[Show abstract][Hide abstract] ABSTRACT: 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. Furthermore, we investigated the impact of general and health-related LS on resilience, anxiety, depression and quality of life in AML survivors following alloSCT.
Forty-one AML survivors (median age at time of assessment = 49.0 years) who had undergone alloSCT (median time since transplantation = 3.1 years) were enrolled in the study. Psychosocial parameters were assessed using the following instruments: FLZ(M) (Questions on Life Satisfaction), EORTC QLQ-C30, HADS (Hospital Anxiety and Depression Scale) and the RS-25 (Resilience Scale-25 items). Correlation analyses were computed to reveal the associations between the different questionnaires.
Independence from help or care, well-regulated living conditions and financial security contributed positively to LS, whereas being off work due to health-reasons and dissatisfaction with physical aspects were negatively associated to the subjective feelings of overall satisfaction. Moreover, a high quality of life was strongly positively correlated with LS (Spearman's rho general LS: 0.643 and health-related LS: 0.726, both p < 0.001). A high degree of resilience was also strongly positively correlated with better LS (general LS: 0.700, health-related LS: 0.675, both p < 0.001). Symptoms of anxiety and depression were associated with an impaired general LS (anxiety: -0.674, depression: -0.698, both p < 0.001).
Our results indicate that LS should be considered an important key contributor to the survivors' well-being following alloSCT. Thus, identifying protective psychological and physical factors that relieve stressors is of high importance in order to support long-term AML survivors with their special needs.
Full-text · Article · Dec 2015 · Health and Quality of Life Outcomes
[Show abstract][Hide abstract] ABSTRACT: Immune checkpoint molecules are highly relevant as potential prognostic markers and therapeutic targets in malignant diseases. HVEM belongs to the TNF receptor family and provides stimulatory as well as inhibitory signals depending on the ligand. Abnormal HVEM expression has been described in various malignancies, but the role in AML is unknown. Here we report extensive data on HVEM surface protein expression analyzed by flow cytometry on bone marrow leukemic cells of 169 AML patients at diagnosis. An independent cohort of 512 AML patients was analyzed for HVEM mRNA expression in bone marrow samples by Affymetrix microarrays. Consistently for both cohorts and methods, we show that HVEM was differentially expressed and that expression levels were associated with defined genetic markers. HVEM expression was lower in cases with FLT3-ITD (p = 0.001, p < 0.001), with mutations in NPM1 (p = 0.001, p < 0.001) or with the combination of NPM1 mutation and FLT3 wild type (p = 0.049, p = 0.050), while a biallelic mutation in CEBPA correlated positively with higher HVEM expression (p = 0.015, p < 0.001). In a differential gene expression analysis, we found 13 genes including HOXA9, MEIS1 and MN1 that were closely associated with HVEM expression. Besides, four gene sets closely linked to immunity were enriched in HVEM (high) samples. Finally, high expression of HVEM was associated with a trend toward longer relapse-free survival. The results of this study provide new information on the potential significance of HVEM in AML.
No preview · Article · Sep 2015 · Cancer Immunology and Immunotherapy
[Show abstract][Hide abstract] ABSTRACT: To date risk stratification in acute promyelocytic leukemia (APL) is based on highly dynamic leukocyte and platelet counts only. To identify a more robust risk stratification model, a molecular risk score was developed based on expression levels of the genes BAALC, ERG and WT1. Hereby, the main focus was on prediction of relapse. The integrative risk score divided patients into two groups with highly significant differences in outcome. It discriminated a high risk group with a high incidence of relapse successfully from a low risk group with no APL-related events after achievement of first remission. Especially the concurrent presence of molecular risk factors showed to be a negative prognostic factor in APL. The molecular risk score might be a promising approach to guide monitoring of APL patients and therapeutic decisions in the future.
No preview · Article · Sep 2015 · Leukemia research
[Show abstract][Hide abstract] ABSTRACT: The adapter protein metastasis suppressor 1 (MTSS1) is implicated as a tumor suppressor or tumor promoter, depending on the type of solid cancer. Here, we identified Mtss1 expression to be increased in AML subsets with favorable outcome, while suppressed in high risk AML patients. High expression of MTSS1 predicted better clinical outcome of patients with normal-karyotype AML. Mechanistically, MTSS1 expression was negatively regulated by FLT3-ITD signaling but enhanced by the AML1-ETO fusion protein. DNMT3B, a negative regulator of MTSS1, showed strong binding to the MTSS1 promoter in PML-RARA positive but not AML1-ETO positive cells, suggesting that AML1-ETO leads to derepression of MTSS1. Pharmacological treatment of AML cell lines carrying the FLT3-ITD mutation with the specific FLT3 inhibitor PKC-412 caused upregulation of MTSS1. Moreover, treatment of acute promyelocytic cells (APL) with all-trans retinoic acid (ATRA) increased MTSS1 mRNA levels. Taken together, our findings suggest that MTSS1 might have a context-dependent function and could act as a tumor suppressor, which is pharmacologically targetable in AML patients.
