Sex-associated differences in frequencies and prognostic impact of recurrent genetic alterations in adult acute myeloid leukemia (Alliance, AMLCG).

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients' sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols.

Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with acute myeloid leukemia.

Previous studies demonstrated that splicing factor mutations are recurrent events in hematopoietic malignancies with both clinical and functional implications. However, their aberrant splicing patterns in acute myeloid leukemia remain largely unexplored. In this study, we characterized mutations in SRSF2, U2AF1, and SF3B1, the most commonly mutated splicing factors.

The clinical mutatome of core binding factor leukemia.

The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10-15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined.

A 29-gene and cytogenetic score for the prediction of resistance to induction treatment in acute myeloid leukemia.

Primary therapy resistance is a major problem in acute myeloid leukemia treatment. We set out to develop a powerful and robust predictor for therapy resistance for intensively treated adult patients. We used two large gene expression data sets (n=856) to develop a predictor of therapy resistance, which was validated in an independent cohort analyzed by RNA sequencing (n=250).

Acute myeloid leukemia with del(9q) is characterized by frequent mutations of NPM1, DNMT3A, WT1 and low expression of TLE4.

Deletions of the long arm of chromosome 9 [del(9q)] are a rare but recurring aberration in acute myeloid leukemia (AML). Del(9q) can be found as the sole abnormality or in combination with other cytogenetic aberrations such as t(8;21) and t(15;17). TLE1 and TLE4 were identified to be critical genes contained in the 9q region.

ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation.

The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A.

Multiplex PCR assay underreports true bloodstream infections with coagulase-negative staphylococci in hematological patients with febrile neutropenia.

SeptiFast multiplex PCR assay was evaluated for detecting true bloodstream infections (BSIs) with coagulase-negative staphylococci (CoNS) in neutropenic hematological patients. Sensitivity for samples representing true CoNS-BSIs was 23.3% with an integrated cutoff and increased to 83.

Factors influencing life satisfaction in acute myeloid leukemia survivors following allogeneic stem cell transplantation: a cross-sectional study.

Background: Allogeneic stem cell transplantation (alloSCT) is the preferred option of postremission therapy for high-risk patients suffering from acute myeloid leukemia (AML). Therefore, monitoring life satisfaction (LS) of long-term survivors following alloSCT is becoming increasingly important for oncologists. The aim of the study was to evaluate individual survivor priority of various general and health-related domains of life and their satisfaction with these domains.

Impact of multiplex PCR on antimicrobial treatment in febrile neutropenia: a randomized controlled study.

Multiplex PCR (mPCR) directly from blood has been suggested as a promising method for rapid identification of pathogens causing sepsis. This study aimed to investigate whether mPCR has any impact on antimicrobial treatment. Hematological patients with febrile neutropenia were randomized into two groups.

Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse.

Monitoring minimal residual disease is an important way to identify patients with acute myeloid leukemia at high risk of relapse. In this study we investigated the prognostic potential of minimal residual disease monitoring by quantitative real-time polymerase chain reaction analysis of NPM1 mutations in patients treated in the AMLCG 1999, 2004 and 2008 trials. Minimal residual disease was monitored - in aplasia, after induction therapy, after consolidation therapy, and during follow-up - in 588 samples from 158 patients positive for NPM1 mutations A, B and D (with a sensitivity of 10(-6)).

Combined molecular and clinical prognostic index for relapse and survival in cytogenetically normal acute myeloid leukemia.

Purpose: Cytogenetically normal (CN) acute myeloid leukemia (AML) is the largest and most heterogeneous cytogenetic AML subgroup. For the practicing clinician, it is difficult to summarize the prognostic information of the growing number of clinical and molecular markers. Our purpose was to develop a widely applicable prognostic model by combining well-established pretreatment patient and disease characteristics.

Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia.

The t(8;21) and inv(16)/t(16;16) rearrangements affecting the core-binding factors RUNX1 and CBFB, respectively, are found in 15% to 20% of adult de novo acute myeloid leukemia (AML) cases and are associated with a favorable prognosis. Since the expression of the fusion genes CBFB/MYH11 or RUNX1/RUNX1T1 alone is not sufficient to cause leukemia, we performed exome sequencing of an AML sample with an inv(16) to identify mutations, which may collaborate with the CBFB/MYH11 fusion during leukemogenesis. We discovered an N676K mutation in the adenosine triphosphate (ATP)-binding domain (tyrosine kinase domain 1 [TKD1]) of the fms-related tyrosine kinase 3 (FLT3) gene.

Identification of a 24-gene prognostic signature that improves the European LeukemiaNet risk classification of acute myeloid leukemia: an international collaborative study.

Purpose: To identify a robust prognostic gene expression signature as an independent predictor of survival of patients with acute myeloid leukemia (AML) and use it to improve established risk classification.

Patients And Methods: Four independent sets totaling 499 patients with AML carrying various cytogenetic and molecular abnormalities were used as training sets. Two independent patient sets composed of 825 patients were used as validation sets.

Acute Myeloid Leukemia (AML): different treatment strategies versus a common standard arm--combined prospective analysis by the German AML Intergroup.

