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Originally published as JCO Early Release 10.1200/JCO.2004.03.012 on August 2 2004 © 2004 American Society of Clinical Oncology. Individual Patient Data–Based Meta-Analysis of Patients Aged 16 to 60 Years With Core Binding Factor Acute Myeloid Leukemia: A Survey of the German Acute Myeloid Leukemia IntergroupFrom the Department of Internal Medicine III, University of Ulm, Ulm; Central Unit of Biostatistics, German Cancer Research Center Heidelberg, Heidelberg; Department of Hematology/Oncology, University of Hannover, Hannover; Department of Internal Medicine A and Department of Medical Informatics and Bioinformatics, University of Münster, Münster; Department of Internal Medicine I, University of Dresden, Dresden; Department of Hematology/Oncology, University of Leipzig, Leipzig; and Ernst von Bergmann Klinik, Potsdam, Germany Address reprint requests to Hartmut Döhner, MD, Department of Internal Medicine III, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany; e-mail: hartmut.doehner{at}medizin.uni-ulm.de
PURPOSE: To evaluate prognostic factors for relapse-free survival (RFS) and overall survival (OS) and to assess the impact of different postremission therapies in adult patients with core binding factor (CBF) acute myeloid leukemias (AML). PATIENTS AND METHODS: Individual patient data–based meta-analysis was performed on 392 adults (median age, 42 years; range, 16 to 60 years) with CBF AML (t(8;21), n = 191; inv(16), n = 201) treated between 1993 and 2002 in prospective German AML treatment trials. RESULTS: RFS was 60% and 58% and OS was 65% and 74% in the t(8;21) and inv(16) groups after 3 years, respectively. For postremission therapy, intention-to-treat analysis revealed no difference between intensive chemotherapy and autologous transplantation in the t(8;21) group and between chemotherapy, autologous, and allogeneic transplantation in the inv(16) group. In the t(8;21) group, significant prognostic variables for longer RFS and OS were lower WBC and higher platelet counts; loss of the Y chromosome in male patients was prognostic for shorter OS. In the inv(16) group, trisomy 22 was a significant prognostic variable for longer RFS. For patients who experienced relapse, second complete remission rate was significantly lower in patients with t(8;21), resulting in a significantly inferior survival duration after relapse compared with patients with inv(16). CONCLUSION: We provide novel prognostic factors for CBF AML and show that patients with t(8;21) who experience relapse have an inferior survival duration.
Cytogenetically, the group of core binding factor (CBF) acute myeloid leukemias (AML) is defined by the presence of the t(8;21)(q22;q22) or the inv(16)(p13q22)/t(16;16)(p13;q22). CBFs are a family of heterodimeric transcriptional regulators containing a common beta subunit (CBFß) associated with one of three alpha subunits (CBF  ). The t(8;21)(q22;q22) fuses the RUNX1 gene located on chromosome 21 to the CBFA2T1 gene located on chromosome 8.1 AMLs carrying the t(8;21) are frequently associated with specific characteristics, such as morphologic presentation with the French-American-British subtype M2 with myeloid precursors containing Auer rods,2 immunophenotypic aberrant expression of the CD19 antigen,3 and, in some patients, by extramedullary disease (granulocytic sarcomas).2,4 Cytogenetically, the specific translocation may be associated with loss of a sex chromosome (LOS) or deletions of the long arm of chromosome 9 [del(9q)].5 Clinically, high complete remission (CR) rates after standard induction therapy and favorable outcome, especially after dose-intensified cytarabine-based postremission therapy, have been reported.6-9 Inferior outcome has been reported in patients with high WBC or absolute granulocyte count,9-11 phenotypical expression of the CD56 antigen,12 additional del(9q),13 or extramedullary disease.4 However, these prognostic factors were identified in small retrospective studies, and only high WBC has been confirmed as a prognostically relevant variable in the French AML Intergroup study.10 In the inv(16) group, the CBFß gene located in 16q22 fuses to the MYH11 gene located in 16p13. AMLs carrying the inv(16) are frequently associated with specific characteristics, such as morphologic presentation with the French-American-British subtype M4eo with an abnormal eosinophilic differentiation14 and, in some patients, extramedullary involvement.2,15 Cytogenetically, the specific aberration may be associated with trisomies of the chromosomes 8, 21, and 22.16,17 Clinically, high CR rates after standard induction therapy and favorable outcome have been reported.6,9,17,18 However, there are conflicting data concerning the dose of cytarabine in postremission therapy.6,7,18,19 Inferior outcome has been reported in patients presenting with high WBC counts9,20 and older age.18 Primary objectives of the present survey were to identify novel prognostic factors for relapse-free survival (RFS) and overall survival (OS) and to assess the impact of different postremission therapies in a large series of young adults with CBF AML.
