Biallelic TET2 mutations confer sensitivity to 5'-azacitidine in acute myeloid leukemia.

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza.

Comparison of five diagnostic flow cytometry scores in patients with myelodysplastic syndromes: Diagnostic power and prognostic impact.

Background: Flow cytometry (FCM) is a co-criterion in myelodysplastic syndromes (MDS) diagnostics according to the WHO classification. The presented study compared diagnostic power and prognostic impact of different FCM-based scores.

Methods: A total of 807 bone marrow (BM) samples of patients with cytopenia (543 MDS, 153 non-clonal cytopenias, 111 non-MDS myeloid malignancies) and 78 healthy controls have been investigated using a standardized 8-color-FCM procedure.

Symptomatic central nervous system involvement in adult patients with acute myeloid leukemia.

Introduction: Acute myeloid leukemia (AML) rarely involves the central nervous system (CNS). Little is known about the clinical course in adult AML patients since most studies examined pediatric patients. Therefore, this study analyzed the data of patients treated in three prospective trials of the "Study Alliance Leukemia" (SAL) study group for CNS involvement.

Marker chromosomes can arise from chromothripsis and predict adverse prognosis in acute myeloid leukemia.

Metaphase karyotyping is an established diagnostic standard in acute myeloid leukemia (AML) for risk stratification. One of the cytogenetic findings in AML is structurally highly abnormal marker chromosomes. In this study, we have assessed frequency, cytogenetic characteristics, prognostic impact, and underlying biological origin of marker chromosomes.

Selective expansion of regulatory T cells during lenalidomide treatment of myelodysplastic syndrome with isolated deletion 5q.

Lenalidomide (LEN) leads to erythroid improvement in the majority of patients with myelodysplastic syndrome and isolated deletion of the long arm of chromosome 5 (MDS-del(5q)). This effect is believed to be exerted via its immunomodulatory properties, although the precise nature is still incompletely understood. We prospectively performed immune profiling in the bone marrow and blood of MDS-del(5q) patients undergoing LEN therapy for a median of 6 cycles.

TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation.

Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT).

Two cycles of risk-adapted consolidation therapy in patients with acute promyelocytic leukemia. Results from the SAL-AIDA2000 trial.

The combination of all-trans retinoic acid (ATRA) and idarubicin (AIDA) for induction therapy followed by three cycles of risk-adapted consolidation cycles is considered standard of care for patients with acute promyelocytic leukemia (APL). We report the outcome of 141 patients (median age 51 years; range, 19-82, 31 % ≥60 years) enrolled into the prospective Study Alliance Leukemia (SAL)-AIDA2000 trial, which comprised AIDA-based induction followed by only two courses of risk-adapted consolidation (daunorubicin or mitoxantrone ± cytarabine) followed by 2-year maintenance treatment. The early death rate was 7 % (median age 66 years), and additional 9 % stopped further treatment after induction.

Outcome of patients with abnl(17p) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation.

Patients with acute myeloid leukemia (AML) and abnormalities of chromosome 17p (abnl(17p)) are at high-risk of treatment failure. Poor outcomes have been reported with conventional chemotherapy. To accurately define the outcome after allogeneic hematopoietic stem cell transplantation (HSCT) in patients with abnl(17p) AML, we analyzed the results of patients with this abnormality who received an allogeneic HSCT between January 2000 and December 2010 in 1 of 4 well-defined cohorts (Fred Hutchinson Cancer Research Center, Haemato Oncology Foundation for Adults in the Netherlands, Study Alliance Leukemia, German Cooperative Transplant Study Group).

Clonal heterogeneity as detected by metaphase karyotyping is an indicator of poor prognosis in acute myeloid leukemia.

Purpose: In acute myeloid leukemia (AML), studies based on whole-genome sequencing have shown genomic diversity within leukemic clones. The aim of this study was to address clonal heterogeneity in AML based on metaphase cytogenetics.

Patients And Methods: This analysis included all patients enrolled onto two consecutive, prospective, randomized multicenter trials of the Study Alliance Leukemia.

Mesenchymal stromal cells from patients with myelodyplastic syndrome display distinct functional alterations that are modulated by lenalidomide.

The contribution of the bone marrow microenvironment in myelodysplastic syndrome is controversial. We therefore analyzed the functional properties of primary mesenchymal stromal cells from patients with myelodysplastic syndrome in the presence or absence of lenalidomide. Compared to healthy controls, clonality and growth were reduced across all disease stages.

Impact of allogeneic haematopoietic stem cell transplantation in patients with abnl(17p) acute myeloid leukaemia.

The role of allogeneic stem cell transplantation (HSCT) as compared to chemotherapy in acute myeloid leukaemia (AML) patients with abnormalities of chromosome 17p [abnl(17p)] has not yet been defined. Therefore, we analysed 3530 AML patients treated in three randomized, prospective, controlled clinical trials and compared post-remission therapies using a multivariate Cox regression analysis to determine whether allogeneic HSCT is superior than chemotherapy in overcoming the detrimental impact of patients with abnl(17p) AML. One hundred and forty-three patients (4%) were identified with abnl(17p) AML.

