Graft--host disease and relapse/rejection-free survival after allogeneic transplantation for idiopathic severe aplastic anemia: a comprehensive analysis from the SAAWP of the EBMT.

Survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for severe idiopathic aplastic anemia (SAA) has improved in recent years, approaching 75% at 5 years. However, an SAA-adapted composite endpoint, graft-versus-host disease (GvHD) and relapse/rejection-free survival (GRFS), may more accurately assess patient outcomes beyond survival. We analyzed GRFS to identify risk factors and specific causes of GRFS failure.

Collaborative Efforts Driving Progress in Pediatric Acute Myeloid Leukemia.

Diagnosis, treatment, response monitoring, and outcome of pediatric acute myeloid leukemia (AML) have made enormous progress during the past decades. Because AML is a rare type of childhood cancer, with an incidence of approximately seven occurrences per 1 million children annually, national and international collaborative efforts have evolved. This overview describes these efforts and includes a summary of the history and contributions of each of the main collaborative pediatric AML groups worldwide.

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia.

IKAROS family zinc finger 1/IKZF1 is a transcription factor important in lymphoid differentiation, and a known tumor suppressor in acute lymphoid leukemia. Recent studies suggest that IKZF1 is also involved in myeloid differentiation. To investigate whether IKZF1 deletions also play a role in pediatric acute myeloid leukemia, we screened a panel of pediatric acute myeloid leukemia samples for deletions of the IKZF1 locus using multiplex ligation-dependent probe amplification and for mutations using direct sequencing.

Insights into cell ontogeny, age, and acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogenous disease of hematopoietic stem cells (HSCs) and progenitor cells (HSPCs). The pathogenesis of AML involves cytogenetic abnormalities, genetic mutations, and epigenetic anomalies. Although it is widely accepted that the cellular biology, gene expression, and epigenetic landscape of normal HSCs change with age, little is known about the interplay between the age at which the cell becomes leukemic and the resultant leukemia.

Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial.

Purpose: Treatment outcomes in younger patients with acute myeloid leukemia (AML) have improved, but optimization and new combinations are needed. We assess three combinations in induction and consolidation.

Patients And Methods: Younger untreated patients with AML (median age, 49 years; range, 0 to 73 years) were randomly allocated to two induction courses of daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = 1983) or ADE versus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida; n = 1268), and to amsacrine, cytarabine, etoposide, and then mitoxantrone/cytarabine (MACE-MidAC) or high-dose cytarabine (n = 1,445) 3 g/m(2) or 1.

Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group.

Purpose: In pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Münster Study Group.

Results of a randomized trial in children with Acute Myeloid Leukaemia: medical research council AML12 trial.

The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of consolidation chemotherapy. 504 children (<16 years) with AML were randomized between mitoxantrone/cytarabine/etoposide or daunorubicin/cytarabine/etoposide as induction chemotherapy and 270 entered a second randomization between a total of four or five courses of treatment. Ten-year event-free (EFS) and overall survival (OS) was 54% and 63% respectively; the relapse rate was 35%.

Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment trials AML 10 and 12.

Purpose: Karyotype is an independent indicator of prognosis in acute myeloid leukemia (AML) that is widely applied to risk-adapted therapy. Because AML is rare in children, the true prognostic significance of individual chromosomal abnormalities in this age group remains unclear.

Patients And Methods: This cytogenetic study of 729 childhood patients classified them into 22 subgroups and evaluated their incidence and risk.

FLT3 and KIT mutated pediatric acute myeloid leukemia (AML) samples are sensitive in vitro to the tyrosine kinase inhibitor SU11657.

New treatment strategies to improve the outcome of pediatric acute myeloid leukemia (AML) are required as 40% of children diagnosed with AML do not survive. Around 30% of pediatric AML patients harbour a mutation in the tyrosine kinases FLT3 (+/-20%) or KIT (+/-10%). In this study we investigated whether pediatric AML samples (N=61) were sensitive to the tyrosine kinase inhibitor SU11657 (similar to the clinically available drug sunitinib) in vitro, and whether sensitivity was related to expression of, and mutations in, FLT3 and KIT.

Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21).

Patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21) comprise a novel and distinct biological subgroup. We prospectively screened 1630 (84%) patients treated on the UK MRC ALL97 protocol for iAMP21 and herein present demographic, clinical, and survival data on the 28 (2%) children found to harbor this abnormality. They had a common or pre-B ALL immunophenotype, were significantly older (median 9 years vs 5 years), and had a lower white cell count (median 3.

A comparison of the in vitro cytotoxicity of daunorubicin and liposomal daunorubicin in pediatric acute leukemia.

Anthracyclines are effective in the treatment of leukemia, but their use is limited because of cardiotoxicity. Liposomal daunorubicin (L-DNR) is potentially less cardiotoxic than daunorubicin (DNR). We compared in vitro cytotoxicity in pediatric acute leukemia samples and found no significant differences between cytotoxicity of DNR and L-DNR.

A diminutive chromosome 21 centromere in acute lymphoblastic leukemia.

A chance observation of a tiny constitutional variant for the centromere of chromosome 21 in two patients with acute lymphoblastic leukemia (ALL), suggested a possible correlation with the cytogenetic findings in their leukemic cells. Interphase FISH revealed three 13/21 centromeric signals and a single MLL signal in the blast cells of each patient. Metaphase FISH with dual-color application of whole-chromosome paint (wcp) and centromeric probes for chromosome 21 showed two copies of chromosome 21, one with a tiny centromeric signal which corresponded to the invisible centromere in the interphase cells.