[Show abstract][Hide abstract] ABSTRACT: Non-relapse mortality after Allo-SCT has significantly decreased over the last years. Nevertheless, relapse remains a major cause for post SCT mortality in patients with AML and high-risk myelodysplastic syndrome (MDS). In this retrospective single-center analysis, we have analyzed the treatment outcomes of 108 patients with AML or MDS, who relapsed after Allo-SCT. Seventy of these patients (65%) were treated with salvage therapies containing chemotherapy alone, allogeneic cell-based treatment or the combination of both. Thirty-eight patients (35%) received palliative treatment. Median OS after diagnosis of relapse was 130 days. Compared with patients who received chemotherapy alone, response to salvage therapy was significantly improved in patients treated with a combination of chemo- and allogeneic cell-based therapy (CR rate 57% vs 13%, P=0.002). Among risk factors concerning pretreatment characteristics, disease status before first Allo-SCT, and details of transplantation, only the time interval from Allo-SCT to relapse was an independent predictor of response to salvage therapy and OS. These data confirmed that time to relapse after transplantation is an important prognostic factor. Up to now, only patients eligible for treatment regimens containing allogeneic cell-based interventions achieved relevant response rates.Bone Marrow Transplantation advance online publication, 19 January 2015; doi:10.1038/bmt.2014.300.
No preview · Article · Jan 2015 · Bone Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Abstract Wilms' Tumor 1 (WT1) is known to be highly expressed in acute promyelocytic leukemia (APL) but information on its impact on prognosis is lacking. WT1 expression was analyzed in bone marrow samples of 79 APL patients at initial diagnosis. Patients had a differing outcome according to their level of WT1 expression. In patients who achieved a CR, low or high WT1 expression was significantly associated with inferior overall survival (OS) compared to intermediate WT1 expression (49% high vs. 63% for low vs. 93% for intermediate expressers; p=0.008). Moreover, there were significant differences in relapse free survival (RFS) between the three expression groups (42% for WT1(high), 63% for WT1(low) and 83% for WT1(int); p=0.047). In multivariable analysis WT1 expression showed independent prognostic impact on OS of responders to induction therapy. In conclusion, the level of WT1 expression can add prognostic information in APL risk stratification.
No preview · Article · Nov 2014 · Leukemia and Lymphoma
[Show abstract][Hide abstract] ABSTRACT: NPM1 mutations represent frequent genetic alterations in patients with acute myeloid leukemia (AML) associated with a favorable prognosis. Different types of NPM1 mutations have been described. The purpose of our study was to evaluate the relevance of different NPM1 mutation types with regard to clinical outcome. Our analyses were based on 349 NPM1-mutated AML patients treated in the AMLCG99 trial. Complete remission rates, overall survival and relapse-free survival were not significantly different between patients with NPM1 type A or rare type mutations. The NPM1 mutation type does not seem to play a role in risk stratification of cytogenetically normal AML.
[Show abstract][Hide abstract] ABSTRACT: Background
The aim of this study was to analyze the long-term survival of AML patients with CEBPA mutations.Patients and methodsWe investigated 88 AML patients with a median age of 61 years and (1) cytogenetically normal AML (CN-AML), (2) monoallelic (moCEBPA) or biallelic (biCEBPA) CEBPA mutation, and (3) intensive induction treatment. 60/88 patients have been described previously with a shorter follow-up.ResultsMedian follow-up time was 9.8 years (95% CI: 9.4-10.1 years) compared to 3.2 and 5.2 years in our former analyses. Patients with biCEBPA survived significantly longer compared to those with moCEBPA (median overall survival (OS) 9.6 years vs. 1.7 years, p¿=¿0.008). Patients¿¿¿60 years and biCEBPA mutations showed a favorable prognosis with a 10-year OS rate of 81%.Both, bi- and moCEBPA-mutated groups had a low early death (d60) rate of 7% and 9%, respectively. Complete remission (CR) rates for biCEBPA- and moCEBPA-mutated patients were 82% vs. 70% (p¿=¿0.17). biCEBPA-mutated patients showed a longer relapse free survival (RFS) (median RFS 9.4 years vs. 1.5 years, p¿=¿0.021) and a lower cumulative incidence of relapse (CIR) compared to moCEBPA-mutated patients. These differences in OS and RFS were confirmed after adjustment for known clinical and molecular prognostic factors.Conclusions
In this long-term observation we confirmed the favorable prognostic outcome of patients with biCEBPA mutations compared to moCEBPA-mutated CN-AML. The high probability of OS (81%) in younger patients is helpful to guide intensity of postremission therapy.
