Chemotherapy-Free Regimen Feasible for Acute Promyelocytic Leukemia

September 24, 2015

New research showed that it appears to be feasible to treat low- and high-risk patients with acute promyelocytic leukemia with the chemotherapy-free regimen of all-trans retinoic acid and arsenic trioxide.

New research showed that it appears to be feasible to treat low- and high-risk patients with acute promyelocytic leukemia with the chemotherapy-free regimen of all-trans retinoic acid (ATRA) and arsenic trioxide. Results of the AML17 study, published recently in Lancet Oncology, found that ATRA plus arsenic trioxide had a high cure rate with less relapse and similar survival to the current standard of care in these patients: ATRA plus chemotherapy.

“This study found that the quality of life did not differ significantly in patients with acute promyelocytic leukemia treated with either ATRA and arsenic trioxide or ATRA and idarubicin,” wrote Alan K. Burnett, MD, FMed Sci, of Nottingham University Hospital NHS Trust in the United Kingdom, and colleagues. “This study also confirms the feasibility and benefit of ATRA and arsenic trioxide treatment as the next stage in treatment de-escalation in low-risk patients with acute promyelocytic leukemia, with excellent outcomes.”

AML17 included patients with acute promyelocytic leukemia confirmed by presence of the PML-RARA fusion transcript. Patients from 81 hospitals in the United Kingdom were enrolled and randomly assigned to ATRA and idarubicin chemotherapy (n = 119) or ATRA and arsenic trioxide (n = 116). Both high- (n = 57) and low-risk patients were included.

This study had a less frequent dosing schedule than the GIMEMA-AMLSG-SAL study, an Italian and German collaboration studying ATRA and arsenic trioxide against standard of care in low-risk patients only.

Here, ATRA was given to participants in a daily divided oral dose of 45 mg/m² until remission, or until day 60, and then in a 2 weeks on/2 weeks off schedule. In the standard-of-care group, idarubicin was given intravenously at 12 mg/m² on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m² on days 1 to 4 of course 2; mitoxantrone at 10 mg/m² on days 1 to 4 of course 3, and then idarubicin at 12 mg/m² on day 1 of course 4 (final course). In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0.3 mg/kg on days 1 to 5 of each course, and at 0.25 mg/kg twice weekly in weeks 2 to 8 of course 1 and weeks 2 to 4 of courses 2 to 5.

The researchers explained that “the attenuated dosing schedule used in this trial offers the obvious advantage of convenience for the patients compared with ATRA and idarubicin, but also reduces administration and acquisition costs of arsenic trioxide.”

High-risk patients were also allowed to receive an initial dose of the immunoconjugate gemtuzumab ozogamicin.

Of the 235 patients, 91% achieved remission. A greater proportion of patients in the ATRA and arsenic trioxide group achieved complete remission compared with the ATRA and idarubicin group. The event-free survival was 80% at 4 years: 82% in low-risk patients and 76% in high-risk patients. Overall, event-free survival was significantly better in patients assigned to ATRA and arsenic trioxide.

No difference in quality of life or 30-day mortality was seen between the two groups.

Fifty-seven patients in the ATRA/idarubicin group and 40 patients in the ATRA/arsenic trioxide group reported experiencing grade 3/4 toxicities.

After the first course of treatment, patients in the ATRA and arsenic group had lower rates of grade 3/4 alopecia (5% vs 23%) and oral toxicity (1% vs 19%) compared with ATRA and idarubicin; however, more raised liver alanine transaminase was reported in patients assigned arsenic (25% vs 10%). After the second course, 28% of patients in the arsenic group reported grade 3/4 alopecia compared with 3% of the ATRA and idarubicin group. No other toxicities reached the 10% level, according to the study.

Finally, the researchers found that patients assigned ATRA and arsenic required significantly less supportive care for all measures in the study except antibiotic use.

“These data raise some questions as to next steps that should be taken in this now highly curable disease,” the researchers wrote. “Acquisition costs, even for the attenuated schedule of arsenic trioxide, are clearly important, and are compounded by an absence of licensing approval for first-line treatment. The schedule for front-line therapy could possibly be attenuated further (ie, reduced treatment and reduced toxicity, which could be especially relevant in children), but attention will now move to substitution with oral formulations, the experience of which suggests equivalence of effect and arguably a better pharmacokinetic profile with consequent potential for reduced toxicity.”