Patient Selection and Review of the Data Between July 1993 and August 2002, patients were prospectively enrolled in one of the eight following German multicenter treatment trials: Sueddeutsche Haemoblastose Gruppe (SHG)-Hannover AML 2/95,21 SHG-Hannover AML 1/99, SHG-Dresden AML 96,22 Acute Myeloid Leukemia Study Group (AMLSG) ULM AMLHD93,9 AMLSG ULM Acute Myeloid Leukemia–Heidelberg 98A,23 Acute Myeloid Leukemia Cooperative Group (AMLCG) 92,24 AMLCG99,25 and Ostdeutsche Studiengruppe Haematologie/Oukologie (033) AML-96. The inclusion criteria of the different trials were concordant, and the inclusion criteria for this survey were as follows: (1) presence of t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) on standard karyotypic analysis or presence of the RUNX1-CBFA2T1 or the CBFß-MYH11 fusion gene by molecular screening, (2) age 16 to 60 years, and (3) availability of clinical data. Demographic, diagnostic, clinical, and laboratory data, cytogenetics, type of induction, postremission and salvage therapy, and outcome information were collected for each patient, sent to a central coordination center, and reviewed for consistency and completeness before analysis. Immunophenotyping of leukemic cells was not included in the analysis because of lack of consistent data.
Cytogenetics
Protocols
Statistical Analysis The median follow-up for survival was calculated according to the method of Korn.36 The definition of CR followed the recommended criteria.37 Because most of the trials followed double induction strategies, evaluation of response was performed after two induction cycles for all trials. OS end points, measured from entry onto one of the prospective studies, were death (failure) and alive at last follow-up (censored).37 RFS end points, measured from the date of documented CR, were relapse (failure), death in CR (failure), and alive in CR at last follow-up (censored).37 Consolidation therapy was classified into cytarabine-based chemotherapy (chemotherapy), autologous stem-cell transplantation (SCT), and allogeneic SCT for intention-to-treat analysis. To assess the impact of dosage of cytarabine on RFS and OS in patients receiving chemotherapy, the intended cumulative dosage over all cycles of chemotherapy was calculated. This was done because considerable amounts of cytarabine were given in induction and consolidation therapy. The total dose varied among the different trials between 20.8 g/m2 and 56.8 g/m2 and was entered as a continuous variable into univariate and multivariate analysis. Testing and estimation of possible cutoff values for continuous variables were done by maximally selected log-rank statistics.38 Pairwise comparisons of patient characteristics were performed by the Mann-Whitney U test for continuous variables and by Fisher's exact test for categoric variables. The Kaplan-Meier method was used to estimate the distribution of RFS and OS. CI estimation for the survival curves was based on the cumulative hazard function using Greenwood's formula for the SE estimation.39 Survival distributions were compared using the log-rank test stratified for the variable study. A Cox model was used to identify prognostic variables.40 Missing data were estimated using a multiple-imputation technique using predictive mean matching with n = 100 imputations.41 A limited backward-selection procedure with was used to exclude redundant or unnecessary variables.41 To provide quantitative information on the relevance of results, 95% CIs of odds ratios and hazard ratios (HR) were computed. The statistical analyses were performed with the statistical software package R, version 1.7.142 together with the Design software library.41
Accrual of Patients and Their Initial Characteristics Between July 1993 and August 2002, 410 patients aged 16 to 60 years with CBF AML were registered. In 18 patients, no clinical data were available, leading to 392 eligible patients for this survey. Table 2 shows the distribution of clinical variables by type of CBF AML. Patients exhibiting inv(16) showed a statistically significant higher WBC count at diagnosis. Some patients had evidence of extramedullary involvement at diagnosis, including lymphadenopathy, granulocytic sarcoma, and CNS involvement. There was a statistically significant higher rate of lymphadenopathy and skin as well as mucosa involvement in the inv(16) group, whereas chloromas were more frequent in the t(8;21) group. However, diagnostic procedures were symptom-orientated, and computed tomography scans and CSF examination were not performed systematically.
Cytogenetics In six of 191 patients, t(8;21) was only identified by molecular techniques; in all six patients, there were no assessable metaphases on conventional cytogenetics. The most common additional aberration was LOS in 49%: 31 of 75 female patients had lost of one X chromosome, 58 of 110 male patients had loss the Y chromosome, and only one male patient had loss of the X chromosome. Del(9q) was present in 17% (Table 3). Variant t(8;21) was identified by conventional cytogenetics and confirmed by molecular techniques in 11 patients.
