AT THE EHA CONGRESS

VIENNA (FRONTLINE MEDICAL NEWS) – Patients with high-risk newly diagnosed acute promyelocytic leukemia derive the same survival benefit from a chemotherapy-free combination as an anthracycline-containing standard of care, according to results of the AML17 APL study.

The 4-year overall survival rates in high-risk patients (WBC > 10 x 109/L) were 87% with arsenic trioxide plus all-trans retinoic acid and 84% with the standard all-trans retinoic acid and idarubicin schedule.

Relapse-free survival rates were superior with the chemotherapy-free combination (100% vs. 74%; P = .008), Dr. Alan Burnett reported at the annual congress of the European Hematology Association.

“One of our rationales for using arsenic as first-line (therapy) was to try and get at the early death that remains a major problem in this disease,” he said.

Arsenic trioxide and gemtuzumab ozogamicin are effective as single agents with the former approved for relapsed disease in patients with APL. The GIMEMA-AMLSG-SAL trial indicated that a daily schedule of arsenic trioxide plus all-trans retinoic acid was at least as effective and may be superior to all-trans retinoic acid plus chemotherapy in low to moderate risk APL patients ( N. Engl. J. Med. 2013;369: 111-21 ).

The AML17 APL trial was designed by the U.K. National Cancer Research Institute with the aim of comparing all-trans retinoic acid and idarubicin with arsenic trioxide in an attenuated dosing schedule plus all-trans retinoic acid. Importantly, high-risk patients were included, with the option to receive a single dose of gemtuzumab ozogamicin (Mylotarg) 6 mg/m2 within the first 4 days of induction, said Dr. Burnett , who performed the research as head of hematology at Cardiff University in Wales and is now global lead for myeloid diseases at CTI BioPharma in Seattle. In the United States, gemtuzumab was withdrawn from the market in 2010 because of safety concerns.

From May 2009 to October 2013, 235 patients with molecularly confirmed APL were randomized at 81 centers to all-trans retinoic acid 45 mg/m2 as a divided daily oral dose to day 60 or complete remission plus arsenic trioxide 0.3 mg/kg on days 1-5 of week 1 and then 0.25 mg/kg twice per week for 7 weeks plus all-trans retinoic acid 45 mg/m2 as a divided daily oral dose to day 60 or complete remission or to idarubicin 12 mg/m2 on days 2, 4, 6, 8 plus all-trans retinoic acid 45 mg/m2 as a divided daily oral dose to day 60.

In the arsenic trioxide plus all-trans retinoic acid arm, this was followed by all-trans retinoic acid 45 mg/m2 as a divided daily dose 2 weeks on and 2 weeks off plus four consolidation courses of arsenic trioxide 0.3 mg/kg days 1-5 of week 1 and then 0.25 mg/kg twice per week for 3 weeks (total 63 days of arsenic trioxide).

Consolidation in the all-trans retinoic acid and idarubicin arm was all-trans retinoic acid 45 mg/m2 as a divided daily dose on days 1-15 plus idarubicin 5 mg/m2 days 1-4 in course 2, mitoxantrone 10mg/m2 days 1-4 in course 3, and idarubicin 12 mg/m2 day 1 in course 4.

No maintenance was given in either arm. The median patient age was 47 years, with about 20% of patients over age 60; over 20% of the patients were high-risk, and they were equally balanced in the two treatment groups.

At 4 years, the overall survival rate among all patients was comparable – 93% with arsenic trioxide plus all-trans retinoic acid and 89% with all-trans retinoic acid and idarubicin.

However, event-free survival was significantly better in the arsenic trioxide plus all-trans retinoic acid cohort (91% vs. 74%; hazard ratio, 0.36; P = .003), as were frank relapse-free survival (97% vs. 83%; HR, 0.24; P = .004) and molecular relapse-free survival (98% vs. 70%; HR, 0.17; P < .0001), Dr. Burnett said.

One patient on arsenic trioxide plus all-trans retinoic acid experienced frank relapse, compared with 13 on all-trans retinoic acid and idarubicin, plus a further 19 molecular relapses occurred on this arm (cumulative incidence of molecular and hematologic relapse 0% vs. 27%, HR, 0.12; P < .0001).

“Once a patient was in molecular remission there were no further relapses in patients on (arsenic trioxide plus all-trans retinoic acid),” he said.

Of the 30 high-risk patients allocated to the chemo-free arm, 28 received gemtuzumab ozogamicin as per protocol. The overall survival at 4 years for these patients was 89%. Of the two patients not treated with gemtuzumab ozogamicin, one died on day 12 due to causes unrelated to treatment.

Among the 49 patients older than 60 years, overall survival was 80% with arsenic trioxide plus all-trans retinoic acid and 74% with all-trans retinoic acid and idarubicin. Similarly, among good-risk patients, relapse-free survival was significantly improved (96% vs. 79%; HR, 0.33; P = .04). Also, overall survival was not inferior at 95% vs. 90%, “very much replicating the outcomes seen in the GIMEMA study,” Dr. Burnett said.

The benefits were also achieved with significantly less grade 3-4 liver toxicity than observed in the GIMEMA study (<10% vs 63%).

There was, however, an excess of cardiac toxicity in course 2 with arsenic trioxide plus all-trans retinoic acid, compared with all-trans retinoic acid and idarubicin (P = .001).

“We’re not totally sure what that’s all due to, but it doesn’t look to be due to a QC prolongation,” he said.

The arsenic trioxide plus all-trans retinoic acid regimen was associated with significant reductions in supportive care requirements including fewer blood and platelet transfusions, days on antibiotics, and days in hospital, with “many patients treated exclusively as outpatients,” he added.

The low risk of relapse with arsenic trioxide plus all-trans retinoic acid also negates the need for minimal residual disease monitoring.

Finally, compared with the GIMEMA study protocol, the attenuated arsenic dosing schedule in AML17 APL resulted in less frequent dosing of arsenic trioxide (63 doses vs. 140 doses) and less drug required (151 vials vs. 280 vials for a 70-kg patient). At an acquisition cost of £350 per vial, this represents a cost savings of £46,000 (nearly $72,000) per patient, not to mention the added convenience to patients, Dr. Burnett observed.

Cancer Research U.K. funded the study. Cephalon provided the arsenic trioxide. Dr. Burnett disclosed part-time employment with CTI LifeSciences and in the last 12 months serving on the advisory boards of Celgene, Agios, Pfizer, and Bristol-Myers Squibb.

pwendling@frontlinemedcom.com

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