Editorial theme | Collateral effects of adding arsenic trioxide to the treatment regimen for patients with acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) involving complex coagulopathy resulting in early mortality due to hemorrhagic events. Currently, all-trans retinoic acid (ATRA) with arsenic trioxide (ATO) is used as a frontline treatment in low-risk APL patients with excellent cure rates. The use of ATRA with ATO for high-risk APL patients is also under investigation. Despite the benefits offered by ATRA + ATO therapy, there are reports of varicella-zoster virus (VZV)—the causative agent of herpes zoster (HZ)—reactivation in APL patients treated with ATO.

A recent study by Glass et al.¹ reported HZ reactivation due to arsenic toxicity when ATO was used in combination with ATRA to treat patients with APL.

Study design

Briefly, data was collected from new and relapsed therapy patients with APL (n = 155) diagnosed between 1995−2019. Patients were grouped in 10-year blocks according to the date of diagnosis to allow adjustment for evolving treatment and supportive regimens.

Other covariates included:

• Prophylactic antiviral treatment given within 5 days before or after initiation of arsenic treatment
• Steroid therapy >5 days or longer
• Treatment with bone marrow transplantation (BMT)

Patients were divided into ATO-treated (n = 102) and nontreated cohort (n = 53).

Results

• Median age was 43 years and median follow-up time was 65 months.
• Overall, patients who received ATO and developed HZ infection were at a cumulative dose of 390 mg within a median of 36 days posttreatment.
• Risk of HZ infection was higher in patients receiving ATO treatment (Table 1). The majority of incidences were recorded in the first 6 months posttreatment.

 

Table 1. Baseline and clinical characteristics of APL patients*

APL, acute promyelocytic leukemia; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; BMT, bone marrow transplant. *Adapted from Glass et al.1
Characteristic	Overall (n = 155)	ATO treated (n = 102)	Not ATO treated (n = 53)
Age at diagnosis, %
<27	21	25	15
27−42	22	19	32
42−57	29	31	28
57	28	25	32
Male, %	57	57	57
Herpes zoster infection, %	10	14	2
Treatments, %
ATRA	98	100	94
Acyclovir	74	75	70
Steroids (>5 days)	64	70	53
BMT	15	19	8
Years of diagnosis, %
1985−1995	4	1	9
1995−2005	46	41	57
2005−2015	36	37	34
>2015	14	21	—
Death, %	15	10	26

• From all the ATO-treated patients who had received viral prophylaxis (13.7%) at the start of therapy, 12.7% developed HZ infection, with 3.9% receiving viral prophylaxis and still developing HZ infection. It was suggested that although viral prophylaxis reduced the frequency of infection, prophylaxis in this cohort was used disproportionately resulting in an increase in HZ infection in high-risk patients (OR: 3.5; p = 0.08).
• After adjustment for age, gender, BMT status, prolonged steroid use, and treatment decade, the ATO treatment showed a significant association with herpes zoster infection (HR: 9.25; p = 0.04) (Table 2).
• Similarly, the BMT status showed a trend toward association (HR: 4.97; p = 0.06) (Table 2).
• Prolonged steroid use and other factors, including gender and treatment decade, were not significantly associated with herpes zoster infection. Steroid-receiving patients who developed HZ infection were at higher dose (2,035 mg prednisone over 43.5 days) compared with patients who did not develop HZ infection (298 mg prednisone over 18 days).

Table 2. Kaplan-Meier landmark analysis of herpes zoster infection*

Treatment	Hazard ratio (95% CI)	p value
ATRA	9.25 (1.13, 75.48)	0.04
BMT	4.97 (0.95, 26)	0.06
Steroids (>5 days)	0.99 (0.34, 2.95)	0.99
ATRA, all-trans retinoic acid; BMT, bone marrow transplant. *Adapted from Glass et al.1

It was suggested that ATO therapy affects T cell-mediated immune response. Furthermore, patients who underwent BMT also had predisposition for zoster infection due to impaired cellular immunity and/or ongoing immunosuppression. Reduction in CD4⁺ effector T cells hampers the ability of T cells against HZ infection. Furthermore, distorted cytokine secretion and higher activity of regulatory T (Treg) cells to suppress immune response, contribute towards HZ reactivation.

Toxicity management

Use of upfront viral prophylaxis with acyclovir should be considered prior to the initiation, and during the first 6 months, of ATO therapy to avoid significant risk of herpes zoster infection.

Conclusion

There is a variety of effective therapeutic agents in use to treat AML where each one of them has a distinctive mechanism of action and unique toxicity profile. However, awareness about the impact of adverse events of any treatment, and knowledge about the extent to which a patient can bear the treatment, allows to maintain a balance between prolonging survival and the quality of life of patients.

Strategies to stimulate normal production of CD4⁺ T cells and/or balance Tregs during the first 6 months of ATO therapy are needed to effectively control herpes zoster reactivation risk.