¹Faculté de médecine, Université de Montréal, Montréal, Québec
²Division of Dermatology, McGill University, Montreal, Quebec

Conflicts of Interest: Ivan V. Litvinov received research grant funding from Novartis, Merck, AbbVie and Bristol Myers Squibb and honoraria from Janssen, Bausch Health, Galderma, Novartis, Pfizer, Sun Pharma, Johnson & Johnson and Actelion. Other authors declare no competing financial interests.

Introduction

Human Papillomavirus (HPV) is the most common sexually transmitted disease. Its lifetime
prevalence is >75% and this rate continues to increase.¹ This virus infects keratinocytes and is primarily transmitted by skin-to-skin contact.²

Chronic HPV infection, especially from low-risk strains such as 6, 11, 42, 43, and 44, plays an important role in the pathogenesis of cutaneous warts.³ For example, HPV strains 6 and 11 are responsible for 90% of anogenital warts (condyloma acuminate).⁴ Warts can also be found in the mouth, throat, penis/vagina and elsewhere on the skin.⁵

While many HPV infections are asymptomatic⁶, some can result in malignancies. A classic example of this in the skin is represented by carcinoma cuniculatum, a rare form of squamous cell carcinoma (SCC) that often presents on feet in the setting of a longstanding exophytic plantar wart, several decades after the initial infection.⁷ High-risks strains with the potential to lead to cancer or squamous intraepithelial lesions include 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 and 70.³ The Canadian Cancer Society lists HPV as the fifth most preventable cause of cancer.⁸ However, this ranking likely underestimates the role of HPV in carcinogenesis since cutaneous SCCs, where HPV is recognized as a co-carcinogen, are not included in cancer statistics. Cutaneous SCCs and Basal Cell Carcinomas (BCCs), together called keratinocyte carcinomas, are the most common cancers with an estimated ~5.4 million new cases diagnosed every year in the United States alone.⁹

Notably, a high proportion of HPV-associated cancers are diagnosed in males.¹⁰ Since males are under-vaccinated and are increasingly disproportionately affected by certain HPV-associated cancers, namely oropharyngeal and penile cancers, current vaccination efforts should be refocused on male patients.^6,11-13 Effective vaccination protocols can help promote both physical health as well as mental health since male patients with HPV often encounter numerous psychosocial impacts secondary to their infection, namely depression, reduction in quality of life and sexual dysfunction.⁶

Male HPV Vaccination Statistics and Guidelines

HPV vaccination programs and guidelines have changed several times in the past decade, causing important gaps in vaccination rates between males vs. females. In 2007, the first Canadian vaccination program for school-aged females was implemented, and by 2010 all Canadian provinces had established vaccination programs for females.⁶ In Alberta, before the start of the vaccination program for school-aged males, 98.3% of vaccinated individuals were females.¹⁴ The first Canadian public vaccination program for males was launched in 2012, while national coverage for the vaccine was only established in 2017.⁶ In Ontario, even after the sex-neutral school vaccination programs were created, there was still a gap in HPV vaccination rates between males and females.⁶ Hence, most males remain unvaccinated for HPV, especially the middle age population, which is at risk of developing the aforementioned cancers in the future. One narrative review investigating reasons for suboptimal vaccination in males found that lack of information, the misconception that the virus only affects females, vaccine hesitancy, lack of recommendations from healthcare providers, costs and logistics all acted as barriers to vaccination.¹⁵

According to the National Advisory Committee on Immunization (NACI) of Canada, the HPV vaccine was previously only recommended for males ages 9 through 26 years to prevent anogenital warts and other HPV-associated cancers.¹⁶ However, now there is no age limit on receiving a quadrivalent or nonavalent HPV vaccine. While the vaccine before was not routinely recommended for males ages 27 to 45 years, the guidelines state that the vaccine may be administered to this age group if there is an ongoing risk of HPV exposure,⁶ for example, healthcare providers treating warts.¹⁷ Recent reports, however, strongly argued that this vaccine should be given to middle aged males.¹⁸ On the other hand, there is currently insufficient research to encourage HPV vaccination in males over 45 years of age.

Natural Immunity Post HPV Exposure in Males and Cancer Risks

There are important differences between males and females regarding their immune response to HPV. A study has shown that males are 4 to 10 times less likely to seroconvert after an HPV infection, regardless of the infected anatomic site.¹⁹ In fact, within 36 months after HPV DNA was detected as a result of an oral, anal or genital HPV infection (strains 6, 11, 16, 18), only 7.7% of men developed detectable serum HPV antibodies.¹⁹ In the same study, the seroconversion rate following a genital HPV 16 infection was only 4.1% in males compared to 60% in females.¹⁹ Further, the HPV in Men (HIM) study showed that healthy males do not have a reduced risk of subsequent HPV oral infection from natural HPV L1 antibodies (immunoglobulin G antibodies to the L1 capsid protein in serum) following an HPV infection, as it was previously thought.²⁰ Thus, these antibodies are not protective against future HPV infection and, unlike females, males are at risk of reinfection with the same HPV strain.²⁰ On the other hand, females’ existing antibodies confer partial immunity.¹⁹ As such, males acquire HPV infections at a steady rate.²¹ The prevalence of male genital HPV infections, which do not decrease with age (Figure 1), highlights the suboptimal natural immunity against HPV in males.

Importantly, in recent years the number of oropharyngeal SCC cancers has surpassed the number of cervical cancers caused by HPV. In fact, most of the oropharyngeal SCC cancer patients are males (Figure 2).²² Cervical cancer rates are declining, whereas oropharyngeal cancer rates in Canadian males are on the rise (Figure 3).¹² Anal cancer rates are also on the rise, while the incidence rates of penile and oral cancers, unfortunately, remain unchanged (Figure 3).^11-13

Some males are at a particularly higher risk for HPV-associated cancers. Males who have sex with males (MSM), especially MSM who have Human immunodeficiency virus (HIV), have higher rates of anal carcinoma.²³ Males who are solid organ transplant recipients also have higher rates of penile and anal cancer.²³ Additionally, there is currently no approved HPV DNA test for males in Canada.²⁴ In contrast, females who get a Pap test can be co-tested for HPV using a sample of cervical cells taken at the same visit.²⁵

Recommendations for Vaccinations Should Focus on Males and Health Care Professionals at Risk of HPV Exposure

Side Effects of Spironolactone

Taking into consideration the above important points, we recommend that all males at risk of exposure to HPV between the ages of 9 and 45 receive the vaccine. Sufficient data exists to update the current guidelines, which only recommend vaccination for males between the ages of 9 and 27.⁶ The recommended vaccine is HPV9 (GARDASIL^®9) a nonavalent vaccine that prevents HPV infections caused by strains 6, 11, 16, 18, 31, 33, 45, 52 and 58²⁶ and received in 2022 Health Canada approval for the prevention of oropharyngeal cancer and other head & neck cancers (along with the prevention of cervical, vulvar, vaginal and anal intraepithelial neoplasia) caused by HPV.²⁷ The nonavalent vaccine is preferred to the quadrivalent vaccine since it protects against a wider range of high-risk strains.²⁸

