Myelodysplastic syndrome after acute promyelocytic leukemia: the European APL group experience

Abstract

With improved treatment of acute promyelocytic leukemia (APL) by all trans retinoic acid (ATRA) combined to anthracycline-aracytin chemotherapy (CT), a larger number of those patients may be at risk of late complications. Recently, the Rome group reported five cases of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML, non-APL) occurring during the course of 77 APL patients (6.5%) in complete remission (CR). From 1991 to 1998, we treated 677 newly diagnosed cases of APL, and 617 of them achieved CR with ATRA combined to CT (n ¼ 579) or CT alone (n ¼ 38); 246 of them received subsequent maintenance CT with 6 mercaptopurine and methotrexate. With a median follow-up of 51 months, 6 patients (0.97%) developed MDS, 13-74 months after the diagnosis of APL. In all six cases, t(15;17) and PMLRARalpha rearrangement were absent at the time of MDS diagnosis, and karyotype mainly showed complex cytogenetic abnormalities involving chromosomes 5 and/or 7, typical of MDS observed after treatment with alkylating agents, although none of the six patients had received such agents for the treatment of APL. Our findings suggest that MDS can indeed be a long-term complication in APL, although probably at lower incidence than that previously reported. Leukemia (2003) 17, 1600-1604. doi:10.1038/sj.leu.2403034 Keywords: acute promyelocytic leukemia-myelodysplastic syndrome; therapy related Introduction Acute promyelocytic leukemia (APL) is a specific type of acute myeloid leukemia (AML) characterized by the morphology of blast cells (M3 according to FAB classification), t(15;17) translocation that fuses the PML gene on chromosome 15 to the RAR alpha gene on chromosome 17, and by specific coagulopathy. 1,2 Anthracycline-aracytin (AraC) chemotherapy (CT), introduced in the 1960s, has yielded cure rates of 35-40% in APL, whereas combination of anthracycline-Ara C or anthracycline alone CT to all trans retinoic acid (ATRA), introduced in the early 1990s, has improved this cure rate to 65-70%, 3-6 thereby increasing the number of patients potentially at risk of late side effects of treatments. In the last 2 years, several case reports of myelodysplastic syndrome (MDS) or AML (different from APL), occurring during the course of APL, have been made. Recently, the Rome group 7 reported five cases of MDS in 77 (6.5%) APL patients treated with CT alone or ATRA combined to CT, suggesting that MDS/AML was possibly a major emerging problem in the follow-up of APL. Those findings prompted us to review cases of MDS or AML (non-APL) occurring during the evolution of APL patients included in multicenter trials of our European group. Patients and treatment PatientsBetween 1991 and 1998, we included 677 newly diagnosed cases of APL in APL 91 and APL 93 trials. Inclusion criteria were: diagnosis of APL based on morphological criteria and subsequently confirmed by presence of t(15;17) or PML-RAR alpha gene rearrangement, 8 age 75 years or less, and a minimum follow-up of 3 years.Treatment 9-11 APL 91 trial design: Patients were randomized to re...

How to manage acute promyelocytic leukemia

“…In the reports of working groups with more intensive chemotherapy, for example, in the GIMEMA group using VP-16, the incidence of MDS or AML after APL treatment was 6.5%, whereas in the studies of European APL group which omitted the application of VP16 that incidence was 0.97%. 99,100 The cheaper prices of ATRA and ATO (provided by the Chinese pharmaceutical manufacturers) make them widely used in China. In some other developing countries like India and Iran ATO is also available, however, these two drugs are more expensive on international markets, especially ATO.…”

Chronic Myeloid Leukemia Developing After Successful Treatment of Acute Promyelocytic Leukemia

“…In APL patients, t-MDS and t-AML are sporadically reported [1,2], which were observed in about 6.5 % patients [3]. Patients usually developed t-MDS or t-AML with a latency ranging from 22 to 46 months after receiving chemotherapy [3].…”

Severe Aplastic Anemia Manifesting After Complete Remission of Acute Promyelocytic Leukemia: Is it a Fortuitous Association?

“…Moreover, therapy related MDS (t-MDS) is a long-term complication in APL. Separate studies by Lobe et al and Singh et al [10,11] reported average latency period of 46.5 and 62 months from onset of therapy for the primary hematological malignancy to the development of t-MDS respectively. Our patient manifested with severe marrow hypoplasia only 7 months after the diagnosis and initiation of APL treatment arguing against a possible diagnosis of t-MDS.…”

“…The evolution of other clonal disorders such as PNH, MDS and AML in AA patients treated with immunosuppressive therapy has since been well recognized [3,4,6]. Similarly secondary MDS or AML developing following treatment of APL is also documented in the literature [10,14]. A primary insult to the bone marrow could simultaneously lead to several abnormal hematopoietic cell clones, with one dominating and others present below the threshold of detection.…”