Arsenic as a Single Agent for Elderly APL Patients

Abstract & Commentary

By William B. Ershler, MD

Synopsis: The experience from Harbin, China, in the treatment of de novo acute promyelocytic leukemia (APL) in patients 60 years and older demonstrates the efficacy and safety of single agent arsenic trioxide. This agent with or without all trans retinoic acid may ultimately prove optimal for induction and maintenance APL treatment in older adults.

Source: Zhang Y, et al. Long-term efficacy and safety of arsenic trioxide for first-line treatment of elderly patients with newly diagnosed acute promyelocytic leukemia. Cancer 2013;119:115-125.

In general, the outcome of patients with acute promyelocytic leukemia (APL) treated with alltrans retinoic acid (ATRA) plus anthracycline-based strategies is excellent.1,2 The treatment of older, and particularly frail adults, remains a challenge. An early death rate among older adults with APL of more than 25% has been reported.3

With this in mind, the recently reported experience from Harbin, China, is of interest. A total of 33 patients aged 60 years or older with de novo APL were treated with single-agent arsenic trioxide (ATO) for remission induction and extended maintenance therapy. ATO at 0.16 mg/kg (maximum 10 mg) was administered daily IV for 28 days. Patients who presented with white counts > 20K/cu mm were also given daunorubicin (40 mg) for 3 days and cytosine arabinoside (50-100 mg) for 5 days. Maintenance therapy consisted of intermittent infusions of ATO at variable doses based on marrow and peripheral blood findings.

Of the 33 patients, 29 (87.9%) achieved a hematologic complete remission. There were three deaths during induction therapy due to intracebral hemorrhage and one death as a result of sepsis. The most common adverse event during remission induction was leukocytosis (63.6%). Definite differentiation syndrome was observed in five patients. Nonhematologic adverse events were all manageable and reversible. Twenty-eight patients proceeded to maintenance therapy and ATO-related adverse events were mild, transient, and required no treatments. No patients died from ATO-related toxicities. With a median follow-up of 99 months, the 10-year cumulative incidence of relapse, overall survival, disease-free survival, and cause-specific survival were 10.3%, 69.3%, 64.8%, and 84.8%, respectively. These results are comparable to those in younger APL-treated patients.

Commentary

There are a number of issues regarding the treatment of APL in elderly patients. The experience from China is notable for several reasons. APL may be less common than other myeloid leukemia variants but it is not rare, and further, one might argue that the years 60-69 (28 of the 33 patients reported in this study) are not truly representative of elderly, particularly the frail elderly. Yet, the results using ATO as a single agent are impressive, and may provide rationale for the use of this drug earlier for certain subsets of patients.

Older patients are more likely to have comorbidities or functional impairments that preclude the administration of intensive cytotoxic chemotherapy. Management of such patients is made more complex by the lack of evidence on which to base treatment. This is primarily because these comorbidities or impairments have been exclusionary criteria for many of the pivotal clinical trials. Yet, in considering APL, unlike most other subtypes of acute myeloid leukemia, older and perhaps frail adults have an excellent chance of tolerating active treatment, particularly ATRA and ATO. Similar to the current report in patients aged 60 years or older, Sanz and colleagues reported the 6-year cumulative incidence of relapse, leukemia-free survival, and disease-free survival was 85%, 91%, and 79%, respectively, for 60+ patients treated with idarubicin/ATRA.4,5 Thus, an attractive strategy for truly elderly patients with APL may be ATRA plus ATO, thereby avoiding toxicities associated with anthracycline-based chemotherapy. Although this combination has not been studied specifically in elderly adults, anecdotal reports and the results in younger adults are quite promising.6-8 Shen et al randomized patients with newly diagnosed APL to ATRA alone, ATO alone, or the combination for induction followed by chemotherapy for consolidation and maintenance and reported a major benefit for the combination.8 Estey et al reported a small Phase 2 trial of ATRA plus ATO with minimal idarubicin or gemtuzumab ozogamicin to control leukocytosis.6 The relapse-free survival was approximately 90% at 2 years.

Elderly adults may benefit from this exciting new strategy of ATRA plus ATO or perhaps ATO alone. The results from China would suggest that a single-agent ATO regimen is safe and effective with long-term durable remission, and could be used as first-line treatment for elderly patients with de novo APL. A confirmatory randomized, multisite trial would be the next step in this regard.

References

1. Ades L, et al. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: The European APL Group experience. Blood 2010;115:1690-1696.

2. Ades L, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): A comparison of French-Belgian-Swiss and PETHEMA results. Blood 2008;111:1078-1084.

3. de la Serna J, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood 2008;111:3395-3402.

4. Sanz MA, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: A multicenter study by the PETHEMA group. Blood 2004;103:1237-1243.

5. Sanz MA, et al. All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia. Blood 2004;104:3490-3493.

6. Estey E, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 2006;107:3469-3473.

7. Mathews V, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: Durable remissions with minimal toxicity. Blood 2006;107:2627-2632.

8. Shen ZX, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sc U S A 2004;101:5328-5335.