In 14 of 201 patients, inv(16) was only identified by molecular techniques: no metaphases were available in four patients, a normal karyotype was found in seven patients, and a del(16)(q22) was detected on conventional cytogenetics in three patients. In all these patients, the CBFß-MYH11 fusion was confirmed by molecular techniques. The evaluation of additional chromosomal aberrations was restricted to cases with karyotypically confirmed inv(16) (Table 2). The most common additional aberration was trisomy 22 in 22%, followed by trisomy 8 in 12%. There was no association between age, sex, and frequency of additional chromosomal aberrations.
Induction Therapy
Survival Analysis
Of 345 patients achieving CR after induction therapy, four and nine patients were ineligible for postremission therapy, leaving 162 and 170 assessable patients in the t(8;21) and the inv(16) groups, respectively. RFS and OS were analyzed on an intention-to-treat basis for both groups. In the t(8;21) group, only two patients were assigned to an allogeneic SCT, and they were therefore not included in the intention-to-treat analysis. There was no difference in RFS between chemotherapy and autologous SCT in the t(8;21) group (P = .81) and between chemotherapy, autologous SCT, and allogeneic SCT in the inv(16) group (P = .22; Fig 3). The as-treated analysis for patients receiving chemotherapy as postremission therapy revealed an estimated RFS and OS after 36 months of 62% (95% CI, 53% to 72%) and 75% (95% CI, 68% to 84%) in the t(8;21) group (n = 136) and 52% (95% CI, 43% to 64%) and 85% (95% CI, 76% to 92%) in the inv(16) group (n = 98), respectively.
Forty-one of 44 and 56 of 58 patients who experienced relapse received intensive reinduction therapy, including four and five patients allocated to allogeneic SCT without reinduction therapy in the t(8;21) and the inv(16) groups, respectively. The second CR rate was significantly lower at 33% (15 of 45 patients) in the t(8;21) group, compared with 78% (45 of 58) in the inv(16) group (P < .001; odds ratio, 7.4; 95% CI, 2.8 to 20.7), leading to a significantly (P = .05) lower percentage of patients receiving an intensive second consolidation therapy (t(8;21): matched related donor [MRD] SCT, n = 17; matched unrelated donor [MUD] SCT, n = 2; autologous SCT, n = 0; inv(16): MRD-SCT, n = 15; MUD-SCT, n = 13; autologous SCT, n = 3; intensive chemotherapy, n = 6). The survival after relapse was significantly better (P = .001) in patients exhibiting inv(16) compared with those exhibiting t(8;21) (Fig 4).
Evaluation of Prognostic Variables in t(8;21) Analyses of prognostic factors for RFS were performed in the subset of patients receiving chemotherapy for postremission therapy (n = 136), as well as in the whole group of patients achieving CR after induction therapy (n = 166). The following variables were evaluated: age, sex, WBC count, WBC index (product of WBC count and percentage of bone marrow blasts),10 bone marrow and peripheral-blood blast cell count, platelet count, hemoglobin level, cumulative dose of cytarabine over all cycles, additional chromosomal aberrations (LOS, del(9q), trisomy 8), and study. The variable treatment (SCT v no SCT) was included on an intention-to-treat basis in the second analysis. All continuous variables were included in the model either continuously or dichotomized, if a cut point in maximally selected log-rank statistics was evident. For WBC count, a cut point was found at 25.4 x 109/L (P = .05), whereas the cut point selection was done between 10.0 and 40.0 x 109/L. For platelet count, a cut point was found at 28 x 109/L (P = .05) with a cut point selection between 10.0 and 40.0 x 109/L. For the other continuous variables, no cut points were evident. The multivariate model for RFS with limited backward selection revealed dichotomized WBC count (high v low) and platelet count (high v low) as prognostic variables in patients receiving chemotherapy as postremission therapy (HR, 2.68; 95% CI, 1.19 to 6.04; and HR, 0.45; 95% CI, 0.23 to 0.90, respectively) as well as in the whole group (HR, 2.39; 95% CI, 1.25 to 4.54; and HR, 0.54; 95% CI, 0.30 to 0.95, respectively). By combining dichotomized WBC and platelet count in a hierarchical model for RFS, three risk groups could be established: a high-risk group with WBC count greater than 25.4 x 109/L, an intermediate-risk group with WBC count  25.4 x 109/L and platelet count 28 x 109/L, and a low-risk group with WBC count 25.4 x 109/L and platelet count greater than 28 x 109/L (Fig 5). There was no impact of the total dose of cytarabine given during induction and consolidation therapy on RFS analyzed on an intention-to-treat basis (P = .85).
