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Treatment of Acute Promyelocytic Leukemia
Robert G. Fenton, MD, PhD, Clinical Associate Professor, Clinical Research Committee Member,University of Maryland, Marlene and Stewart Greenebaum Cancer Center. Dr. Fenton reports no financial relationships relevant to this field of study.
Although the combination of atra with anthracyclines has remarkable activity against low-risk APL (WBC < 5,000 and platelets > 20,000) (OS of 80%-90%), it is less active in patients with high-risk disease. Furthermore, there are long-term toxicities associated with the use of anthracyclines, including second malignancies (e.g., MDS and acute leukemia) and dilated cardiomyopathy.
During the past decade, ATO has been shown to be effective in inducing remission in patients with relapsed and newly diagnosed AML.1,2 ATO is now accepted as the single-most active agent in APL. ATO exerts dose-dependent effects on APL cells with low doses, inducing differentiation and higher doses, causing apoptosis.
Both ATRA and ATO induce the degradation of the PML-RAR fusion protein, providing a rational basis for targeted therapy in APL and possible synergy between these agents. Molecular studies indicate that ATRA targets the RARa domain and ATO targets the PML domains of the fusion protein.3,4 ATRA increases ATO uptake by leukemia cells through transcriptional upregulation of aquaglyceroporin 9.5 In-vitro studies demonstrate a synergistic interaction between ATRA and ATO and enhanced activity in xenograft models.6
Important clinical and basic-science questions include: 1) How best to use ATO in a way that will mitigate toxicity in patients with low- and intermediate-risk disease; 2) How to incorporate ATO into regimens with that will lead to higher OS in high-risk disease; and 3) To understand the molecular mechanisms of ATO activity in APL. This review will first discuss recent clinical trials incorporating ATO into APL treatment regimens, and then discuss new data suggesting the mechanism by which ATO directly targets the PML-RARa gene product, leading to the cure of APL.
CLINICAL Trials Incorporating ATO into APL Treatment Regimens
The Chinese group7 treated 61 newly diagnosed APL patients with ATRA induction as a single agent (25 mg/m2) unless there was a high WBC, in which case, hydroxyurea or idarubicin + Ara-C (100 mg/m2 for 3-5 days) was added. Patients in CR received consolidation with three regimens: 1) Daunorubicin + Ara-C (7+3); 2) Ara-C pulse (2.5 g/m2 for 3 days); 3) Ara-C infusion (100 mg/m2 for 7 days). Finally, patients in CR were randomized to maintenance with: Group 1: ATRA 25 mg/m2 for 30 days + either 6-MP 100 mg/d x 30d or 15 mg MTX per week x4; Group 2: ATO 0.16 mg/kg/d for 30 days + either 6-MP or MTX; or Group 3: ATRA for 30 days, then ATO for 30 days, then either 6-MP or MTX. They were given five cycles of maintenance. After a median of 18 months, all 20 patients receiving ATRA + ATO maintenance (Group 3) were in CR, while seven of 37 cases on monotherapy maintenance (Groups 1, 2) had relapsed, suggesting a benefit by the addition of ATO. Beginning in 2005, this group treated the next 85 APL patients using the combined ATRA+ATO maintenance regimen. Eighty patients entered CR (94%), with a DFS of 95% and OS of 97% at 5 years. Five patients died within 15 days of induction (three intracranial hemorrhages, one DIC, one retinoic acid syndrome). Importantly, the clinical outcome, when using this regimen, was not influenced by the initial WBC count or FLT3 mutation status.
Ravandi et al treated 82 newly diagnosed APL patients with ATRA + ATO.8 Patients with WBC > 10,000 also received gemtuzumab ozogamicin (GO) on day 1. The CR rate was 92%. Seven patients died in the first week of treatment. The three-year OS was 85%. One hundred-eleven patients were treated with ATRA + ATO for induction and consolidation (no cytotoxic chemotherapy), with a CR rate of 86% and a three-year RFS rate of 93%.9 Some hepatotoxicity occurred due to the addition of ATO during induction, but this decreased during consolidation.
