Very Long Term Outcome of Acute Promyelocytic Leukemia After Treatment with All Trans Retinoic Acid and Chemotherapy: The European APL Group Experience.

APL is highly curable with the combination of ATRA and anthracycline based chemotherapy (CT), but very long term results of this treatment remain unpublished. We present here the very long term results of APL93, that included newly diagnosed patients ( pts) between 1993 and 1998, with a 10 year median follow-up, particularly focusing on late events.

For induction treatment. Pts aged ≤65 years with WBC < 5,000/μL were randomized between ATRA 45 mg/m2/d followed by CT (DNR 60 mg/m2/d × 3 d + AraC 200 mg/m2/d for 7 d :ATRA→CT group) or ATRA plus CT (ATRA+CT), where the same CT was started on day 3 of ATRA treatment. After CR achievement, they received 2 consolidation courses of DNR and AraC (the first identical to the induction course, the second with DNR 45 mg/m2/d for 3 days and 1g/m2/12h AraC for 4 days). Pts with baseline WBC> 5,000/μL (irrespective of their age) and pts aged 66-75 years with WBC count ≤ 5,000/μL were not randomized but received ATRA with addition of CT on day 1 of ATRA treatment (high WBC group) and the same schedule as in the ATRA→CT group (elderly group), respectively. The elderly group received only the first consolidation course. For maintenance, pts were randomized to receive or not (2×2 analysis) intermittent ATRA (45 mg/m2 /d, 15 days every 3 months) and to receive or not continuous CT with 6MP (90 mg/m 2 /d, orally) and MTX (15 mg/m 2 /wk, orally) scheduled for 2 years. Interim results of this trial have been published (Blood 1999, vol 94, 1192-200).

In the 576 APL included, the CR rate was 87.3% and 90.7% in the elderly and the high WBC groups, respectively (resp), and ,in randomized pts, was 92.6% and 96.2% in the ATRA→CT and ATRA+CT groups , resp(p= 0.19). With a median follow-up of 121 months, 142 (26.6%) pts had relapsed, 59 (11%) had died in CR and 329 (61.7%) remained in first CR. 18 (12.7% of the relapses, 3.3% of the patients in CR), 9 and 3 relapses occurred after 4, 6 and 8 years, resp. Based on initial stratification, the 10-year cumulative incidence of relapse (CIR) was 16.5% in pts <65 years with WBC<5,000/μl, 37.9% in the high WBC group and 9.3% in the elderly group (p<0.0001). 10-year OS was 77% in the whole population, and 78.6%, 63.1% and 58.1% in randomized, high WBC and elderly groups, resp (p<0.0001). In pts <65 years with WBC<5,000/μl ( ie randomized at diagnosis), , 10-year EFS (primary end point of the 1^stRandomization) was 64.4% in the ATRA→CT group and 76.3% in the ATRA+CT group (p=0.019), 10-year CIR was 21.6% in the ATRA→CT group and 13.2% in the ATRA+CT group (p=0.087); and 10-year OS was 81.8% vs. 85.0% in the ATRA→CT and ATRA+CT groups, respectively (p=0.23). Regarding maintenance, 10-year CIR (Primary endpoint of the 2^ndrandomization) was 43.2%, 33%, 23.4% and 13.4%, after no maintenance, maintenance with ATRA alone, CT alone and both, resp (p<0.0001). In pts with WBC >5,000/μl, the 10-year CIR was 68.4%, 53.1%, 32.8% and 20.6% with no maintenance, ATRA alone, CT alone and both, resp (p < 0.0001). In pts with WBC < 5000/μL, the 10-year CIR was 29.2%, 22.9%, 21.0% and 11.5% with no maintenance, ATRA alone, CT alone and both, respectively (p =0.069). 41/322 pts received maintenance <1 yr due to side effects or to patient or physician's decision. Hazard of relapse was significantly increased in pts who received maintenance <1 yr vs > 1 yr (HR= 0.16 p< 0.0001). 59 patients (11%) died in first CR ( 10-year cum incidence (CI) of 5.7%, 15.4% and 21.7% in patients aged < 55, 55-65 , > 65 y, resp). Sepsis secondary to neutropenia (occurring during consolidation but also in 6 cases, during maintenance) and solid tumors accounted for 39% and 15% of death in CR, respectively. CI of secondary tumors and MDS was 1.4% and 0.2% at 5 years, 2.7% and 1.1% at 10 years.

Our results with a median follow-up of 10 years, confirm that the combination of ATRA and chemotherapy can cure > 75% of APL and show the long term usefulness of sufficiently prolonged maintenance treatment, particularly in pts with initial WBC counts >5000/μl and, in pts with WBC counts <5000/ul, the probable benefit of early addition of CT to ATRA. Very few long-term complications were seen. However, reduction of the incidence of deaths in CR in this highly curative disease is mandatory and requires reduction in the use of myelosuppressive drugs.

No relevant conflicts of interest to declare.