Abstract
Acute Promyelocytic Leukemia (APL) is a unique subtype of acute myeloid leukemia that is highly responsive to minimally myelosuppressive therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). We and others have observed a higher than expected incidence of herpes zoster reactivation in APL patients treated with ATO. Memorial Sloan Kettering Cancer Center (MSKCC) has been using ATO since 1997 in all relapsed APL patients, and more recently has included it in our front-line APL regimens. Here we present a retrospective analysis of the factors contributing to herpes zoster reactivation among APL patients.
Keywords: Acute promyelocytic leukemia, arsenic trioxide, herpes zoster
Introduction:
Acute promyelocytic leukemia (APL) is caused by a translocation between the long arms of chromosomes 15 and 17 resulting in the fusion of the promyelocytic leukemia and retinoic acid receptor α genes. The resulting protein binds to DNA with increased affinity, repressing transcription and blocking the normal progression of granulopoiesis. Clinically, APL is characterized by a profound and complex coagulopathy likely involving disseminated intravascular coagulation, fibrinolysis, and direct proteolysis.1 As a result, early mortality due to hemorrhagic events is substantially higher than in other acute leukemias, particularly in patients with higher risk disease.2
Current standard treatment of APL involves the use of All-trans retinoic acid (ATRA) and chemotherapy which results in remission rates of 90% without primary resistance and cure rates greater than 80%.3 Arsenic trioxide (ATO) was initially used in the US for relapsed APL and has been included more recently in almost all front-line regimens, resulting in additional improvement in cure rates.4, 5 For low risk APL, ATRA with ATO is now the standard front-line treatment, eliminating the use of chemotherapy with minimal myelosuppression for 75% of patients,6 resulting in excellent cure rates.7, 8 For patients with high risk disease, most research protocols now incorporate ATO as well.
Methods:
We evaluated records of all patients with APL treated at MSKCC beginning in 1995 with diagnostic and treatment information recorded in our institutional databases. Patients were grouped in 10-year blocks according to the date of diagnosis to allow adjustment for evolving treatment and supportive regimens. Patients in this cohort represented a mix of new and relapsed cases. Initial treatment modalities including the use and dosage of ATRA and arsenic were evaluated. Evaluation of cytotoxic chemotherapy was also considered, was not used due to incomplete treatment records for patients referred from outside institutions. Prophylactic antiviral treatment instituted within 5 days before or after initiation of arsenic treatment was identified and included as a covariate. In addition, steroid therapy for 5 days or longer was included to account for possible immunosuppressive effects. Treatment with bone marrow transplantation (BMT) was also specifically identified to adjust for increased susceptibility to viral infection in the post-transplant setting.
Herpes zoster events following the initiation of therapy were identified using a set of ICD-10 diagnosis codes corresponding to new zoster diagnoses. Diagnostic codes were assigned by the treating physician for outpatient visits and by coders for inpatient visits based on physician notes. The resulting set of cases includes a composite of cases based on clinical diagnosis, PCR testing, and other laboratory testing. The cumulative incidence of zoster reactivation was estimated using Kaplan-Meier method at a landmark of 14 days following the first arsenic dose to ensure that the analysis captured the initial course of arsenic therapy. The use of Arsenic, ATRA, high dose steroids, and cytotoxic chemotherapy were included as time-dependent covariates in Cox proportional hazards model after adjusting for decade of treatment (1995-2005, 2005-2015, 2015-present), age quintile (<27, 27-42, 42-57, >57) and gender (M,F). Deaths from all causes were censored on the date of the event. Cytotoxic chemotherapy use was subsequently dropped due to a strong association with the decade of treatment, infrequent use in the ≥ 2015 cohort, and lack of association with zoster risk. In a similar fashion, ATRA was also removed from the model due to its near universal use and lack of association with herpes zoster incidence. The association of antiviral prophylaxis with zoster events in the cohort of patients treated with arsenic was determined using Fisher’s exact test.
