[Show abstract][Hide abstract] ABSTRACT: Sympathetic and frank communication about the terminal nature of advanced cancer is important to improve patients' prognostic understanding and, thereby, to allow for adjustment of treatment intensity to realistic goals; however, decisions against aggressive treatments are often made only when death is imminent. This qualitative study explores the factors that hinder such communication and reconstructs how physicians and nurses in oncology perceive their roles in preparing patients for end-of-life (EOL) decisions.
[Show abstract][Hide abstract] ABSTRACT: This largest prospective multicenter trial for adult patients with Burkitt lymphoma/leukemia aimed to prove efficacy and feasibility of a short-intensive chemotherapy combined with the anti-CD20 antibody Rituximab. 363 patients 16 to 85 years old (median 42 yrs) were recruited in 98 centers from 8/2002 until 06/2011. Treatment consisted of 6 five-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years received a reduced regimen. Rituximab was given d -1 before each cycle and twice as maintenance, for a total of 8 doses. The complete remission rate was 88% (319/363), the overall survival (OS) at 5 years 80%, and the progression-free survival (PFS) 71%, with significant difference between adolescents (≥15-25 yrs), adults (26-55 yrs) and elderly (>55 yrs) patients with an OS of 90%, 84%, and 62%. Full treatment could be applied in 86% of the patients. Most important prognostic factors were IPI (0-2 vs. 3-5, p=0.0005), aaIPI (0-1 vs. 2-3, p=0.0001), and gender (male vs. female, p=0.004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, also in elderly patients. The study is registered to www.clinicaltrials.gov as NCT00199082.
[Show abstract][Hide abstract] ABSTRACT: Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients.
[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: Cyclic cytotoxic maintenance therapy can be applied to patients with AML in post-remission. We studied the immune status of AML patients in complete remission and the effect of maintenance therapy on different immune cell populations. Patients in complete remission had reduced NK, TH and Treg counts and a reduced NK activation capacity. In the course of cytotoxic maintenance therapy, NK counts further declined, while TH and Treg cells increased, with lower proliferative potential of TH cells. We conclude that immunotherapeutic approaches in post-remission have to consider reduced NK cell function and further impairment of cellular immune responses during cytotoxic therapy.
[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.
Journal of Clinical Oncology 04/2014; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mantle-cell lymphoma (MCL) is a distinct B-cell lymphoma associated with poor outcome. In 2008, the MCL International Prognostic Index (MIPI) was developed as the first prognostic stratification tool specifically directed to patients with MCL. External validation was planned to be performed on the cohort of the two recently completed randomized trials of the European MCL Network.
Data of 958 patients with MCL (median age, 65 years; range, 32 to 87 years) treated upfront in the trials MCL Younger or MCL Elderly were pooled to assess the prognostic value of MIPI with respect to overall survival (OS) and time to treatment failure (TTF).
Five-year OS rates in MIPI low, intermediate, and high-risk groups were 83%, 63%, and 34%, respectively. The hazard ratios for OS of intermediate versus low and high versus intermediate risk patients were 2.1 (95% CI, 1.5 to 2.9) and 2.6 (2.0 to 3.3), respectively. MIPI was similarly prognostic for TTF. All four clinical baseline characteristics constituting the MIPI, age, performance status, lactate dehydrogenase level, and WBC count, were confirmed as independent prognostic factors for OS and TTF. The validity of MIPI was independent of trial cohort and treatment strategy.
MIPI was prospectively validated in a large MCL patient cohort homogenously treated according to recognized standards. As reflected in current guidelines, MIPI represents a generally applicable prognostic tool to be used in research as well as in clinical routine, and it can help to develop risk-adapted treatment strategies to further improve clinical outcome in MCL.
Journal of Clinical Oncology 03/2014; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Loss of heterozygosity (LOH) is a common event in malignant cells. In this work we introduce a new approach to identify patients with loss of heterozygosity in the HLA region either at first diagnosis or after HLA mismatched allogeneic HSCT. Diagnosis of LOH requires a high purity of recipient target cells. FACS is time consuming and also frequently prevented by rather nonspecific or unknown immune phenotype. The approach for recipient cell enrichment is based on HLA targeted complement-dependent cytotoxicity (CDC). Relative fluorescent quantification (RFQ) analysis of HLA intron length polymorphisms then allows analysis of HLA heterozygosity. The approach is exemplified in recent clinical cases illustrating the detection of an acquired allele loss. As illustrated in one case with DPB1, distinct HLA loci in donor and patient were sufficient for both proof of donor cell removal and evaluation of allele loss in the patient's leukemic cells. Results were confirmed using HLA-B RFQ analysis and leukemia-associated aberrant immunophenotype (LAIP) based cell sort. Both results confirmed suspected loss of HLA heterozygosity. Our approach complements or substitutes for FACS-based cell enrichment; hence it may be further developed as novel routine diagnostic tool. This allows rapid recipient cell purification and testing for loss of HLA heterozygosity before and after allogeneic HSCT in easily accessible peripheral blood samples.
