Therapy Related APL (tAPL). Prospective Analysis of Etiological Factors In Recent Cases, and Comparison with De Novo Cases

Our group (JCO, 1992 10:1430; JCO 2003,21:2123) and others have reported tAPL to occur at increased frequency (from 5% of APL between 1984 and 1993 to 22% between 1994 and 2000 in our experience), generally less than 3 years after a primary neoplasm (mainly breast carcinoma) treated with the combination of anthracyclines (anthr) and cyclophosphamide (CY), radiotherapy (RT) and less often VP 16, but our last published series analyzed patients (pts) diagnosed before 2001. In addition, characteristics and outcome of tAPL are considered similar to those of de novo APL, but all reported comparisons were retrospective. We took advantage of our current multicenter APL 2006 trial, which includes both de novo and tAPL, to analyze possible recent changes in etiological factors of tAPL cases, and to prospectively compare them with de novo APL.

In APL 2006 trial, pts <70 years with WBC<10 G/l, received ATRA+Idarubicin+AraC for induction, followed by 2 consolidation courses with (randomized) Ida+AraC, ida+ATO or Ida+ATRA. Pts<70 y with WBC>10 G/l, received the same induction treatment, followed by 2 consolidation courses with (randomized) ida+AraC or Ida+AraC+ATO. Pts >70y received the same induction course with reduced dose of Ida and two consolidation courses (Ida+ATO and ATO+ATRA). All patients received 2 y maintenance therapy combining continuous 6MP+ MTX and intermittent ATRA.

Between Nov 2006 and March 2010, 280 pts entered the trial, including 42 (15 %) tAPL. By comparison to our tAPL diagnosed before 2001 (JCO 2003, 21, 2123) the primary tumor was less often breast carcinoma (35.7% vs 56.6%, p=0.03), and more often prostate carcinoma (26.2% vs 4.7%; p<10-3) and other solid tumors (45.2% vs 18.8% p=0.02). Treatment of the primary tumor, in APL 2006 trial cases and tAPL diagnosed before 2001, respectively, included chemotherapy (CT) alone in 21.4% vs 27.3% pts (p= 0.535), RT alone in 40.5% vs 25.4% pts (p= 0.077) and RT+CT in 28.6% vs 47.2%(p= 0.044), and, in pts who received CT, at least one alkylating agent in 90.5% vs 86% pts (p=ns), at least one topo II inhibitor in 61.9% (including anthr in 47.6% and VP 16 in 14.2%) vs 77% pts (including anthr in 37.9% and VP 16 in 24.1%), and including mitoxantrone in 0% vs in 36.4% pts (p<10-3). Hormone therapy was used in 42.9% (including antioestrogen (n=7), aromatase inhibitors (n=7) GnRH analogues (n=4), and anti androgens (n=4)) vs 24.5% (no details available), resp. Median interval from primary tumor to tAPL was 48 months (range 6.9 to 299) in tAPL included APL 2006 trial, compared to 25 months in our previous tAPL series.

In APL 2006 trial, characteristics of tAPL were similar to those of de novo APL, with regards to WBC count (21.4% WBC>10 G/l vs. 22.3% in de novo APL, respectively) and M3 variant (14% in the 2 groups). However, tAPL were older (mean 60.2y vs 48.7y in de novo cases, p<0.0001) and had a higher frequency of bcr3 breakpoint (36% vs 54%, p=0.015).

The CR rate was 97.6% (41/42) in tAPL and 93.4% in de novo APL (p=0.48). The 18-month cumulative incidence of relapse was 0% and 1.2% in tAPL and de novo APL respectively (p=0.43). 18 months OS was 96.4% and 97.0%, respectively (p=0.83, log-rank test). The 18 month rate of death in CR was 3.6% in both tAPL and de novo APL (p=0.97),

In this series of recently diagnosed tAPL, by comparison to our tAPL diagnosed before 2001, the primary tumor was less often breast carcinoma and more often another solid tumor (especially prostate). A combination of CT and RT had been less often used, hormone therapy more often, and mitoxantrone had no more been used. Prospective comparison with de novo APL included in the same trial showed tAPL to be characterized by older age and more frequent bcr3 breakpoint, but there were no differences in outcome between the 2 subgroups

Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.