Chemotherapy for patients with acute promyelocytic leukemia (APL) considered not to be high risk may be on the way out.
A randomized European Phase III trial comparing a synergistic targeted therapy of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) vs. ATRA plus standard chemotherapy showed both two-year event-free and overall survival rates that were superior in patients who received the non-chemotherapy dual-differentiation agents. The full journal write-up of the study reported in abstract form in the plenary session of the most recent American Society of Hematology Annual Meeting (OT, 1/25/13 issue) was published in the July 13 issue of the New England Journal of Medicine (2013;369:111-121).
Researchers from Italy and Germany concluded that ATRA plus ATO is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL (i.e., white blood cell counts at diagnosis of 10 109/L or less).
The 162 patients in the cohort were randomly selected to receive ATRA combined with ATO followed by post-remission therapy with ATO or induction chemotherapy with idarubicin and ATRA followed by anthracycline-based post-remission therapy.
The two-year event-free survival rates were 97 percent for use of ATRA-ATO and 86 percent for ATRA-chemotherapy, with overall survival rates of 99 and 91 percent, respectively. All 77 patients in the ATRA-ATO group had achieved complete remissions at a median follow-up of 34.4 months, as did 75 of the 79 patients in the ATRA-chemotherapy group (95 percent).
“It is clearly time to move this regimen to front-line for standard-risk APL,” said the first author, Francesco Lo-Coco, MD, Chair of the APL Subcommittee of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA Group) and Professor of Hematology in the Department of Biomedicine and Prevention at University Tor Vergata in Rome.
In an e-mail exchange, he said that GIMEMA will start a new trial for high-risk patients comparing a considerably reduced chemotherapy with ATO-ATRA regimen vs. the ATRA-chemotherapy alone. “We believe the new regimen may be applied to high-risk disease, but that some reduced chemotherapy such as two days of idarubicin early in therapy will be needed to lower WBC count,” he said.
The ATRA-ATO regimen is not being used clinically in Europe, Lo-Coco added. “Unfortunately, ATO is very expensive and not registered for front-line use in Europe, although in Germany it is now commonly used and reimbursed through insurance,” he said. “We are struggling to get the drug front-line with the European national regulatory agencies and with the company that manufactures the ATO.”
Forty centers from GIMEMA and 27 centers from the German-Austrian Acute Myeloid Leukemia Study Group and Study Alliance Leukemia participated. The trial was sponsored by the Italian Association Against Leukemia and others.
Results Better than Previous Studies
Asked for his opinion for this article, Martin S. Tallman, MD, Chief of the Leukemia Service at Memorial Sloan-Kettering Cancer Center, said the ATRA-ATO regimen has been in use there for APL for several years: “The regimen is my choice of treatment for patients with low-risk APL,” he said, adding that Memorial is now conducting a study that adds an ATO-containing maintenance to ATRA-ATO.
“Our focus is on ATRA-arsenic and minimizing chemotherapy,” he said.
Tallman, Chair of the Leukemia Committee of the Eastern Cooperative Oncology Group, said that there has been a series of studies in APL in conjunction with the other cooperative groups in North America, “and the outcome with this [European] trial appears much better than anyone has previously reported.”
In the new study, he noted, four patients in the ATRA-chemotherapy group died during induction therapy (two from differentiation syndrome, one from ischemic stroke, and one from bronchopneumonia) but no deaths in the ATRA-ATO group: “Four out of 79 isn't too bad, but in this disease, among people who get through the initial therapy and don't die early, almost everyone with low- and intermediate-risk disease is cured of their disease.
Less toxicity was also an important advance, he said. “If we can spare people chemotherapy, we have done them well.”
Whether ATRA-ATO is as good in high-risk patients remains to be determined, Tallman said. “But for low-risk patients in this trial the results are spectacular,” he said. “That the results were achieved with no chemotherapy is astounding.”
Not The Standard, But A Standard
Tallman said a major question being asked is whether this is a new standard of care. “I think the answer is yes, the prospective, randomized trial with well-balanced arms showed significant benefit to the ATRA-arsenic arm. But the ATRA-chemotherapy arm showed excellent results also. So I don't think [ATRA-ATO] is the only way to treat APL, but I think it does establish a new standard of care, one of several.”
In an editorial accompanying the NEJM article, Sai-Juan Chen, MD, PhD, and Zhu Chen, MD, PhD, from the State Key Laboratory of Medical Genomics and the Shanghai Jiao Tong University School of Medicine, pointed out that while significantly fewer hematologic toxic effects and fewer infections were reported for the ATRA-ATO group, the hepatic toxic effects and prolongation of the corrected QT interval were more obvious with ATRA-ATO, although those effects disappeared after temporary discontinuation of ATO, ATRA, or both.
The editorialists questioned whether the median follow-up of 34.4 months was sufficient to claim non-inferiority.
“Although this is generally an adequate follow-up period in patients treated with chemotherapy, in whom relapses tend to occur mostly in the first two years after treatment, it could be too early to evaluate the omission of maintenance therapy in the ATRA-arsenic trioxide group.”
The editorial also asked whether the current risk-stratification system for APL (low, medium, and high risk), based only on white-cell count and platelet count, is still adequate, given the discovery of new genetic biomarkers. The editorialists also recommended that for high-risk patients, new trials might include chemotherapy and other agents targeting additional genetic defects in malignant cells along with ATRA-ATO.
Abnormalities Specific to APL Targeted
The GIMEMA authors explained that ATO acts through specific binding of the promyelocytic leukemia (PML) protein moiety of the disease-specific PML-retinoic acid receptor alpha (RARA) oncoprotein, leading to its degradation and resulting in partial differentiation and induction of apoptosis of leukemic promyelocytes.
Synergy of arsenic trioxide and ATRA, which binds the RARA moiety of PML-RARA, has been shown at both the biologic and clinical levels.
The team pointed out, though, that while good news for patients with APL, this highly specific targeting also means it is not likely to be effective in other hematologic malignancies.