopoyetico alogenico con celulas progenitoras extraidas de la sangre periferica / Allogenic hematopoietic transplantation with peripheral blood progenitor cells

Cinquenta y tres pacientes (ptes) recibieron transplante alogénico con células progenitoras extraídas de la sangre periférica (PSP); 25 ptes eran mujeres y 28 varones. La edad media del grupo fue de 20 años, (rango 2-550. Los diagnósticos fueron leucemia mieloide aguda (LMA) en 16 ptes, leucemia linfoblástica aguda (LLA) en 15, leucemia mieloide crónica (LMC) en primera fase crónica en 12, aplasia medular en 4, síndrome mielodisplásico en 3 y Enfermedad de Hodgkin en recaída luego de trasplante autólogo, talasemia mayor y síndrome de Hunter en 1 caso, respectivamente. Los acondicionamientos fueron en 38 ptes radioterapia corporal total 1200 cGy y ciclofosfamida 120 mg/kg EV; en 10 ptes busulfán 16 mg/kg y ciclosfosfamida 120 mg/kg EV, 3 ptes radioterapia linfoide total (RLT) y ciclosfosfamida, 2 ptes con otros agentes quimioterápicos. Los PSP se infundieron a través de un catéter sin ningún tipo de manipulación. La profilaxis de injerto vs huésped (EICH) se realizó con ciclosporina y metotrexato. Los donantes fueron familiares con HLA compatibles 6/6 y un caso 5/6 de los antígenos. Previo a la extración de PSP, recibieron G-DSF (filgrastim) 10 mug/kg/día sc. Cuatro días. El quinto día se realizó la féresis, en los primeros treinta casos se hizo la extracción adicional de médula ósea. Las medias de CD34, CD3, CD4, CD8, CD56, CD19 (cel x 10(6)/kg de peso) 4.12; 4.59; 2.57; 1.9; 0.55 y 0.68 respectivamente. La mediana de recuperación de nuetrófilos > 500 se obtuvo el día = 11 y de plaquetas > 20000, + 13. El tiempo de internación fue de 26 días (18-39) y la media de días con antibióticos parenterales fue de 12.2 días (5-45). La mortalidad relacionada al trasplante fue del 15 por ciento. EICH aguda se observó en el 43.4 por ciento de los ptes, con sólo 5 ptes con EICH aguda grado III o IV. En 43 ptes se pudo evaluar la aparición de EICH crónica con un tiempo medio de seguimiento de 18 meses (4-39). En la presente experiencia el trasplante de PSP alogénicos mantuvo una aceptable incidencia de EICH crónica; dados los recientes informes de aumento de esta complicación, parece lógico desaconsejar el uso de PSP en patología no maligna en la que no importaría la potencia del efecto injerto versus leucemia.