Transitioning to Pegylated Interferon for the Treatment of Cutaneous T-Cell Lymphoma: Meeting the Challenge of Therapy Discontinuation and a Proposed Algorithm

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Introduction
Cutaneous T-cell lymphomas (CTCLs) are a group of non-Hodgkin's lymphomas that arise in the skin and are of T cell origin [1].Te most recognized subtypes of CTCL include mycosis fungoides (MF) and Sezary syndrome (SS).MF is an indolent lymphoma of mature T cells that primarily afects the skin and makes up 60% of cases of CTCL.Te clinical course often begins with patches that progress to plaques and eventually tumors over the course of years in a subset of patients [1].SS, in comparison, is a leukemic form of CTCL that arises from thymic memory T cells and manifests with signifcant blood involvement, pruritic erythroderma, and generalized lymphadenopathy.SS accounts for 2% of all CTCL cases [1].Te incidence of CTCL in the US between 1973 and 2002 has been 6.4-9.6/100,000 and is most prevalent in patients between the ages of 55 and 60, with a higher incidence in men than women [2].
Interferon (IFN) gained traction as a treatment modality for CTCL in 1984 and has since been integrated into CTCL guidelines internationally (Figure 1) [3][4][5].Interferon is a naturally occurring cytokine that functions as part of the innate immune response to interfering with viral replication in addition to cytostatic and immunomodulating roles [6][7][8].Recombinant interferons have been manufactured in three forms: α-2a, α-2b, and c.IFN-α2a and -α2b have been studied more extensively for the management of CTCL than IFN-c, with the diference between the two forms being a single amino acid that results from purifcation [8].Te immunomodulatory efects of IFN-α are benefcial in combatting immune dysfunction in CTCL by activating CD8+ T cells and natural killer cells to suppress an increase in T2 activity that is typically mediated by malignant T cells in MF/SS [8].Furthermore, IFN augments cytotoxic efects by increasing MHC class I molecules on lymphocytes and inhibits excess production of interleukin-5 and, subsequently, the proliferation of eosinophils (peripheral eosinophilia is associated with worse prognosis in the context of MF/SS) [8].
IFN-α is traditionally administered as a subcutaneous injection three times weekly at a dose of 3-6 million units (MU); however, a large range of dosing regimens have been reported in the literature for treatment of MF and SS [15][16][17][18][19].In clinical use, lower doses at initiation ranging from 1 to 2 MU are useful to improve tolerance, particularly in individuals who are elderly or frail.Doses can be escalated gradually every four to twelve weeks as tolerated, as a full dose is more efective in achieving complete remission [20].Acute side efects associated with IFN-α include fu-like symptoms such as fever, fatigue, chills, myalgias, arthralgias, and headaches.Adverse events associated with IFN-α are dose-related and often decline in severity over time.Other acute side efects include dose-related cytopenias.Chronic side efects include fatigue, decreased appetite, and weight loss [8].Less common side efects include depressed mood and increased irritability, impaired cognitive function (more signifcant in the elderly population), cardiac arrhythmias, hypothyroidism and thyroiditis, altered taste, diarrhea, elevated liver enzymes, and rarely sensory disturbances.Interferon should be used with caution in individuals with preexisting autoimmune disorders and CD8+ cytotoxic T-cell lymphomas, as it may fare the underlying disorder [20].
In Calgary, IFN-α-2b subcutaneous (SC) injection was the standard of care for patients with mycosis fungoides and Sezary syndrome.However, IFN-α-2b was subject to product discontinuation by Merck citing "business reasons" in 2019 [12][13][14].Tis sudden discontinuation highlights the fragility of treatment plans in the face of rare diseases like CTCL.As a consequence of IFN-α-2b discontinuation, patients treated with SC IFN-α-2b were transitioned to a pegylated IFN-α-2a formulation.Polyethylene glycol (PEG) as a drug adjuvant is well-established as it is an inert, water-soluble, and nontoxic modifcation that prolongs the clearance of proteins [21].Te addition of PEG to drugs such as IFN allows for the prolongation of serum half-life, such that dosing can be reduced to once weekly rather than three times weekly [22].Pegylation ofers the theoretical advantages of improved pharmacologic activity, prolonged half-life, improved safety and tolerability, increased patient adherence due to reduced toxicity, protection against enzymatic breakdown, improved solubility, and enhanced potency [21,23].Tese advantages, however, have not always been demonstrated clinically [24].
Te current report will detail the experience with a series of eight patients for which the initiation of pegylated interferon (PEG-IFN) in place of IFN-α-2b was carried out from February to July 2021 due to product discontinuation.Additionally, a proposed management algorithm is presented.Tere are few publications assessing treatment outcomes with pegylated interferon in the forms of case reports and clinical trials [24][25][26][27][28][29][30][31][32]; therefore, a review of the literature assessing the efcacy of PEG-IFN for treatment of CTCL will be presented and discussed.

