This protocol has been superseded as arsenic is uncommonly used in the relapsed setting.
Acute promyelocytic leukemia (APML) is a biologically and clinically distinct variant of acute myeloid leukaemia. APML was classified as AML-M3 in the older French-American-British (FAB) classification system and is currently classified as acute promyelocytic leukemia with t(15;17)(q22;q12);PML-RARalpha in the WHO classification system. The vast majority of patients with newly diagnosed APML can obtain a complete remission with induction therapy that incorporates all-trans retinoic acid (ATRA) together with chemotherapy. Despite this, relapse occurs in 5% to 10% of patients with APML and in about 20% to 30% of those with high-risk disease. Investigators from China reported in the early 1990s that arsenic trioxide (ATO) could induce complete remissions in patients with APML. Preclinical studies suggested that this agent induced apoptosis; however, subsequent studies suggested that leukemic cells differentiated after prolonged exposure to the drug. Subsequent clinical studies have demonstrated that complete remission can be obtained in 83.9% to 100% of patients when used as monotherapy in patients with relapsed disease (see Table 1). ATO is able to penetrate the blood-brain barrier and so can be useful in patients with CNS involvement. This therapy is then followed by consolidation treatment, which should be selected based upon the depth of response and patient characteristics.
It is unclear whether adding ATRA to ATO is better than ATO alone in patients with relapsed APML. One small prospective study by Raffoux et al (2003)r reported on 20 patients and showed no benefit of the addition of ATRA, however the median time from the last ATRA exposure was only 5 months suggesting that patients were resistant to ATRA. However, there is evidence that the combination is superior in newly diagnosed patients. Shen et al (2004)r reported on a study in 61 patients whom were randomised to receive either ATRA alone, ATO alone or ATRA + ATO. Whilst the CR rates were high in all 3 groups (95%, 90% and 95.2% respectively), time to remission in the combination group was significantly shorter (40.5, 31 and 25.5 days respectively). Also, after a median follow up of 18 months, all 20 patients in the combination group remained in CR, whereas 2/18 patients who received ATO alone relapsed. As a result of this, all patients with newly diagnosed APML presenting to the Shanghai Institute of Hematology since 2004 have been treated with ATRA + ATO. Hu et al (2009)r reported on 85 patients on this treatment. CR was achieved in 94.1% with 5 year overall survival and event-free survival being 91.7% and 89.2% respectively.
The best consolidation strategy after achieving CR2 is not known. Options include continued treatment with repeated cycles of ATO (e.g 5 doses per week for 5 weeks each cycle), the use of standard chemotherapy in combination with ATRA and/or ATO or autologous or allogeneic transplantation.
Efficacy
Table 1. Summary of studies using arsenic trioxide monotherapy in relapsed acute promyelocytic leukaemia
Study |
No. relapsed pts |
Regimen |
Response |
Survival |
Comment |
Shen et al 1997r |
10 |
Daily ATO up to 44 days |
CR 90% |
Not stated |
Initial Chinese study in relapsed APML |
Niu et al 1999r |
47 (31 received ATO alone) |
Daily ATO 10 mg up to 76 days (median 31 days) |
CR 83.9% |
OS 1 & 2 yrs:72.1% & 50.2%.
DFS 1 & 2 years: 63.6 & 41.6% |
|
Camacho et al 2000r |
26 |
Daily ATO 0.06 mg/kg to 0.17 mg/kg for median 47 days (15 to 83 days) |
CR 88% |
Not stated |
Differentiation syndrome 31% |
Soignet et al 2001r |
40 (21 1st relapse, 19 2nd relapse) |
Daily ATO 0.15 mg/kg up to max of 60 doses or BM cleared |
CR 88% |
OS at 18 months: 65%
DFS 56% |
Differentiation syndrome 25% |
Lazo et al 2003r |
12 |
Daily ATO 0.15 mg/kg up to 60 doses or BM cleared. Median 42 days (27 to 75 days) |
CR 100% |
OS at 98 weeks 67% (all remain in CR) |
|
Shigeno et al 2005r |
34 |
Daily ATO up to 0.15 mg/kg up to 60 doses or BM cleared |
CR 91% |
OS at 2 years 56% |
|
Toxicity
Many side effects associated with arsenic trioxide treatment are mild but common including pruritus, nausea and vomiting, diarrhoea, headache, fatigue, arthralgia and myalgia, mildly abnormal liver function tests and electrolyte abnormalities. Cytopenias, including a decrease in neutrophil, platelet and haemoglobin levels are also common, while febrile neutropenia is rare. ECG abnormalities, particularly QTc prolongation, are common, particularly in hypokalaemic patients. Careful monitoring and supplementation to maintain adequate serum potassium and serum magnesium levels is critical, and ECG monitoring throughout treatment is required. QTc prolongation leading to torsade de pointes-type ventricular arrhythmia is rare, but may be fatal. Hyperleukocytosis (WBC greater or equal to 100 x109/L) occurs in up to 50% of patients treated with arsenic trioxide, and an APML differentiation syndrome frequently occurs, ranging in severity from isolated hyperleukocytosis to ventilation-dependant respiratory failure. Prophylaxis with corticosteroids is recommended, however APML differentiation syndrome may still occur, in which case, early recognition and prompt treatment with high dose IV corticosteroids is essential.r Peripheral neuropathy may occur and may progress to significant impairment if arsenic trioxide treatment is continued in the presence of established neuropathy.
Summary of toxicities from Shigeno et al (2005):r
© International journal of hematology 2005