Results:
The study was comprised of 155 APL patients treated at Memorial Sloan Kettering Cancer Center between 1995-2019 with a median follow-up time of 65 months (Table 1). Patients in this cohort represent a mixture of new and relapsed / refractory cases. The frequency and timing of arsenic use in this cohort matches the evolving role it has played in the treatment of APL. Initially, it was used as an investigational agent for relapsed disease, as reflected in the longer time between APL diagnosis and first arsenic dose in the 1995-2005 cohort compared to others (Figure 1a). Among patients who received arsenic and experienced a herpes zoster infection, the timing of the infection was generally during or shortly after the course of arsenic (Figure 1b). At the time of infection, patients had received a median of 36 days of arsenic treatment with a median cumulative dose of 390mg.
Table 1:
Baseline and cinical characteritiscs of APL patients. The median age was 41.6 years.
| Characteristics | Overall N=155 (%) |
ATO treated N=102 (%) |
Not ATO treated N=53 (%) |
|---|---|---|---|
| Age at diagnosis: | |||
| <27 | 33 (21%) | 25 (25%) | 8 (15%) |
| 27-42 | 34 (22%) | 19 (19%) | 17 (32%) |
| 42-57 | 45 (29%) | 32 (31%) | 15 (28%) |
| 57 | 43 (28%) | 26 (25%) | 17 (32%) |
| Gender: | |||
| M | 88 (57%) | 58 (57%) | 30 (57%) |
| F | 67 (43%) | 44 (43%) | 23 (43%) |
| Herpes zoster infection | 15 (10%) | 14 (14%) | 1 (2%) |
| Treatments: | |||
| ATRA | 152 (98%) | 102 (100%) | 50 (94%) |
| Acyclovir | 114 (74%) | 77 (75%) | 37 (70%) |
| Steroids (> 5 days) | 99 (64%) | 71 (70%) | 28 (53%) |
| Bone marrow transplant | 23 (15%) | 19 (19%) | 4 (8%) |
| Year of diagnosis: | |||
| 1985-1995 | 6 (4%) | 1 (1%) | 5 (9%) |
| 1995-2005 | 72 (46%) | 42 (41%) | 30 (57%) |
| 2005-2015 | 56 (36%) | 38 (37%) | 18 (34%) |
| >2015 | 21 (14%) | 21 (21%) | - |
| Death | 24 (15%) | 10 (10%) | 14 (26%) |
Figure 1.
Arsenic usage and temporal association witn herpes zoster infection. (a) Frequency of arsenic use in APL patients stratified by decade. Arsenic was initially used in trials and for relapsed disease (1995-2005), but subsequently was incorporated into frontline therapy with greater frequency. (b) Duration of arsenic before and after herpes zoster diagnosis and bone marrow transplant (BMT) events. As shown here, herpes zoster was diagnosed in the majority of patients either during or closely following arsenic therapy. Bone marrow transplants were performed in a subset of patients, but none closely preceding herpes zoster diagnoses.
We found that the risk of herpes zoster infection was significantly higher among patients treated with ATO in a landmark analysis anchored at 14 days after initiation of arsenic therapy (Figure 2a). The majority of these cases occurred within the first 6 months of treatment. Among the patients who experienced herpes zoster infection, the only one not to receive ATO was diagnosed with zoster shortly after BMT (Figure 2b).
Figure 2.
Arsenic predisposes to herpes zoster reactivation. (a) Landmark analysis of herpes zoster incidence starting 14 days from the time of arsenic therapy. The risk of herpes zoster reactivation is significantly greater in APL patients receiving arsenic therapy. (b) Clinical context of herpes zoster including arsenic treatment, prolonged steroid use, acyclovir use, and bone marrow transplant (BMT). Herpes zoster diagnosis occurs at the right end of the colored bar. Ongoing therapy following herpes zoster diagnosis is indicated by arrows following the bar.