In patients who experienced relapse, only univariate analyses were performed because of the low patient number. The analyses revealed that LOS (P = .04) and WBC count at diagnosis of greater than 25.4 x 109/L (P = .01) but not duration of first CR with a cut point of 1 year (P = .08) were variables associated with an inferior survival after relapse. There was an interaction between LOS and duration of first CR, with a significantly shorter duration of first CR in patients with loss of the Y chromosome (P = .03).
Finally, we applied the prognostic factors to OS of all assessable t(8;21) patients. The Cox regression model revealed platelet count
Evaluation of Prognostic Variables in inv(16) Analyses of prognostic factors for RFS were performed in the subset of patients receiving chemotherapy for postremission therapy (n = 98), as well as in the whole group of patients achieving CR after induction therapy (n = 178). The following variables were evaluated: age, sex, WBC count, bone marrow and peripheral-blood blast cell count, platelet count, hemoglobin level, cumulative dose of cytarabine over all cycles, additional chromosome aberrations (trisomy 22, trisomy 8), and study. The variable treatment was included on an intention-to-treat basis in the second analysis. For continuous variables no cut points were evident; therefore, they were included in the models as continuous variables. There was an interaction between WBC count and trisomy 22, with significantly lower WBC count at diagnosis in patients exhibiting the additional aberration (P = .0002). The multivariate model for RFS with limited backward selection revealed trisomy 22 as the only prognostic variable in patients receiving chemotherapy as postremission therapy (HR, 0.37; 95% CI, 0.13 to 1.04), as well as in the whole group (HR, 0.35; 95% CI, 0.15 to 0.80; Fig 7). There was no prognostic impact of the cumulative dose of cytarabine on RFS analyzed on an intention-to-treat basis (P = .19). In patients who experienced relapse, no prognostic variable was evident in univariate analyses.
Finally, we applied the prognostic factors for RFS to OS of all inv(16) patients. The Cox regression model did not reveal a prognostic impact of trisomy 22 on OS.
This meta-analysis of several German AML trials was conducted because patient numbers in prospective AML studies are too low to produce conclusive results in cytogenetic subgroups. Individual patient data–based meta-analyses are not able to substitute prospective trials, and inhomogeneities such as different randomization strategies among trials have to be taken into account. Entering individual patients' characteristics, however, provides a tool to increase statistical power. This survey is based on 392 young adult patients with CBF AML and is, to our knowledge, the largest cohort so far presented. Induction therapies resulted in high CR rates, consistent with data from others.5,6,17,18 In accordance with the French AML Intergroup,18 we identified an association between high WBC count and ED/HD in the inv(16) group. In contrast, we were not able to define a cut point for WBC count or to confirm the prognostic value of low platelet count and trisomy 22 for induction failure. The intention-to-treat analysis for postremission therapy revealed no difference in RFS and OS between chemotherapy and autologous SCT in t(8;21) leukemias and similarly no difference in RFS and OS between chemotherapy, autologous transplantation, and allogeneic transplantation in inv(16) leukemias, which is consistent with the data from the MRC AML-10 trial and the French AML Intergroup.6,18 However, the median follow-up time is still short, especially for patients after autologous and allogeneic transplantation. For patients receiving cytarabine-based consolidation therapy, we were not able to show an interaction between RFS and intended total dose of cytarabine, which ranged from 20.8g/m2 to 56.8g/m2. This is at variance with the data reported by Cancer and Leukemia Group B that showed a significantly better RFS for patients assigned to repetitive cycles of high-dose cytarabine in both types of CBF AML.7,8,19 Our data are in accordance with those of the French AML Intergroup,10,18 which showed no difference between intermediate- and high-dose cytarabine in postremission therapy with respect to RFS. There were major differences between the two types of CBF AML with respect to outcome after relapse. The CR rate after reinduction therapy was significantly lower in patients with t(8;21) compared with patients with inv(16) (33% and 79%, respectively). As a consequence, there was a significantly lower proportion of patients who experienced relapse with t(8;21) receiving intensive consolidation therapy, resulting in a significantly inferior survival after relapse (Fig 4). The reason why leukemias with t(8;21) are less sensitive to salvage therapy remains unclear. In accordance with the French AML Intergroup,10 WBC count was identified as a prognostic marker in the t(8;21) group. In our