The effectiveness of the vaccine in males aged 27 to 45 is inferred from the efficiency data in females of the same age and by the immunogenicity data from the Mid-Adult-Aged Men (MAM) Trial.²⁹ The MAM Trial evaluating response to the quadrivalent vaccine showed a 100% seroconversion rate 6 months after vaccination in 150 males between the ages of 27 and 45.²⁸ Another study reported 95% seroconversion rate 28 weeks following the quadrivalent vaccine administered in males with HIV between the ages of 22 and 61.³⁰

The vaccine is also proven to be safe. In fact, a study demonstrating the safety profile of the quadrivalent HPV vaccine in adult men 27 to 45 years of age with HIV-1 found no grade 4 (life-threatening) or 5 (death) adverse events.²⁹ Most adverse events were of either mild or moderate intensity.²⁹ Given these promising results, the vaccine should be strongly recommended to unvaccinated males aged 27 to 45.

HPV Vaccination for Healthcare Professionals

HPV vaccination is also recommended to all physicians, nurses and residents in obstetrics and gynecology, oncology, dermatology and any staff that treat patients with warts.³¹ HPV DNA was found in the vapour of 62% and 57% of plantar warts treated with ablative laser and electrocautery, respectively.³² Normal non-lesioned skin was shown to contain in >60% of cases pathogenic HPV strains.³³ Hence, use of cautery on normal skin can too produce plume with HPV particles. This poses an occupational risk for dermatologists and other health care providers,¹⁷ which is why the vaccine is highly recommended in this group. In addition, reports indicate that (1) using local exhaust ventilation, (2) general room ventilation and (3) full personal protective equipment including a fit tested particulate respirator of at least N95 grade can decrease operator from HPV inhalation exposure.³⁴ Another study mentions that even though protective equipment, mainly gloves, can get contaminated with HPV, transmissions to medical professional is less likely to occur if the equipment is disposed of properly.³⁵

Conclusion

While the incidence of cervical cancer is decreasing in females, the incidence of oropharyngeal and other HPV-driven cancers is increasing at an alarming rate, especially in males. As such, vaccination efforts should be aimed at addressing this important public health concern. Males are significantly under-vaccinated compared to females and acquire HPV infections at a steady rate, with a very low rate of seroconversion following infection. Therefore, we advocate to provide routine vaccination against HPV in all males between the ages of 27 and 45, and continue to actively vaccinate males ages 9 to 26. Vaccines are effective, as shown by the high rate of post-vaccination seroconversion, which is an important factor in preventing oropharyngeal SCCs and other HPV-related cancers. Finally, it is crucial to routinely promote the HPV vaccination for all patients and healthcare professionals at risk of exposure to HPV, the same way we promote sun safety for all.

Melinda J. Gooderham, MSc, MD, FRCPC^1,2; H. Chih-ho Hong, MD, FRCPC^2,3; Ivan V. Litvinov, MD, PhD, FRCPC⁴

¹Skin Centre for Dermatology, Peterborough, ON, Canada
²Probity Medical Research, Waterloo, ON, Canada
³Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁴Division of Dermatology, Department of Medicine, McGill University, Montreal, QC, Canada

Conflict of interest:
M. Gooderham has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Akros Pharma, Amgen, AnaptysBio, Arcutis Biotherapeutics, Arena Pharmaceuticals, Asana BioSciences, ASLAN Pharmaceuticals, Bausch Health/Valeant, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, GSK, ICPDHM, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Merck, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, Takeda, and UCB. H. C. Hong has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Amgen, Arcutis, Bausch Health, Boehringer-Ingelheim, Bristol Meyers Squibb, Celgene, Cutanea, Dermira, Dermavant, DS Biopharma, Eli-Lilly, Galderma, GSK, ICPDHM, Incyte, Janssen, Leo Pharma, Medimmune, Merck, Mirimar, Novartis, Pfizer, Regeneron, Roche, Sanofi-Genzyme, Sun Pharma, and UCB. I. Litvinov has received a grant or an honorarium from AbbVie, Actelion, Bausch Health, Bristol-Myers Squibb, Galderma, ICPDHM, Janssen, Johnson & Johnson, Merck, Novartis, Pfizer, and Sun Pharmaceuticals.

Funding for this manuscript was provided in the form of an educational grant from Bristol Myers Squibb Canada Co.

Abstract:
Moderate to severe chronic plaque psoriasis may be difficult to control using current therapies, which has led to development of a novel class of therapy, selective tyrosine kinase 2 (TYK2) inhibitors, to address this unmet need. Oral deucravacitinib is a first-in-class selective TYK2 inhibitor, which has shown efficacy in moderate to severe chronic plaque psoriasis from two phase III pivotal trials (POETYK PSO-1 and PSO-2), whereby response rates were significantly higher with deucravacitinib vs. placebo or apremilast for Psoriasis Area Severity Index (PASI) 75 and static Physician’s Global Assessment (sPGA) 0/1. Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast. Although deucravacitinib is a type of Janus kinase (JAK) inhibitor, it only blocks specific cytokine-driven responses, potentially reducing off-target effects more commonly associated with other JAK inhibitors on the market. Incidence rates of serious adverse events, such as serious infections, malignancies, thrombosis, cardiovascular events, creatinine kinase elevation, hematologic changes, and lipid profile abnormalities were absent or low.

Key Words:
plaque psoriasis, TYK2 inhibitor, deucravacitinib, apremilast, clinical trial, efficacy, safety, PASI, sPGA

Introduction

Psoriasis is a common, chronic, immune-mediated inflammatory disease, estimated to affect 1 million people in Canada.^1,2 The most common type is chronic plaque psoriasis, which affects 90% of this patient population.¹

Moderate chronic plaque psoriasis is typically defined as involving ≥3-10% body surface area (BSA), with severe disease involving more than 10% BSA.³ When inadequately treated, this can cause severe psychosocial impact and impair patients’ quality of life (QoL).³

Currently, various oral systemic agents, biologic agents, and phototherapy have Health Canada-approved indications for management of moderate to severe chronic plaque psoriasis. Despite numerous treatment options, unmet needs still exist. An emerging class of therapy in development are selective tyrosine kinase 2 (TYK2) inhibitors, which may meet those needs. Oral deucravacitinib is a first-in-class selective TYK2 inhibitor, recently US FDA approved and currently under review by Health Canada. Other oral selective TYK2 inhibitors for treatment of moderate to severe plaque psoriasis in various stages of development include GLPG3667 and NDI-034858.^4,5