Of the 102 patients treated with ATO, 14 (13.7%) received viral prophylaxis at the start of therapy. Within this same group, there were 13 (12.7%) herpes zoster infections, with 4 (3.9%) both receiving viral prophylaxis and developing herpes zoster. Given the small number of overlapping events, we evaluated for association between prophylaxis and herpes zoster infection using Fisher’s exact testing. Although viral prophylaxis has been shown to reduce the frequency of infection in patients at risk,9 we found a trend toward a higher proportion of herpes zoster infections among patients receiving prophylaxis (OR: 3.5, p=0.08). This would suggest that prophylaxis in this cohort was used disproportionately in higher risk patients.
After adjustment for age, gender, BMT status, prolonged steroid use, and treatment decade, arsenic treatment showed a significant association with herpes zoster infection (HR: 9.25, 95% CI 1.13-75.48, p=0.04) (Table 2). BMT status likewise showed a trend toward association (HR: 4.97, 95% CI (0.95,26), p=0.06). Prolonged steroid use, defined as greater than 5 days of oral or IV steroids, and other factors including gender and treatment decade were not significantly associated with herpes zoster infection (Table 2). Among the 11 patients who received prolonged steroids and experienced zoster reactivation, the median pre-zoster cumulative dose was 2,035mg prednisone or calculated equivalent10 (range: 494 – 35,970mg) over 43.5 days (range: 12-114 days). Among the 88 patients with greater than 5 days of steroid treatment who did not experience zoster reactivation, the median total cumulative dose was 298mg of prednisone or calculated equivalent10 (range: 1.7-71,500mg) over 18 days (range: 2-378 days).
Table 2:
Kaplan Meier landmark analysis of herpes zoster infection. A landmark of 14 days after the start of arsenic therapy was used.
| Variable | Hazard ratio (95% CI) | P value |
|---|---|---|
| Treatment: | ||
| Arsenic | 9.25 (1.13,75.48) | 0.04 |
| BMT | 4.97 (0.95,26) | 0.06 |
| Steroids | 0.99 (0.34,2.95) | 0.99 |
| Gender: | ||
| Male | 0.43 (0.15,1.25) | 0.12 |
| Female | Reference | - |
| Age at diagnosis: | ||
| <27 | Reference | - |
| 27-42 | 0.68 (0.1,4.55) | 0.69 |
| 42-57 | 1.17 (0.26,5.14) | 0.84 |
| > 57 | 1.75 (0.41,7.57) | 0.45 |
| Treatment decade: | ||
| 1995-2005 | 1.41 (0.25,7.91) | 0.70 |
| 2005-2015 | 1.33 (0.26,6.86) | 0.74 |
| > 2015 | Reference | - |
Discussion:
We found a significant association between ATO treatment and herpes zoster infection during the first 6 months of therapy despite the minimally myelosuppressive nature of ATO and ATO containing regimens. Our institutional findings are consistent with those seen elsewhere,11-13 with the benefit of a larger patient cohort over a longer period of time. Patients who had previously undergone BMT showed a trend toward increased zoster infection, likely due to impaired cellular immunity and/or ongoing immunosuppression. However, other factors including age, gender, and treatment decade did not contribute significantly. This indicates a fundamental mechanism linking ATO treatment and impaired immune function irrespective of medical co-morbidities, treatment regimens, and improvements in supportive care regimens.
During the initial course of APL therapy, there is a significant risk of differentiation syndrome, leading some regimens to include prophylactic corticosteroid administration.5 Given the frequency of steroid use in APL treatment, it was included as a covariate in the model. Although there was not a significant association between prolonged steroid use and zoster infection after adjustment, slightly higher cumulative steroid doses were noted in those with zoster infections, suggesting a more subtle dose effect that could be elucidated in a larger cohort.
