CHEMO FREE REGIMEN FOR APL

VIENNA — The groundbreaking chemotherapy-free combination of arsenic trioxide and all-trans retinoic acid (ATO/ATRA) is effective in the treatment of high-risk acute promyelocytic leukemia (APL) patients but with less toxicity and significantly lower cost than chemotherapy plus ATRA, new research shows.

"ATO/ATRA is at least equivalent to [chemotherapy] and is safe in high-risk patients given prophylaxis," said study author Alan K. Burnett, MD, of Cardiff University School of Medicine, Cardiff, United Kingdom, and the UK National Cancer Research Institute AML Working Group.

Dr Burnett presented the late-breaking research here at the 20th Congress of the European Hematology Association.

The chemo-free ATO/ATRA approach was established as being feasible and effective as chemotherapy in the GIMEMA-AMLSG-SAL trial, published in 2013 in the New England Journal of Medicine . However, that study only included low-to-intermediate-risk patients, Dr Burnett explained.

"The findings from the GIMEMA trial applied only to patients defined as lower risk, with a white blood cell (WBC) count of less than 10, however that misses about 75% of APL patients," he said.

The new study, the NCRI AML 17 trial, addresses that issue and includes patients across the spectrum of risk.

Conducted at 81 centers, the study involved 235 patients over the age of 16 with molecularly confirmed APL, including 57 patients who were high risk (WBC > 10x10⁹/L).

The patients were randomized to either a combination of anthracycline and ATRA (AIDA; n = 119) or the chemotherapy-free combination of ATO/ATRA (n = 116).

Patients in the high-risk group had the option of receiving a single dose of gemtuzumab ozogamicin (GO; 6 mg/m²) during induction. The high-risk patients were also nearly equally randomized in the two groups, with 27 in the AIDA group and 30 in the ATO/ATRA group.

The median age of patients in both groups was 47 years (16 to 77).

Outcomes and AEs 

Dosing in the chemotherapy-free ATO/ATRA group consisted of an 8-week induction followed by four consolidation courses over 4 weeks.

The schedule was less intense than in the GIMEMA study.

"We realized we could use less frequent dosing of the arsenic trioxide, so patients were not dosed every day, as they were in the GIMEMA study, and the total number of infusions was about half in this study," Dr Burnett said.

In the AIDA group, the chemotherapy consisted of idarubicin and mitoxantrone as well as ATRA.

Based on a follow-up of an average of 30.5 months (range 0.2 to 56.1), patients in the chemo-free ATO/ATRA group had a mean 4-year overall survival of 93% vs 89% in the AIDA group, which was not statistically significant (P = .2).

However, event-free survival was superior in the ATO/ATRA group (91%) compared with AIDA (74%; P = .003).

In terms of outcomes for high-risk patients, the overall survival across both groups was 86%, and 77% for high-risk patients over the age of 60.

In high-risk patients, the rate of relapse-free survival in the ATO/ATRA arm who achieved molecular remission was 100% compared with 74% in the AIDA group; however, there were no significant differences between overall survival (87% vs 84%; P= .8).

"None of the high risk patients who achieved molecular remission relapsed during the study, and that is still the case," Dr Burnett said.

Of the 30 high-risk patients allocated to the chemo-free arm, 28 received GO as per protocol, and the four-year overall survival rate in that group was 89%.

Of the two patients who were not treated with GO, one died on day 12.

The two treatment groups showed no significant differences in overall rates of complete remission (AIDA 89% vs chemo-free 94%; P = .18), and mortality rates were similar at day 30 (6% vs 4%) and day 60 (9% vs 5%; P = .2).

Patients in the chemo-free arm had significantly less alopecia, less grade 3/4 liver toxicity, and less gastrointestinal toxicity.

They also required fewer blood and platelet transfusions, fewer days on antibiotics, and fewer days in the hospital.

Quality-of life assessments did not show significant differences in the two groups. But Dr Burnett questioned those findings.

"It's hard to believe [chemo-free] patents who only have to come in twice a week as opposed to five times a week feel no different in their quality of life, so I don't think the instrument used adequately picked up that benefit in this study," he commented.

Importantly, the significantly lower use of ATO in the new study compared with the GIMEMA study (151 vials vs 280 vials for a 70-kg patient) resulted in the potential for substantial cost savings, Dr Burnett said.

"Cost is a key issue with this," he said. "With [ATO/ATRA], the total would be about 151 vials, which, at about 350 British pounds [GBP] per vial, comes to about 52,000 GBP, which sounds like a lot, but the GIMEMA regimen required about 280 vials, so nearly doubling the cost to about 98,000 GBP."

Hervé Dombret, MD, director at University Institute of Hematology, in Paris, France, who comoderated the session, agreed that the findings offer important insights on the effect of the chemo-free treatment on high-risk APL patients.

"The study [suggests] that all APL patients could be treated with ATO/ATRA without chemotherapy [and that] lower and less expensive ATO dosing could work as well as standard doses," he told Medscape Medical News.

[There are] claims that all these novel therapies are too expensive, which is true in a sense, but this has to be compared with the costs associated with previous standard therapies," Dr Dombret said.

He noted that a limitation of the study is the relatively small number of high-risk patients.

"The effect reported in high WBC count patients results from an underpowered subset analysis in a quite small population of patients," he said. "As acknowledged by Dr Burnett, this has to be confirmed in a larger study."

Dr Burnett is a part-time employee of CTI Life Sciences and is on the advisory boards for Celgene, Agios, Pfizer, and Bristol-Myers Squibb. Dr Dombret has received research support from Teva. 

20th Congress of the European Hematology Association (EHA): Abstract LB2067. Presented June 14, 2015.