Arsenic trioxide in acute promyelocytic leukemia: potion not poison

Keywords::

• acute promyelocytic leukemia
• arsenic trioxide

Arsenic, a chemical that immediately gets the attention and sometimes strikes fear into the heart of patients and their families is changing the landscape of treatment for acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) is a highly effective treatment for relapsed APL, for which it is US FDA approved. It also has a dramatic impact in patients with newly diagnosed APL, either as part of initial induction therapy or as consolidation therapy for patients in remission.

APL: the disease

Acute promyelocytic leukemia accounts for approximately 10% of acute myeloid leukemia (AML) cases (∼600–800 cases per year) in the USA. APL has well-defined clinical and pathologic features. APL is classified as the M3 subtype of AML in the French American British (FAB) system and classified as APL with t(15;17) (q22;q12), promyelocytic leukemia– retinoic acid receptor-α (PML–RARα) by the WHO. The unique features include a characteristic morphologic appearance with prominent granules and frequent Auer rods [1], often presenting with pancytopenia; however, those with the microgranular variant (M3V) often present with leukocytosis, monocytic appearing nuclei, few or no cytoplasmic granules and absent or rare Auer rods. APL has a younger age of onset compared with other AML subtypes [2], with a high incidence of severe coagulopathy at diagnosis and early hemorrhagic deaths [3,4]. The consumptive coagulopathy is often exacerbated by chemotherapy-induced leukemia cell lysis with release of intracellular contents [5,6].

Leukemia cells from most patients with APL have a reciprocal translocation between the long arms of chromosomes 15 and 17 [7], and contain two fusion genes, PML–RARα and RARα–PML, which are the result of this translocation [8,9]. The PML–RARα gene, a fusion of sequences from the PML gene at chromosome band 15q22, with the RARα gene at band 17q11–12, is expressed in leukemia cells from t(15;17)-positive APL patients. This fusion transcript is involved in the pathogenesis of this disease and is also the target of all-trans-retinoic acid (ATRA; tretinoin). ATRA overcomes the effect of the PML–RARα fusion to induce differentiation and apoptotic cell death of the APL cells. The PML–RARα fusion transcript also provides an important molecular marker for the diagnosis and monitoring of APL using a reverse transcriptase PCR (RT-PCR) assay.

APL therapy prior to ATO

Conventional induction chemotherapy regimens with cytarabine and daunorubicin yield complete remissions (CRs) in approximately 70% of patients and 5-year disease-free survival in 35–45% [10,11]; two-thirds of patients achieved CR with this treatment in the first North American Leukemia Intergroup trial [12].

The treatment and prognosis of APL changed dramatically with incorporation of ATRA into induction and/or maintenance therapy. Current standard induction therapy for newly diagnosed patients with APL is a combination of ATRA plus an anthracycline, with or without cytarabine; these combinations yield remission rates of at least 90%. Clinical trials have shown the efficacy of ATRA plus chemotherapy [12–14]. The best results have been achieved with concurrent ATRA plus chemotherapy when compared with ATRA followed by chemotherapy [13]. For patients with low- or intermediate-risk disease (white blood cell [WBC] ≤10 × 10⁹/l) ATRA is usually started 1–2 days before chemotherapy. For patients with high-risk disease (WBC >10 × 10⁹/l) ATRA and chemotherapy should be started concurrently since ATRA can increase leukocytosis and therefore increase the potential for coagulopathy and for the APL differentiation syndrome.

Role of ATO in APL treatment

Treatment of relapse

The effectiveness of ATO in patients with relapsed APL was first described by investigators from Shanghai in the 1990s [15,16]. The impressive results were confirmed by trials in the USA [17,18], which led to approval of ATO for patients with relapsed APL. ATO, alone or in combination with ATRA, remains the treatment of choice for patients with either molecular or hematologic relapse of APL, yielding CR rates greater than 80% and prolonged remissions in many. It is not as clear what treatment to use as consolidation therapy after a second CR is achieved. Options include further ATO alone or in combination with ATRA and/or chemotherapy or high-dose therapy with hematopoietic stem cell transplant. Fortunately, with current advances in induction and consolidation therapies relapses are increasingly rare.

Consolidation treatment

The North American Leukemia Intergroup study C9710 demonstrated a highly significant (p < 0.0001) improvement in event-free (EFS) and disease-free (DFS) survival with the addition of ATO as initial consolidation therapy for patients with APL in first CR. [19]. A total of 481 adult patients (age ≥15 years) with untreated APL were randomized to receive either a standard induction regimen of ATRA, cytarabine and daunorubicin, followed by two courses of consolidation therapy with ATRA plus daunorubicin or to receive the same induction and consolidation regimen plus two 25-day courses of ATO as initial consolidation therapy. After consolidation, patients in CR were randomized to 1 year of maintenance therapy with either ATRA alone or ATRA plus methotrexate and mercaptopurine. In total, 90% of patients achieved remission with standard induction therapy and were eligible to receive their assigned consolidation therapy. EFS, the primary end point, was 80% at 3 years for patients assigned to receive ATO as initial consolidation therapy followed by standard consolidation treatment, compared with 63% for patients who received standard consolidation without ATO (p < 0.0001). DFS was also significantly better in the ATO arm, 90% at 3 years compared with 70% in the standard arm (p < 0.0001). The 219 patients randomized to the investigational arm who achieved a remission were eligible to receive consolidation therapy; 196 received at least one dose of ATO and only seven of these 196 patients (4%) had relapsed at the time of publication. In this Phase III trial patients in all risk groups, defined by white blood cell and platelet counts, benefited from the addition of ATO consolidation therapy. These exciting results were achieved with little or no additional toxicity [19].

In a smaller Phase II trial similar outcomes have been described using a single course of consolidation therapy using cytarabine followed by 30 doses of ATO [20].

Induction treatment

The obvious next step is to move ATO into induction therapy for patients with untreated APL. Phase II trials have demonstrated safety and efficacy for ATO alone [21,22] or ATRA plus ATO [23,24] as induction regimens for patients with newly diagnosed APL. The combination of ATRA, gemtuzumab, ozogamicin and ATO has also been evaluated as induction therapy with encouraging results [24,25]; the combination is currently being tested as induction therapy in the North American Leukemia Intergroup study S0535 in patients with high-risk APL; a primary objective is to decrease early deaths, the major cause for failure among patients in the high-risk group (WBC >10,000). ATO-based induction treatments have resulted in CR rates ≥86% with durable response in over two-thirds of patients with newly diagnosed APL.

Summary & future directions

Clinical trials have established ATO as a highly effective and well tolerated treatment of APL as both salvage therapy for relapsed APL or as consolidation treatment for patients in first CR. More recent trials also support the use of ATO as part of induction therapy for patients with newly diagnosed APL. ATO will likely allow us to decrease the exposures to more toxic chemotherapy agents without compromising short- or long-term outcomes. In C9710 the addition of ATO to consolidation treatment negated all previously identified prognostic factors. ATO may have a similar impact when incorporated into initial induction treatments. There is also great interest in the use of ATO as an oral agent in patients with APL.

Clearly, ATO is the most effective single agent for treatment of APL. When used to treat APL, ATO is definitely not a poison; the data suggest that it is more of a magic potion.

Acknowledgement

The author thanks Ms Lisa Burnett for her expert assistance with preparation of this manuscript.

Financial & competing interests disclosure

Bayard Powell has received honoraria from Cephalon Oncology. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.