A NEW COMBINATION FOR APL

A new combination of therapies has been shown to be effective in the treatment of acute promyelocytic leukemia (APL).

All-trans retinoic acid (ATRA) combined with arsenic trioxide was not inferior to the standard treatment of ATRA plus chemotherapy, and might even be superior in patients with low- to intermediate-risk APL, according to a study published in the July 11 issue of the New England Journal of Medicine.

A complete remission was achieved in all 77 (100%) patients in the ATRA-arsenic trioxide group and in 75 of 79 (95%) patients in the ATRA-chemotherapy group (P = .12).

Two-year event-free survival rates were better in the ATRA-arsenic trioxide group than in the ATRA-chemotherapy group (97% vs. 86%; P <.001 for noninferiority and P = .02 for superiority). Overall survival was better in the ATRA-arsenic trioxide group (P = .02).

"Although longer follow-up will be needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic trioxide act synergistically to eradicate APL," write the authors, led by Francesco Lo-Coco, MD, from University Tor Vergata on Rome, Italy.

Concerns Remain

In an accompanying editorial, 2 experts note that even though the first eventual cure of APL by "means of a synergistic targeted strategy without chemotherapy is heralded," this study hasn't addressed all concerns.

The follow-up period is not long enough, write Sai-Juan Chen, MD, PhD, from the State Key Shanghai Institute of Hematology in China, and Zhu Chen, MD, PhD, from the Shanghai Jiao Tong University School of Medicine in China. The data on survival rates beyond 2 years are not available.

"Although this is generally an adequate follow-up period in patients treated with chemotherapy, in whom relapses tend to occur mostly in the first 2 years after treatment, it could be too early to evaluate the omission of maintenance therapy in the ATRA-arsenic trioxide group," they explain.

Another concern is that the risk-stratification system currently used for APL (low, medium, and high risk) is based only on white cell and platelet counts. However, with the discovery of new genetic biomarkers, "the few patients with APL who have an inferior prognosis" in the clinically apparent low- to intermediate-risk group, such as the 2 patients in the ATRA-arsenic trioxide group who relapsed, "could eventually be predicted," the editorialists write.

In addition, new trials of more sophisticated therapies are warranted for high-risk patients. "Early death before the therapeutic agents take effect, often encountered in this group, should be handled with the use of a multidisciplinary approach," they note.

As an example, chemotherapy and other agents that target additional genetic defects in malignant cells need to be more "appropriately incorporated into an ATRA-arsenic trioxide regimen in order to get closer to our goal of curing all patients with APL," the editorialists conclude.

Study Details

Current ATRA and anthracycline-based chemotherapy regimens have made APL a highly curable condition, with overall remission rates of up to 95% and cure rates now exceeding 80%. However, arsenic trioxide is also highly effective for APL.

Dr. Lo-Coco and colleagues point out that results from pilot studies have been encouraging when arsenic was used a single agent, particularly for patients with low- to intermediate-risk disease. Aspreviously reported by Medscape Medical News, research suggests that it is a highly effective treatment for patients with relapsed APL, and that benefit might extend to newly diagnosed patients.

The researchers compared ATRA plus arsenic trioxide with ATRA plus chemotherapy in low- to intermediate-risk APL patients (with a white cell count of 10 × 10^(9)/L or less). The prospective randomized phase 3 trial was designed to show that 2-year event-free survival with ATRA plus arsenic trioxide was not inferior to that with ATRA plus chemotherapy.

Patients were randomized to 1 of 2 groups: ATRA plus arsenic trioxide for induction and consolidation therapy (n = 77); or standard ATRA plus idarubicin induction therapy followed by 3 cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA (n = 79).

Of the 156 patients in the intention-to-treat population, 150 patients were evaluable. In this cohort, 72 of 74 patients (97%) in the ATRA-arsenic trioxide group were alive and event-free at 2 years, as were 65 of 76 patients (86%) in the ATRA-chemotherapy group, for an absolute difference of 11 percentage points.

Noninferiority Confirmed, Better Survival

"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 < .001)," Dr. Lo-Coco and colleagues note. In addition, the log-rank test for the difference in event-free survival curves indicated the superiority of ATRA-arsenic trioxide (P = .02).

The 2-year cumulative incidence of relapse was lower in the ATRA-arsenic trioxide group than in the ATRA-chemotherapy group (1% vs 6%; P = .24). However, the 2-year overall survival probability was higher in the ATRA-arsenic trioxide group than in the ATRA-chemotherapy group (99% vs 91%; P = .02).

There was less hematologic toxicity in the ATRA-arsenic trioxide group than in the ATRA-chemotherapy group (26 vs 59 episodes; P < .001). However, there were more grade 3 or 4 hepatic toxic effects in the ATRA-arsenic trioxide group (63% in vs 6%; P < .001).

The study is supported by grants from Associazione Italiana contro le Leucemie, the Associazione Italiana per la Ricerca sul Cancro, and the German Ministry of Education and Research.

N Engl J Med. 2013;369:111-121, 186-187. Abstract, Editorial