Pathogenesis of Plaque Psoriasis

The pathogenesis of chronic plaque psoriasis starts with environmental, immunologic, and/or genetic triggers that can lead to release of cytokines from innate immune cells, activating myeloid dendritic cells.^6,7 Activated myeloid dendritic cells present antigens to T cells and release cytokines, including interleukin (IL)-23 and IL-12;^6-8 both IL-23 and IL-12 signal through TYK2-mediated pathways. IL-12 contributes to T helper (Th)1-cell differentiation and IL-23 activates keratinocytes via pro-inflammatory Th17 cells;⁶ both processes lead to tumor necrosis factor (TNF)-α and interferon (IFN)-γ production. Cytokines secreted by Th17 and Th1 cells activate keratinocytes;⁹ this is one of the first steps in the development of psoriatic lesions. A positive feedback loop recruits other immune cells, further potentiating the inflammatory process.⁶

Rationale for Targeting TYK2 in Plaque Psoriasis Treatment

TYK2 is a Janus kinase (JAK) enzyme that is coded by the TYK2 gene and constitutively expressed in immune cells.¹⁰ Mutations and polymorphisms in TYK2 impact IL-23, IFN-α/β, and IL-12 immune-mediated signalling, and are associated with an altered risk for psoriasis; for example, loss of function mutations in TYK2 have been found to be protective against autoimmunity, including psoriasis.¹⁰ Selective TYK2 inhibition blocks IL-23, IL-12, and type I IFN-driven responses, but not those driven by other JAKs (Figure 1).^11-13

Deucravacitinib: Mechanism of Action

Deucravacitinib is a specific, oral, intracellular TYK2 inhibitor that targets immune responses driven by type 1 IFN and IL-23 that contribute to psoriasis pathogenesis, including IL-17 production and Th1/Th17 polarization.^12-14 It binds with high specificity to the TYK2 regulatory domain, blocking kinase activity and conferring selective inhibition of TYK2-mediated pathways that contribute to psoriasis pathogenesis (Figure 2).^12-14

Deucravacitinib uniquely binds to the regulatory domain of TYK2 and only blocks specific cytokine-driven responses, leading to a broad therapeutic range while reducing off-target effects.^11-13 In contrast, JAK 1–3 inhibitors bind to the active domain adenosine triphosphate (ATP) binding site common to all JAK molecules (including TYK2) to mediate both immune responses and broader systemic processes (e.g., myelopoiesis, granulopoiesis, lymphoid cell maturation and function, hematopoiesis, growth factor response, metabolic activity regulation, lipid metabolism, etc.), some of which are necessary for normal physiologic functioning, resulting in a narrower therapeutic range.¹³

Efficacy of Deucravacitinib: Key Evidence from Pivotal Phase III Clinical Trials

In a phase II trial of patients with psoriasis, deucravacitinib demonstrated superior efficacy vs. placebo based on ≥75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) over 12 weeks.¹⁴ Efficacy results from two phase III pivotal trials of deucravacitinib were recently reported and confirmed results from the phase II trial.

In the 52-week, double-blinded, phase III POETYK PSO-1 trial, participants with moderate to severe chronic plaque psoriasis were randomized 2:1:1 to deucravacitinib 6 mg once daily (n=332), placebo (n=166), or apremilast 30 mg twice daily (n=168).¹⁵ Similarly, participants in the 52-week, doubleblinded, phase III POETYK PSO-2 trial were randomized 2:1:1 to deucravacitinib 6 mg once daily (n=511), placebo (n=255), or apremilast 30 mg twice daily (n=254).¹⁶

The coprimary endpoints of both trials were response rates for PASI 75 and static Physician’s Global Assessment score of 0 or 1 (sPGA 0/1) with deucravacitinib vs. placebo at week 16.^15,16 Key secondary endpoints included the scalp-specific Physician’s Global Assessment (ss-PGA) and patient-reported symptoms and signs of psoriasis (evaluated using the Psoriasis Symptoms and Signs Diary [PSSD]) and QoL (evaluated using the Dermatology Life Quality Index [DLQI]).¹⁵

In both PSO-1 and PSO-2 trials, PASI 75 response rates at week 16 were significantly higher with deucravacitinib (58.4% and 53.0%) vs. placebo (12.7% and 9.4%) or apremilast (35.1% and 39.8%). Response rates for sPGA 0/1 were also significantly higher with deucravacitinib (53.6% and 50.3%) vs. placebo (7.2% and 8.6%) or apremilast (32.1% and 34.3%) (Table 1).^15,16 Deucravacitinib responses improved beyond week 16 and were maintained through week 52.¹⁵ Furthermore, patients who switched from placebo to deucravacitinib at week 16 demonstrated PASI 75 and sPGA 0/1 responses at week 52 comparable to those observed in patients who received continuous deucravacitinib treatment from day 1.¹⁵

Regarding key secondary endpoints, significantly greater proportions of patients in the deucravacitinib vs. placebo and apremilast arms achieved ss-PGA 0/1 and DLQI 0/1 responses, as well as greater reduction from baseline in PSSD symptom scores at week 16 and week 24 (Table 1).^15,16

Table 1. POETYK PSO-1 and PSO-2 efficacy results

Pooled PSO-1 and PSO-2 data showed that significantly greater proportions of patients receiving deucravacitinib achieved absolute PASI ≤1, ≤2, and ≤5 vs. patients receiving placebo (week 16) or apremilast (weeks 16 and 24), and proportions of patients achieving different PASI thresholds with deucravacitinib increased from week 16 to week 24.¹⁷

In an analysis of PSO-1 and PSO-2 that compared efficacy of deucravacitinib vs. placebo and apremilast in individual scoring components (erythema, induration, desquamation) and body regions of PASI (head/neck, upper extremities, trunk, lower extremities), deucravacitinib was associated with numerically greater percent reductions from baseline in each PASI body region and component scores at week 16 than placebo and apremilast.¹⁸ Higher proportions of patients in the deucravacitinib vs. placebo and apremilast groups achieved ≥75% reduction at week 16 in each PASI body region and PASI scoring; differences in efficacy when compared to apremilast were maintained at week 24.¹⁸ For patients in the deucravacitinib group, improvements occurred as early as week 1 and increased over time on treatment.¹⁸

In a long-term extension study of PSO trials, investigators analyzed the efficacy of deucravacitinib in patients who did not respond adequately to treatment with apremilast by week 24. Patients initially randomized to apremilast who failed to achieve a PASI 50 in PSO-1 (n=54) or PASI 75 in PSO-2 (n=111) were switched to deucravacitinib through week 52. After switching from apremilast to deucravacitinib, 46.3% of PASI 50 nonresponders and 42.3% of PASI 75 non-responders achieved PASI 75 by week 52.¹⁹ Improvements were also seen for sPGA 0/1, DLQI 0/1, and mean change from baseline PSSD symptom score.¹⁹