[Show abstract][Hide abstract] ABSTRACT: Isolated trisomy 13 (AML+13) is a rare chromosomal abnormality in acute myeloid leukemia (AML), and its prognostic relevance is poorly characterized. We analyzed the clinical course of 34 AML+13 patients enrolled in the German AMLCG-1999 and SAL trials and studied their biological characteristics by exome sequencing, targeted sequencing of candidate genes and gene expression profiling. Relapse-free (RFS) and overall survival (OS) of AML+13 patients were inferior compared to other ELN Intermediate-II patients (n=855) (median RFS, 7.8 vs 14.1 months, p=0.006; median OS 9.3 vs. 14.8 months, p=0.004). Besides the known high frequency of RUNX1 mutations (75%), we identified mutations in spliceosome components in 88%, including SRSF2 codon 95 mutations in 81%, of AML+13 patients. Moreover, recurring mutations were detected in ASXL1 (44%) and BCOR (25%). Two patients carried mutations in CEBPZ, suggesting that CEBPZ is a novel recurrently mutated gene in AML. Gene expression analysis revealed a homogenous expression profile including upregulation of FOXO1 and FLT3 and downregulation of SPRY2. This is the most comprehensive clinical and biological characterization of AML+13 to date, and reveals a striking clustering of lesions in a few genes, defining AML+13 as a genetically homogenous leukemia subgroup with alterations in a few critical cellular pathways. These studies were registered at clinicaltrials.gov, identifiers: AMLCG-1999: NCT00266136; AML96: NCT00180115; AML2003: NCT00180102; and AML60+: NCT00893373.
[Show abstract][Hide abstract] ABSTRACT: In acute myeloid leukemia (AML), assessment of minimal residual disease (MRD) by flow cytometry (flow MRD) after induction and consolidation therapy has been shown to provide independent prognostic information. However, data on the value of earlier flow MRD assessment is lacking. Therefore, the value of flow MRD detection was determined during aplasia in 178 patients achieving complete remission after treatment according to AMLCG induction protocols. Flow MRD-positivity during aplasia predicted poor outcome (5-year relapse-free survival (RFS) 16% vs 43%, P<0.001) independently from age and cytogenetic risk group (hazard ratio for MRD-positivity 1.71; P=0.009). Importantly, the prognosis of patients without detectable MRD was not impacted by morphological blast count during aplasia nor by MRD status post-induction. Early flow MRD was also evaluated in the context of existing risk factors. Flow MRD was prognostic within the intermediate cytogenetic risk group (5-year RFS 15% vs. 37%, p=0.016) as well as for patients with normal karyotype and NPM1 mutations (5-year RFS 13% vs. 49%, P=0.02) or FLT3-ITD (3-year RFS rates 9% vs. 44%, P=0.016). Early flow MRD assessment can improve current risk stratification approaches by prediction of RFS in AML and might facilitate adaptation of post-remission therapy for patients at high risk of relapse.Leukemia accepted article preview online, 10 June 2014; doi:10.1038/leu.2014.186.
[Show abstract][Hide abstract] ABSTRACT: Monitoring of minimal residual disease represents an important diagnostic tool to identify patients with acute myeloid leukemia at high risk for relapse. In this study the prognostic potential of minimal residual disease monitoring by quantitative real-time PCR of NPM1 mutations of patients treated in the AMLCG trials 1999, 2004 and 2008 was investigated. Minimal residual disease monitoring was performed in 588 samples of 158 NPM1 mutation A, B and D positive patients at diagnosis, in aplasia, after induction therapy, after consolidation therapy, and during follow-up with a sensitivity of 10-6. 127 patients (80.4%) achieved complete remission after induction therapy and of these 56 patients (44.1%) relapsed. At each checkpoints, minimal residual disease cut-offs were calculated. After induction therapy a cut-off NPM1 mutation ratio of 0.01 revealed a high hazard ratio of 4.26 and the highest sensitivity of 76% for the prediction of relapse. This was reflected in a cumulative incidence of relapse after 2 years of 77.8% for cut-off positive patients versus 26.4% for cut-off negative patients, respectively. In the favorable subgroup according to European LeukemiaNet, the cut-off after induction therapy also separates the cohort into two prognostic groups with a cumulative incidence of relapse of 76% versus 6% after 2 years. Our data demonstrate that in addition to pre-therapeutic factors, the individual minimal residual disease course is an important prognostic factor and could be included into clinical trials for the guidance of postremission therapy. Trials were registered at www.clinicaltrials.gov (#NCT01382147, #NCT00266136) and at the European Leukemia Trial Registry (#LN_AMLINT2004_230).
