The evolving role of arsenic trioxide in the treatment of APL

Issue: August 10, 2013

ByDebbie Blamble, PharmD, BCOP

Acute promyelocytic leukemia, a variant of acute myeloid leukemia, is characterized by unique molecular and clinical properties.

In most cases, acute promyelocytic leukemia (APL) develops as a result of a rearrangement of the PML and RARA genes on chromosomes 15 and 17.

The PML-RARA fusion protein disrupts normal myeloid differentiation. Patients with newly diagnosed APL frequently present with or develop coagulopathies, which can result in bleeding, a common cause of early death in these patients. Those patients with elevated white blood cell counts at diagnosis are at highest risk of bleeding complications, as well as a poorer outcome overall, thereby placing these patients in a high-risk group.

Debbie Blamble

Standard treatment

The standard treatment for patients with newly diagnosed APL is the combination of all-trans retinoic acid (ATRA) and chemotherapy. Chemotherapy during induction and consolidation has typically consisted of an anthracycline — specifically, daunorubicin or idarubicin — with or without cytarabine.

Some regimens have included a maintenance phase that consists of ATRA with oral methotrexate and mercaptopurine.

In the clinical trial setting, complete remission rates with the combination of ATRA and anthracycline-containing chemotherapy exceed 90%, and most of these patients are cured of their leukemia. However, population-based data suggest higher rates of early death, as well as death due to APL, than what is observed in clinical trials.

Despite a highly effective induction program, approximately 20% to 30% of patients will relapse. Historically, reinduction usually consisted of ATRA plus chemotherapy. Some relapsed patients may have been and continue to be consolidated with stem cell transplantation. In 2000, arsenic trioxide (ATO; Trisenox, Cephalon) was approved as a single agent for the treatment of APL patients with relapsed or refractory disease. ATO degrades the PML-RARA fusion protein, and it causes differentiation and apoptosis of the APL cells. The approval of ATO was based on a small pilot study that demonstrated a complete remission rate of 85% with the use of ATO alone for induction and consolidation. Given the activity of ATO in APL, subsequent investigations have examined the incorporation of ATO into the management of newly diagnosed patients (see Table).

ATO induction

A number of studies have investigated the use of ATO as a single agent for induction therapy of newly diagnosed APL patients. All of these studies allowed the use of concomitant chemotherapy (hydroxyurea or anthracycline, with or without cytarabine) in patients who present with or develop high white blood cell counts during induction.

Complete remission rates have been slightly lower than those seen with the combination of ATRA and chemotherapy in clinical trials, ranging from 85% to 90%. Long-term DFS has been reported to be 65% to 80%.

ATO also has been studied in combination with ATRA as induction therapy. Complete remission rates have been around 90% to 95%, similar to what can be achieved with ATRA plus chemotherapy.

Table. Clinical trials including arsenic trioxide as a component of therapy for newly diagnosed APL.

All of these studies allowed the use of concomitant chemotherapy in patients who present with or develop high white blood cell counts during induction. In most of these studies, consolidation consisted of combinations of ATRA plus chemotherapy. However, one study used the combination of ATRA and ATO throughout induction and consolidation, with the exception of a single dose of gemtuzumab ozogamicin (Mylotarg, Wyeth) in those patients with a high white blood cell count during induction. For all studies, DFS or RFS exceeds 85% at the last published follow-up.

Two recent investigations into the use of ATO during remission induction are worth reviewing in detail.

The APML4 trial from the Australasian Leukaemia and Lymphoma Group evaluated the combination of ATO, ATRA and idarubicin for induction therapy. Consolidation consisted of two cycles of ATRA and ATO alone, and maintenance consisted of 2 years of ATRA, methotrexate and mercaptopurine. The trial included 124 patients. The complete remission rate was 95%. DFS at 2 years was 97.5%. Therapy generally was well tolerated. Additionally, the patients’ exposure to an anthracycline was reduced while maintaining the positive outcomes expected in this population.

Preliminary results from a study by the Italian and German Cooperative Groups were presented at the ASH Annual Meeting in December. This randomized trial compared the combination of ATRA plus ATO induction and consolidation (arm A) with ATRA plus chemotherapy induction, consolidation and maintenance (arm B).

High-risk patients and those patients aged older than 70 years were not included in this trial. Of the 154 evaluable patients, complete remission was achieved by 100% of patients in arm A and by 95% of patients in arm B. EFS at 2 years, the primary endpoint, was 97% in arm A and 86.7% in arm B (P=.03). OS also was significantly higher in arm A (98.7% vs. 91.1%, P=.03). However, DFS was not significantly different (97% vs. 91.6%, P=.19). Based on this preliminary analysis, ATRA plus ATO demonstrates at least similar — if not better — outcomes as standard APL therapy for non-high-risk patients, and that regimen allowed most of the patients in arm A to avoid exposure to chemotherapy.

ATO in consolidation

Given the activity of ATO in APL, there also has been interest in incorporating ATO into the consolidation strategies of treating newly diagnosed patients. Obviously, many of the studies mentioned in this article continued ATO as part of consolidation therapy. But there have been specific attempts to add ATO into consolidation therapy and assess the outcomes of that strategy.

Researchers in one multicenter, single-arm trial added ATO to a single cycle of cytarabine and daunorubicin consolidation after standard induction therapy. After consolidation, all responding patients proceeded to 2 years of maintenance therapy with ATRA (with mercaptopurine and methotrexate if they were high risk). Forty-five patients received therapy as part of the study. DFS at 3 years was 88.7%.