Two-year data from a long-term extension of both PSO trials showed that deucravacitinib had durable clinical efficacy, including mean response rates of 79.8% for PASI 75 and 60.7% for sPGA 0/1 at week 60, regardless of which treatment was initiated at week 16 (when patients in the placebo group could switch to deucravacitinib) or at week 24 (when apremilast nonresponders could switch to deucravacitinib) in the parent study.²⁰

Deucravacitinib: Safety and Tolerability Profile

During weeks 0–16 and weeks 0–52 assessment periods in both PSO trials, overall adverse event (AE) rates were similar across all 3 treatment groups (deucravacitinib, placebo, and apremilast).^15,16,21 The most frequent AEs in patients treated with deucravacitinib were nasopharyngitis (9.0%) and upper respiratory tract infection (5.5%). The most frequent AEs in apremilast-treated patients were diarrhea (11.8%), headache (10.7%), nausea (10.0%), and nasopharyngitis (8.8%); placebotreated patients most frequently experienced nasopharyngitis (8.6%) and diarrhea (6.0%).16,21 Incidence rates for AEs of interest, including skin events (e.g., acne and folliculitis), herpes zoster, serious infections, malignancies, thrombotic events, cardiovascular events, creatinine kinase elevation, changes in complete blood count, and changes in lipid profile were absent or low in the deucravacitinib group.¹⁵

The frequency of serious adverse events (SAEs) reported in weeks 0–16 were low across all groups (1.8% in deucravacitinib treated patients vs. 2.9% with placebo and 1.2% with apremilast).^16,21 Discontinuation rates due to AEs were lowest in the deucravacitinib group (2.4%) vs. placebo (3.8%) and apremilast (5.2%).^16,21

A pooled analysis of PSO-1 and PSO-2 trials confirmed that deucravacitinib was well tolerated for up to 52 weeks across patient subgroups based on baseline characteristics of age, sex, race, and body weight. The frequency and type of AEs and SAEs in each subgroup were consistent with the overall patient population, with similar trends for overall AEs and AE classes in the placebo and apremilast groups across subgroups.²¹

In the long-term extension trial, safety results were consistent with those reported in PSO-1 and PSO-2 trials. SAEs remained low, including those that led to discontinuation. There were no new safety signals or clinically meaningful changes in laboratory values.²⁰ The most common AEs included nasopharyngitis (16.8% at 1 year; 17.8% at 2 years), upper respiratory tract infection (9.1% at 1 year; 9.9% at 2 years), headache (5.9% at 1 year; 6.5% at 2 years), diarrhea (5.1% at 1 year; 5.5% at 2 years), and arthralgia (4.0% at 1 year; 5.6% at 2 years).²⁰ An increase in serious infections was observed, which the authors concluded was attributable to COVID-19 infections due to the ongoing pandemic (studies were conducted during the pandemic through the cut-off date of October 1, 2021, prior to widespread availability of vaccines).

These safety results have not as of yet uncovered treatmentemergent SAEs that are more commonly associated with JAK inhibitors, such as herpes zoster, malignancies, thrombosis, major adverse cardiovascular events (MACE), creatinine kinase elevation, hematologic changes, lipid profile abnormalities, and renal and hepatic abnormalities.^20-24

Discussion

Selective TYK2 inhibition is a promising novel target for the treatment of moderate to severe chronic plaque psoriasis. Molecules that confer selective inhibition of TYK2-mediated pathways that contribute to psoriasis pathogenesis, without involvement of other JAKs, can lead to a broad therapeutic range while reducing off-target effects such as serious infections, malignancies, thrombosis, and MACE.

Key data from the pivotal phase III POETYK PSO-1 and PSO-2 clinical trials showed that patients with moderate to severe chronic plaque psoriasis treated with the first-in-class, oral, selective TYK2 inhibitor deucravacitinib achieved statistically significant PASI 75 and sPGA 0/1 outcomes that were superior to placebo and apremilast at week 16.^15,16 Additionally, significantly greater proportions of patients achieved absolute PASI ≤1, ≤2, and ≤5 with deucravacitinib vs. placebo or apremilast.¹⁷ Body region-specific data showed that deucravacitinib had numerically larger percentage improvements at weeks 16 and 24 from baseline vs. apremilast and placebo, across all components of scoring and with onset of action as early as week 1.¹⁸

Deucravacitinib was efficacious at week 52 in patients who had inadequate responses to apremilast at week 24 and subsequently switched to deucravacitinib, which was demonstrated in physician-assessed endpoints (PASI 75/90, percentage change from baseline in PASI, and sPGA 0/1) and in patient-reported outcomes (DLQI 0/1 and change from baseline in PSSD symptom score).¹⁹

Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast, with overall AE rates similar across all 3 treatment groups.^15,21 The most common AEs in patients treated with deucravacitinib were nasopharyngitis and upper respiratory tract infection, while incidence rates of SAEs and AEs of interest were low.^15,21

1. What are the off-target serious adverse effects associated with JAK inhibitors?
2. In the PSO-1 and PSO-2 clinical trials, what were the outcomes of apremilast non-responders who were switched to deucravacitinib at week 24?

Conclusion

Selective TYK2 inhibition is a novel target in the treatment of moderate to severe plaque psoriasis. The first-in-class oral TYK2 inhibitor deucravacitinib, already approved by the FDA in the US, has been shown to be efficacious, safe, and tolerable for up to 2 years of use. It is expected that deucravacitinib, and potentially other oral TYK2 inhibitors in development, will offer dermatologists and their patients with a convenient, effective, and safe alternative to other currently available oral systemic agents biologic agents, and phototherapy for the management of moderate to severe chronic plaque psoriasis.

Acknowledgements

The authors wish to thank Teri Morrison and Athena Kalyvas from the International Centre for Professional Development in Health and Medicine (ICPDHM) for editorial support.