Treatment for myeloid leukaemia of Down syndrome: population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials.

Down syndrome (DS) children are at an increased risk of developing myelodysplasia and acute myeloid leukaemia (AML). We retrospectively analysed the population-based data on 81 children with myeloid leukaemia of Down syndrome (ML-DS) from the UK National Registry of Childhood Tumours and experience in the Medical Research Council (MRC) AML 10 and AML 12 trials, which enrolled 46 children with ML-DS from 1988 to 2002. Eight per cent of UK children with AML had DS, but DS children comprised only 5% of children registered in MRC trials.

In vitro sensitivity and cross-resistance to deoxynucleoside analogs in childhood acute leukemia.

Background And Objectives: Cytarabine (ara-C) is a key drug in the treatment of acute leukemia. Resistance to ara-C might be circumvented by the use of other deoxynucleoside analogs.

Design And Methods: Using the MTT assay, we determined in vitro sensitivity and cross-resistance to deoxynucleoside analogs in 362 acute leukemia samples from untreated children and 32 normal bone marrow mononuclear cell samples.

Haematopoietic stem cell transplantation for Shwachman-Diamond disease: a study from the European Group for blood and marrow transplantation.

This report assessed the results of allogeneic stem cell transplantation (allo-SCT) in 26 patients with Shwachman-Diamond disease (SDS) and severe bone marrow abnormalities. The conditioning regimen was based on busulphan (54%), total body irradiation (23%), fludarabine (15%) or other chemotherapy combinations (8%). Standard prevention of graft versus host disease (GVHD) with cyclosporin +/- methotrexate was adopted in 54% of the patients whilst in vivo or in vitro T-cell depletion was used in 17 and four patients respectively.

In vitro profiling of the sensitivity of pediatric leukemia cells to tipifarnib: identification of T-cell ALL and FAB M5 AML as the most sensitive subsets.

Although the prognosis of pediatric leukemias has improved considerably, many patients still have relapses. Tipifarnib, a farnesyl transferase inhibitor (FTI), was developed to target malignancies with activated RAS, including leukemia. We tested 52 pediatric acute myeloid leukemia (AML) and 36 pediatric acute lymphoblastic leukemia (ALL) samples for in vitro sensitivity to tipifarnib using a total cell-kill assay and compared these results to those obtained with normal bone marrow (N BM) samples (n = 25).

Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia.

This study of children and adults with acute lymphoblastic leukaemia (ALL) is the largest series of patients with hypodiploidy (<46 chromosomes) yet reported. The incidence of 5% was independent of age. Patients were subdivided by the number of chromosomes; near-haploidy (23-29 chromosomes), low hypodiploidy (33-39 chromosomes) and high hypodiploidy (42-45 chromosomes).

Outcome heterogeneity in childhood high-hyperdiploid acute lymphoblastic leukemia.

High hyperdiploidy (HeH) (51 to 65 chromosomes) is found in one third of children with acute lymphoblastic leukemia and is associated with a good prognosis. Cytogenetic features may further refine this prognosis and identify patients with a poor outcome. We examined the effect of sex, age, individual trisomies, modal number, and structural abnormalities on survival among 700 children with HeH.

Intraocular relapse of childhood acute lymphoblastic leukaemia.

Relapse of childhood acute lymphoblastic leukaemia (ALL) involving the eye is a rare but challenging problem. Twenty cases occurred in patients treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia XI and ALL97 trials between 1991 and 2001, representing 2.2% of ALL relapses.

Prognostic factors and outcome for children after second central nervous system relapse of acute lymphoblastic leukaemia.

The Medical Research Council acute lymphoblastic leukaemia trials (UKALL X and XI) recruited 3,702 children with ALL between January 1985 and March 1997. Seventy-nine children had central nervous system (CNS) involvement in their first two relapses. Fourteen children survived at a median follow-up of 22 months from second relapse; seven (9%) in third remission, two in later remissions and five with disease.

The investigation and management of neonatal haemostasis and thrombosis.

These guidelines address developmental aspects of neonatal haemostasis and thrombosis, the laboratory investigation of the neonate, and the diagnosis and clinical management of haemostatic and thrombotic conditions occurring in this period (defined as the first 4 weeks of life following birth). Relevant scientific papers were identified by a systematic literature review from Medline 1975-2000 using index terms which incorporated the various component subjects of these guidelines. Further publications were obtained from the references cited and from reviews known to the members of the working party and to the Haemostasis and Thrombosis Task Force.

Failure of a new protocol to improve treatment results in paediatric lymphoblastic leukaemia: lessons from the UK Medical Research Council trials UKALL X and UKALL XI.

The impact of various types of intensification therapy was examined in a cohort of 3617 children aged 1-14 years with acute lymphoblastic leukaemia (ALL) enrolled in the Medical Research Council (MRC) UKALL X (1985-90) and UKALL XI (1990-97) trials. UKALL XI was modified in 1992 to incorporate the "best arm" of UKALL X with two 5-d intensification blocks at 5 and 20 weeks, and an additional randomization in respect of a third intensification at 35 weeks but omission of two consecutive injections of daunorubicin during induction. All children were eligible for randomization irrespective of risk group.