Classical and biological treatments in mycosis fungoides/Sézary syndrome. New horizons in oncodermatology

Topical treatment

For early-stage MF, the principal treatment modality mainly encompasses topical therapies, due to their efficacious outcomes and minimized systemic side effects [5].

Glucocorticosteroids

Topical corticosteroids are frequently employed as an initial treatment strategy. In a study conducted by Zackheim et al. [6], 79 patients with patch or plaque stage MF were treated with topical corticosteroids of class I to III b.i.s. for 3 months. The overall response rate (ORR) was 94% for patients with stage T1 and 82% with stage T2 disease.

Chlormethine gel

An alternative topical therapy is chlormethine gel. In a clinical trial conducted by Lessin et al. [7] evaluating patients with early-stage MF (IA–IIA) a daily monotherapy of 0.02% gel was prescribed for a duration of 12 months. The results indicated an ORR of 58.5% with 13.8% achieving complete remission rate (CRR). Additionally although FDA prescribing guidelines recommend daily application of chlormethine gel, off-label modifications to the dosing schedule and the concomitant use of topical steroids are practiced by experienced clinicians. These adjustments may enhance treatment tolerance by minimizing adverse reactions, particularly during the initial months of therapy [8, 9]. Furthermore, the PROVe (a PROspective, observational study assessing outcomes, adverse events (AEs), treatment patterns, and quality of life (QoL), in patients diagnosed with MF treated with Valchlor and the other therapies) study demonstrated that chlormethine gel is an effective therapeutic option which effectively reduces skin lesion severity and improves QoL in real-world clinical practice [10]. In the PROVe study, 298 patients with MF were monitored. At 12 months, 44.4% (chlormethine + corticosteroids + other) and 45.1% (chlormethine + other) of efficacy-evaluable patients were responders. Peak response was observed at 18 months in the chlormethine + other group.

Bexarotene gel

Another option is the application of bexarotene gel 1%, a derivative of retinoid. In Phase I and II Breneman’s [11] clinical trials evaluating bexarotene gel 1% b.i.s. for 10.5 months for dermal-directed therapy in patients with MF/SS, an ORR of 63% was observed.

Topical Toll-like receptor (TLR) agonists

Additionally, topical Toll-like receptor (TLR) agonists like imiquimod 5% and resiquimod 0.03/0.06% represent a novel class of topical treatments. Imiquimod functions through the activation of TLR7, culminating in the subsequent release of cytokines and elicitation/induction of an inflammatory cascade. In a cohort study, 20 patients at early MF stages were treated with imiquimod 5%, as a result the ORR was 80% and CRR was 45% [12]. Resiquimod exhibits the potential to stimulate systemic cells by activation in circulating dendritic cells (DCs) and natural killer (NK) cells. In a Phase I clinical trial involving 12 patients with stage IA–IIA, 0.03% and 0.06% topical resiquimod gel treatments q.d. for 24 weeks led to ORR of 75% and CRR of 30% [13].

Phototherapy

Phototherapy represents a crucial therapeutic approach that can be employed either as a standalone treatment or in conjunction with topical therapies for patients with limited-stage disease [14]. These methods encompass narrowband ultraviolet B (NBUVB, 311 nm) and the combination of 8-methoxypsoralen or 5-methoxypsoralen plus ultraviolet A (PUVA). NBUVB is administered for early-stage MF and in those cases the CRR was from 90% to 95%. Meanwhile, PUVA therapy is generally preferred for patients with darker skin tones, with thick plaques and those who relapse after initial NBUVB therapy [12]. This treatment involves the administration of a photosensitizing drug metoxalen which, when activated by UVA light, induces changes in the DNA of skin cells to slow their growth. PUVA CRRs were calculated to be 85% for stage IA, 65% for stage IB, and 85% for stage IIA [15].

Methotrexate

A retrospective survey of 48 patients with MF/SS treated with low-dose methotrexate (MTX) and followed for at least 1 year was conducted by Alenezi et al. [16]. The initial weekly dosage of MTX ranged from 10 to 25 mg for 3.5 months. CRR was achieved in 10 (21%) patients and partial response rate (PRR) in 25 (52%) patients. Among the 35 responders, 57% relapsed after a median of 11 months. Methotrexate was discontinued in 44 patients, mainly due to primary or secondary failure and toxicity. Despite these limitations, the benefit/risk ratio of low-dose methotrexate remains favourable even though the study by Abd-el-Baki et al. [17] revealed that the incidence of transformation of MF to large cell lymphoma (LCL) was significantly higher in patients who received MTX compared to those who did not (14.3% vs. 1.8%, p = 0.03).

