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(The) treatment of Acute Promyelocytic Leukemia (APL) in older patients

Project Scientific Background

Acute promyelocytic leukemia (APL) is a clinically and biologically unique subset of acute myeloid leukemia cases characterized by a translocation between chromosomes 15 and 17 leading to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor α (RARα) gene, resulting in disruption of normal cell differentiation. APL accounts for a minority of AML cases but often presents as a medical emergency with disproportionately high rates of early mortality frequently related to bleeding complications secondary to disseminated intravascular coagulation. Despite this, APL has a high response and cure rate if diagnosed and managed appropriately with current therapies that include use of all-trans retinoic acid (ATRA) which overcomes the differentiation block. When suspected, treatment with ATRA should begin immediately. Curative treatment based on recent randomized trials includes induction with ATRA plus either arsenic trioxide (ATO) or an anthracycline chemotherapy depending upon risk categorization (low/intermediate risk versus high risk respectively). Some evidence supports use of ATRA+ATO for patients of all risk groups. For older patients of any risk categorization in particular ATRA+ATO may be a preferred first line treatment to minimize risk of chemotherapy-related toxicity and early death. Induction therapy is often followed by consolidation with or without maintenance therapy with cure rates often exceeding 75% in clinical trials.

While less common among older adults, there remain significant disparities in outcomes by age warranting attention to the management of older adults specifically. Remission rates in older adults with APL are high in clinical trials although remission rates and corresponding survival remain substantially lower than in younger patients. For example, population based data from the Netherlands (years 1989-2012) showed 5-year survival rates of 84%, 75%, 54%, 37% for APL patients aged 18-40, 41-60, 61-70, >70 years respectively. Older adults remain under-represented on clinical trials with most studies including few patients >70 years. Despite high potential response rates among older adults, competing comorbidity, functional limitations and access to care may complicate management and contribute to inferior outcomes. Specific topics of uncertainty in management include optimal induction for high risk older adults as well as the optimal consolidation and the role of maintenance therapy. An optimal approach for older patients in regions of the world where ATO may be unavailable is also an important topic of consideration. In addition, the impact of treatment on health related quality of life and functional independence warrants attention to optimize patient-centered care. Finally, aging-related issues which may impede timely work-up and management of this potentially treatable condition warrant attention in an effort to improve outcomes. Guidelines focused specifically on older adults with APL would address an unmet need and provide a tool for education to facilitate optimal therapy for this subset of AML patients with highly treatable disease.

Task force members

Heidi Klepin (USA) & Raul Cordoba (Spain)
Francesco Lo-Coco (Italy)
Massimo Breccia (Italy)
Richard A. Larson (USA)
Marije Hamaker (Netherlands)
Pau Montesinos (Spain)
Young SIOG Representative: Nina Neuendorff (Germany)

This project is supported by an unrestricted grant from Teva.