Mechanistically, the early risk of zoster reactivation associated with ATO therapy could be explained by profound ATO-mediated T cell dysregulation. Varicella zoster virus (VZV) is the causative agent for herpes zoster, after which the virus remains dormant in the dorsal root ganglia. Patients with impaired cellular immunity are at increased risk for VZV reactivation as well as its associated complications such as post-herpetic neuralgia, aseptic meningitis, and secondary bacterial infections of the zoster rash.14 Low levels of CD4+ T cells have been associated with acute herpes zoster infection, with lower levels corresponding to higher disease severity.15 Environmental arsenic has been shown to impair T cell proliferation and cytokine secretion,16 and in vitro studies show that low levels of arsenic may increase the number of regulatory T cells (Tregs), which normally play a role in limiting immune responses.17 This increase may be due in part to increased differentiation of CD4+ T cells into Tregs rather than into effector cells.18 Taken together, these data suggest that ATO therapy affects the T cell mediated immune response via multiple mechanisms. Decreased numbers of CD4+ effector T cells impair the ability of T cells to combat zoster infection, which is worsened by altered cytokine secretion and the increased suppressive effect of a larger pool of Tregs.
The role of T cell dysfunction in conferring risk of herpes zoster infection is also consistent with the observation that T-cell depleting diseases such as HIV and T-cell directed immunosuppressive agents such as cyclosporine are associated with higher rates of herpes zoster reactivation.19 Our observation of more frequent VZV reactivations among ATO treated patients despite the minimally myelosuppressive nature of the therapy is consistent with this finding.
Current American Society of Clinical Oncology (ASCO) and Infectious Diseases Society of America (IDSA) guidelines for antiviral prophylaxis are typically based on cytopenias or viral seropositivity for herpes simplex virus.20 Our data suggest that ATO confers a significant risk of herpes zoster infection and that upfront viral prophylaxis with acyclovir should be considered prior to the initiation of and during the first 6 months of ATO therapy. Given the central role CD4+ T cells and Tregs appear to play, research into safe and effective ways to stimulate normal production of the CD4+ T cell fraction and/or suppress Tregs during the first 6 months of therapy may also lead to more effective mitigation of herpes zoster reactivation risk.
Highlights.
Acute promyelocytic leukemia is highly responsive to minimally myelosuppressive therapy with all-trans retinoic acid and arsenic trioxide
Arsenic trioxide increases the risk of herpes zoster infection
Acyclovir prophylaxis is recommended for all patients receiving arsenic trioxide
acknowledgements
We would like to acknowledge Joseph Schmeltz for his assistance in querying the data used for this study.
Financial support:
This research was funded in part through the National Institute of Health/National Cancer Institute (NIH/NCI) Cancer Center Support Grant P30 CA008748. JG is funded by NIH/NCI K08 CA230172 01A1.
Footnotes
Details of nature of conflict of interest:
J.L.G. has consulted for GLG. A.K. has consulted for Genentec. R.L.L. is on the supervisory board of Qiagen and is a scientific advisor to Loxo (until 2019), Imago, C4 Therapeutics, Mana, Auron, Ajax, Kurome, Mission Bio, Scorpion, and Isoplexis, which each include an equity interest. He receives research support from and consulted for Celgene and Roche, he has received research support from Constellation, Roche, and Prelude Therapeutics, and he has consulted for Bridge Therapeutics, BMS, Lilly, Incyte, Novartis and Janssen. He has received honoraria from Astra Zeneca, Constellation, Lilly and Amgen for invited lectures and from Gilead for grant reviews. M.S.T. receives research support from AbbVie, Cellerant, Orsenix, ADC Therapeutics, Biosight, Glycomimetics, Rafael Pharmaceuticals, Amgen. He serves on the Advisory Boards of AbbVie, BioLineRx, Daiichi-Sankyo, Orsenix, KAHR, Rigel, Nohla, Delta Fly Pharma, Tetraphase, Oncolyze, Jazz Pharma, Roche, Biosight, and Novartis. He receives royalties from UpToDate.
