Retinoic acid plus arsenic trioxide demonstrate antileukemic effect in acute promyelocytic leukemia

All-trans-retinoic acid and arsenic trioxide induced stronger and more sustained antileukemic activity than all-trans-retinoic acid and chemotherapy among patients with low- or intermediate-risk acute promyelocytic leukemia, according to final results of the phase 3, open-label APL0406 randomized trial.

The initial results of the trial showed that all-trans-retinoic acid (ATRA) combined with arsenic trioxide (ATO) was not inferior to ATRA and chemotherapy, the standard of care for patients with low- or intermediate-risk acute promyelocytic leukemia (APL).

“Despite providing high cure rates, [ATRA and chemotherapy] is associated with frequent severe hematologic toxicity and development of secondary myeloid neoplasms in approximately 2% of patients,” Francesco Lo-Coco, MD, professor of hematology and head of the Laboratory for Integrated Diagnosis of Oncohematologic Diseases at University Tor Vergata in Rome, and colleagues wrote. “The introduction of ATO in APL treatment has resulted in similarly high remission and survival rates, coupled with significantly reduced myelosuppression.”

Lo-Coco and colleagues reported the final results of the trial, which randomly assigned 276 adult patients (median age, 46.6 years; range, 18-70.3) to ATRA with ATO (n = 129) or chemotherapy (n = 137).

The researchers reported on 263 patients evaluable for response (ATRA–ATO, n = 127; ATRA–chemotherapy, n = 136).

Median follow-up was 40.6 months.

All evaluable patients assigned the ATRA–ATO combination achieved complete remission, along with 97% (n = 132) of patients assigned ATRA with chemotherapy.

However, more patients assigned ATRA–ATO achieved 50-month EFS (97.3% vs. 80%; P < .001) and 50-month OS (99.2% vs. 92.6%; P = .0073), and fewer experienced relapse (1% vs. 13.9%; P = .0013).

Six patients died in complete remission. One of these patients was assigned ATRA–ATO and died of bronchopneumonia driven by the H1N1 virus; the other patients were in the ATRA and chemotherapy cohort and died of hemorrhagic shock, pulmonary embolism, secondary myelodysplastic syndrome (n = 1 for each) and bronchopneumonia (n = 2).

Two patients assigned ATRA and chemotherapy experienced molecular resistance after third consolidation, compared with no patients in the ATRA–ATO arm.

More patients in the ATRA and chemotherapy cohort relapsed after confirmed complete remission (15 vs. 2); the median time to remission in the chemotherapy arm was 14 months (range, 2.5-39.8). The two patients assigned ATRA and ATO relapsed at 22 months and 27 months.

Sixty-five patients experienced a total of 95 serious adverse events (ATRA–ATO, n = 43; ATRA–chemotherapy, n = 52).

More patients assigned ATRA and chemotherapy experienced grade 3 or grade 4 neutropenia or thrombocytopenia at all induction and consolidation phases (P < .001). More patients in this cohort also experienced febrile neutropenia during induction (75 vs. 30; P < .001) and during the second consolidation (46 vs. 4; P < .001).

Two patients assigned ATRA and chemotherapy developed a secondary myeloid neoplasm, including a fatal myelodysplastic syndrome. The other patient developed therapy-related acute myeloid leukemia, but remained alive and in complete remission.

“In line with the results of pilot studies and those of the recent randomized National Cancer Research Institute trial, our results support the use of ATRA–ATO in patients with newly diagnosed APL and point to this strategy as the new standard of care for low- or intermediate-risk patients,” Lo-Coco and colleagues wrote. “Studies exploring the role of ATRA–ATO are warranted in other APL subsets including high-risk, pediatric and elderly patients.” – by Cameron Kelsall

Disclosure: Lo-Coco reports honoraria from, as well as consultant and speakers bureau roles with, Baxalta, Lundbeck, Novartis and Teva Pharmaceutical Industries. Please see the full study for a list of all other researchers’ relevant financial disclosures.