Audit Program Database.
Patients in the Calgary Cutaneous Lymphoma Program actively treated with IFN-α-2b were identifed from the program database, and records were obtained from their charts by LS and JH.

Treatment Algorithm and Management Protocol.
All patients receiving IFN-α-2b were transitioned to 90 ug/week of pegylated interferon [33].Patients were monitored for constitutional symptoms, including fatigue, chills, weight loss, and fever, in addition to any fu-like symptoms and mood changes.Complete blood counts, thyroid hormone levels, and liver enzymes (ALT, AST) were monitored to assess for thyroid or liver toxicity in addition to cytopenias and myelosuppression [33,34].A treatment algorithm is shown in Figure 2.

Response to Date.
Treatment response was monitored by the modifed severity-weighted assessment tool (mSWAT) and the SkinDex-29 survey.[35,36] Time-to-next-treatment (TTNT) was calculated as the duration between the initiation of one treatment and the next line therapy [37].
2.4.Literature Review.On January 6 th 2022, a search of Medline, EMBASE, and PubMed was conducted for publications referring to the treatment of cutaneous T-cell lymphoma (CTCL) with pegylated interferon using the search terms: (T-cell lymphoma OR T-cell lymphoma with an adjacency of 5 cutaneous OR mycosis fungoides OR Sezary syndrome) AND (pegylated interferon OR PEG-IFN OR Pegasys OR PegIntron).A total of 56 publications were retrieved from the EMBASE database, 5 publications were retrieved from PubMed, and 12 publications were retrieved from Ovid MEDLINE, which included ahead of print, inprocess, in-data-review, and other nonindexed citations.Publications were included in the literature review if they met the following criteria: (i) referred to cutaneous T-cell lymphoma in the title or abstract and (ii) referred to the use of pegylated interferon for the treatment of CTCL upon fulltext review.Review papers were excluded.Furthermore, while conducting full-text reviews, reference sections were searched to ensure all relevant literature were included.Publications were fltered based on language to include literature written in English.No other limits were imposed on the search strategy.A single reviewer independently reviewed the literature and extracted the relevant data from each publication (SO).A total of 9 publications were chosen for inclusion in the literature review according to the inclusion and exclusion criteria detailed above.One study used pegylated interferon in addition to an intralesional biologic, however, which was not included in the analysis as data from the pegylated interferon cohort were not separated from the cohort that received an intralesional biologic alone [38].Results of each publication are specifed in Table 1.An example of the search strategy employed for MEDLINE is demonstrated in the Appendix.