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References
- 1.Stein E, McMahon B, Kwaan H, Altman JK, Frankfurt O, Tallman MS. The coagulopathy of acute promyelocytic leukaemia revisited. Best Pract Res Clin Haematol. 2009;22(1):153–163. [DOI] [PubMed] [Google Scholar]
- 2.Mantha S, Goldman DA, Devlin SM, et al. Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. Blood. 2017;129(13):1763–1767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. The New England journal of medicine. 2013;369(2):111–121. [DOI] [PubMed] [Google Scholar]
- 4.Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116(19):3751–3757. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Iland HJ, Bradstock K, Supple SG, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012;120(8):1570–1580; quiz 1752. [DOI] [PubMed] [Google Scholar]
- 6.Altman JK, Rademaker A, Cull E, et al. Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death. Leuk Res. 2013;37(9):1004–1009. [DOI] [PubMed] [Google Scholar]
- 7.Platzbecker U, Avvisati G, Cicconi L, et al. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol. 2017;35(6):605–612. [DOI] [PubMed] [Google Scholar]
- 8.Lo-Coco F, Di Donato L, Gimema Schlenk RF, German-Austrian Acute Myeloid Leukemia Study G, Study Alliance L. Targeted Therapy Alone for Acute Promyelocytic Leukemia. The New England journal of medicine. 2016;374(12):1197–1198. [DOI] [PubMed] [Google Scholar]
- 9.Gold D, Corey L. Acyclovir prophylaxis for herpes simplex virus infection. Antimicrob Agents Chemother. 1987;31(3):361–367. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Singer M, Webb AR. Oxford handbook of critical care. 3rd ed. Oxford ; New York: Oxford University Press, 2009. [Google Scholar]
- 11.Freyer CW, Peterson CE, Man Y, Przespolewski A, Baron J, Luger SM. Herpes zoster during arsenic trioxide therapy for acute promyelocytic leukemia. Leuk Lymphoma. 2021;62(3):696–702. [DOI] [PubMed] [Google Scholar]
- 12.Au WY, Kwong YL. Frequent varicella zoster reactivation associated with therapeutic use of arsenic trioxide: portents of an old scourge. J Am Acad Dermatol. 2005;53(5):890–892. [DOI] [PubMed] [Google Scholar]
- 13.Yamakura M, Tsuda K, Ugai T, et al. High frequency of varicella zoster virus reactivation associated with the use of arsenic trioxide in patients with acute promyelocytic leukemia. Acta Haematol. 2014;131(2):76–77. [DOI] [PubMed] [Google Scholar]
- 14.Cohen JI. Clinical practice: Herpes zoster. The New England journal of medicine. 2013;369(3):255–263. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Xing Q, Hu D, Shi F, Chen F. Role of regulatory T cells in patients with acute herpes zoster and relationship to postherpetic neuralgia. Arch Dermatol Res. 2013;305(8):715–722. [DOI] [PubMed] [Google Scholar]
- 16.Morzadec C, Bouezzedine F, Macoch M, Fardel O, Vernhet L. Inorganic arsenic impairs proliferation and cytokine expression in human primary T lymphocytes. Toxicology. 2012;300(1-2):46–56. [DOI] [PubMed] [Google Scholar]
- 17.Hernandez-Castro B, Doniz-Padilla LM, Salgado-Bustamante M, et al. Effect of arsenic on regulatory T cells. J Clin Immunol. 2009;29(4):461–469. [DOI] [PubMed] [Google Scholar]
- 18.Gera R, Singh V, Mitra S, et al. Arsenic exposure impels CD4 commitment in thymus and suppress T cell cytokine secretion by increasing regulatory T cells. Sci Rep. 2017;7(1):7140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Gnann JW, Whitley RJ. Clinical practice. Herpes zoster. The New England journal of medicine. 2002;347(5):340–346. [DOI] [PubMed] [Google Scholar]
- 20.Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin Oncol. 2018; JCO1800374. [DOI] [PubMed] [Google Scholar]