The AML Intergroup: A Model of Cross-Trial Networking

Authors: T. Büchner, H. Döhner, G. Ehninger, A. Ganser, D. Niederwieser, J.Hasford, R. Hehlmann, D. Hoelzer, M. Schaich, R. Schlenk and M. Pfirrmann (for the AML Intergroup)

The AML Intergroup is a cooperation of independent groups conducting clinical trials on AML in Germany. After two of the initial five groups have fused, the Intergroup is now comprised of four different trial groups.

AML Intergroup Cross-Trial Networking

In order to combine the efforts of all pre-existing trial groups the participants of the Intergroup designed a structure of cross-trial networking (Figure 1). The main instruments combining the single trials to a network are a common standard treatment arm and a general upfront randomization (1). The common standard arm has been derived from a strategy by the CALGB (2) where standard dose araC/daunorubicin (7+3) for induction is followed by three courses of postremission therapy with high-dose araC 3g/m² x 6 in a monthly sequence. By the general upfront randomization 10% of patients in each trial are assigned to the common standard arm. This design provides a comparison of the therapeutic outcome from each trial with the outcome in the standard arm and indirectly with the outcomes in the other single trials. The number of recruited patients now amounts to 2909 with 288 in the common standard arm. The first official update in 2004 is shown in Figure 2. Figure 3 shows the official 2006 update of the survival probabilities estimated by the Kaplan- Meier method. In addition to the overall survival, also the relapse-free survival, event-free survival, and relapse-risk show similar results between the common arm and the study groups with no significant differences among the compared endpoints. New important conclusions may be drawn after this preliminary
data will be confirmed by a forthcoming update.

AML Intergroup Cross-Trial Networking in Older Patients

While present networking is limited to patients younger than 60 years a new similar network has been activated for patients 60 years of age and older with no age limit. For his age group chemotherapy has been adapted in that patients receive postremission therapy by two instead of three monthly courses of high-dose araC and 1 instead of 3g/m² q 12 hr x 6.

Meta-analyses of the AML Intergroup

In addition to the networking projects the AML Intergroup is used for metaanalyses of patient populations characterized by particular cytogenetic abnormalities.
Thus, new insights could be obtained by an Intergroup-wide investigation on CBF-leukemias in the largest number of patients published so far (3). A recent similar meta-analysis has focused on patients exhibiting trisomy 8 (4).

Prognosis of AML Patients ≤ 60 years with +8

Schaich M., Schlenk RF, Al-Ali HK, et al. Haematologica 92:763-70, 2007 [SCHAICH2007SCHAICH2007] Individual patient data-based metaanalysis was performed on 131 patients (median age 50 (18-60) years) with +8 as a sole aberration or +8 with one additional aberration treated between 1993 and 2002 in eight prospective German AML treatment trials. All patients received state-of-the-art treatment including high-dose cytarabine with the option for autologous or allogeneic hematopoietic stem cell transplantation (HSCT). In total, the 131 patients had a 3-year overall survival (OS) of 29% and a 3-year relapse-free survival (RFS) of 32%. Independent prognostic factors contributing to shorter OS were age ≥ 45 years, extramedullary disease, and a percentage of +8 positive metaphases ≥ 80%. Combining these three prognostic variables established a hierarchical model for OS. The 3-year OS was 13% for the high-risk group, 36% for the intermediate-risk group, and 55% for the low-risk group (p<0.0001). Age <45 years and allogeneic HSCT (as treated) were independent prognostic factors for longer RFS. Additional cytogenetic aberrations other than t(8;21), inv(16), t(16;16), t(15;17) or 11q23 had no influence on treatment outcome. We provide a new prognostic model for risk stratification of AML patients with +8. The data indicate that allogeneic HSCT may prolong RFS compared to that achieved with other strategies of postremission therapy (Figure 4).

The European AML Network: Progress and Outlook

Following the previous status report in the first ELN Information Letter in August 2005 the European AML Network performed further steps of achievement.
The AML Intergroup as a European pilot project has almost now been entering 3000 patients of < 60 years. While the update of 2004 due to restricted observation time did not allow to draw anyconclusions, the 2006 update strongly suggests comparable outcomes among the different strategies and the standard arm. In the meantime, an AML Intergroup network for patients of ≥ 60 years has been activated and recruited 350 patients so far.
In February 2006 and 2007 the AML Intergroup conducted two international symposia, addressing “AML in the Elderly” and “Randomization Strategies”, reported in the minutes.
The two EL N workpackages 5 (AML) and 8 (MDS) have been increasingly coordinating their work by sharing a part of their group sessions at the occasions of the annual EL N symposia in Heidelberg and the EHA annual meetings, thus combining the efforts of both groups in classification, molecular genetics and treatment. In order to elaborate European guidelines in AML and APL, a conference of international experts was held at Frankfurt Airport on November 27, 2006. At this meeting outlines were discussed and panels were appointed. In the meantime, drafts are in progress.
The panel members for the APL guidelines in alphabetic order are:
Thomas Büchner, Alan Burnett, Elihu H. Estey, Pierre Fenaux, David Grimwade, Eva Lengfelder, Francesco LoCoco, Bob Löwenberg, Tomoki Naoe, Miguel Sanz, Martin Tallman.
Members of the AML panel are:
Sergio Amadori, Frederick R. Appelbaum, Alan Burnett, Clara Bloomfield, Thomas Büchner, Hartmut Döhner, Hervet Dombret, Elihu H. Estey, Pierre Fenaux, David Grimwade, Rüdiger Hehlmann, Wolfgang Hiddemann, Graham Jackson, Richard A. Larson, Bob Löwenberg, Dietger Niederwieser, Gert Ossenkoppele, Miguel Sanz, Martin Tallman.
The next steps of the European AML Network will:

  • assess more detailed differences in outcome in the AML Intergroup trial
  • assess novel biomarkers on the basis of a large scale prospective multicenter AML trial
  • conduct a new international symposium in February 2008 focusing on allogeneic transplantation
  • combine efforts in AML and MDS at molecular and therapeutic levels
  • establish and publish European AML and APL guidelines

References:

  1. Büchner T, Döhner H, Ehninger G, Ganser A, Hasford J; German AML Intergroup. Up-front randomization and common standard arm: a proposal for comparing AML treatment strategies between different studies. Leuk Res 26:1073-5, 2002
  2. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 6:896-942,1994
  3. Schlenk R, Benner A, Krauter J, et al. Individual patient databased meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol 15; 22:3741-50, 2004