Outcome of high-risk acute myeloid leukemia after allogeneic hematopoietic cell transplantation: negative impact of abnl(17p) and -5/5q-.

The European LeukemiaNet classification combines a heterogeneous group of aberrations as adverse-risk abnormalities. Our goal was to investigate the outcomes associated with distinct high-risk chromosomal abnormalities in acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). We performed a retrospective cohort analysis in patients with high-risk AML who received first, HLA-compatible, allogeneic HSCT between January 2005 and December 2008.

Clonal evolution including partial loss of human leukocyte antigen genes favoring extramedullary acute myeloid leukemia relapse after matched related allogeneic hematopoietic stem cell transplantation.

Background: Relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) leaves few therapeutic options, and mechanisms of immune escape of recurring leukemic cells remain poorly understood. Recently, acquired loss of mismatched human leukocyte antigen (HLA) was demonstrated in patients with AML undergoing haploidentical allogeneic HSCT and was suggested not to occur in HLA-matched HSCT. We hypothesized that this mechanism applies to extramedullary AML relapse which occurs frequently after allogeneic HSCT and might also not be restricted to haploidentical HSCT.

¹⁸F-FDG-PET/CT for detection of extramedullary acute myeloid leukemia.

Myeloid sarcoma in acute myeloid leukemia has been clearly defined by the World Health Organization but studies regarding the prevalence and the prognostic impact of extramedullary acute myeloid leukemia have not been conducted. We performed (18)Fluoro-deoxy-Glucose Positron Emission Tomography/Computed Tomography scans in 10 patients with de novo and relapsed acute myeloid leukemia and histologically proven extramedullary disease. The scans were able to detect the known extramedullary lesions in 9 out of 10 patients (90%).

Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system.

Purpose: The current European LeukemiaNet (ELN) recommendations for acute myeloid leukemia (AML) propose a new risk reporting system, integrating molecular and cytogenetic factors and subdividing the large heterogenous group of intermediate-risk patients into intermediate-I (IR-I) and intermediate-II (IR-II). We assessed the prognostic value of the new risk classification in a large cohort of patients.

Patients And Methods: Complete data for classification were available for 1,557 of 1,862 patients treated in the AML96 trial.

Cytarabine dose of 36 g/m² compared with 12 g/m² within first consolidation in acute myeloid leukemia: results of patients enrolled onto the prospective randomized AML96 study.

Purpose: To assess the optimal cumulative dose of cytarabine for treatment of young adults with acute myeloid leukemia (AML) within a prospective multicenter treatment trial.

Patients And Methods: Between 1996 and 2003, 933 patients (median age, 47 years; range 15 to 60 years) with untreated AML were randomly assigned at diagnosis to receive cytarabine within the first consolidation therapy at either a intermediate-dose of 12 g/m² (I-MAC) or a high-dose of 36 g/m² (H-MAC) combined with mitoxantrone. Autologous hematopoietic stem-cell transplantation or intermediate-dose cytarabine (10 g/m²) were offered as second consolidation.

A novel prognostic model in elderly patients with acute myeloid leukemia: results of 909 patients entered into the prospective AML96 trial.

We present an analysis of prognostic factors derived from a trial in patients with acute myeloid leukemia older than 60 years. The AML96 trial included 909 patients with a median age of 67 years (range, 61-87 years). Treatment included cytarabine-based induction therapy followed by 1 consolidation.

Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells.

Treatment of acute myeloid leukemia (AML) remains challenging with many patients harboring unfavorable prognostic parameters such as FLT3 internal tandem duplication (FLT3-ITD) mutations leading to a constitutively activated FLT3-receptor tyrosine kinase (RTK). Activation of proteins by phosphorylation of tyrosine residues is a common mechanism in leukemia development. Therefore, specific tyrosine kinase inhibitors (TKI) have been developed for AML therapy and are currently under investigation.

Monitoring of donor chimerism in sorted CD34+ peripheral blood cells allows the sensitive detection of imminent relapse after allogeneic stem cell transplantation.

Analysis of donor chimerism is an important diagnostic tool to assess the risk of relapse after allogeneic stem cell transplantation, especially in patients lacking a specific marker suitable for monitoring of minimal residual disease. We prospectively investigated the predictive value of donor chimerism analyses in sorted CD34(+) peripheral blood cells in 90 patients with acute leukemia and myelodysplastic syndrome. The cumulative incidence of relapse after four years was significantly increased in cases with decreasing or incomplete CD34(+) donor chimerism (57% vs.

HLA-DRneg patients without acute promyelocytic leukemia show distinct immunophenotypic, genetic, molecular, and cytomorphologic characteristics compared to acute promyelocytic leukemia.

Background: Loss of HLA-DR and CD34 is a well-known characteristic of malignant promyelocytes in acute promyelocytic leukemia (APL). However, this immunophenotype is not specific for APL. The purpose of this study was to investigate whether further biological characterization of the HLA-DR(neg) acute myeloid leukemia patients would allow more clearly define criteria to separate APL from non-APL patients.