Page 110 - 2018_12-Haematologica-web

L. Adès et al.
Introduction
Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia (AML) characterized by its mor- phology, the presence of t(15;17), and marked sensitivity to the differentiating effect of all-trans retinoic acid (ATRA) and the pro-apoptotic effect of arsenic trioxide (ATO).1 The combination of ATRA and anthracycline-based chemother- apy has been the mainstay of the treatment of newly diag- nosed APL over the last two decades.2–4 Published results have shown that cytarabine (cytosine arabinoside, AraC) could be omitted from chemotherapy in standard-risk APL [i.e., with a baseline white blood cell count (WBC) <10x109/L] but appeared to be useful in high-risk APL (with a WBC >10x109/L), possibly at high doses, to reduce the incidence of relapse.5 A beneficial role for prolonged main- tenance treatment with continuous low-dose chemothera- py (6-mercaptopurine and methotrexate) and intermittent ATRA was also suggested, especially in high-risk APL, fol- lowing in particular randomized results from our group,5,6 and from a recent meta-analysis7 of several trials. With regards to anthracyclines, at least one study suggested that idarubicin gave better results than daunorubicin,8 while non-randomized studies suggested a potential benefit of adding ATRA during consolidation cycles, at least if AraC was omitted.2,4
Recently, however, ATO has been demonstrated to have pronounced efficacy in newly diagnosed APL. In particular, it was shown in two large randomized trials that the com- bination of ATO and ATRA without chemotherapy was at least equal and, with longer term follow-up, even superior to ATRA plus chemotherapy combinations in standard-risk APL.9,10,11 In high-risk APL, ATO plus ATRA combinations, with very limited added chemotherapy, also appear very promising,10,12 and are currently being compared with the conventional ATRA chemotherapy approach in random- ized trials.
When the APL 2006 trial was launched, ATO was mainly considered as an adjunct to ATRA chemotherapy combina- tions in the first-line treatment of APL, aimed at reducing the relapse rate (especially in high-risk APL) and/or dimin- ishing the amount of chemotherapy administered (espe- cially in standard-risk APL).
Based on the results of the APL 2006 trial, reported here, we evaluated the role of ATO in the treatment of standard- and high-risk APL, in addition to the “classical” ATRA plus chemotherapy backbone regimens.
Methods
Patients
Between 2006 and 2013, patients from French, Belgian and Swiss centers with documented (by cytogenetics and or molecular biology), newly diagnosed APL who were aged 70 years or less were eligible for inclusion in the APL 2006 trial, after giring informed consent. The trial was approved by local ethical commit- tees (ClinicalTrials.gov Identifier: NCT00378365). Eligibility crite- ria in this trial were a morphological diagnosis of APL based on French-American-British criteria and no contraindication to inten- sive chemotherapy. No minimal performance status was required and patients with therapy-related APL could be enrolled.
Induction treatment consisted of ATRA 45 mg/m2/day until complete remission with idarubicin 12 mg/m2/day for 3 days and AraC 200 mg/m2/day for 7 days starting on day 3.
Patients with a baseline WBC <10x109/L who achieved a com- plete remission were randomized for consolidation between three groups given treatment containing AraC, ATO or ATRA. The AraC group (standard group) received a first consolidation course with idarubicin 12 mg/m2/day for 3 days and AraC 200 mg/m2/day for 7 days, a second consolidation course with idarubicin 9 mg/m2/day for 3 days and AraC 1 g/m2/12 h for 4 days, and main- tenance therapy for 2 years with intermittent ATRA 15 days/3 months and continuous treatment with 6 mercaptopurine (90 mg/m2/day orally) and methotrexate (15 mg/m2/week orally).
The ATO and ATRA groups received the same treatment as the AraC group, but AraC was replaced by, respectively, ATO 0.15 mg/kg/day on days 1 to 25 and ATRA 45 mg/m2/day on days 1 to 15 for both consolidation courses. The rationale for the ATRA con- solidation treatment was based on results of a Spanish PETHEMA group trial, suggesting that AraC could be omitted from chemotherapy consolidation cycles in standard-risk APL, and that there could be a benefit from adding ATRA to consolidation cycles. The use of prolonged maintenance treatment was based on our previous results in a randomized phase III trial supporting the interest of this approach in reducing relapses after a conventional ATRA chemotherapy regimen.
Patients with a baseline WBC >10x109/L were randomized to consolidation with either chemotherapy or chemotherapy com- bined with ATO. The chemotherapy group received a first con- solidation course with idarubicin 12 mg/m2/day for 3 days and AraC 200 mg/m2/day for 7 days, a second consolidation course with idarubicin 9 mg/m2/day for 3 days and AraC 1 g/m2/12 h for 4 days, and 2-year maintenance therapy with intermittent ATRA and continuous 6-mercaptopurine plus methotrexate. The chemotherapy plus ATO group received the same treatment except that ATO 0.15 mg/kg/day was added from day 1 to day 25 during both consolidation courses. After a first interim analy- sis in September 2010 on data from 81 patients, AraC was delet- ed from consolidation cycles of the chemotherapy plus ATO group.
Treatment of coagulopathy during the induction phase was based on platelet support to maintain the platelet count at a level greater than 50x109/L until the disappearance of the coagulopathy. The use of heparin, tranexamic acid, fresh-frozen plasma, and fib- rinogen transfusions was optional, according to each center's poli- cy.
Prophylaxis and treatment of ATRA syndrome consisted of dex- amethasone 10 mg/12 h given intravenously for at least 3 days if the WBC was above 10x109/L (before or during treatment with ATRA) or at the earliest sign of the ATRA syndrome (dyspnea, lung infiltrates, pleural effusion, unexplained renal failure). In the absence of rapid improvement of symptoms (within 24 h), ATRA was transiently stopped until clinical control was obtained.
Statistical methods
The primary endpoint was event-free survival from the time of achieving complete remission. Relapse, survival, side effects of the treatment and duration of hospitalization were secondary end- points.
Analyses were performed on a modified intent-to-treat princi- ple, excluding only diagnostic errors and withdrawals of consent. Censored endpoints were estimated by the nonparametric Kaplan- Meier method13 and then compared between randomized groups by the log-rank test. In estimating relapses, we took into account competing risks, i.e., deaths in first complete remission, using cumulative incidence curves and then compared results using the Gray test, whereas a cause-specific Cox model was used to esti- mate cause-specific hazard ratios.14 The type I error was fixed at the 5% level. All tests were two-tailed. Statistical analyses were
2034
haematologica | 2018; 103(12)