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Including arsenic trioxide in induction, consolidation therapy shows promise for APL
The addition of arsenic trioxide to initial therapy induction and consolidation may reduce the risk for relapse in patients with acute promyelocytic leukemia, according to the results of a phase 2 study.
Comparison with historical data showed the incorporation of arsenic trioxide may also prolong EFS and OS.
Harry J. Iland
“Acute promyelocytic leukemia (APL), which was previously associated with a very poor prognosis, has become one of the most curable forms of acute leukemia,” Harry J. Iland, MBBS, FRACP, FRCPA, clinical hematologist at Royal Prince Alfred Hospital and clinical professor of medicine at University of Sydney, told HemOnc Today. “The addition of tretinoin (all-trans retinoic acid) to anthracycline-based chemotherapy has dramatically improved the outcome for patients with APL. However, patients with high-risk disease remained at increased risk for early death and relapse, prompting the use of risk-adapted chemotherapy intensification during consolidation.”
Iland and colleagues from the Australasian Leukaemia and Lymphoma Group sought to determine whether the combination of arsenic trioxide, tretinoin and idarubicin in induction therapy — as well as the addition of arsenic trioxide to tretinoin for consolidation therapy — would reduce the risk for relapse.
APML4 is a nonrandomized phase 2 trial of patients with previously untreated APL. Eligibility criteria included ECOG performance status between 0 to 3, age older than 1 year and no serious comorbidity. Further, researchers excluded patients with genetic variants of APL, such as the fusion of genes other than PML with RARA.
Induction therapy consisted of daily oral tretinoin (45 mg/m2) in four divided doses on days 1 to 36, along with IV idarubicin (6–12 mg/m2) on days 2, 4, 6 and 8 (adjusted by age) and IV arsenic trioxide (0.15 mg/kg) daily on days 9 to 36.
Patients received blood products for protocol-specified hemostatic targets, as well as daily prophylactic prednisone (1 mg/kg) against differentiation syndrome as supportive therapy.
The researchers assigned patients to two consolidation cycles with tretinoin and arsenic trioxide without anthracycline or cytarabine chemotherapy, followed by maintenance therapy comprised of oral tretinoin, 6-mercaptopurine and methotrexate for 2 years.
Freedom from relapse and early death — defined as death within 36 days of treatment initiation — served as primary endpoints. The researchers assessed improvement compared with 2-year interim results.
To assess durability of remission, researchers compared the primary endpoints, as well as 5-year DFS and OS, with the 2-year interim data from the current analysis and data from the earlier, APML3 study, which excluded arsenic trioxide.
The current analysis included data from 124 patients (median age, 44 years; range, 3-78). Twenty-three patients had high-risk disease, defined by an initial white blood cell count greater than 100 x 109/L. Three percent of patients (n = 4) died early.
After a median follow-up of 4.2 years (interquartile range, 3.2-5.2), 95% of patients (95% CI, 89-98) achieved 5-year freedom from relapse, 95% (95% CI, 89-98) achieved 5-year DFS, 90% (95% CI, 83-94) achieved 5-year EFS and 94% (95% CI, 89-97) achieved 5-year OS.
Compared with historical data, the addition of arsenic trioxide significantly improved freedom from relapse (HR = 0.23; 95% CI, 0.08-0.64), DFS (HR = 0.21; 95% CI, 0.07-0.59), EFS (HR = 0.34; 95% CI, 0.16-0.69) and OS (HR = 0.35; 95% CI, 0.14-0.91).
“Of particular importance was the finding that DFS in patients with high-risk disease was 95%, which was almost identical with the result in standard-risk patients (96%),” Iland said. “Furthermore, these results were obtained without any protocol-associated deaths in remission, whereas risk-adapted chemotherapy intensification has been associated with a 5% risk of death in remission.
“The combination of arsenic trioxide with all-trans retinoic acid and idarubicin for induction, followed by arsenic trioxide with all-trans retinoic acid in consolidation, is safe and effective in patients with previously untreated APL, and the APML4 protocol is currently included in the recommended treatment options for high-risk APL by the National Comprehensive Cancer Network,” Iland added. “The main issue that requires further improvement is the problem of early death, which is still unacceptably high in patients with high-risk disease. OS was 87% in our high-risk group, compared with 96% for patients with standard-risk disease, and this difference was primarily due to a higher early death rate.”
Vikram Mathews, MBBS, MD, DM, professor and head of the department of hematology at Christian Medical College in Vellore, India, echoed these concerns regarding the high-risk population in an accompanying editorial.
“Previous data and experience suggest that APL could be cured in 40% to 60% of patients with use of arsenic trioxide, and that for the remaining patients with low-risk and intermediate-risk disease, combined tretinoin and arsenic trioxide would suffice,” Mathews wrote. “The study by Iland and colleagues is especially relevant since ….. it also included patients with high-risk disease. For patients with truly high-risk disease, the addition of an anthracycline-based chemotherapy regimen, at least for induction therapy, is probably warranted, although the usefulness of maintenance therapy needs to be assessed further. On the basis of research experience so far, demanding longer follow-up data within studies and in real-world settings seems reasonable.” – by Cameron Kelsall
For more information:
Harry J. Iland, MBBS, FRACP, FRCPA, can be reached at Institute of Hematology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, Australia 2050; email: harryiland@gmail.com.
Disclosure: Phebra provided funding for this study. Iland and one other researcher report consultant roles with Phebra. The other researchers and Mathews report no relevant financial disclosures.