A large, multicenter, randomized clinical trial undertaken by five North American cooperative groups evaluated the role of ATO in post-remission therapy. Patients were randomly assigned to either complete standard induction followed by two cycles of ATRA-plus-daunorubicin consolidation or the same therapy with two cycles of ATO consolidation between induction and ATRA-plus-daunorubicin consolidation.

Four hundred eighty-one patients were randomly assigned; 85% of patients completed all planned consolidation. EFS at 3 years, the primary endpoint, was significantly better for patients assigned to ATO as part of consolidation (80% vs. 63%, P<.0001). DFS also was significantly better for patients assigned to ATO (90% vs. 70%, P<.0001).

OS, however, was not significantly different at 3 years (86% vs. 81%, P=.07). Outcomes in the standard APL treatment arm were lower than one would expect, making the results difficult to interpret. However, there was minimal additional toxicity with the addition of ATO, making it a feasible option for future clinical trials.

There has been — and will continue to be — interest in incorporating ATO into the treatment regimens offered to patients with newly diagnosed APL because of its overall effectiveness and its ability to minimize administration of chemotherapy. However, ATO administration has its own administration and toxicity issues that must be considered.

Administration and monitoring

ATO is commercially available as an IV medication and should be administered for 1 to 2 hours. The approved dose is 0.15 mg/kg, but in a few of the ATO induction studies, a flat dose of 10 mg was used. During induction, ATO is given daily until complete remission (approximately 30 days). During consolidation, ATO is most commonly given daily for 5 days per week for 5 weeks to complete a consolidation cycle. One or more consolidation cycles may be given, depending on the treatment protocol. There is some variability in ATO dosing schemas in the published data of first-line therapy, but most of it aligns closely with the prescribing information.

Most of the induction cycle will be spent in a hospitalized setting, so daily dosing is not too burdensome to the patient and caregivers. During consolidation, most of these patients are outpatients. Patients, caregivers and providers must accommodate the need for daily visits to the treating facility.

In the North American Intergroup Study, approximately 10% of patients failed to receive any doses of ATO consolidation and an additional 10% failed to complete all ATO therapy. Reasons for nonadherence were not available for many of these patients, but one wonders if the dosing schedule was a barrier.

The adverse effect profile for ATO includes some unique toxicities. First, ATO can cause differentiation syndrome similar to ATRA. The occurrence of differentiation syndrome is limited to the induction cycle. During that time, patients should be monitoring for unexplained fever, dyspnea, weight gain, pulmonary infiltrates, pleural or pericardial effusions, and leukocytosis. Differentiation syndrome is managed with the immediate initiation of high-dose corticosteroids (eg, dexamethasone 10 mg IV twice daily) and supportive care. In severe cases, the ATO may need to be temporarily halted.

ATO also can cause QT interval prolongation. In the registration trial to obtain FDA approval for ATO in the salvage setting, a corrected QT (QTc) interval of >500 ms was observed at least once in 40% of patients. QTc prolongation has also been reported in subsequent clinical trials. The prescribing information recommends that a 12-lead electrocardiogram be performed at baseline and weekly during induction and consolidation therapy. Levels of potassium, magnesium and calcium should be monitored and abnormalities should be corrected in patients receiving ATO therapy.

Other potential toxicities include liver function abnormalities, peripheral neuropathy, gastrointestinal effects, rash, hyperglycemia and myelosuppression. Most toxicity can be managed with supportive care, ATO dose reduction, temporarily withholding ATO treatment or a combination of these options.

Summary

Many questions remain in the treatment of APL, such as the best way to decrease early deaths, the optimal amount of chemotherapy to administer, the role of maintenance therapy and which anthracycline should be used.

Another important question is how to transfer the positive results seen in clinical trials to the general population.

The utilization of ATO in newly diagnosed patients only adds to the questions — and may help answer some of the ones mentioned in this article, as well.

Providers should remain aware of the unique issues encountered when managing patients with APL — such as coagulopathies, differentiation syndrome and treatment based on risk stratification — as well as the evolving literature regarding optimal therapy. Patients with newly diagnosed APL should be encouraged to participate in clinical trials whenever possible.

References:

Breccia M. Expert Opin Pharmacother. 2012;13:1031-1043.
Iland HJ. Curr Treat Options Oncol. 2013. [Published online ahead of print Jan. 16]
Park JH. Blood. 2011;118:1248-1254.
Sanz MA. J Clin Oncol. 2011;29:495-503.

Table references:

Dai CW. Acta Haematol. 2009;121:1-8.
Ghavamzadeh A. J Clin Oncol. 2011;29:2753-2757.
Gore SD. J Clin Oncol. 2010;28:1047-1053.
Hu J. Proc Natl Acad Sci USA. 2009;106:3342-3347.
Iland HJ. Blood. 2012;120:1570-1580.
Lo-Coco F. Abstract #6. Presented at: ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta.
Lou Y. Leuk Res. 2013;37:37-42.
Mathews V. J Clin Oncol. 2010;28:3866-3871.
Powell BL. Blood. 2010;116:3751-3757.
Ravandi F. Abstract #1080. Presented at: ASH Annual Meeting and Exposition; Dec. 4-7, 2010; Orlando, Fla.
Ravandi F. J Clin Oncol. 2009;27:504-510.
Shen ZX. Proc Natl Acad Sci USA. 2004;101:5328-5335.
Zhang Y. Cancer. 2013;119:115-125.

Debbie Blamble, PharmD, BCOP, is an oncology clinical pharmacy specialist at The University of Texas MD Anderson Cancer Center. She can be reached at The University of Texas MD Anderson Cancer Center, Division of Pharmacy, 1515 Holcombe Blvd., Houston, TX 77030; email: dblamble@mdanderson.org.

Disclosure: Blamble reports no relevant financial disclosures.