Enrollment and Characteristics of the Patients

Table 1. Table 1. Demographic, Clinical, and Biologic Characteristics of the Patients at Diagnosis.

Figure 2. Figure 2. Study Enrollment, Randomization, and Retention. In the ATRA–arsenic trioxide group, both the patients who did not complete induction therapy and the patient who discontinued treatment after induction therapy owing to a major protocol violation could be evaluated for postconsolidation polymerase-chain-reaction status and event-free survival at 2 years and thus were included in the intention-to-treat analysis. Two patients in the ATRA–arsenic trioxide group (one who withdrew from the study and one who was lost to follow-up during the fourth cycle of consolidation therapy) and one patient in the ATRA–chemotherapy group (who withdrew from the study after the third cycle of consolidation therapy) could not be evaluated for the primary end point owing to insufficient follow-up.

Enrollment of the prespecified 162 patients was started in October 2007 and was completed in September 2010. The present analysis was performed in November 2012, with a median follow-up of 34.4 months (range, 0.5 to 55.8). Genetic tests ruled out a diagnosis of PML-RARA–positive APL in 3 patients. Three of 159 patients with genetically confirmed APL did not start the assigned treatment (1 withdrew consent, and 2 had major protocol violations). The intention-to-treat analysis included all 156 patients who received at least one dose of the assigned therapy after randomization. The main demographic, clinical, and biologic characteristics of these 156 patients are shown in Table 1. There were no significant differences in the baseline characteristics between the two cohorts. The disposition of the patients, including reasons for exclusion, is illustrated in Figure 2.

Induction Therapy

A total of 77 patients in the ATRA–arsenic trioxide group and 79 patients in the ATRA–chemotherapy group could be evaluated for a response to induction therapy. Hematologic complete remission was achieved in all 77 patients in the ATRA–arsenic trioxide group (100%) and in 75 of the 79 patients in the ATRA–chemotherapy group (95%) (P=0.12). The median time to hematologic complete remission was 32 days (range, 22 to 68) in the ATRA–arsenic trioxide group and 35 days (range, 26 to 63) in the ATRA–chemotherapy group (P=0.61). Four patients in the ATRA–chemotherapy group died during induction therapy: 2 from the differentiation syndrome, 1 from ischemic stroke, and 1 from bronchopneumonia. Induction therapy was terminated early in 2 patients in the ATRA–arsenic trioxide group: in 1 because of a major protocol violation, and in the other because of severe prolongation of the QTc interval and electrolyte abnormalities on day 3. Both these patients could be evaluated for a molecular response after consolidation therapy was given off protocol; thus, they were included in the intention-to-treat analysis (see below).

The differentiation syndrome, including moderate and severe forms,34 developed in 15 patients in the ATRA–arsenic trioxide group (19%) and in 13 patients in the ATRA–chemotherapy group (16%) (P=0.62). Severe differentiation syndrome occurred in 10 patients (5 [6%] in each group, P=0.99) and was fatal in 2 patients assigned to ATRA–chemotherapy.

Leukocytosis, defined as a white-cell count of more than 10×109 per liter, developed during induction therapy in 35 of 74 patients in the ATRA–arsenic trioxide group (47%) and in 19 of 79 patients in the ATRA–chemotherapy group (24%) (P=0.007). All cases were successfully managed with hydroxyurea therapy as recommended in the protocol.

Consolidation Therapy

A total of 146 of 152 patients in hematologic complete remission proceeded to consolidation therapy. Two patients in the ATRA–chemotherapy group did not receive consolidation therapy because of a cardiac toxic effect and loss to follow-up. Besides the 2 patients who went off protocol during induction therapy, 2 additional patients in the ATRA–arsenic trioxide group were taken off protocol after induction therapy owing to a toxic effect (repetitive tachycardia) and a major protocol violation. However, the patient with the protocol violation could be evaluated for the primary end point.

Four patients died during consolidation therapy (three in the ATRA–chemotherapy group and one in the ATRA–arsenic trioxide group). The three patients in the ATRA–chemotherapy group died from hemorrhagic shock, pulmonary embolism, and bronchopneumonia. The patient in the ATRA–arsenic trioxide group died from bronchopneumonia associated with H1N1 virus infection.

After the third consolidation cycle, molecular complete remission was achieved in all 145 patients who could be evaluated for a molecular response (75 in the ATRA–arsenic trioxide group and 70 in the ATRA–chemotherapy group). Four patients in the ATRA–arsenic trioxide group did not proceed to the fourth consolidation cycle (2 declined to continue treatment and 2 had major protocol violations). Three patients in the ATRA–arsenic trioxide group did not complete the fourth consolidation course owing to withdrawal of consent, loss to follow-up, and the treating physician's decision.

