Secondary Acute Myeloid Leukemia and Myelodysplastic Syndromes Following ATRA and Anthracycline Monochemotherapy Treatment for Acute Promyelocytic Leukemia.
Authors: Montesinos Pau , Gonzalez Jose D. , Rayon Chelo , de la Serna Javier , Bergua Juan , Esteve Jordi , Tormo Mar , Vellenga Edo , Amutio Elena , Deben Guillermo , Sanz Miguel 
Published: April 2020

Abstract
Background: With the improved survival of patients with acute promyelocytic leukemia (APL) treated with all trans retinoic acid (ATRA) combined to anthracycline chemotherapy, acquired therapy-related myelodysplasia (tMDS), acute myelogenous leukaemia (tAML), or both, can be an emerging problem.
Objectives: Analyze the incidence and characteristics of tMDS/tAML in 740 patients with newly diagnosed APL enrolled in the PETHEMA LPA96 and LPA99 trials.
Methods: From 1996 to 2005, 740 patients (median age 40 years, range 2–83) were included in the LPA96 and LPA99 trials (176 and 564 patients, respectively). Induction therapy consisted of ATRA and idarubicin, followed by three consolidation courses of anthracycline monochemotherapy with or without ATRA. Maintenance therapy consisted of low-dose oral chemotherapy (mercaptopurine and methotrexate with ATRA). We measured the cumulative incidence (CI) of tMDS/tAML during the course of APL patients who achieved the complete remission (CR).
Results: CR was achieved in 667 patients (90%). The median follow-up of the cohort was 66 months (range 20–127 months). Overall, 12 patients presented a tMDS/tAML, after a median of 43 months (range 23–55) from the achievement of CR. Six patients were diagnosed of tAML and 6 were diagnosed of tMDS. In all patients, RT-PCR monitoring and/or cytogenetic analysis indicated first complete remission of APL at the time of diagnosis of tMDS/tAML. Cytogenetic characterization revealed −5/del(5q) and/or −7/del(7q) abnormalities in 7 of 12 patients, whereas 11q23 rearrangements were observed in 2 patients. In spite of intensive chemotherapy (with allogeneic stem-cell transplantation in 3 patients), the course of tAML was aggressive (5 of 6 patients dead after a median of 7 months from diagnosis). Five patients with tMDS received only supportive treatment, and the remaining patient received chemotherapy and allogeneic stem-cell transplantation. Survival was also poor, with 4 patients dead after a median of 6 months, and 2 patients alive after 3 and 5 months from tMDS diagnosis. The median age at diagnosis of tMDS/tAML was 58 years (range 29–68). Four and 8 patients followed the LPA96 and the LPA99 trial, respectively. At the initial diagnosis, APL were classified, according to the Sanz score, as high-, intermediate- and low-risk, in 0, 7, and 5 patients, respectively. The overall 5 year CI of tMDS/tAML was 2.1%. The 5 year CI of tMDS/tAML in high-, intermediate- and low-risk patients was 0%, 2.2% and 4.2%, respectively (low- vs high-risk log-rank test; p=0.06). The 5 year CI of tMDS/tAML in patients &lt;50 years and ≥50 years was 1% and 4.6%, respectively (p=0.009).
Conclusion: In this large series of APL patients treated with ATRA and anthracycline monochemotherapy, the 5 year CI of tMDS/tAML was 2.1%. tMDS/tAML can be a long-term therapeutic complication, affecting more frequently patients aged ≥50 years and conferring a poor prognosis. Despite the lack of alkylating agents in the therapy of APL, cytogenetic abnormalities involving chromosomes 5 and 7 were frequently observed.