Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia

NUP98 fusions comprise a family of rare recurrent alterations in AML, associated with adverse outcomes. In order to define the underlying biology and clinical implications of this family of fusions, we performed comprehensive transcriptome, epigenome, and immunophenotypic profiling of 2,235 children and young adults with AML and identified 160 NUP98 rearrangements (7.2%), including 108 NUP98-NSD1 (4.8%), 32 NUP98-KDM5A (1.4%) and 20 NUP98-X cases (0.9%) with 13 different fusion partners. Fusion partners defined disease characteristics and biology; patients with NUP98-NSD1 or NUP98-KDM5A had distinct immunophenotypic, transcriptomic, and epigenomic profiles. Unlike the two most prevalent NUP98 fusions, NUP98-X variants are typically not cryptic. Furthermore, NUP98-X cases are associated with WT1 mutations, and have epigenomic profiles that resemble either NUP98-NSD1 or NUP98-KDM5A. Cooperating FLT3-ITD and WT1 mutations define NUP98-NSD1, and chromosome 13 aberrations are highly enriched in NUP98-KDM5A. Importantly, we demonstrate that NUP98 fusions portend dismal overall survival, with the noteworthy exception of patients bearing abnormal chromosome 13 (clinicaltrials gov. Identifiers: NCT00002798, NCT00070174, NCT00372593, NCT01371981).</p

Double umbilical cord blood transplantation in patients with hematologic malignancies using a reduced-intensity preparative regimen without antithymocyte globulin.

Reduced-intensity conditioning (RIC) regimens in cord blood transplant (CBT) are increasingly utilized for older patients and those with comorbidities. However, the optimal conditioning regimen has not yet been established and remains a significant challenge of this therapeutic approach. Antithymocyte globulin (ATG) has been incorporated into conditioning regimens in order to decrease the risk of graft failure; however, use of ATG is often associated with infusion reactions and risk of post-transplant complications. We report the results of a non-ATG-containing RIC regimen, where patients received 2 Gy TBI unless they were considered to be at higher risk of graft failure, in which case they received 3 Gy of TBI. Thirty patients underwent CBT using this protocol for high-risk hematological malignancies. There was only one case of secondary and no cases of primary graft failure. At 1 year, estimates of non-relapse mortality, OS and PFS were 29%, 53% and 45%, respectively. The cumulative incidences of grade III-IV acute and chronic GVHD were 14% and 18%, respectively. In summary, the results of this study demonstrate that this non-ATG-containing conditioning regimen provides a low incidence of graft failure without increasing regimen-related toxicity.Bone Marrow Transplantation advance online publication, 17 December 2012; doi:10.1038/bmt.2012.243

Criopreservação de medula óssea e células pluripotentes periféricas utilizando um congelador programável: experiência em 86 congelamentos Cryopreservation of bone marrow and peripheral blood stem cells using a controlled rate freezing system. Experience on 86 procedures

A infusão de células hematopoéticas totipotentes criopreservadas permite a recuperação da hematopoese após quimioterapia mieloablativa. OBJETIVO. A formação de cristais de gelo durante o processo de congelamento é o fator principal que causa ruptura das estruturas celulares. A criopreservação dessas células a uma taxa constante preveniria os danos causados pelo congelamento brusco. MÉTODOS. Vinte e três pacientes com mediana de 25 anos (variação 3-57) tiveram a medula óssea e/ou células-tronco periféricas (CTP) coletadas no período de março de 1993 a outubro de 1994, totalizando 86 congelamentos. Os pacientes apresentavam as seguintes neoplasias: linfoma não-Hodgkin (n=5), leucemia mielóide aguda (n=8), leucemia linfóide aguda (n=6), doença de Hodgkin (n=3) e mieloma múltiplo (n=1). O congelamento foi controlado por um computador, acoplado ao sistema, às seguintes temperaturas: -1°C/min até -45°C e depois a -10°C/min até -80°C. Após o congelamento, as células foram mantidas em freezer a -110°C até o momento da infusão. Para obtenção das CTP, empregou-se o fator de crescimento estimulante de granulócitos (G-CSF). RESULTADOS. Uma mediana de 3,16 x 10(8) céls./kg (variação 0,86-24,22) de CTP e 2,03 x 10(8) céls./kg (variação 0,19-12,21) de medula óssea foi congelada. A mediana para atingir granulócitos maior ou igual a 500/µL e plaquetas maior que 20.000/µL foi de 12 dias (variação 8-40) e 31 dias (variação 8-80), respectivamente. Todos os pacientes tiveram recuperação hematopoética após a infusão das células criopreservadas. CONCLUSÃO. A criopreservação em congelador programável permite o armazenamento de células hematopoéticas e, potencialmente, pode causar menor dano celular.<br>The cryopreservation of hematopoietic stem cells can be used for rescuing the hematopoiesis after high dose chemotherapy. PURPOSE. The ice cristal formation during the freezing procedure is the key point that can be harmful to the cells. The cryopreservation of hematopoietic stem cells in a controlled-rate freezer could decrease the cell damage. METHODS. Twenty-three patients with a median age of 26 years (range 03-57) had bone marrow and/or peripheral blood stem cells harvested from March 1993 through October 1994, ending up to 86 freezing procedures. The patient's diagnoses are as follows: Non-Hodgkin's Lymphoma (n=5); Acute Myelogenous Leukemia (n=8); Acute Lymphocytic Leukemia (n=6); Hodgkin's disease (n=3); Multiple Myeloma (n=1). The cells were frozen away in a controlled-rate freezer chamber at the folowing rate: -1°C/min from room temperature to -45°C and then, at -10°C/min down to -80°C. After freezing, the cells were kept into mechanical freezers until the marrow infusion. To mobilize PBSC (peripheral blood stem cells), G-CSF (granulocyte colony stimulating factor) was given. RESULTS. A median of 3.16x10(8) cells/kg (range 0.86-24.22) of PBSC and 2.03x10(8) cells/kg (0.19-12.21) of bone marrow cells were frozen. The median time to reach granulocytes greater than 500/µL and platelets greater than 20,000/µL was 12 days (range 8-40) and 31 days (range 8-80), respectively. All patients had marrow engraftment after infusion of hematopoietic stem cells. CONCLUSION. The cryopreservation procedure using a controlled-rate freezer can store hematopoietic stem cells and potentially, cause less damage to the cells