Maintenance Therapy

A total of 67 of the 70 patients who completed consolidation therapy in the ATRA–chemotherapy group proceeded to maintenance therapy. Three patients went off protocol after consolidation therapy owing to withdrawal of consent, a major protocol violation, and a toxic effect. Two patients did not complete maintenance therapy because of prolonged myelosuppression (>50 days).

Event-free Survival

Seven patients had a relapse during follow-up (two in the ATRA–arsenic trioxide group, at 22 and 27 months after diagnosis, and five in the ATRA–chemotherapy group, at 8, 14, 16, 21, and 35 months). In two of the seven patients with disease recurrence, a relapse was detected at the molecular level before detection of the hematologic relapse, leading to early administration of salvage therapy.

Of 156 patients in the intention-to-treat population, 6 (4%) could not be evaluated at 24 months for the primary analysis because a molecular evaluation was not performed after the third consolidation cycle or follow-up was insufficient. Of the remaining 150 patients, 97% in the ATRA–arsenic trioxide group (72 of 74 patients) were alive and free of events at 24 months, as compared with 86% in the ATRA–chemotherapy group (65 of 76 patients) (difference, 11 percentage points; 95% confidence interval [CI], 2 to 22). Since the lower bound of the 95% confidence interval for the difference in event-free survival rates was not lower than −5%, the noninferiority of ATRA–arsenic trioxide was confirmed (P<0.001). Furthermore, the log-rank test for the difference in event-free survival curves indicated the superiority of ATRA–arsenic trioxide (P=0.02).

In the per-protocol population, the event-free survival rates were 97% in the ATRA–arsenic trioxide group (64 of 66 patients) versus 85% in the ATRA–chemotherapy group (61 of 72) (difference, 12 percentage points; 95% CI, 2 to 23; P<0.001 for noninferiority).

Secondary End Points

Overall Survival, Disease-free Survival, and Cumulative Incidence of Relapse

Figure 3. Figure 3. Outcome Estimates.

The 2-year overall survival probability was 99% (95% CI, 96 to 100) in the ATRA–arsenic trioxide group and 91% (95% CI, 85 to 97) in the ATRA–chemotherapy group (P=0.02). The 2-year disease-free survival rate was 97% (95% CI, 94 to 100) in the ATRA–arsenic trioxide group and 90% (95% CI, 84 to 97) in the ATRA–chemotherapy group (P=0.11). The 2-year cumulative incidence of relapse was 1% (95% CI, 0 to 4) in the ATRA–arsenic trioxide group and 6% (95% CI, 0 to 11) in the ATRA–chemotherapy group (P=0.24). Outcome estimates are shown in Figure 3.

Kinetics of Minimal Residual Disease

The kinetics of PML-RARA transcript reduction after induction and consolidation therapy were assessed in 63 unselected patients. There were no significant differences between the two groups (Table S2 in the Supplementary Appendix).

Hematologic Toxicity

Figure 4. Figure 4. Hematologic Toxic Effects.

Grade 3 or 4 neutropenia lasting more than 15 days and grade 3 or 4 thrombocytopenia lasting more than 15 days were significantly more frequent both during induction therapy and after each consolidation course in the ATRA–chemotherapy group than in the ATRA–arsenic trioxide group (Figure 4). Counting together fever of unknown origin and documented infectious episodes occurring during either induction or consolidation therapy, we recorded 26 episodes in the ATRA–arsenic trioxide group and 59 episodes in the ATRA–chemotherapy group (P<0.001).

Nonhematologic Toxicity

A total of 43 of 68 patients in the ATRA–arsenic trioxide group (63%) and 4 of 69 patients in the ATRA–chemotherapy group (6%) had grade 3 or 4 hepatic toxic effects during induction or consolidation therapy (for patients in the two groups) or during maintenance therapy (for patients in the ATRA–chemotherapy group) (P<0.001). In all cases, the toxic effects resolved with temporary discontinuation of arsenic trioxide, ATRA, or both or with temporary discontinuation of chemotherapy during the maintenance phase (for patients in the ATRA–chemotherapy group).

Prolongation of the QTc interval occurred in 12 patients in the ATRA–arsenic trioxide group (16%) and in no patients in the ATRA–chemotherapy group (P<0.001). In 1 of the 12 patients with a prolonged QTc interval, arsenic trioxide was permanently discontinued, and the patient went off protocol. Information on nonhematologic toxic effects is shown in Table S3 in the Supplementary Appendix.