NEW YORK (Reuters Health) Nov 22 - An oral arsenic-based formula treats acute promyelocytic leukemia (APL) as effectively as an IV formulation, auguring the promise of out-patient treatment for this condition, Chinese researchers say.
In a multicenter phase III trial reported online October 14 in the Journal of Clinical Oncology, they compared the oral formula, Realgar-Indigo naturalis (RIF) containing tetra-arsenic tetra-sulfide (As4 S4), to intravenous arsenic trioxide (ATO), for induction and maintenance.
The components of RIF include Indigo naturalis and Radix salviae miltiorrhizae, which promote transport of arsenics intracellularly. Triggered by higher aquaglyceroporin 9 (AQP9) expression, they have clear synergistic effects with As4S4 on the differentiation and apoptosis of APL cells, according to senior author Dr. Xiao-Jun Huang of the Peking University People's Hospital in Beijing and colleagues.
In all, 242 patients with newly-diagnosed APL were randomly assigned to oral RIF (60 mg/kg) or ATO (0.16 mg/kg). All patients also received all-trans retinoic acid (ATRA; 25 mg/m2) during induction therapy.
Patients who achieved complete remission (CR) then received consolidation chemotherapy with homoharringtonine, cytarabine, daunorubicin, and mitoxantrone.
Maintenance treatment consisted of sequential ATRA plus either RIF or ATO for two years.
The primary end point was the rate of disease-free survival (DFS) at two years, which was assessed for noninferiority with a 10% noninferiority margin.
After a median follow-up time of 39 months the results show DFS at two years was 98.1% (106 of 108) in the RIF group and 95.5% (107 of 112) in the ATO group. The DFS difference was 2.6%, and the lower limit of the 95% CI of DFS difference was greater than the 10% noninferiority margin, confirming noninferiority (p<0 .001="" p="">
No significant differences were noted between the RIF and ATO groups in complete remission rate (99.1% vs 97.2%; p=0.62) or in overall survival at 3 years (99.1% vs 96.6%; p<0 .18="" p="">
Rates of adverse events were similar in the two groups.
The authors also note that the toxicity of arsenic-containing agents is a major concern. However, this study showed no severe adverse effects despite the two-year continuation period, with a cumulative dose of approximately 2,500 mg.
Analysis of arsenic levels in the plasma, urine, nails, and hair of patients indicated that there was no significant accumulation.
The authors note that previous studies have shown, as did theirs, that the frequency and extent of arsenic toxicity are much milder during maintenance therapy than during induction therapy.
The early death rate (death during induction therapy) did not differ significantly between the RIF and ATO groups (0.9% v 2.6%; p<0 .60="" achieve="" also="" an="" authors="" cr.="" death="" early="" low="" more="" note="" opportunity="" p="" patients="" provided="" rates="" that="" the="" to="" with="">
"Other contributing factors were sufficient support therapy, enrolling only patients with a white blood cell count less than 50x10 to the 9th per liter, favorable characteristics of the enrolled patients (good performance status and exclusion of patients older than age 60 years), and experience in treating APL22; the latter is recognized as a potentially important factor in the outcome," the authors write.
Acute promyelocytic leukemia (APL) is characterized by the translocation t(15;17) and the expression of a PML/RAR alpha fusion protein that is diagnostic of the disease. To closely observe the molecular kinetics, the study authors also analyzed serial bone marrow samples from 93 patients. Expression of PML-RAR alpha in the RIF and ATO groups was similar at diagnosis.
They found, at the end of consolidation therapy, that the PML-RAR transcript was undetectable in any patient in either group. The two relapsed patients had detectable PML-RAR transcript levels before hematologic relapse.
The authors conclude "oral RIF plus ATRA is not inferior to intravenous ATO plus ATRA as first-line treatment of APL and may be considered as a routine treatment option for appropriate patients."
Dr. Francesco Lo-Coco, a hematologist at the University of Tor Vergata in Rome and an expert on the use of arsenic trioxide in PML, told Reuters Health by email that the study was well-conducted and represented "remarkable progress."
"This study hold promise that in the near future we will be able to cure APL not only sparing chemo but also on an outpatient basis (after the initial two to three weeks, when patients have to stay in hospital given the hemorrhagic risk)," Dr. Lo-Coco said.
He says toxicity profiles are similar and patients receiving the oral treatment will clearly have better quality of life.
"In fact, the IV infusion patients have to spend almost half a day in hospital each day. This affects negatively their normal life, work and other activities," he writes.
He says that just because the authors of the present study did not include patients older than 60 years, does not mean it doesn't work in the elderly.
"We know from other studies it works equally well," he said.
SOURCE: http://bit.ly/19OmLbw
J Clin Oncol 2013.
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