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¹Division of Dermatology, McGill University, Montreal, QC, Canada
²Brunswick Dermatology Center, Fredericton, NB, Canada
³Division of Clinical Dermatology & Cutaneous Science, Dalhousie University, Halifax, NS Canada
⁴Probity Medical Research, Waterloo, ON, Canada
⁵Department of Dermatology, Discipline of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
⁶Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁷Division of Dermatology, University of Ottawa, Ottawa, ON, Canada
⁸Division of Hematology, Department of Medicine, McGill University, Montreal, QC, Canada
⁹Division of Dermatology, University of Alberta, Edmonton, AB, Canada
¹⁰Division of Dermatology, University of Toronto, Toronto, ON, Canada

Conflict of interest: Elena Netchiporouk has received grants, research support from Novartis, Sanofi, Sun Pharma, AbbVie, Biersdorf, Leo Pharma, Eli Lilly; speaker fees/honoraria from Bausch Health, Novartis, Sun Pharma, Eli Lilly, Sanofi Genzyme, AbbVie, Galderma, Novartis, Sanofi Genzyme, Sun Pharma, Bausch Health and Leo Pharma and consulting fees from Bausch Health, Novartis, Sun Pharma, Eli Lilly, Sanofi Genzyme, AbbVie, Galderma, Novartis, Sanofi Genzyme, Sun Pharma, Bausch Health and Leo Pharma. Irina Turchin served as advisory board member, consultant, speaker and/or investigator for AbbVie, Amgen, Arcutis, Aristea, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Incyte, Janssen, Kiniksa, Leo Pharma, Mallinckrodt, Novartis, Pfizer, Sanofi, UCB. Wayne Gulliver received grants/research support from AbbVie, Amgen, Eli Lilly, Novartis and Pfizer; honoraria for advisory boards/invited talks from AbbVie, Actelion, Amgen, Arylide, Bausch Health, Boehringer, Celgene, Cipher, Eli Lilly, Galderma, Janssen, Leo Pharma, Merck, Novartis, PeerVoice, Pfizer, Sanofi-Genzyme, Tribute, UCB, Valeant and clinical trial (study fees) from AbbVie, Asana Biosciences, Astellas, Boehringer-Ingelheim, Celgene, Corrona/National Psoriasis Foundation, Devonian, Eli Lilly, Galapagos, Galderma, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, UCB. Gizelle Popradi has received honoraria or speaker fees from Jazz Pharma, Seattle Genetics, Abbvie, Kite Gilead, Pfizer, Taiho, Servier, Novartis, Merck, Kyowa Kirin, Abbvie, Avir Pharma, Mallinckrodt. Robert Gniadecki reports carrying out clinical trials for Bausch Health, AbbVie and Janssen and has received honoraria as consultant and/or speaker from AbbVie, Bausch Health, Eli Lilly, Janssen, Mallincrodt, Novartis, Kyowa Kirin, Sun Pharma and Sanofi. Charles Lynde was a consultant, speaker, and advisory board member for Amgen, Pfizer, AbbVie, Janssen, Novartis, Mallincrodt, and Celgene, and was an investigator for Amgen, Pfizer, AbbVie, Janssen, Lilly, Novartis, and Celgene. Ivan V. Litvinov received research grant funding from Novartis, Merck, AbbVie and Bristol Myers Squibb and honoraria from Janssen, Bausch Health, Galderma, Novartis, Pfizer, Sun Pharma, Johnson & Johnson and Actelion. Topics included in this article were based on, but not limited to, broad discussions at an advisory board meeting, which was sponsored and funded by Mallinckrodt, Inc. Consultancy fees were paid to meeting participants (EN, IT, WG, JD, MK, RG, CL and IVL). All other authors declare no existing competing interests.

Abstract:
Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used for over 35 years to treat numerous conditions. ECP was initially approved by the US FDA in 1988 for the treatment of Sézary syndrome, a leukemic form of cutaneous T-cell lymphoma (CTCL). Although CTCL remains the only FDA-approved indication, ECP has since been used off-label for numerous other conditions, including graft-versus-host disease (GvHD), systemic sclerosis, autoimmune bullous dermatoses, Crohn’s disease, and prevention of solid organ transplant rejection. In Canada, ECP is mainly used to treat CTCL, acute and chronic GvHD, and in some instances systemic sclerosis. Herein, we review the current concepts regarding ECP mechanism of action, treatment considerations and protocols, and efficacy.

Key Words:
extracorporeal photopheresis, cutaneous T-cell lymphoma, S.zary syndrome, systemic sclerosis, graft-versus-host disease, safety.

Introduction

Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used for over 35 years to treat numerous conditions (Figure 1).^1,2 ECP was initially approved by the Food and Drug Administration (FDA) in the United States in 1988 for the treatment of S.zary syndrome (SS), a leukemic form of cutaneous T-cell lymphoma (CTCL) with an aggressive clinical course, characterized by a triad of circulating neoplastic T-cells, erythroderma, and lymphadenopathy.¹ Although CTCL remains the only FDA-approved indication, ECP has since been used as an off-label treatment for numerous other conditions, including graft-versus-host (GvHD) disease, systemic sclerosis (SSc), autoimmune bullous dermatoses, Crohn’s disease, and to prevent solid organ transplant rejection.^1,2 In Canada, ECP is mainly used to treat CTCL, acute and chronic GvHD, and in some instances systemic sclerosis (Tables 1-2). The goal of this article is to review the current concepts regarding ECP mechanism of action, treatment considerations as well as suggested treatment protocols and efficacy in CTCL, GvHD, systemic sclerosis and other skin diseases.

Table 1. The use of ECP by hospital and by city in Canada in 2020.

Table 2. The use of ECP by city and by indication in Canada in 2020.

ECP involves placing a catheter to gain access to the venous circulation and collecting blood via continuous or discontinuous cycles, which is then centrifuged to create a leukocyte-rich buffy coat. The isolated leukocytes are then placed in a sterile treatment cassette, injected with liquid 8-methoxypsoralen (8-MOP) and exposed to ultraviolet A (UVA) radiation. Afterwards, the photochemically-altered white blood cells are returned to the patient’s venous circulation (Figure 1).^1,2 The Therakos^® ECP machine (the only available unit for this treatment) represents an automated closed system. Each treatment lasts approximately 1.5-3 hours, and the scheduling and frequency of treatments depend on the disease being treated.

The exact mechanism of action of ECP remains unknown, however, in CTCL, it is believed that the procedure leads to DNA-crosslinking and apoptosis of pathogenic T cells induced by 8-MOP with UVA exposure, the differentiation of monocytes to dendritic cell that present tumor antigens from apoptotic lymphocytes, stimulation of anti-tumor immune responses, and shifting of immunoregulatory cytokines to Th1 cytokine profile, such as interferon-gamma and tumor necrosis factor (TNF) alpha, thus restoring the Th1/Th2 balance.^1-4 In particular, ECP targets mostly tumor cells since the absolute number of normal T cells remains relatively stable after the procedure.¹ Given its therapeutic benefit in transplant rejection and autoimmune diseases, ECP is also believed to have unique immunomodulatory properties generating needed responses in an autoimmune setting, which are thought to be similarly mediated by DNA-crosslinking and apoptosis of autoreactive leucocytes (natural killer (NK) and T cells) and induction of T-regulatory cells after treatment, although this phenomenon was not observed in patients with SS.² However, unlike immunosuppressive therapies, ECP is not associated with an increased risk of opportunistic infections.² In fact, ECP is overall well-tolerated, with no reports of post-treatment Grade III or IV side effects, as per the World Health Organization classification.² In particular, ECP is not associated with side-effects that are observed with skin systemic psoralen with UVA (PUVA) therapy, since the psoralen is not ingested orally nor applied to the skin.² The side-effects are primarily related to fluid shifts and the need for a central catheter. Rare side-effects of ECP include nausea, photosensitivity, transient hypotension, flushing, tachycardia, congestive heart failure and thrombocytopenia.^1,2 Contraindications to the use of ECP are summarized in Table 3. Currently, ECP is available in over 200 treatment centers across the world treating numerous diseases.² The use of ECP by hospital, region and indication in Canada is summarized in Tables 1-2. Unfortunately, treatment access is limited in Canada and significant knowledge gaps are recognized (i.e., paucity of randomized clinical trials and real-world evidence) amongst physicians and patients. As a result, this treatment may be significantly underused in Canada.

