Results with ATRA and Anthracycline Based Chemotherapy (CT) in Acute Promyelocytic Leukemia (APL) in a Developing Country. Should Dose Intensity Be Reduced to Obtain Acceptable Results?
Authors: Jeddi Ramzi , Ghédira Hèla , Stambouli Hèla , amor Ramzi Ben , Kacem Karima , Abdennebi Yosr Ben , Zarrouk Mohamed , Neji Hend Ben , Lakhal Raihane ben , Aissaoui Lamia , Menif Samia , Gouider Emna , Abid Hèla Ben , Hadjali Zaher Ben , Fenaux Pierre , Meddeb Balkis 
Published: October 2019

Abstract
Abstract 4271

Background:
In Tunisia, before 1998, ATRA was not available in APL, and we reported CR rates of 37.5% (unpublished results). The ATRA era began in 1998 with the consecutive use of two regimens combining ATRA and an anthracycline with AraC (APL93 trial), and without AraC (LPA99 trial). We report outcome of those clinical trials in our country, whose yearly GDP is about 8000 USD/inhabitant (ranking n°55 in the world).

Methods:
Between 1998 and 2010, consecutive patients with genetically confirmed APL were treated, until 2004 (n= 27 patients, median age, 27 years) with the European APL93 trial induction treatment with ATRA 45 mg/m2 from day (D)1 and DNR (60mg/m2/d x3)+ AraC (200mg/m2/d x7) started from D1 if WBC ≥ 5G/L and D3 if WBC < 5G/L.Patients achieving CR received a first consolidation course with the same CT and a second with DNR at 45 mg/m2/dx3 and AraC 1g/m2/12h x8. Maintenance treatment consisted of a combination of ATRA 45 mg/m2 for 15 days every 3 months,6MP at 50 mg/m2/d and MTX 15mg/m2/week (Adès L.Blood 2010;115:1690). Between 2004 and 2010, 51 patients (median age,30 years) received the Spanish PETHEMA LPA 99 protocol (Induction with ATRA 45 mg/m2/day and idarubicin 12 mg/m2 on days 2, 4, 6, 8); 2 risk-adapted consolidation courses with IDA, with ATRA (only for Int- and high-risk patients) and for all patients one consolidation course with mitoxantrone 10mg/m2 for 5 days, followed by the same maintenance therapy as in the European APL trial. (Sanz MA, Blood 2008;112:3130). During induction therapy coagulopathy was treated with fresh-frozen plasma(FFP) and apheresis platelets with the objective of maintaining platelet counts above 30G/L, prothrombin time >50% and, fibrinogen >1 g/L. Heparin was not used. During maintenance treatment, all patients were monitored clinically every month and molecularly for PML-RARA every 3–4 months.

Results:
The two patient cohorts were comparable except for the incidence of M3v (1/27 in APL93 vs. 12/51 in LPA 99,P=0.023).34.6% (27/78) of patients were HR Sanz’ score.With the European trial (26 patients treated, one patient died before treatment), the CR rate was 77%, while 23 % patients (6/26) had early death: 4 from hemorrhage and 2 from DS (overall incidence of DS: 15%).4 year event free survival (EFS), cumulative incidence of relapse (CIR) and overall survival (OS) was 61.5%, 14.2%, 65% respectively. In high risk patients (n=9), 5 achieved CR,2 relapsed, and 3 were long term survivors. With LPA 99 trial, 43 (86%) pts achieved CR. The remaining 7 (14%) pts had early death (one died before treatment onset): 4 from DS (overall incidence of DS: 32%) and 3 from CNS hemorrhage. 2 pts relapsed at 35 and 36 months of CR. 2 pts developed secondary MDS and 2 died in CR,from sepsis during the third consolidation course and one from cardiac failure after 15 months of CR, respectively. With a median follow-up of 50 months, 5 year CIR, EFS and OS were 4.7%, 74% and 78%, respectively. In high risk patients (n=18), the CR rate,5 year CIR, EFS and OS were 70.5 %,0%,64.7 %,64.7%, respectively.
The only prognostic factor of death during induction for the whole study population was high baseline WBC > 10G/L (P=0.003). Male gender (P=0.77), M3v (P=0.23),CD56 positivity (P=0.49), and WBC > 10G/L (P=0.71) were not predictive of relapse.
Median transfusion requirement during induction treatment was: 8 PRBC in APL93 trial (range, 3–18) and 4 in LPA 99 trial (range, 3–11); 6 apheresis platelet concentrates in APL 93 trial (range, 3–11) and 4 in LPA 99 trial (range, 1–16); 11 FFP concentrates (range, 0–53) and 7 (range, 0–36), respectively.

Conclusion:
Despite more limited resources than in industrialized countries, and non availability of arsenic derivatives, our results are quite acceptable. The CR rate we observed is still inferior to what is reported in international trials but, our results improved over time especially with the less myelosuppressive Spanish trial, including in patients with WBC > 10 G/l. Our results suggest that there is probably no need to adapt protocols by reducing dose-intensity in APL trials in developing countries, at least if an adequate transfusion program and adequate management of DS can be implemented during induction treatment.

Disclosures:
Fenaux: Celgene: Honoraria, Research Funding.