Dermatologic Terapy
All eight patients were initiated on a once weekly subcutaneous injection of 90 ug (0.5 mL) PEG-IFN, with the exception of one (patient 8), who was initiated on 45 ug (0.25 mL) weekly.Tis was due to the absence of a specifc dosing algorithm at the time.Tere were 4 males and 4 females included in the study.All the included patients were Caucasian.Te median age of patients in the cohort was 68, ranging from 50 to 86.All patients had histologically confrmed CTCL ranging from stages IIB to IVB [1], with one patient demonstrating the folliculotropic subtype of MF and three patients having large cell transformation (LCT) on histopathology (Table 2).
After initiation of PEG-IFN treatment, one patient (patient 7) met the Grade II criteria for anemia and subsequently received a dose reduction to 45 ug weekly (0.25 mL).A second patient (patient 3) experienced mood side efects and received a dose reduction to 70 ug (0.4 mL) weekly.All other patients had normal blood counts and thyroid and liver function tests throughout the duration of treatment and had no additional side efects upon switching to PEG-IFN.Two patients were being treated for SS, while six patients were being treated for MF.Tree of the six patients with MF had large cell transformation, and a single patient had folliculotropic MF.Te stages of CTCL in the presented cohort ranged from IIB to IVB.Almost all patients except one were being treated with concurrent therapies including extracorporeal photopheresis (ECP), UVB phototherapy, topical carmustine 0.4% ointment, acitretin, imiquimod (3.75%), topical corticosteroids (5%), and systemic retinoids during both interferon and pegylated interferon treatment.Mogamulizumab was initiated as the next line of treatment in two patients, a decision that had been made prior to the initiation of pegylated interferon.In these cases, the switch to pegylated interferon was simply a bridging therapy between interferon and mogamulizumab.Te time on pegylated interferon for patients 1 and 2 switched to mogamulizumab was 24 and 37 days, respectively.Patient 5 was similarly planned to initiate romidepsin under the same circumstances, with pegylated interferon as a bridging therapy for 4 months before romidepsin initiation.Patient 6 was initiated on total skin electron beam (TSEB) therapy in addition to pegylated interferon after 36 days on pegylated interferon alone.Clinical images prior to switching to pegylated interferon and after the switch are shown in Figures 3 and 4. We see that in Figure 3, the patient (patient 3) had relatively stable disease after initiation of PEG-IFN.Tis patient was further treated with home phototherapy, topical carmustine 0.4%, and topical tazarotene.Interestingly, this was a patient in whom the dose of pegylated interferon was stepped down due to adverse efects, and his subsequent mSWAT and SkinDex-29 scores were worse.Te patient in Figure 4 (patient 4) had some improvement in disease with pegylated interferon, in addition to topical imiquimod 3.75% and oral acitretin.Terapies trialed prior to interferon are shown in Table 3.

Literature Review.
A total of 66 cases of CTCL treated with pegylated interferon were included in the literature review through case series, case reports, and retrospective cohort studies (Table 1).Pegylated interferon was not often administered as monotherapy but rather was combined with phototherapy, psoralen plus ultraviolet-A radiation (PUVA), systemic retinoids, methotrexate, topical therapies (clobetasol, chlormethine gel, topical chemotherapy agents), and ribavirin (Table 1).Pegylated interferon has been reported for the treatment of Stage IA to IV CTCL.Te most common starting doses of pegylated interferon reported were a combination of either weight-adjusted dosing of 1.5 μg/kg/week or a fat dose of 180 μg/week.Reasons for discontinuation of pegylated interferon included disease progression, heart failure, cytopenias, toxicity, mood changes, exacerbation of other skin diseases, and hepatotoxicity.Te most common adverse efects experienced with pegylated interferon were constitutional symptoms, hematologic abnormalities/cytopenias, liver toxicity, GI symptoms, and neuropsychiatric symptoms.

Discussion
Given the heterogeneity of the patients in the present cohort with respect to prior therapies, duration of interferon, duration of pegylated interferon, and concurrent therapies administered, it is difcult to ascertain the extent of CTCL response to the switch from interferon to pegylated interferon.However, we aim to outline our single-center experience with the product discontinuation of interferon and the impact on treatment.Of the eight patients that were switched to pegylated interferon after having been initiated on interferon due to product discontinuation, three patients were switched to a previously planned alternative line of treatment and fve continued on pegylated interferon with no additional side efects than those initially experienced with the nonpegylated form.Interestingly, four of the eight patients had been on interferon as a prior therapy (Table 3) and then subsequently were reinitiated on interferon later on in their disease course.Interferon is unique in which it can be trialed multiple times, and failing treatment once is not a contraindication to initiating it again later in the disease course.One patient who continued on pegylated interferon had total skin electron beam therapy (TSEB) added.Te dose of pegylated interferon administered was 90 ug/week, which perhaps falls in the subtherapeutic dosing range when compared to the literature, and it would be reasonable to increase the dosing if tolerated by the patient.It would further be reasonable to suggest premedication with analgesics/antipyretics to mitigate fu-like symptoms that can be associated with interferon when initiating a switch to pegylated interferon.Once weekly dosing regimen with pegylated interferon is more convenient for administration compared to the thrice weekly regimen required for interferon.We have demonstrated a starting point for switching patients to pegylated interferon in light of the discontinuation of interferon-α2b and interferon-α2a.