Purpose: Identifying true therapeutic progress in patients with acute myeloid leukemia (AML) requires a comparison of treatment strategies and results on the basis of uniform patient selection. To foster comparability across five clinical studies, we introduced a common standard arm combined with a general upfront randomization and performed prospective analyses with adjustment for differences in prognostic baseline characteristics.

Patients And Methods: Whereas the studies' own regimens differed in chemotherapies, risk adaption, and guidelines for allogeneic stem-cell transplantation, the standard arm contained uniform cytarabine- and anthracycline-based standard-dose remission induction and high-dose consolidation courses.

RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes.

Background: The RUNX1 (AML1) gene is a frequent mutational target in myelodysplastic syndromes and acute myeloid leukemia. Previous studies suggested that RUNX1 mutations may have pathological and prognostic implications.

Design And Methods: We screened 93 patients with cytogenetically normal acute myeloid leukemia for RUNX1 mutations by capillary sequencing of genomic DNA.

GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia.

Cytogenetically normal acute myeloid leukemia (CN-AML) with biallelic CEBPA gene mutations (biCEPBA) represents a distinct disease entity with a favorable clinical outcome. So far, it is not known whether other genetic alterations cooperate with biCEBPA mutations during leukemogenesis. To identify additional mutations, we performed whole exome sequencing of 5 biCEBPA patients and detected somatic GATA2 zinc finger 1 (ZF1) mutations in 2 of 5 cases.

Monoallelic CEBPA mutations in normal karyotype acute myeloid leukemia: independent favorable prognostic factor within NPM1 mutated patients.

We and others have shown that cytogenetically normal (CN)-AML patients with biallelic CEBPA gene mutations (biCEBPA) represent a molecularly distinct group with a favorable prognosis. Patients carrying a monoallelic CEBPA mutation (moCEBPA), however, show no different outcome compared to patients with wildtype CEBPA, and these mutations are frequently associated with mutated NPM1 or FLT3-ITD. So far, no molecular or clinical hallmark has been identified to prognostically distinguish moCEBPA patients from patients with wildtype CEBPA.

Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes.

Background: About 50% of patients (age ≥60 years) who have acute myeloid leukaemia and are otherwise medically healthy (ie, able to undergo intensive chemotherapy) achieve a complete remission (CR) after intensive chemotherapy, but with a substantially increased risk of early death (ED) compared with younger patients. We verified the association of standard clinical and laboratory variables with CR and ED and developed a web-based application for risk assessment of intensive chemotherapy in these patients.

Methods: Multivariate regression analysis was used to develop risk scores with or without knowledge of the cytogenetic and molecular risk profiles for a cohort of 1406 patients (aged ≥60 years) with acute myeloid leukaemia, but otherwise medically healthy, who were treated with two courses of intensive induction chemotherapy (tioguanine, standard-dose cytarabine, and daunorubicin followed by high-dose cytarabine and mitoxantrone; or with high-dose cytarabine and mitoxantrone in the first and second induction courses) in the German Acute Myeloid Leukaemia Cooperative Group 1999 study.

Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome.

Purpose: CEBPA mutations are found as either biallelic (biCEBPA) or monoallelic (moCEBPA). We set out to explore whether the kind of CEBPA mutation is of prognostic relevance in cytogenetically normal (CN) acute myeloid leukemia (AML).

Patients And Methods: Four hundred sixty-seven homogeneously treated patients with CN-AML were subdivided into moCEBPA, biCEBPA, and wild-type (wt) CEBPA patients.

ERG expression is an independent prognostic factor and allows refined risk stratification in cytogenetically normal acute myeloid leukemia: a comprehensive analysis of ERG, MN1, and BAALC transcript levels using oligonucleotide microarrays.

Purpose: Recently, several novel molecular prognostic markers were identified in cytogenetically normal acute myeloid leukemia (CN-AML). In addition to the well-known influence of FLT3, NPM1, and CEBPA mutations, high transcript levels of the ERG, BAALC, and MN1 genes have been associated with inferior outcomes, but the relative importance of these risk markers remains to be defined.

Patients And Methods: We analyzed ERG, BAALC, and MN1 expression levels in a cohort of 210 patients with CN-AML who received intensive chemotherapy.

Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Myeloid Leukemia Cooperative Group.

Purpose: The purpose of the study was to assess the contribution of age and disease variables to the outcome of untreated patients with acute myeloid leukemia (AML) receiving varying intensive induction chemotherapy.

Patients And Methods: Patients 16 to 85 years of age with primary AML, known karyotype, and uniform postremission chemotherapy enrolled onto two consecutive trials were eligible and were randomly assigned to induction either with a standard-dose (cytarabine, daunorubicin, and 6-thioguanine) and a high-dose (cytarabine and mitoxantrone) combination, or with two courses of the high-dose combination. Subgroups were defined by karyotype, nucleophosmin and FLT3 mutation, WBC count, serum lactate dehydrogenase, and residual blasts.

An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia.

Patients with cytogenetically normal acute myeloid leukemia (CN-AML) show heterogeneous treatment outcomes. We used gene-expression profiling to develop a gene signature that predicts overall survival (OS) in CN-AML. Based on data from 163 patients treated in the German AMLCG 1999 trial and analyzed on oligonucleotide microarrays, we used supervised principal component analysis to identify 86 probe sets (representing 66 different genes), which correlated with OS, and defined a prognostic score based on this signature.