[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.
PLoS ONE 01/2014; 9(3):e89560. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hyperleukocytosis in AML with leukostasis is a serious life-threatening condition leading to a high early mortality which requires immediate cytoreductive therapy. Therapeutic leukapheresis is currently recommended by the American Society of Apheresis in patients with a WBC>100 G/l with signs of leukostasis, but the role of prophylactic leukapheresis before clinical signs of leukostasis occur is unclear.
We retrospectively analyzed the role of leukapheresis in 52 patients (median age 60 years) with hyperleukocytotic AML with and without clinical signs of leukostasis. Since leukapheresis was performed more frequently in patients with signs of leukostasis due to the therapeutic policy in our hospital, we developed a risk score for early death within seven days after start of therapy (EDd7) to account for this selection bias and to independently measure the effect of leukapheresis on EDd7.
20 patients received leukapheresis in combination to chemotherapy compared to 32 patients who received chemotherapy only. In a multivariate logistic regression model for the estimation of the probability of EDd7 thromboplastin time and creatinine remained as independent significant parameters and were combined to create an EDd7 risk score. The effect of leukapheresis on EDd7 was evaluated in a bivariate logistic regression together with the risk score. Leukapheresis did not significantly change early mortality in all patients with a WBC≥100 G/l.
Prophylactic leukapheresis in hyperleukocytotic patients with and without leukostasis did not improve early mortality in our retrospective study. Larger and prospective clinical trials are needed to validate the risk score and to further explore the role of leukapheresis in AML with hyperleukocytosis.
PLoS ONE 01/2014; 9(4):e95062. · 3.53 Impact Factor
[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.
PLoS ONE 01/2014; 9(10):e109759. · 3.53 Impact Factor
[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.
Journal of Clinical Oncology 12/2013; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antibody-based immunotherapy represents a promising strategy to target and eliminate chemoresistant leukemic cells. Here, we evaluated the CD33/CD3-bispecific BiTE® antibody (AMG 330) for its suitability as therapeutic agent in AML. We first assessed CD33 expression levels by flow cytometry and found expression in >99% of patient samples (n=621). CD33 was highest expressed in AMLs with NPM1 mutations (p<0.001) and lower in AMLs with complex karyotypes and t(8;21) translocations (p<0.001). Furthermore, leukemic stem cells within the CD34(+)/CD38(-) compartment displayed CD33 at higher levels than healthy donor stem cells (p=0.047). In MS-5 feeder cell-based long-term cultures that supported the growth of primary AML blasts for up to 36 days, AMG 330 efficiently recruited and expanded residual CD3(+)/CD45RA(-)/CCR7(+) memory T-cells within the patient sample. Even at low effector to target ratios, the recruited T-cells lysed autologous blasts completely in the majority of samples and substantially in the remaining samples in a time- dependent manner. This study provides the first correlation of CD33 expression levels with AML genotype in a comprehensive analysis of adult patients. Targeting CD33 ex-vivo using AMG 330 in primary AML samples led to T-cell recruitment and expansion and remarkable antibody-mediated cytotoxicity suggesting efficient therapeutic potential in-vivo.
[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: We present a case of a 42-year old female with the rare diagnosis of a myeloproliferative syndrome harboring both a BCR-ABL transclocation and a JAK2V617F mutation.Initially diagnosed with a CML, the patient underwent treatment with imatinib followed by dasatinib. Despite a major molecular response, the patient developed a thrombocytosis. Molecular analyses revealed a heterozygous JAK2V617F mutation, which was detected retrospectively in the bone marrow at the time of CML diagnosis.This case underlines the complexity of MPS pathogenesis. For the clinician, a JAK2 mutational screening should be performed in CML patients without hematological response in the absence of BCR-ABL.
[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).