Extracorporeal photopheresis (ECP)

During ECP, whole blood is collected from a cubital vein or implanted catheter, and leukocytes are separated. The leukocytes, or buffy coat, are then exposed to UVA irradiation in the presence of the photosensitizing agent 8-methoxypsoralen before being reinfused into the patient [18]. In the context of extended observation of MF/SS patients subjected to treated with ECP, CRR was 41% after a median of 19.6 months, meaning 40 ECP treatments/cycles. ECP was administered on 2 consecutive days every 4 weeks until a threshold skin response was observed or after 12 treatments. If needed, ECP could have been accelerated to two treatments every 14 days for up to four cycles, or until a successful response was achieved [19].

Radiotherapy (RT)

MF/SS are radiosensitive diseases, so radiation therapy, administered with a curative intent, is a viable treatment option for patients with localized MF both limited and advanced-stage MF or SS [3].

In a study by O’Malley et al. [20], low-dose radiotherapy (LDRT, 8 Gy) administered to MF patients resulted in clone eradication in 5 of 16 lesions and a > 90% reduction in 11 of 16 lesions, with no recurrences. A retrospective review further showed that early-stage, high-risk MF patients who received radiation had significantly prolonged overall survival compared to those who did not, highlighting the potential benefit of incorporating radiotherapy into treatment regimens for these patients.

Brachytherapy is another treatment option for patients with MF. In a study by Kamieniecka et al. [21], 3D superficial brachytherapy was used to preserve lens function while successfully treating malignant lesions on the left upper eyelid and forehead. The patient received 10 Gy in 5 fractions, with the lens receiving 5 Gy (45–55% isodose range). High-dose-rate brachytherapy using an iridium-192 source and Flexitron afterloading was employed. Regression of the lesions was observed 3 weeks post-treatment.

Total skin electron beam therapy (TSEBT)

In addition to local radiation therapy, low-dose TSEBT treats widespread disease by irradiating the superficial dermis while sparing deeper tissues. Targeted external beam radiation therapy (EBRT) is effective for large plaques or nodules [22]. The current therapeutic inclination favours low-dose TSEBT, typically 10–12 Gy administered across 6–8 fractions. In one observation for 9.6 months the CRR was 92% with mild toxicities [23].

Bexarotene

The oral rexinoid bexarotene, selective to retinoid X receptors (RXR), was approved by the FDA in 1999 for CTCL treatment, and subsequently as a topical gel. In Poland, as part of a drug program, bexarotene is made available to patients with MF and SS in monotherapy. Bexarotene treatment triggers apoptosis in MF/SS cells by downregulating both its receptors and the apoptosis inhibitor surviving. Patients receiving oral doses of 300 mg/m²/day achieved ORR of 45% in 48 weeks [24].

Interferons a and g

Interferons (INF), namely INF α-2b and INF g-1b, manifest pleiotropic and immunomodulatory actions in MF/SS. These multifaceted effects are correlated with ORR ranging from 50% to 70% and CRR falling within the 20% to 30% range for 14.9 months. Such therapeutic efficacy is predominantly observed in patients with limited-stage disease [25, 26]. IFN-α, generated by plasmacytoid dendritic cells (DC), is specifically targeted to counteract various immunological deficiencies inherent in MF/SS, thereby assisting in the enhancement of the anti-tumour response [27]. IFN-γ mechanisms of action are analogous to those of IFN-α, serving to activate CD8+ T lymphocytes and NK cells.

Brentuximab vedotin

The study of brentuximab vedotin vs physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA) validates the therapeutic superiority associated with brentuximab vedotin (BV). Patients received either BV (1.8 mg/kg IV every 3 weeks, up to 16 cycles) or the physician’s choice of MTX (5–50 mg orally weekly) or bexarotene (300 mg/m² orally daily, up to 48 weeks). Within the MF patient population, final data showed that BV significantly outperformed physician’s choice, with an objective response rate at 4 months (ORR4) of 54.7% vs 12.5% and CRR of 17.2% vs 1.6% [28]. In Poland, as part of a drug program, BV is available to patients with MF in monotherapy.

