Chemotherapy-Free Regimen Tops Standard for Treating Patients with Acute Promyelocytic Leukemia

Charles Bankhead

January 2013, Vol 4, No 1 - ASH Annual Meeting


Atlanta, GA—A chemotherapy-free regimen for patients with acute promyelocytic leukemia (APL) achieved a 2-year survival of almost 100% with less toxicity compared with cytotoxic regimens, according to a study reported at the 2012 American Society of Hematology (ASH) meeting.

The combination of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) led to a 2-year event-free survival (EFS, primary end point) of 97% and disease-free survival (DFS) of 97% in standard-risk patients. By comparison, idarubicin-ATRA induction followed by anthracycline maintenance therapy led to an EFS of 86.7% and DFS of 91.6%.

Although statistically powered to demonstrate noninferiority, the trial showed that the ATO-ATRA regimen outperformed standard therapy with respect to all key end points, said Francesco Lo-Coco, MD, Professor of Hematology at University Tor Vergata in Rome, Italy. As a result, the chemotherapy-free regimen warrants consideration as a standard of care for standard-risk patients with APL, he added.

ATRA has been used clinically in APL since the 1980s, after evidence showed that the retinoid induces differentiation in leukemia cells. ATO, which has been used to treat APL for a decade or more, is believed to induce apoptosis, Dr Lo-Coco said during a press conference at the ASH meeting. In addition, altered protein in patients with APL has binding sites specific for both ATO and ATRA.

The ATO-ATRA regimen is being evaluated in several ongoing clinical trials. Dr Lo-Coco presented results from the first randomized trial comparing ATO-ATRA with ATRA-anthracycline, the current standard of care for patients with APL.

Investigators at sites in Italy and Germany randomized 162 standard-risk patients to the 2 regimens. By Sanz’s risk classification, 61.8% of the patients were intermediate risk and 38.2% were low risk.

Patients in the ATO-ATRA arm received both drugs daily, until they achieved a complete remission, followed by 4 cycles of ATRA administered on a schedule of 4 weeks on therapy and 4 weeks off.

The standard arm consisted of ATRA-idarubicin induction, 3 cycles of ATRA-anthracycline consolidation therapy, and then maintenance with ATRA and low-dose chemotherapy.

The primary end point was EFS at 2 years.

When the results were analyzed, 154 patients were evaluable for response. All 75 patients in the ATO-ATRA arm achieved a complete response, as did 75 of the 79 patients in the ATRA-anthracycline arm. Cumulative recurrence rates were 1.6% with ATO-ATRA and 4.3% with ATRA-anthracycline.
The difference in 2-year EFS proved to be statistically significant (P = .03). After a median follow-up of 31 months, overall survival was 98.7% with ATO-ATRA and 91.1% with standard therapy, a difference that also achieved statistical significance (P = .03).

Fever, prolonged (≥15 days) ≥grade 3 neutropenia, and thrombocytopenia all occurred significantly more often with the standard regimen (P <.001). Differentiation syndrome, elevated liver enzymes, and other adverse effects occurred in a similar proportion of patients in each arm, said Dr Lo-Coco. Two patients in the ATO-ATRA group developed QTc prolongation, which resolved after discontinuation of ATO.

“This is the first curative treatment for acute promyelocytic leukemia that does not include myelosuppressive chemotherapy,” said William G. Woods, MD, a hematologist at Children’s Healthcare of Atlanta and moderator of a press conference before Dr Lo-Coco’s presentation at ASH.

“This is a huge step toward first-line use of targeted drugs for acute leukemia.”