German Clinical Trials Register

Acronym/abbreviation of the study

PROMYSE

URL of the study

http://www.leukemia-net.org/content/leukemias/aml/apl/apl_register/index_eng.html

Brief summary in lay language

Acute promyelocytic leukemia (APL) is a rare myeloid neoplasm comprising approximately 5 to 10% of cases with acute myeloid leukemia. The diagnosis is proven by typical genetic changes of the leukemic cells (the chromosomal aberration t(15;17) and the corresponding fusion genes PML-RARA and RARA-PML). In the past, APL was the most aggressive and life threatening type of leukemia due to the high rate of fatal bleeding caused by the frequently associated coagulopathy. The introduction of several antileukemic agents (special chemotherapeutics (anthracyclines), the Vitamin A drivative (all-trans retinoic acid, abbreviated ATRA, compounds of arsenic) led to a stepwise improvement of prognosis. At present, 80% of APL patients having undergone treatment with ATRA and chemotherapy can be cured and only around 10% experience a relapse (recurrence of leukemia). The relapse therapy of APL is not standardized. Re-treatment with ATRA and intensified chemotherapy is mostly no longer curative and associated with considerable side effects. To achieve cure, subsequent autologous or allogeneic blood stem cell or bone marrow transplantation is required. Arsenic derivatives have few side effects and represent the most effective single agent in treatment of APL. The drug directly targets to the APL specific molecular defect and induced normalization of the bone marrow (remission) via simultaneous differentiation and cell death (apoptosis) of the leukemic cells (blasts). ATO is approved for treatment of relapsed APL since 2003. ATO is regarded as the treatment of choice for relapsed APL. The published data of ATO in APL relapse are based on several studies mostly including small patient’ numbers with short follow up. In these studies, remission rates around 86% were reached with ATO. In the largest study including 40 patients with relapsed APL, 66% of patients were alive after 1.5 years. ATO-based relapse therapy further enabled a higher rate of subsequent transplantation associated with less frequent complications compared to conventional chemotherapy. At present, the optimal therapy after remission induction with ATO is not defined. As stable remissions are also observed with prolonged therapy with ATO or with intensified chemotherapy, the advantage of transplantation is still discussed. Lacking larger prospective trials, the definitive cure rate in relapsed APL is difficult to estimate. Therefore, more data to assess the long-term prognosis of relapse APL are of high interest, in particular, if ATO was used. Because of the rarity of APL relapses and of different regulations in the European countries, a controlled clinical study could not be realized. Therefore in 2008, an expert panel established a European register for relapsed APL. It is the aim to register the data and long-term follow up of larger patients’ numbers with relapsed APL. There is a special interest in the results with ATO. A further goal is to better assess the impact of the different options for post-consolidation therapy after ATO – of allogeneic and autologous blood stem cell or bone marrow transplantation as well as of transplantation-free approaches.

Brief summary in scientific language

Organization of the European registry of relapsed APL: The register was established under the auspices of the European LeukemiaNet (ELN). Participation is open for interested European countries. In each country a coordinator is responsible for the collection and correct input of data in the online database. In addition, the respective coordinator is the contact person for queries coming from his/her own country and for the central registry coordinator. The central data registration and care of the online database are in the responsibility of the central coordinator located at the University Hospital Mannheim, (Prof. Dr. med. Eva Lengfelder, III. Medizinische Universitätsklinik Mannheim, Hematology and Oncology, University of Heidelberg). The availability of uniform on online case record forms enables the homogenous documentation of data. Therapy: The therapy is not defined and is only at the discretion of the treating physician/center. If ATO-based therapy is considered, the administration should be performed according to the recommendation of the European expert group, available at the website of the ELN website and in der paper of Sanz et al (Haematologica 2005;90:1231-1235). Important Steps or therapy are the remission induction with ATO+/-ATRA followed by one consolidation course with ATO+ATRA. After consolidation the RT-PCR of PML-RARA is mandatory for further treatment decisions. For continuation of therapy with the aim to further stabilize the remission, various treatment options are available (allogeneic or autologous transplantation, intensified or dose-reduced chemotherapy, further ATO cycles or variable maintenance therapy), to be selected according to age and performance status of the patient, status of molecular remission, first remission duration, type of frontline therapy and donor availability. Evaluation of data: Data should be evaluated according to treatment groups with or without ATO and according to first or later relapse. Within these groups, the clinical course should be evaluated according to hematological, molecular and extramedullary relapse, The comparison of the outcome after allogeneic or autologous or without transplantation is important, as well. Parameters to assess the effects of therapy are represented by the rates of hematological and molecular remission, by the rates of early death and of resistance, as well as by overall, event free and relapse free survival and by the cumulative incidence of relapse. Evaluations will be based on commonly used statistical methods. The assessment of prognostic parameters by multivariate analysis, if possible, would be of further interest. The comparison of chemotherapy- and ATO-based relapse would be desirable.