Outcome of Therapy-Related Acute Promyelocytic Leukemia (t-APL) with or without Arsenic Trioxide (ATO) as a Component of Frontline Therapy.

T-APL occurs frequently as a result of prior treatment with topoisomerase-II inhibitors (Mistry AR et al., NEJM, 2005). We have recently reported that the combination of all-trans retinoic acid (ATRA), ATO, with the addition of gemtuzumab ozogamicin for patients with a high presenting WBC, is effective in producing molecular remissions that are durable in APL (Ravandi F et al., JCO, 2009). Given the history of prior exposure to anthracycline chemotherapy in many patients with t-APL, an effective non-chemotherapy containing frontline regimen would be attractive in this patient population.

To examine the outcome of patients with t-APL, treated with ATO as part of the frontline regimen, and compare it to that of patients treated with standard ATRA plus anthracycline-based chemotherapy regimens.

We searched the database of the Leukemia Department at the University of Texas - M D Anderson Cancer Center (from 1980-2008) to identify patients with t-APL and define their characteristics and outcome.

Thirty six patients with t-APL were identified. Their median age was 54 years (range 26 to 81 years), and the median WBC count at presentation was 1,600/ul (range 500-162,500/ul). Most common prior malignancies were breast cancer (31%), prostate cancer (17%) and lymphomas (11%). Prior therapy included chemotherapy alone, radiation alone, or a combination of the two in 19%, 33%, and 47% of patients, respectively. Fifty percent of patients had been previously exposed to topoisomerase-II inhibitors. Median time from primary cancer to the diagnosis of t-APL was 3.5 years. The incidence of t-APL has increased with advancing decades: 9% of all patients with APL from 1980-99 vs. 16% from 2000-08 (P=0.07). Cytogenetic abnormalities in addition to t(15;17) occurred in 14/36 patients (39%) and most frequently involved chromosome 8 (4/36 patients, 11%). Among 25 patients with available PCR data, detection of the short PML-RARA isoform (14/25, 56%) was associated with a shorter survival compared to the long isoform (11/25, 44%) (161 weeks vs. 344 weeks; P= 0.29).The combination of ATO and ATRA (n=17) for induction resulted in a higher complete remission (CR) rate compared to ATRA plus chemotherapy (n=12) (88% vs. 67%; P= 0.35). The median overall survival for the patients treated with ATRA plus ATO was not reached compared to that for patients treated with ATRA plus chemotherapy (161 weeks; P=0.79). The median age for patients treated with ATRA plus ATO and ATRA plus chemotherapy was 53 and 56.5 years, respectively. The proportion of patients with a presenting WBC > 10,000/ul was 41% (7/17) in patients treated with ATRA plus ATO vs. 25% (3/12) in patients treated with ATRA plus chemotherapy.

In our cohort of t-APL patients, outcomes with ATO and ATRA appear to be comparable to anthracycline containing induction regimens. This combination may be preferable in these patients in order to avoid any risk of anthracyclin-induced cardiomyopathy.

Ravandi:Cephalon: Honoraria, Membership on an entity's Board of Directors or advisory committees.