Table 3. Summary of contraindications to the use of ECP

CTCL

CTCL represents a group of lymphoproliferative disorders where there is an accumulation of malignant T-cell clones in the skin.² The most commonly recognized forms of CTCL are mycosis fungoides (MF) and SS. There are currently no curative treatments for CTCL, except for allo-transplantation which has been successful in select patients.² ECP is often used as a first-line treatment for SS, as well as for patients with erythrodermic MF or advanced CTCL.¹ Its use in early stages of CTCL remains controversial and impractical in Canada as many other effective treatment modalities are available (Table 4).^5,6 ECP can be used as monotherapy or it can be safely given in combination with phototherapy (narrow band or broadband UVB), radiotherapy, total skin electron beam (TSEB), systemic retinoids, interferons, anti-CCR4 monoclonal antibodies, histone deacetylase inhibitors, methotrexate, and/or other treatments.^1,2 One meta-analysis of 400 patients with all stages of CTCL showed a combined overall response rate (ORR) of 56% both when ECP was used as monotherapy and in combination with other therapies.² The complete response (CR) rates were 15% and 18% for monotherapy and combination therapy, respectively.² However, the ORR and CR were 58% and 15%, respectively, in erythrodermic patients, and 43% and 10% in patients with SS.² The CR was defined as a complete resolution of clinical evidence of disease and for normalization of CD4/CD8 ratio for at least 1 month. The partial response (PR) was defined as greater than 25% but less than 100% decrease in lesions and no development of new lesions for at least 1 month. ORR was defined as a sum of PR and CR. Furthermore, the United Kingdom consensus statement analyzed 30 studies between 1987 to 2007 and determined that the mean ORR and CR rates were 63% (range 33-100%) and 20% (range 0-62%), respectively, with higher response rates observed in erythrodermic patients. Many factors can explain the variability in the results of these studies, such as patient selection bias, stage of the disease, ECP treatment schedule, prior treatments, and end-point definitions.² In addition, there is a significant amount of inter-subject variability in response rates to ECP and factors that predict treatment response, as summarized in Table 5.²

Table 4. Treatment options for CTCL (MF)

Table 5. Baseline parameters and predictors of response to ECP in the treatment of cutaneous T-cell lymphoma, as per the European Dermatology Forum.

Different countries have varying guidelines with respect to the use of ECP in CTCL. Most recently, the European Dermatology Forum (EDF) published new recommendations in 2020. They recommend considering ECP as first-line therapy in patients with MF clinical stages IIIA or IIIB (erythroderma), or MF/SS stages IVA1 or IVA2 (Tables 6-7). Treatments are recommended every 2 weeks for the first 3 months, then every 3-4 weeks, with a treatment period of at least 6 months or until remission is achieved, followed by a maintenance period (Table 8).² ECP can take 3-6 months before a clinical response is appreciated, and therefore, no conclusions regarding its success should be drawn before that timeframe in erythrodermic patients.^1,2

Table 6. TNMB classification of MF and SS

Table 7. Clinical staging for MF and SS.

Table 8. ECP recommendations by cutaneous disease, as per the revised guidelines by the European Dermatology Forum in 2020.

GvHD

GvHD can be either acute or chronic based on clinical presentation and time to disease development.¹ Classic acute GvHD (aGvHD) occurs within 100 days of the transplantation with typical features, whereas chronic GvHD (cGvHD) presents after 100 days. However, persistent, recurrent or lateonset aGvHD can occur after 100 days with typical features of aGvHD. If features of both aGvHD and cGvHD are present, it is considered an overlap syndrome.⁷ cGvHD occurs in 30- 50% of patients receiving an allogenic transplant, involves multiple systems and most commonly presents with mucosal, skin, gastrointestinal and liver involvement.² First-line therapy consists of systemic glucocorticosteroids with or without a calcineurin inhibitor. Second-line therapies include ruxolitinib, ECP, mycophenolate mofetil, mTOR inhibitors, methotrexate, calcineurin inhibitor. Second-line therapies include ruxolitinib, ECP, mycophenolate mofetil, mTOR inhibitors, methotrexate, imatinib, ibrutinib and rituximab.² Notably, phase III randomized clinical trials evaluating ruxolitinib versus best available therapy for steroid refractory or dependent cGvHD demonstrated superiority of this drug when compared to ECP and other agents (ORR 50% vs. 26%, p<0.001).⁸ The average response rate to ECP is approximately 60% and studies have shown ORR rates ranging from 36-83%. In addition, CR in the skin, oral disease, and liver ranged from 31-93%, 21-100% and 0-84%, respectively.² Best responses using ECP are seen in skin followed by gastrointestinal and then hepatic GvHD. The EDF recommends considering ECP as an additional secondline therapy in patients with cGvHD that is steroid-dependent, steroid-intolerant, or steroid-resistant, as well as for those with recurrent infections or with a high-risk of relapse (Table 8). Also, steroid-dependent patients (i.e., inability to reduce corticosteroid dose to <0.5 mg/kg/day without recurrence of Grade II or worse cGvHD) could benefit from ECP.

Similarly, systemic glucocorticoids are currently used as firstline therapy for aGvHD.² However, response rates are <50%.² In 2019, the US FDA approved ruxolitinib for steroid-refractory aGVHD in adult and pediatric patients ≥12 years of age. This approval was based on an open-label, single-arm, multicenter study of ruxolitinib that enrolled 49 patients with steroidrefractory aGVHD Grades II-IV occurring after allogeneic hematopoietic stem cell transplantation.⁹ Clinical trials have shown the superiority of ruxolitinib therapy when compared to ECP and other treatments (ORR 62% vs. 39%, p<0.001).¹⁰ In these patients, ECP may serve as an additional second-line treatment with ORR of 65-100% in the skin, 0-100% in the liver, and 40-100% in the gastrointestinal tract.² As such, the EDF recommends adjunct ECP, as second-line therapy, in patients not responding to appropriate doses of systemic corticosteroids (Table 8). Interestingly, it is also showing promising results as a prophylaxis therapy to prevent cGvHD.¹ This treatment option may be considered by dermatologists consulting on these patients in acute setting in the hospital especially at times when the diagnosis is uncertain, as ECP is recognized as not being an immunosuppressive therapy.