In a very important recent study,10 72 patients were treated with single-agent ATO used for induction, consolidation, and maintenance (patients received no ATRA or cytotoxic chemotherapy). ATO was given daily for up to 60 days for remission induction; after one month, two courses of consolidation with four weeks ATO were given. Maintenance was 10 days of ATO per month for six months. This study included pediatric patients; only five patients were older than 55. Of the 22 patients with low-risk disease (defined as WBC < 5,000, platelets > 20,000), there was an OS at five years of 100%. High-risk patients had an EFS of only 70% (in part due to seven patients who died during induction from intra-cranial hemorrhage), supporting the addition of ATRA (and perhaps chemotherapy) to ATO in this group. Thirty-three percent of patients had FLT3 mutation, and 23% had an additional cytogenetic change with no effect on clinical outcome.11 This study could set a new standard of care for patients with low-risk disease that would eliminate anthracyclines, Ara-C, and maintenance cytotoxic therapy, thus preventing the grave long-term consequences that can occur with these agents. However, these data must be confirmed in future studies using patient populations that more clearly represent those treated by adult oncologists. Furthermore, the optimal treatment for patients with high-risk disease remains to be determined, but will certainly include both ATRA and ATO, with the likely addition of some (hopefully low) dose of anthracyclines (or gemtuzumab ozogamicin).
Recent studies have shed light on the molecular mechanisms for the clinical efficacy of ATO. Both PML and the PML-RARa fusion protein contain a zinc-finger motif whose sulfhydryl residues are covalent targets of ATO binding.12 This induces a conformal change that induced the multimerization of PML and PML-RARa homodimers and heterodimers, which targets them for modification with SUMO moieties by the E3 ligase UBC9. SUMO, like its molecular relative ubiquitin, targets proteins to specific intracellular localizations, and sometimes for degradation, which is the case here. Therefore, by directly binding to PML, ATO promotes the degradation of PML-RARa in an analogous way that ATRA targets the RARa domain of the fusion protein, enhancing its degradation. Hence, the combination of ATRA and ATO provide a pharmaceutical one-two punch whose combined pharmacodynamic endpoint is the destruction of PML-RARa, leading to leukemia cell differentiation or apoptosis.
Clinical data outlined above suggest that single-agent ATO can cure low-risk APL. In other subtypes of AML, attaining a CR leads to cure in only 25%-30% of patients, and only after multiple cycles of high-dose, multi-agent chemotherapy. Relapse from the minimal residual disease state is thought to be due to the resistance of leukemia stem cells (or leukemia initiating cells, LIC) to chemotherapy due to low cell-cycling percentages, abundant ABC-transporter proteins, etc. Why is the situation with ATO in APL different? Recent studies provide one possible explanation that will require further experimental confirmation.13 It appears that the APL LIC is very dependent on the PML-RARa for its survival. Studies performed in vitro and in animal models show that ATO potently eliminates PML-RARa from LIC, and that ATRA is synergistic both for PML-RARa proteasomal degradation in LIC and cure of animals in xenograft models. This could represent the first example of targeted therapy for cancer that directly targets the cancer stem cell, and demonstrates just how effective this strategy can be.
1. Soignet SL, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852-3860.
2. Mathews V, et al. Arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: A single center experience. Am J Hematol. 2002;70:292-299.
3. Raelson, JV et al. The PML/RAR alpha oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells. Blood. 1996;88:2826-2832.
4. Lallemand-Breitenbach V, et al. Arsenic degrades PML or PML-RAR alpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol. 2008;10:547-555.
5. Leung J, et al. Relationship of expression of aquaglyceroporin-9 with arsenic uptake and sensitivity in leukemia cells. Blood. 1009:740-746.
6. Jing Y, et al. Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic cells in vitro and in vivo. Blood. 2001;97:264-269.
7. Shen Z-X, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA. 2004;101:5328-5335.
8. Ravandi F, et al. Effective treatment of acute promyelocytic leukemia with all-trans retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009;27:504-510.
9. Dai CW, et al. Use of all-trans retinoic acid in combination with arsenic trioxide for remission induction in patients with newly diagnosed acute promyelocytic leukemia and for consolidation/maintenance in CR patients. Acta Haematol. 2009;121:1-8.
10. 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.
11. Mathews V, et al. Impact of FLT3 mutations and secondary cytogenetic changes on the outcome of patients with newly diagnosed acute promyelocytic leukemia treated with a single agent arsenic trioxide regimen. Haematologica. 2007;92:994-995.
12. Zhand X-W, et al. Arsenic trioxide controls the fate of the PML-RARa oncoprotein by directly binding PML. Science. 2010;328:240-243.
13. Nasr R. Eradication of acute promyelocytic leukemia-initiating cells by PML/RARa-targeting. Int J Hematol. 2010;91:742-747.