Recent Achievements
Acute Myeloid Leukemia (AML) in “young” patients (< 60 years)
Final results of the AML-10 phase III EORTC-GIMEMA 06931 trial comparing Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy were published (Mandelli et al. J Clin Oncol. 2009).
The AML-12 EORTC-GIMEMA 06991 trial included randomization at diagnosis for remission induction using high- dose ARA-C compared to the “best” remission induction schedule of the previous AML-10 trial; a total of 2112 patients were registered (the randomization was completed in January 2008). A second randomization evaluated the role of maintenance therapy with low-dose subcutaneous interleukin-2 versus no further treatment; a total of 550 patients were randomized for this second step (randomization closed in June 2008). Younger patients (< 45-55 years) with an HLA identical family donor were scheduled for allogeneic transplantation. The final analysis is foreseen in 2011.
An EORTC/GIMEMA network of laboratories in The Netherlands, Belgium, and Italy and coordinated by Dr Joop Jansen (EORTC) and Dr Francesco LoCoco (GIMEMA) monitored minimal residual disease by molecular techniques to identify prognostic factors.
The phase I-II EORTC-GIMEMA 0606 trial is testing the addition of low dose clofarabine to the idarubicin-ARA-C combination and is now open in a limited number of large centers for the phase I part of this trial. The maximum tolerable dose (MTD) has been reached and the expansion cohort is continuing with the expected recommended dose. Preparations are underway for initiating the phase II part of this trial.
The LG is also participating in a large intergroup study, the EORTC 06071 trial, led by CALGB for young patients with flt3-positive AML. This study aims to determine if the addition of midostaurin to daunorubicin/cytarabine induction followed by high-dose cytarabine consolidation and continuation therapy improves the outcome of these patients. This study has reached full accrual, however there is a proposal to accrue more patients.
In elderly patients (> 60 years) with AML, the LG completed the EORTC 06012 AML-17 intergroup trial with GIMEMA. In 61-75 year old patients in good physical condition, this trial assessed the anti-leukemic activity of a sequential treatment with Mylotarg (anti-CD33+calicheamycin) followed by “standard” chemotherapy with mitoxantrone, Ara-C and Etoposide as a front-line therapy in previously untreated AML. This regimen is compared to “standard” chemotherapy. The target sample size for this study was reached and the accrual was closed in August 2007 with a total of 473 patients randomized. Patient follow-up and data collection are ongoing.
The EORTC-GIMEMA 06031AML-19 trial was designed for “frail” patients (> 75 or 61-75 years with co-morbidity) who are usually not treated with intensive chemotherapy. The aim of this phase II-III trial is to compare low doses of Mylotarg versus palliative care. During the phase II part, activity of two different schedules of low dose Mylotarg have been assessed (84 patients have been entered in the phase II), and results were published recently (Amadori et al, Br J Haematol. 2010). The phase III part has been open to accrual since September 2007 and patients are being randomized between supportive care and the “best” low dose Mylotarg schedule following analysis of the phase II results. For this trial, 125 of the 184 patients needed have been entered. Discussions are ongoing with Pfizer on the possibility of upgrading this to a registration trial after the recent rejection of Mylotarg by FDA in AML patients treated with Mylotarg and chemotherapy.
Myelodysplastic Syndromes
Final results of the prospective EORTC 06961 CRIANT trial which assessed the value of allogeneic stem cell transplantation versus autologous stem cell transplantation and chemotherapy in patients with MDS and secondary AML (sAML) were published recently (de Witte T, et al. Haematologica. 2010).
The randomized EORTC 06011 phase III trial of the LG and the German MDS Group assessing the value of decitabine versus best supportive care in high risk MDS patients >60 years old, recruited 233 patients in 46 centers. The final results were presented at the 2008 American Society of Hematology (ASH) meeting. The manuscript was accepted to be published pending modifications by JCO.
The EORTC 06013 phase II trial assessing the activity and toxicity of Idarubicin and Ara-C in combination with Gemtuzumab-Ozogamycin (IAGO) in untreated high risk MDS or sAML patients recruited 31 patients in five centers. The accrual was completed in 2006. The database was locked in 2010, and the final analysis report was performed.
The randomized phase II EORTC 06023 trial assessing the value of two doses of infliximab (Remicade) in patients with MDS and a relatively low risk of developing acute leukemia recruited 46 patients in 19 centers. The accrual was completed in 2006, and the database was locked in 2010. At the time of the final analysis the median follow-up was five years. A manuscript is in preparation. Two new studies for patients with MDS have been approved by the EORTC Executive Committee.
Acute Lymphoblastic Leukemia (ALL)
Final results of the ALL-4 phase III trial comparing Dexamethasone versus prednisolone in adults with ALL or lymphoblastic lymphoma were published recently (Labar et al. Haematologica. 2010).
A new ALL first line therapy (with stratification: 18-40 years, 41-70 years) with a randomization for -/+ clofarabine i.v. during induction and intensification using a pediatric-like regimen in “young” ALL has been activated by HOVON (HOVON 100 ALL) and will soon be activated by the EORTC (the EORTC 06083 trial). The primary endpoint will be event free survival (EFS), and the secondary endpoint will be molecular residual disease.