SSc

SSc is a multisystemic connective tissue disease characterized by collagen deposits in the skin and other visceral organs.^1,11 Although there are currently no FDA-approved treatments for cutaneous involvement in SSc, limited studies have investigated the use of ECP and have shown promising results.¹¹ For example, one multicenter trial showed that ECP was well-tolerated and improved disease severity, the mean percentage of skin involvement (-7.7% from baseline after 10 months, p=0.01) and the mean oral aperture measurements (+2.1 mm from baseline after 10 months, p=0.02).^11,12 Other studies have shown that ECP leads to improvement in dermal edema and skin elasticity, normalization of collagen synthesis, and improvement of extracutaneous symptoms, and that ECP-treated patients with SSc have a favorable long-term survival.^1,13 Further, one study found that, in most patients, ECP leads to a reduced usage of corticosteroids and other immunosuppressive agents, which have numerous adverse effects.¹⁴ The EDF currently recommends ECP as second-line or adjuvant therapy for SSc, either as monotherapy or in combination with other treatments (Table 8).¹¹

Other Cutaneous Conditions

ECP has been studied in numerous other cutaneous diseases, including atopic dermatitis (AD), immunobullous diseases, eosinophilic fasciitis and others. Although there are many other treatment options for AD, including emollients, topical therapies, phototherapy/photochemotherapy, immunosuppressive medications, targeted therapies¹⁵ and monoclonal antibodies, several small open-label trials have shown that ECP is beneficial in patients with severe AD, including erythrodermic AD, that are not responding to standard therapy. Although previous guidelines have not recommended routinely treating AD with ECP given the lack of consistent findings and the multiple other treatment options available, the EDF’s revised guidelines recommend its use as second-line therapy in patients that meet specific criteria (Table 8).¹¹ However, as new effective treatments are emerging for the treatment of AD, ECP should only be reserved for exceptional patients. Studies have also shown promising results for the use of ECP in pemphigus. One study of 11 patients with severe treatment-resistant pemphigus vulgaris or foliaceus showed an OR rate of 91% and CR rate of 73%.¹¹ As such, the EDF recommends ECP in patients with pemphigus vulgaris or foliaceus that is recalcitrant to conventional first- and second-line therapies.¹¹ Further, the EDF recommends considering ECP for severe epidermolysis bullosa acquisita (EBA) and erosive oral lichen planus that is refractory to conventional topical and/or systemic therapies.¹¹ Low level evidence suggests a possible role for ECP in the treatment of lupus erythematosus, however, further controlled clinical trials are needed to assess its efficacy. For this reason, no official recommendations for the use of ECP in lupus erythematosus have been published to date.¹¹ Studies have also investigated the use of ECP in other cutaneous diseases, including psoriasis, nephrogenic fibrosing dermopathy, morphea and scleromyxedema, however, the results have been inconclusive.¹¹

Pediatric Population

Many studies support the use of ECP in a pediatric population. It has been used as an off-label treatment for various conditions, including aGvHD and cGvHD.¹¹ In this patient population, the ECP protocol is adapted and can vary depending on the patient’s weight. Importantly, very few side effects are reported in this population, which further supports the favorable safety profile of ECP.¹¹

Conclusion

In conclusion, ECP has been used on- and off-label for decades to treat numerous diseases, including SS, CTCL, GvHD, and SSc, among others. Results from multiple studies have shown promising response rates, and ECP has an overall excellent safety profile with very few adverse events reported.^2,11 Unlike many other immunomodulatory therapies, an increased risk of infection has not been observed with ECP, which can be a significant cause of morbidity and mortality for patients on other immunosuppressive therapies.¹¹ Although ECP is still being studied for multiple diseases, in Canada clinicians should restrict its use to the diseases that have been extensively studied, as per the EDF guidelines.

Funding: The genesis of the paper was initiated at a meeting organized by a pharmaceutical company (Mallinckrodt Inc.) and EN, IT, WG, JD, MK, RG, CL and IVL were provided honoraria to attend that meeting. No funding bodies or other organizations had any role in data collection and analysis, decision to publish, or preparation of the manuscript.

Acknowledgment: We thank RBC Consultants for editorial support, facilitating the preparation of tables, and coordinating the review of the manuscript.

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¹Division of Dermatology, McGill University Health Centre, Montréal, QC, Canada
²Division of Allergy and Immunology, McGill University Health Centre, Montréal, QC, Canada
³Division of Infectious Diseases, McGill University Health Centre, Montréal, QC, Canada
⁴Division of Hematology, McGill University Health Centre, Montréal, QC, Canada

Authorship statement:
N. Merati: reviewed literature, prepared the manuscript;
S. Sivachandran: addressed reviewer comments, reviewed literature and co-wrote the paper;
A. Jfri: contributed to the review of literature and preparation of the manuscript;
M. Ben-Shoshan: contributed to the review of literature and preparation of the manuscript;
D. C. Vinh: contributed to the review of literature and preparation of the manuscript;
G. Popradi: contributed to the review of literature and preparation of the manuscript;
I. V. Litvinov: supervised the study, reviewed literature and co-wrote the paper.

Conflict of interest:
The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: None.

Abstract:
Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) is a primary immunodeficiency syndrome. Patients with WHIM syndrome are more susceptible to human papillomavirus (HPV) infections and commonly present to a dermatologist with recalcitrant to treatment warts. Other cardinal features of WHIM syndrome include recurrent sinopulmonary bacterial infections, neutropenia/lymphopenia, low levels of immunoglobulins (IgG, IgA, IgM) and myelokathexis. Research demonstrated that truncating gain-of-function mutations of the C-X-C chemokine receptor type 4 gene (CXCR4) are responsible for this disease. Plerixafor, a specific small molecule antagonist of CXCR4, is currently used for peripheral blood hematopoietic stem cell (HSC) mobilization in stem cell transplant recipients. It has recently shown promise for the treatment of WHIM syndrome in phase I/II clinical trials. In this paper we review the emerging patient clinical data for this medication and highlight the role of CXCR4 in other important skin diseases including keratinocyte carcinomas, psoriasis and cutaneous T-cell lymphoma.

Key Words:
plerixafor, warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome, C-X-C chemokine receptor type 4 (CXCR4), stromal cell-derived factor-1 (SDF-1), CXCL12, recalcitrant warts

Introduction

Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) is a primary immunodeficiency syndrome. As the name suggests, patients with WHIM syndrome are more susceptible to human papillomavirus (HPV),¹ which can cause warts and potentially lead to squamous cell carcinomas; hypogammaglobulinemia; recurrent bacterial infections, such as otitis media, cellulitis, pneumonia and sinusitis; and bone marrow myelokathexis, characterized by a retention and apoptosis of mature neutrophils resulting neutropenia. The laboratory manifestations include severe neutropenia, significant lymphopenia, leukopenia, and monocytopenia.