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Dermatologic Terapy  Prior to Switch to PEG-IFN  Pegylation of pharmacologic agents has been cited as ofering theoretical advantages of improved pharmacologic activity, prolonged half-life, improved safety and tolerability, increased patient adherence due to reduced toxicity, protection against enzymatic breakdown, improved solubility, and enhanced potency compared to their nonpegylated counterparts [21,23].Tere are no studies directly comparing PEG-IFN-α to IFN-α alone in the context of CTCL to highlight these advantages; however, a retrospective study by Hüsken et al. compared PEG-IFNα-2b in conjunction with psoralen PUVA to standard IFN-α-2a plus PUVA in patients with CTCL [24].Tis study found that ultimately, overall response to treatment (complete and partial remission) was higher in the PEG-IFN arm; however, there was a higher incidence of liver toxicity and myelosuppression, which contradicts the theoretical advantage of reduced toxicity with pegylation.With that said, the PEG-IFN group had a lower rate of constitutional side efects and a higher 5-year relapse-free survival rate (75%) compared to the standard IFN group (50%) [24].
Other studies comparing PEG-IFN and IFN-α alone have been done in the context of high-risk melanoma.A multi-center prospective randomized phase III trial done by Eigentler et al. compared overall survival, distant metastasisfree survival, and disease-free survival associated with the use of PEG-IFN-α compared to IFN-α in patients with resected cutaneous melanoma (stages IIA-IIIB) [40].Te major fndings included no signifcant diferences in distant metastasis-free survival, disease-free survival, or overall survival between the two interventions.Te PEG-IFNα arm of the study had higher rates of leukopenia and elevation of liver enzymes, while quality of life (QoL) assessment was identical between the two groups across all domains (QoL assessment was done through SF-36 questionnaires at regular intervals over 24 months).Ultimately, it was concluded that PEG-IFN-α, despite the once weekly dosing, did not improve outcomes compared to IFN-α three times weekly, and a higher proportion of patients on PEG-IFN discontinued treatment due to toxicity [40].Further work by Grob et al. compared PEG-IFN-α2b and IFN-α2b in the context of patients with melanoma and macrometastatic nodes.It was similarly found that there were no diferences in outcomes between the interventions, with a higher risk of adverse events and discontinuation of treatment reported in the PEG-IFN-α2b arm [41].
Rare diseases like MF and SS are at risk of abrupt product discontinuation, requiring a change in treatment planning.We have demonstrated a management algorithm for patients with CTCL who have been afected by the business decision of Merck to discontinue interferon production, involving a switch to the pegylated form.Pegylated interferon has been shown in the limited literature to be at least as good as or better than its standard counterpart; however, a potential limitation is that pegylated interferon is more expensive than its nonpegylated counterpart, which may preclude use in certain regions.Another limitation of the present analysis is the fact that all patients who transitioned to pegylated interferon were Caucasian, therefore making it difcult to ascertain the efects of race and ethnicity.Te management algorithm demonstrated here uses a lower dose of pegylated interferon than previously described in order to mitigate adverse events and discontinuation, and it is up to the clinician's discretion to use higher doses as have been reported in the literature (Table 1) and, if tolerated, increase dosing over time.Pegylated interferon can be used in combination with a variety of systemic treatments and modalities in addition to topical therapies, making it a versatile option for patients with CTCL (Tables 1 and 2).

Figure 3 :
Figure 3: Clinical images from patient 3, prior to initiation of pegylated interferon (a) and after the switch (b).

Figure 4 :
Figure 4: Clinical images from patient 4, prior to initiation of pegylated interferon (a) and after the switch (b).

Table 1 :
Summary of literature review of PEG-IFN treatment in CTCL.

Table 2 :
Patient demographics, clinical features, and outcomes.

Table 3 :
Prior therapies to interferon that were trialed in the presented cohort of patients.