Acute Myeloid Leukemia (AML) in patients younger than 60 years of age
The EORTC 06991 GIMEMA (AML-12) trial included two randomization questions: 1) the role of intensification by high dose Ara-C in adult AML patients (2112 patients), and 2) the role of maintenance therapy with low-dose subcutaneous interleukin-2 (550 patients). Allogeneic transplantation was allowed for suitable patients. Results were presented at the 2011 American Society of Hematology Meeting, and several manuscripts are in preparation.
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 its prognostic importance.
The EORTC 06061 - GIMEMA (AML-14A) trial is an open label, 2-arm multicenter trial with a sequential phase I-II design. The main objective of the phase I trial was to determine the optimum dose of Clofarabine in combination with cytosine arabinoside and idarubicine to be recommended for the phase II trial. Phase I trial testing was completed and was presented at the 2011 American Society of Hematology Meeting. The main objective of the randomized phase II trial is to explore the antitumor activity of the above mentioned treatment combination using the recommended dose of Clofarabine defined in the phase I. The phase II trial is now open in a limited number of large centers with a total of 24 patients foreseen in each arm.
The EORTC 06071 Intergroup CALGB 10603/CTSU C10603 trial led by CALGB was a large phase III randomized, double-blind study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy with midostaurin (pkc412) or placebo in newly diagnosed patients with FLT3 mutated AML. This study aimed to determine if the addition of midostaurin to daunorubicin/cytarabine induction followed by high-dose cytarabine consolidation and continuation therapy improves the overall survival of these patients. The challenge of this trial was to obtain molecular data on fresh blasts within three working days, a delay compatible with the beginning of induction treatment of AML. The targeted recruitment of 719 patients was reached in October 2011 and an abstract was presented at the 2011 ASCO Annual Meeting.
Acute Myeloid Leukemia in patients older than 60 years of age
EORTC 06012-GIMEMA (AML-17) is a randomized phase III trial of Gemtuzumab ozogamicin (anti-CD33+calicheamycin) combined with standard intensive chemotherapy compared to standard intensive chemotherapy alone for induction/consolidation in patients 61-75 years old with previously untreated AML. The target sample size of 473 patients was reached and accrual closed in August 2007. Results were presented at the 2012 European Hematology Association meeting, and a manuscript was submitted for publication. Gemtuzumab ozogamicin did not increase remission rate or survival in this patient population.
EORTC 1215 platform (LG-ETF)
Although it is agreed that comorbidities are an important risk for outcome in older AML patients, there are no validated standardized assessment tools. Many current tools, e.g. HSCT comorbidity index, were not developed specifically for elderly patients. In collaboration with the EORTC Cancer in the Elderly Task Force, we are developing a large prospective diagnostic and therapeutic registry for elderly patients with AML. The primary aim is to create a database of patient characteristics, cytogenetic and biological features, objective AML-GA score, QoL (EORTC-QLQ-C30 and ELD-15), treatments received, and clinical outcomes of a large number of elderly patients to enable the standardization of an AML-GA score. This information will be used to propose feasibility cut-offs for intensive chemotherapy. Secondary objectives include centralization of biologic samples for translational research. The study has been endorsed by the EORTC Board and is under PRC review.
EORTC trial 1301 is one of the first protocols within the EORTC 1215 platform. This large intergroup phase III study of decitabine versus conventional chemotherapy in elderly AML and high-risk MDS is in development. The study has been endorsed by the EORTC Board and will be led by the EORTC Leukemia Group in collaboration with the CELG, GIMEMA and German MDS Groups.
Acute Myeloid Leukemia in AML patients who are not eligible for intensive chemotherapy (older than 75 or 61-75 years)
EORTC06031-GIMEMA (AML-19) is a multicenter randomized phase II/III trial which prospectively compared two strategies of treatment for previously untreated elderly AML patients ineligible for intensive chemotherapy: supportive care versus gemtuzumab monotherapy for induction/continuation. The trial will be conducted according to a sequential phase II-III design using the best induction regimen selected after phase II. Results were published (Br J Haematol 2010;149(3):376-382). The phase III part has been open to accrual since September 2007, and the trial will be completed in 2013. Discussions on the possibility of upgrading this to a registration trial after the rejection by the US Food and Drug Administration of gemtuzumab in AML patients treated with gemtuzumab and chemotherapy are are ongoing with Pfizer.
EORTC 06011 - German MDS Study Group randomized phase III study aimed to assess the efficacy, toxicity, duration of hospitalization and quality of life of low dose decitabine versus supportive care in elderly patients with a myelodysplastic syndrome. It recruited 233 patients from 46 centers. The study showed that Decitabine is active in older patients with higher-risk MDS and improved OS and AMLFS (nonsignificant), PFS and AML transformation (significant), and QOL. Short MDS duration was an independent adverse prognosticator. Results were published (J Clin Oncol 2011;29(15):1987-1996).
Acute Lymphoblastic Leukemia (ALL)
EORTC 06083-HOVON (HOVON 100 ALL) is a phase II-III study of Clofarabine added to prephase and consolidation therapy in acute lymphoblastic leukemia in adults using a pediatric-like regimen. The study is led by HOVON and aims to improve the event free survival. A total of 148 patients have been randomized so far.
Supportive Care: Antifungal therapy
EORTC trial 65091-06093, an open label phase III trial with the EORTC Infectious Disease Group, is investigating empirical versus pre-emptive (diagnostic-driven) antifungal therapy with caspofungin of patients treated for hematological malignancies or receiving an allogeneic stem cell transplant. The primary end point is assessing the survival rates 42 days (6 weeks) after initial randomization. This study has a strong translational research component with mandatory collection of biological material during the study from all recruited subjects including validation of mycological evidence tools.