WHIM syndrome is a rare disease with ~70 cases reported in the medical literature to date.^2,3 In 2003, the cause of WHIM syndrome was traced to a heterozygous, truncating gain-of-function mutations of the C-X-C chemokine receptor type 4 gene (CXCR4) on chromosome 2 (2q22.1), resulting in a hyperactive signalling of this G-protein coupled receptor. While not yet fully deciphered, it is postulated that increased CXCR4 receptor activity upon binding of its cognate stromal cell-derived factor-1 (SDF-1; also known as CXCL12) ligand, prevents the release of mature neutrophils and promotes their apoptosis in the marrow (Figure 1A-B). This cellular mechanism drives myelokathexis that is observed clinically in affected patients. The CXCR4 mutations are inherited in autosomal dominant manner. Some patients with WHIM syndrome, however, do not have a detectable CXCR4 gene mutation, suggesting that mutations in other genes may be involved.

The diagnosis of WHIM syndrome relies on identifying the clinical features, a detailed patient medical history, family history, and genetic testing. In particular, patients with recalcitrant HPV warts and recurrent sinopulmonary bacterial infections should be further evaluated with a complete blood count and differential (to detect neutropenia and lymphopenia), and immunoglobulins (IgG, IgA, IgM) to detect hypogammaglobulinemia. Family history may reveal vertical transmission in autosomal dominant fashion, if more than one generation is affected. A bone marrow biopsy may be performed to detect myelokathexis.

While potential molecular mechanisms have been elucidated, the effectiveness of standard WHIM syndrome therapies is variable and more targeted therapies are urgently needed. Until recently most patients were managed using a combination of granulocyte colony stimulating factor (G-CSF), skin-directed treatments of warts, prophylactic antibiotics, and intravenous gamma globulin (IVIG) therapy.

In 2009, a group of researchers sought to therapeutically target the CXCR4 receptor. Plerixafor, a specific small molecule antagonist of CXCR4 (Figure 1C), was originally licensed by the United States Food and Drug Administration for peripheral blood hematopoietic stem cell (HSC) mobilization in stem cell transplant recipients. Plerixafor (Mozobil^®) has been used in Canada and in the United States since 2012.⁴ Notably, a novel application for this medication has been defined, where McDermott and colleagues conducted a phase I clinical trial (NCT00967785) using plerixafor as a treatment for 20 patients with WHIM syndrome.^3,5-7 They found that 9 patients who received low-dose plerixafor safely mobilized neutrophils and had an improvement in all other leukocyte subsets.^3,5-7 A follow-up study in 3 of the participants demonstrated sustained responses for at least 6 months using a dosage of 0.02-0.04 mg/kg/day subcutaneously with no new warts developing and regression of old warts. In 2014, these promising results led the investigators to conduct a phase III randomized, double-blinded, crossover trial (NCT02231879) to establish safety and efficacy of plerixafor compared to standard G-CSF treatment in patients aged 10-75 years with WHIM syndrome. Nineteen patients were randomized to 1 year of G-CSF and 1 year of plerixafor using a crossover design, allowing direct comparison of infection severity during treatment with both agents. Doses were personalized to each patient’s neutrophil response. Study participants had a clinical diagnosis of WHIM syndrome and were proven to have a heterozygous mutation in the CXRC4 gene.⁸ While the trial is currently ongoing, some early data is beginning to emerge from this group.

During recruitment, McDermott and colleagues identified 3 patients who were ineligible to participate in the larger study as they could not receive G-CSF. The researchers began a concomitant study with these patients, treating them with plerixafor (according to their phase 1 protocol) for 20-50 months. These findings have been published in the New England Journal of Medicine. McDermott et al. reported improvement in all 3 patients’ white cells counts, platelet counts and hemoglobin levels.⁹ In 2 out of 3 patients these results were observed after discontinuing G-CSF, which was deemed ineffective. Bone marrow biopsies revealed marked amelioration of severe pre-treatment myelofibrosis and myelokathexis in 2 of the patients after using plerixafor for 24 and 52 months.⁹ With the adjunct use of imiquimod in 2 of the patients and double HPV vaccination in 1 of the patients, HPV-associated wart burden improved noticeably on the hands, feet and genitals. Mixed results though were obtained with HPV-associated tumors, which were managed with debulking and surgery. Susceptibility to infections and inflammation also differed amongst the patients; however, 1 patient was noted to have a marked reduction in infection frequency compared to his pre-treatment baseline, and a significantly higher quality of life, where he was able to exercise, enjoy the outdoors and work without being fearful of recurrent infections and hospitalizations.

The results of these case studies are exciting and suggest that clinicians and patients with WHIM syndrome might expect favorable clinical outcomes with plerixafor. However, as with any new therapeutic indication, we must await the efficacy and safety results of the phase III trial, especially considering that chronic leukocyte mobilization from bone marrow with plerixafor could result in as of yet undescribed cumulative toxicities.^10,11 It will also be crucial to determine the effect of plerixafor on immune cell function including mitogen induced T-cell proliferation and T-cell dependent humoral immunity.

Also, another phase II/III clinical trial (NCT03005327) is being conducted by researchers in Florida, investigating the use of mavorixafor (X4P-001), a different small molecule targeting hyperactive CXCR4 receptor.¹² Funded by X4 Pharmaceuticals, researchers have demonstrated positive preliminary clinical findings using mavorixafor in a group of 6 WHIM patients, showing increased white cell counts and improved clinical outcomes. Unlike plerixafor, mavorixafor is administered orally.¹³ Additional phase II results published on 8 patients in Blood demonstrated that this medication was well tolerated by patients (with no treatment-related serious adverse events) using a dose of 400 mg daily and led to neutrophil mobilization, reduced infection rates and reduction in the number of warts.¹⁴

Conclusion

Emerging molecular experimental and clinical data suggests that CXCR4 may play an important role in other skin and systemic diseases including mycosis fungoides/Sézary syndrome, neurofibromatosis type 1 tumors, allergic reactions, Waldenström macroglobulinemia, melanoma, non-melanoma skin cancers and other solid tumors (Table 1). Hence, ability to target the CXCR4 may improve our abilities to treat a number of these diseases in the not-too-distant future. In fact, a number of trials using mavorixafor are underway evaluating efficacy in the treatment of Waldenström macroglobulinemia, renal cell carcinoma and other cancers, where CXCR4 inhibitors are actively being evaluated as cancer immunotherapy treatments.^15,16

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