[Show abstract][Hide abstract] ABSTRACT: 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.
Two prognostic indices for CN-AML (PINA), one regarding overall survival (OS; PINAOS) and the other regarding relapse-free survival (RFS; PINARFS), were derived from data of 572 patients with CN-AML treated within the AML Cooperative Group 99 study (www.aml-score.org.
On the basis of age (median, 60 years; range, 17 to 85 years), performance status, WBC count, and mutation status of NPM1, CEBPA, and FLT3-internal tandem duplication, patients were classified into the following three risk groups according to PINAOS and PINARFS: 29% of all patients and 32% of 381 responding patients had low-risk disease (5-year OS, 74%; 5-year RFS, 55%); 56% of all patients and 39% of responding patients had intermediate-risk disease (5-year OS, 28%; 5-year RFS, 27%), and 15% of all patients and 29% of responding patients had high-risk disease (5-year OS, 3%; 5-year RFS, 5%), respectively. PINAOS and PINARFS stratified outcome within European LeukemiaNet genetic groups. Both indices were confirmed on independent data from Cancer and Leukemia Group B/Alliance trials.
We have developed and validated, to our knowledge, the first prognostic indices specifically designed for adult patients of all ages with CN-AML that combine well-established molecular and clinical variables and that are easily applicable in routine clinical care. The integration of both clinical and molecular markers could provide a basis for individualized patient care through risk-adapted therapy of CN-AML.
[Show abstract][Hide abstract] ABSTRACT: About 30% of patients with acute myeloid leukemia (AML) harbour mutations of the receptor tyrosine kinase FLT3, mostly internal tandem duplications (ITD) and point mutations of the second tyrosine kinase domain (TKD). It was the aim of this study to comprehensively analyze clinical and functional properties of various FLT3 mutants.
In 672 normal karyotype AML patients FLT3-ITD, but not FLT3-TKD mutations were associated with a worse relapse free and overall survival in multivariate analysis. In paired diagnosis-relapse samples FLT3-ITD showed higher stability (70%) compared to FLT3-TKD (30%). In vitro, FLT3-ITD induced a strong activating phenotype in Ba/F3 cells. In contrast, FLT3-TKD mutations and other point mutations – including two novel mutations – showed a weaker but clear gain-of-function phenotype with gradual increase in proliferation and protection from apoptosis. The pro-proliferative capacity of the investigated FLT3 mutants was associated with cell surface expression and tyrosine 591 phosphorylation of the FLT3 receptor. Western blot experiments revealed STAT5 activation only in FLT3-ITD positive cell lines, in contrast to FLT3-non-ITD mutants, which displayed an enhanced signal of AKT and MAPK activation. Gene expression analysis revealed distinct difference between FLT3-ITD and FLT3-TKD for STAT5 target gene expression as well as deregulation of SOCS2, ENPP2, PRUNE2 and ART3.
FLT3-ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. Although poor prognosis in AML is only associated with FLT3-ITD, all activating FLT3 mutations can contribute to leukemogenesis and are thus potential targets for therapeutic interventions.
[Show abstract][Hide abstract] ABSTRACT: The majority of patients with acute myeloid leukemia (AML) who achieve complete remission (CR) relapse with conventional postremission chemotherapy. Allogeneic stem-cell transplantation (alloSCT) might improve survival at the expense of increased toxicity. It remains unknown for which patients alloSCT is preferable.
We compared the outcome of 185 matched pairs of a large multicenter clinical trial (AMLCG99). Patients younger than 60 years who underwent alloSCT in first remission (CR1) were matched to patients who received conventional postremission therapy. The main matching criteria were AML type, cytogenetic risk group, patient age, and time in first CR.
In the overall pairwise compared AML population, the projected 7-year overall survival (OS) rate was 58% for the alloSCT and 46% for the conventional postremission treatment group (P = .037; log-rank test). Relapse-free survival (RFS) was 52% in the alloSCT group compared with 33% in the control group (P < .001). OS was significantly better for alloSCT in patient subgroups with nonfavorable chromosomal aberrations, patients older than 45 years, and patients with secondary AML or high-risk myelodysplastic syndrome. For the entire patient cohort, postremission therapy was an independent factor for OS (hazard ratio, 0.66; 95% CI, 0.49 to 0.89 for alloSCT v conventional chemotherapy), among age, cytogenetics, and bone marrow blasts after the first induction cycle.
