Risk-Adapted Treatment of Acute Promyelocytic Leukemia: Results of the PETHEMA LPA2005 Trial Using All-Trans Retinoic Acid and Anthracycline with Cytarabine for High-Risk Patients

Background: A previous report of the PETHEMA Group (Sanz et al, Blood 2004) showed that a risk-adapted strategy combining ATRA and anthracycline monochemotherapy for induction and consolidation (LPA99 trial), followed by ATRA and low dose methotrexate and mercaptopurine for maintenance therapy, resulted in high antileukemic efficacy, moderate toxicity, and a high degree of compliance. A critical analysis of this study led us to consider the following opportunities for improvement in a new trial:

1. the observation of a lack of relapses in non high-risk patients (WBC counts <10 × 10⁹/L) who had received incomplete consolidation therapy due to the occurrence of severe complications, led us to consider that there was room for a reduction of chemotherapy in this potentially overtreated setting;

2. the outstanding results reported by the Italian GIMEMA Group in high-risk patients < 60 years combining ATRA, anthracycline and cytarabine in consolidation (Lo- Coco et al, ASH 2004) led us to investigate a similar strategy looking for a synergistic effect of this triple combination of drugs.

Thus, a new risk-adapted PETHEMA trial (LPA 2005) was designed and initiated in July 2005.

Methods: AIDA regimen (ATRA 45 mg/m²/d ATRA until CR and idarubicin 12 mg/m²/d on days 2, 4, 6 and 8) was given as induction therapy. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy as follows: i.”low-risk” patients (WBC <10×10⁹/l and platelets >40×10⁹/l) received ATRA (45 mg/m²/d × 15) simultaneously with idarubicin 5 mg/m²/d × 4 (course #1), mitoxantrone 10 mg/m²/d × 3 (course #2), and idarubicin 12 mg/m²/d × 1 (course #3); ii.”intermediaterisk” patients (WBC <10×10⁹/l and platelet <40×10⁹/l) received ATRA (45 mg/m²/d × 15) in combination with reinforced chemotherapy (idarubicin 7 mg/m²/d in the course #1 and 2 days instead of 1 in the course #3). Both risk groups received mitoxantrone × 3 in course #2 instead of × 5 in the LPA99 trial; and iii.”high-risk” patients (WBC >10×10⁹/l) < 60 years received ATRA (45 mg/m²/d × 15) and idarubicin in courses #1 and #3 at the same dose than for low-risk patients but with the addition of cytarabine (1000 mg/m²/d × 4 in course #1 and 150 mg/m²/8 h days 1 to 4 in course #3) and 2 more days of mitoxantrone in course #2 (5 days instead of 3). Maintenance therapy consisted of 50 mg/m²/d mercaptopurine orally, 15 mg/m²/week methotrexate intramuscularly, and 25 mg/m²/d ATRA for 15 days every three months during 2 years.

Results: Of 319 patients enrolled in the LPA 2005 trial between July 2005 and July 2008, data on baseline characteristics and induction outcome was available from 290 patients. CR was achieved in 268 patients (92%). No resistant cases were observed. Toxicity was manageable during consolidation and there were 2 deaths in CR during consolidation. The median follow-up of the cohort was 21 months (range, 2–38). Six patients presented hematological relapse and 3 molecular relapse. Overall, the 2-year cumulative incidence of relapse (CIR), disease-free survival, and overall survival were 5%, 94%, and 92%, respectively. The 2-year CIR for low-, intermediate- and high-risk patients were 0%, 6% and 8%, respectively. A comparison of these results with those obtained with the LPA99 trial show a statistically significant lower CIR in high-risk patients (p=0.047).

Conclusions: The significant improvement of the outcome observed in high-risk patients suggests a synergistic effect of the triple combination of ATRA, anthracycline and cytarabine.