survey, the optimal cut point defined by maximally selected log-rank statistics was 25.4 x 109/L and nearly reproduced the cut point of 30.0 x 109/L reported by the French AML Intergroup.18 The WBC index, defined as product of WBCs and percentage of bone marrow blasts,10 did not add prognostic information to WBC count in our survey. Thus the definition of high-, intermediate-, and low-risk patients proposed by the French AML Intergroup could not be reproduced in our series. In contrast, we identified platelet count with a cut point at 28 x 109/L as second prognostic variable for RFS, and by combining dichotomized WBC and platelet count, we were able to build a prognostic model for RFS that identified high-, intermediate-, and low-risk patients (Fig 5). Two large studies by the British Medical Research Council6 and Cancer and Leukemia Group B17 analyzed the impact of additional chromosomal aberrations in CBF AML. In both studies, there was no influence of additional chromosomal aberrations on either RFS or OS. In contrast, in our survey, which is based on a significantly larger patient number, we were able to identify two additional chromosomal aberrations that appeared as independent prognostic variables. LOS in t(8;21) leukemias was a weak but significant prognostic factor for OS. When analyzing by sex, we found that this effect was exclusively due to the negative impact of loss of Y chromosome in male patients (Fig 6). This effect was independent of age (data not shown). Furthermore, we identified trisomy 22 in inv(16) leukemias as an independent predictor for superior RFS (Fig 7). Interestingly, trisomy 22 was the sole independent prognostic factor, whereas clinical variables as previously9,18,19 reported did not enter the model. Age was not a significant prognostic factor, possibly because our study was restricted to young adults (16 to 60 years) and did not include children.6,18 In contrast to the French study, trisomy 22 in our series was associated with significantly lower WBC counts. The mechanism by which this aberration improves outcome remains elusive. This meta-analysis comprises a large series of young adult patients with CBF AML receiving state-of-the-art therapy. In this survey, we were able to identify novel biologic risk factors that could help to stratify such patients in the future.
The appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF (via Adober Acrobat Readerr) version.
SHG-Hannover-AML-2/9521 and 01/99 trials. All patients were assigned to intensive, response-adapted induction and consolidation therapy. Induction therapy consisted of a course of idarubicin, cytarabine, and etoposide (IVA; 12 mg/m2 of idarubicin on days 2, 4, and 6; 100 mg/m2 of cytarabine continuously on days 1 through 7; 100 mg/m2 of etoposide on days 3 through 7), followed by a second course of IVA in patients responding to the first course of induction therapy, or by a course of a HDAMA (2/95 trial; 1 g/m2 of cytarabine every 12 hours on days 1 through 4; 90 mg/m2 of m-AMSA on days 3 through 5) or FLAG-Ida (filgrastim 5 µg/kg days 0 until recovery, fludarabine 30 mg/m2 days 1 to 4, cytarabine 1 g/m2 days 1 to 4, idarubicin 8 mg/m2 days 1 and 3; 1/99-trial) in patients with IVA-refractory disease. Response assessment was scheduled on day 15 of first induction therapy and after hematologic reconstitution after second induction therapy. First consolidation therapy consisted of a course of HAD-1 (1 g/m2 of cytarabine every 12 hours on days 1 through 4; 45 mg/m2 of daunorubicin on days 5 and 6). Second consolidation therapy differed between the two trials. In the 2/95 trial, all patients with core binding factor acute myeloid leukemia (CBF AML) were assigned to a course according to the HAD-2 protocol (3 g/m2 of cytarabine every 12 hours on days 1 through 6; 45 mg/m2 of daunorubicin on days 7 through 9). In the 1/99 trial, patients with CBF-AML and good response to IVA-1 were randomly assigned to a course according to the HAD-2 protocol or an autologous stem-cell transplantation (SCT).
SHG Dresden AML 96 trial.22
AMLCG9223 and AMLCG9924 trials.
OSHO33 AML-96 trial.
AMLSG ULM AMLHD939 and AML HD98A23trials.
The authors indicated no potential conflicts of interest.
We thank Silke Soucek from the Department of Internal Medicine I of the University of Dresden, Irina Schäfer from the Department of Hematology/Oncology of the University of Hannover, and Brigitte Füllgraf from the Department of Internal Medicine III of the University of Ulm, for excellent technical assistance, and Claudia Schoch, MD, from the Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilians-University of Munich, Munich, Germany, for providing us with the cytogenetic and molecular analyses of the AMLCG92 and AMLCG99 trials.
Supported by grant No. 01GI9981 from the Bundesministerium für Bildung und Forschung (Kompetenznetz "Akute und chronische Leukämien"), Germany. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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INTRODUCTION
