Front Line Treatment of Elderly Patients with Acute Promyelocytic Leukemia: Long-Term Results of the German AML Cooperative Group
Authors: Lengfelder Eva , Hanfstein Benjamin , Haferlach Claudia , Braess Jan , Krug Utz , Spiekermann Karsten , Haferlach Torsten , Kreuzer Karl-Anton , Serve Hubert , Horst Heinz A. , Schnittger Susanne , Erben Philipp , Woermann Bernhard J , Berdel Wolfgang E. , Sauerland Maria-Christina , Heinecke Achim , Hofmann Wolf-Karsten , Hehlmann Rüdiger , Hiddemann Wolfgang , Buchner Thomas 
Published: October 2019

Abstract
Abstract 425
The introduction of all-trans-retinoic acid (ATRA) in front line therapy of acute promyelocytic leukemia (APL) has improved the outcome of all age groups. In the elderly patients (pts), multi-morbidity and higher vulnerability to chemotherapy-related toxicity are the main problems reducing the chance of cure. This has led to recommendations to reduce the intensity of therapy in elderly APL pts. We report on the long-term outcome of pts with newly diagnosed APL registered in two prospective studies of the German AML Cooperative Group (AMLCG) from December 1994 until June 2011. The therapy consisted of ATRA and anthracycline/ara-C-based induction and consolidation therapy (TAD/HAM–TAD) followed by maintenance therapy as reported previously in younger APL pts (Lengfelder et al. Leukemia 2009;23:2248–2258). In pts ≥60 years (y), the administration of the second induction cycle (HAM with an age adapted cumulative ara-C dose of 6g/sqm) was at the discretion of the treating physician. After December 2005, the pts were included in the ongoing APL protocol and randomized between the AMLCG strategy and the protocols of the Spanish PETHEMA. Among 295 adult pts with newly diagnosed APL, 83 pts (28%) were ≥60y of age. Seventeen elderly pts (20%) were not enrolled in the study, due to death before start of therapy, contraindications against chemotherapy or concomitant other malignancy. Eleven pts randomized in the PETHEMA arm were excluded from the present analysis to cover homogeneity of therapy. In 53 of 55 pts treated according to the AMLCG protocol, results are available. Median age was 67 y (range 60 to 83); 58% were male, 42% female; 68% had low/intermediate and 32% high risk according to Sanz score. Morphology was FAB M3 in 62%, M3v in 38%. Cytogenetics showed t(15;17) alone in 52%, and combination with other abnormalities in 48% of pts. The bcr1/bcr2 transcript of PML/RARA was found in 41% and the bcr3 transcript in 59% of pts. Forty-four pts (83%) achieved complete remission (CR). Early death (ED) occurred in 9 pts (17%). Median time to ED was 12 days (range 2 to 19) after start of therapy. Causes of ED were bleeding, multi-organ failure and sepsis. Manifest APL differentiation syndrome occurred in 25% of pts and WHO grade '3 bleeding, fever/infection or cardiac failure in 8%, 43% and 17% of pts, respectively. After consolidation therapy, 96% of pts were in molecular remission. After a median follow up of 5.3 y (1 day to 12.8 y), the 6-year overall (OS), event free (EFS) and relapse free survival (RFS) and the cumulative incidence of relapse (CIR) were 45%, 41%, 50% and 26%, respectively. The outcome was further analyzed according to risk group, number of induction cycles, and age ≥60y to 69y and ≥70y. Pts with pretreatment white blood cell (WBC) count <10 × 109/L (low/intermediate risk; n=36) had a significantly superior outcome compared to pts with high WBC counts (high risk; n=17) resulting in a CR rate of 92% vs. 65% and ED rate of 8% vs. 35%, respectively (p=0.02). The 6-year OS, EFS, RFS and CIR of the low/intermediate risk pts was 56%, 53%, 60% and 14%, respectively, compared to 25%, 15%, 23% and 58% in high risk pts (p=0.006, p=0.0004; p=0.008; p<0.01). All 12 pts, who had received two induction cycles achieved CR, and no relapse occurred so far resulting in a significantly superior outcome compared to patients, who had received only one induction cycle (OS: p=0.007; EFS: p=0.0002; RFS: p=0.01). In the pts '70y (n=17), 71% entered CR and 29% died from ED. Separated according to low and high WBC counts, the CR rate of this group was 83% vs. 40% and the ED rate 17% vs. 60% (p=0.07), respectively, resulting in an inferior OS (p=0.08) of the pts with high WBC count. Conclusions: Among our elderly pts, we found a high proportion of pts with high risk profile and a high rate of exclusion from the study due to death before the start of therapy or poor condition. In patients included in our study, high WBC count and advanced age are associated with a high risk of ED. The inferior outcome in pts, who received only one induction cycle, suggests that intensification of chemotherapy should be considered in elderly APL pts, if possible. The incorporation of arsenic trioxide might be an alternative, which could be investigated in future trials.

Disclosures:
No relevant conflicts of interest to declare.