Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results

Abstract

All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 ؋ 10 9 /L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P ‫؍‬ .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 ؋ 10 9 /L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 ؋ 10 9 /L or more, however, the CR rate (95.1% vs 83.6% P ‫؍‬ .018) and 3-year survival (91.5% vs 80.8%, P ‫؍‬ .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P ‫؍‬ .12), suggesting a beneficial role for AraC in those patients. IntroductionAcute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by its morphology, t(15; 17) translocation leading to PML-RARa fusion gene, and by a life-threatening coagulopathy. 1-5 All-trans retinoic acid (ATRA) combined with anthracycline-based chemotherapy yield complete remission (CR) rate in approximately 90% of newly diagnosed APLs and 25% to 30% subsequently relapse. 6 Maintenance treatment (especially combining continuous 6-mercaptopurine [6MP] and methotrexate [MTX] to ATRA) appears to further reduce the relapse risk to 10% to 15%. 6-9 Pretreatment white blood cell (WBC) count is the main factor associated with relapse in APL and a predictive model for relapse risk (Sanz score) based on pretreatment WBC and platelet counts allowing for the distinction among low-risk patients (with WBC count Ͻ 10 ϫ 10 9 /L and platelet count Ͼ 40 ϫ 10 9 /L), intermediaterisk patients (with WBC count Ͻ 10 ϫ 10 9 /L and platelet count Ͻ 40 ϫ 10 9 /L), and high-risk patients (with WBC count Ն 10 ϫ 10 9 /L). 10 Another sizable subset of patients die in CR from complications of consolidation treatment, mainly from infection due to chemotherapy-induced myelosuppression. 7,[11][12][13] To decrease mortality in CR, the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) group reduced the intensity of consolidation chemotherapy by avoiding cytosine arabinoside (AraC) in the chemotherapy regimen. 8,9 They observed CR rates comparable with regimens using a combination of AraC with anthracycline, a lower rate of death in CR (2%) and a low cumulative incidence of relapse (10%). On the other hand, the French-Belgian-Swiss APL group, i...

Long‐term follow‐up of European APL 2000 trial, evaluating the role of cytarabine combined with ATRA and Daunorubicin in the treatment of nonelderly APL patients

“…We had concluded from the comparative analysis that AraC was probably not required in standard-risk APL, if the anthracycline used was idarubicin (and mitoxantrone) at the cumulative doses reported by Sanz et al [7]. Longterm results of APL 2000 trial presented here confirm that, on the contrary, AraC may not be dispensable in standardrisk APL if DNR is the anthracycline used (at least at the usually recommended cumulative doses, i.e., <500 mg/ m 2 ).…”

“…On the other hand, our APL 2000 trial randomizing AraC during induction and consolidation treatment, in patients aged 60 years with WBC count <10 G/l, was closed after the first interim analysis, made after a median follow-up of 24 months, due to significantly higher 2 year cumulative incidence of relapse (CIR) in the group without AraC [6,7].…”

“…Reducing the amount of CT in APL patients has been investigated in order to limit its toxicity. The PETHEMA and GIMEMA groups, in particular, reported very few relapses and deaths in CR with regimens combining ATRA and intercalating agents (idarubicin and mitoxantrone) without AraC, suggesting that AraC can be omitted from the treatment of APL, at least in standard-risk patients [i.e., with white blood cell (WBC) count <10,000/mm 3 ] [4,5].On the other hand, our APL 2000 trial randomizing AraC during induction and consolidation treatment, in patients aged 60 years with WBC count <10 G/l, was closed after the first interim analysis, made after a median follow-up of 24 months, due to significantly higher 2 year cumulative incidence of relapse (CIR) in the group without AraC [6,7].We present here long-term results of this trial, 7 years after the last patient inclusion, with a median follow-up of 103 months. …”

How to manage acute promyelocytic leukemia

“…At present, ATRA combined with chemotherapy became the classic treatment of APL owing to the significantly improved long-term survival rate. The further amelioration of chemotherapy in the past two decades, for example, the application of high-dose cytosine arabinoside to high-risk patients 2,3 and the recognition of the importance of maintenance therapy, 4 has led to further improvement of APL survival. 5 However, it has always been our dream to lower the relapse rate and to reduce side effects through even more effective therapy targeting APL cells.…”

“…In a joint analysis of results from a LPA 99 trial Programa para el Estudio de la Terapeutica en Hemopatia Maligna (PETHEMA group), where patients received no Ara-C in addition to ATRA, a high cumulative dose of idarubicin, and mitoxantrone and an APL 2000 trial (French --Belgian --Swiss APL group), where patients received Ara-C in addition to ATRA and a lower cumulative dose of daunorubicin, 3-year survival was similar in patients with a WBC count less than 10 Â 10 9 /l; although, 3-year cumulative incidence of relapse was significantly lower in the LPA 99 trial: 4.2 versus 14.3% (P ¼ 0.03). 4 However, for high-risk (WBC count410 Â 10 9 /l) patients, large doses of Ara-C could act better. 2,4,56 Although ATRA plus chemotherapy gained great effects, there are still problems such as relapse, severe side effects of chemotherapy and so on.…”