Maria Cristina Sauerland

Patients with de novo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment: a study of 90 patients

The clinical significance of complex chromosome aberrations for adults with acute myeloid leukaemia (AML) was assessed in 920 patients with de novo AML who were karyotyped and treated within the German AML Cooperative Group (AMLCG) trials. Complex chromosome aberrations were defined as three or more numerical and/or structural chromosome aberrations excluding translocations t(8;21)(q22;q22), t(15;17)(q22;q11–q12) and inv(16)(p13q22). Complex chromosome anomalies were detected in 10% of all cases with a significantly higher incidence in patients  60 years of age (17·8% vs. 7·8%, P < 0·0001). Clinical follow‐up data were available for 90 patients. Forty‐five patients were < 60 years of age and were randomly assigned to double induction therapy with either TAD‐TAD [thioguanine, daunorubicin, cytosine arabinoside (AraC)] or TAD‐HAM (high‐dose AraC, mitoxantrone). Twenty‐one patients achieved complete remission (CR) (47%), 20 patients (44%) were non‐responders and 9% of patients died during aplasia (early death). The median overall survival (OS) was 7 months and the OS rate at 3 years was 12%. Patients receiving TAD‐HAM showed a significantly higher CR rate than patients receiving TAD‐TAD (56% vs. 23%, P = 0·04). Median event‐free survival was less than 1 month in the TAD‐TAD group and 2 months in the TAD‐HAM group, respectively (P = 0·04), with a median OS of 4·5 months vs. 7·6 months (P = 0·13) and an OS after 3 years of 7·6% vs. 19·6%. Forty‐five patients were  60 years of age: 28 of these patient were treated for induction using one or two TAD courses and 17 cases received TAD‐HAM with an age‐adjusted reduction of the AraC dose. The CR rate was 44%, 38% were non‐responders and 18% experienced early death. The median OS was 8 months and the OS rate at 3 years was 6%. In conclusion, complex chromosome aberrations in de novo AML predicted a dismal outcome, even when patients were treated with intensive chemotherapy. Patients under the age of 60 years with complex aberrant karyotypes may benefit from HAM treatment during induction. However, long‐term survival rates are low and alternative treatment strategies for remission induction and consolidation are urgently needed.

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. Risk prediction was validated in an independent cohort of 801 patients (aged >60 years) with acute myeloid leukaemia who were given two courses of cytarabine and daunorubicin in the Acute Myeloid Leukaemia 1996 study. FINDINGS Body temperature, age, de-novo leukaemia versus leukaemia secondary to cytotoxic treatment or an antecedent haematological disease, haemoglobin, platelet count, fibrinogen, and serum concentration of lactate dehydrogenase were significantly associated with CR or ED. The probability of CR with knowledge of cytogenetic and molecular risk (score 1) was from 12% to 91%, and without knowledge (score 2) from 21% to 80%. The predicted risk of ED was from 6% to 69% for score 1 and from 7% to 63% for score 2. The predictive power of the risk scores was confirmed in the independent patient cohort (CR score 1, from 10% to 91%; CR score 2, from 16% to 80%; ED score 1, from 6% to 69%; and ED score 2, from 7% to 61%). INTERPRETATION The scores for acute myeloid leukaemia can be used to predict the probability of CR and the risk of ED in older patients with acute myeloid leukaemia, but otherwise medically healthy, for whom intensive induction chemotherapy is planned. This information can help physicians with difficult decisions for treatment of these patients. FUNDING Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft.

Double induction strategy including high dose cytarabine in combination with all- trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia

A prospective multicenter study was performed to investigate the clinical and molecular results of intensified double induction therapy including high-dose cytarabine (ara-C) in combination with ATRA in newly diagnosed acute promyelocytic leukemia (APL), followed by consolidation and 3 years maintenance therapy. Fifty-one patients, diagnosed and monitored from December 1994 to June 1999, were evaluated. The median age was 43 (16–60) years. The morphologic diagnosis was M3 in 40 (78%) and M3v in 11 (22%) patients. In 15 (30%) patients the initial white blood cell counts were ⩾5 × 109/l. The cytogenetic or molecular proof of the translocation t(15;17) was a mandatory prerequisite for eligibility. The diagnosis was confirmed by karyotyping in 46 and by RT-PCR of the PML/RARα transcript in 45 cases. The rate of complete hematological remission was 92% and the early death rate 8%. Monitoring of minimal residual disease by RT-PCR of PML/RARα (sensitivity 10−4) showed negativity in 29 of 32 (91%) evaluable cases after induction, in 23 of 25 (92%) after consolidation, and in 27 of 30 (90%) during maintenance, after a median time of 2, 4 and of 18 months after diagnosis, respectively. After a median follow-up of 27 months, the estimated actuarial 2 years overall and event-free survival were both 88% (79, 97), and the 2 years relapse-free survival 96% (90, 100). The high antileukemic efficacy of this treatment strategy is demonstrated by a rapid and extensive reduction of the malignant clone and by a low relapse rate. The results suggest that the intensity of the induction chemotherapy combined with ATRA is one of the factors which may have a critical influence on the outcome of APL. A randomized trial should assess the value of an induction therapy including ATRA and high-dose ara-C in comparison to standard-dose ara-C.

Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia.

The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients.

significance of Age in Acute Myeloid Leukemia Patients Younger Than 30 Years : a Common Analysis of the Pediatric Trials Aml-bfm 93/98 and the Adult Trials Amlcg 92/99 and Amlsg Hd93/98a

Data on the impact of age in acute myeloid leukemia (AML) patients <30 years treated in pediatric and adult trials are scarce.

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. Both GATA2 and CEBPA are transcription factors crucial for hematopoietic development. Inherited or acquired mutations in both genes have been associated with leukemogenesis. Further mutational screening detected novel GATA2 ZF1 mutations in 13 of 33 biCEBPA-positive CN-AML patients (13/33, 39.4%). No GATA2 mutations were found in 38 CN-AML patients with a monoallelic CEBPA mutation and in 89 CN-AML patients with wild-type CEBPA status. The presence of additional GATA2 mutations (n=10) did not significantly influence the clinical outcome of 26 biCEBPA-positive patients. In reporter gene assays, all tested GATA2 ZF1 mutants showed reduced capacity to enhance CEBPA-mediated activation of transcription, suggesting that the GATA2 ZF1 mutations may collaborate with biCEPBA mutations to deregulate target genes during malignant transformation. We thus provide evidence for a genetically distinct subgroup of CN-AML. The German AML cooperative group trials 1999 and 2008 are registered with the identifiers NCT00266136 and NCT01382147 at www.clinicaltrials.gov.

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. Notably, patients from different sets were treated with different protocols, and their gene expression profiles were derived using different microarray platforms. Cox regression and Kaplan-Meier methods were used for survival analyses. RESULTS A prognostic signature composed of 24 genes was derived from a meta-analysis of Cox regression values of each gene across the four training sets. In multivariable models, a higher sum value of the 24-gene signature was an independent predictor of shorter overall (OS) and event-free survival (EFS) in both training and validation sets (P < .01). Moreover, this signature could substantially improve the European LeukemiaNet (ELN) risk classification of AML, and patients in three new risk groups classified by the integrated risk classification showed significantly (P < .001) distinct OS and EFS. CONCLUSION Despite different treatment protocols applied to patients and use of different microarray platforms for expression profiling, a common prognostic gene signature was identified as an independent predictor of survival of patients with AML. The integrated risk classification incorporating this gene signature provides a better framework for risk stratification and outcome prediction than the ELN classification.

The significance of trisomy 8 in de novo acute myeloid leukaemia: the accompanying chromosome aberrations determine the prognosis

Trisomy 8 is the most frequent numerical chromosome aberration in acute myeloid leukaemia (AML). It occurs either as the sole anomaly or together with other clonal chromosome aberrations. We investigated whether accompanying chromosome anomalies influence the clinical outcome in patients with trisomy 8 and de novo AML. Since 1986, in 713 AML cases treated according to the protocols of the German AMLCG trials, chromosome analyses have been successfully performed. The overall incidence of trisomy 8 was 7.6%. Complete clinical follow‐up data were available for 51 patients who were divided into three different categories: group 1: trisomy 8 as the sole cytogenetic anomaly (n = 20); group 2: trisomy 8 in addition to favourable chromosome aberrations (t(8;21)(q22;q22), t(15;17)(q22;q21), inv(16)(p13q22)) (n = 10); and group 3: trisomy 8 accompanied by other anomalies, in most cases of complex type (n = 21). Complete remission (CR) rates were 70%, 90% and 67% for groups 1, 2 and 3, respectively. Event‐free survival (EFS) at 3 years differed significantly between patients with trisomy 8 only (37.5%), patients with trisomy 8 in combination with favourable aberrations (55.0%) and patients with trisomy 8 and other accompanying anomalies, mostly complex chromosome aberrations (9.0%) (group 1 v group 2: P = 0.12; group 1 v group 3: P = 0.005; group 2 v group 3: P = 0.05). In this study patients with +8 as the sole cytogenetic anomaly had an intermediate prognosis, patients with +8 in addition to favourable chromosome aberrations maintained a good clinical outcome, and patients with +8 in combination with other abnormalities showed the worst prognosis.

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. PATIENTS AND METHODS 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). RESULTS 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. CONCLUSION 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.

Allogeneic Transplantation Versus Chemotherapy as Postremission Therapy for Acute Myeloid Leukemia: A Prospective Matched Pairs Analysis

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.