AlloSCT is the most potent postremission therapy for AML and is particularly active for patients 45 to 59 years of age and/or those with high-risk cytogenetics.
Full-text · Article · Dec 2013 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Chemo-modulation of cytarabine by fludarabine has been attributed with a higher anti-leukemic efficacy, but randomized trials to address this question are rare. We therefore conducted a multicenter, randomized phase III study to evaluate the antileukemic efficacy of adding fludarabine to sequential high-dose cytarabine+idarubicin (SHAI) re-induction chemotherapy in relapsed or refractory acute myeloid leukemia (AML). Patients (n=326, 281 evaluable) were randomly assigned to SHAI (cytarabine 1 g/m(2) bid days 1-2 and 8-9 [3 g/m(2) for patients60 years with refractory AML or2nd relapse], idarubicin 10 mg/m(2) daily days 3-4 and 10-11) or F-SHAI (SHAI with fludarabine 15 mg/m(2) 4 hours prior to cytarabine). While complete remission (CR) rates (35% SHAI and 44% F-SHAI) and overall survival did not differ between both regimens, fludarabine prolonged time-to-treatment failure from 2.04 months to 3.38 months (median, P<0.05). Twenty-seven percent of patients proceeded to allogeneic SCT, with a significantly higher number of patients in CR or CRi in the F-SHAI group (22% versus 10%, P<0.01). In conclusion, fludarabine has a beneficial though moderate impact on the antileukemic efficacy of high-dose cytarabine based salvage therapy for relapsed and refractory AML.Leukemia accepted article preview online, 22 October 2013; doi:10.1038/leu.2013.297.
No preview · Article · Oct 2013 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: We investigated whether octogenarian patients with acute myeloid leukemia enrolled onto Cooperative Group clinical trials and treated with intensive induction therapy could be cured, and whether karyotype and selected molecular markers had any prognostic significance in these patients. Among 138 patients with cytogenetic results, normal karyotype was the most common (47.1%) followed by complex karyotype (14.5%) and sole +8 (9.4%). Among these patients, the relapse-free survival (RFS) rate at 1 year was 37% and 13% at 3 years, and the respective overall survival (OS) rates were 24% and 8%. Whereas the 90 patients who survived beyond 30 days had the same RFS rates, their 1-year and 3-year OS rates were 36% and 11%, respectively. Of the 66 patients surviving beyond 30 days who could be classified into the European LeukemiaNet (ELN) Genetic Groups, those in the Intermediate-I Group had better OS than patients in the Adverse Group (P=.01). Among patients with cytogenetically normal acute myeloid leukemia who were tested for the ELN-associated molecular alterations, FLT3-internal tandem duplication and NPM1 mutations, FLT3-internal tandem duplication (detected in 29% of patients) did not associate with OS (P=.31), whereas NPM1 mutations (30%) were associated with a significantly longer OS (P=.002). We conclude that intensive induction is effective and indicated in selected octogenarians with acute myeloid leukemia, that their OS varies among the ELN Genetic Groups and that NPM1 mutations may be of prognostic significance among octogenarian patients with cytogenetically normal acute myeloid leukemia.
[Show abstract][Hide abstract] ABSTRACT: The t(8;21) and inv(16)/t(16;16) rearrangements affecting the core-binding factors, RUNX1 and CBFB, respectively, are found in 15-20% of adult de novo AML cases and are associated with a favourable 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 ATP-binding domain (TKD1) of the fms-related tyrosine kinase 3 (FLT3) gene. In a cohort of 84 de novo AML patients with a CBFB/MYH11 rearrangement and in 36 patients with a RUNX1/RUNX1T1 rearrangement, the FLT3 N676K mutation was identified in 5 and 1 patients, respectively (5/84, 6%; 1/36, 3%). The FLT3-N676K mutant alone leads to factor-independent growth in Ba/F3 cells and, together with a concurrent FLT3-ITD, confers resistance to the FLT3 PTK inhibitors PKC412 and AC220. Gene expression analysis of AML patients with CBFB/MYH11 rearrangement and FLT3 N676K mutation showed a trend towards a specific expression profile. Ours is the first report of recurring FLT3 N676 mutations in CBF leukemias and suggests a defined subgroup of CBF leukemias. Registered at www.clinicaltrials.gov: AMLCG-1999 trial (NCT00266136).