Classical systemic chemotherapy

In MF/SS sustained therapeutic responses to conventional chemotherapeutic regimens remain elusive, with the median interval to subsequent treatment interventions typically demarcated in months [29]. In the pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma (PROPEL) study patients with confirmed CTCL who had progressed after at least one prior therapy received pralatrexate 30 mg/m² weekly for 6 weeks in 7-week cycles. Of the 115 patients enrolled, 111 were treated, and the RR among 109 evaluable patients was 29% (31 of 109), including CR 12 (11%) and 20 PR (18%), with a median duration of 10.1 months [30]. In the study by Fierro et al. [31], 35 patients with MF/SS were treated with 6 cycles of cyclophosphamide, vincristine, and prednisone (COP) or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) at standard doses. The ORR was 40%, with the CRR of 23%.

Gemcitabine, a pyrimidine antimetabolite, has shown to be an effective monotherapy in patients with advanced-stage MF/SS who have undergone extensive prior therapy. In a study by Zinzani et al. [32], 70% of the patients with relapsed MF (21 out of 30) achieved CR or PR. Pegylated liposomal doxorubicin, a liposome-encapsulated form of doxorubicin, allows higher tumour concentrations with improved safety. A prospective multicentre study by Quereux et al. [33] reported 56% RR in MF/SS patients (14/25).

Allogeneic blood stem cell transplantation

Allogeneic blood stem cell transplantation (alloSCT) has shown a strong graft-versus-lymphoma (GvL) effect in MF/SS. In a trial with 80% of around 20 advanced MF/SS patients achieved durable remissions after 3 years following alloSCT [34]. AlloSCT should be considered for patients with advanced disease and poor prognosis, but without comorbidities. Optimal results are achieved with complete or near-complete remission before transplantation [4].

Mogamulizumab

Mogamulizumab (KW-0761) is a defucosylated, humanized monoclonal antibody that selectively targets the C-C chemokine receptor type 4 (CCR4), thereby enhancing antibody-dependent cell-mediated cytotoxicity (ADCC). CCR4, involved in lymphocyte skin trafficking is consistently expressed on tumour cells in T-cell malignancies like CTCL including MF and SS. In the clinical trial called ”Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma“ (MAVORIC), the patients treated with 0.32 mg/kg mogamulizumab for 24 weeks, observed ORR of 50% [35].

The ongoing MAVORIC retrospective study, which is actively enrolling patients, aims to assess real-world outcomes of mogamulizumab treatment in Europe. A post hoc subgroup analysis of ORRs by clinical stage showed higher response rates in advanced stages: 26% in stage III, 36% in stage IV, 16% in stage IIB, and 19% in stages IA/IIA. Compartment-specific ORRs were 42% for skin, 68% for blood, and 17% for lymph nodes [36]. In 2018, the FDA approved mogamulizumab for the treatment of CTCL in patients who have failed at least one prior systemic therapy. In Poland, as part of a drug program, mogamulizumab is also available as monotherapy for patients with MF and SS, when the stage of MF is classified as IB or higher, according to the TNMB staging system (ISCL and EORTC classification), and after the patient had previously undergone at least one line of systemic therapy.

HDAC inhibitors

Vorinostat (suberoylanilide hydroxamic acid, SAHA) and romidepsin (depsipeptide) serve as examples of histone deacetylase (HDAC) inhibitors, specifically targeting and impeding the enzymatic functions of class I and II HDACs. By modulating the deacetylation of histones and non-histone proteins, these inhibitors exert a regulatory influence over gene expression and chromatin structure [37, 38].

In a trial conducted by Olsen et al. [39], a dose of 400 mg q.d. of oral vorinostat was established for 74 MF/SS patients. The observed ORR was 30%, with a median duration of response of 185 days. In two clinical trials, romidepsin was administered as a 4-hour i.v. infusion at a dose of 14 mg/m² on days 1, 8, and 15 of a 4-week cycle. The data revealed the ORR of 38% in patients with advanced-stage disease, with the median duration of response surpassing 12 months.

Ongoing emerging clinical studies highlight the need for novel therapeutic agents and updated treatment standards for patients with MF/SS. These advancements are driven by extensive research into the molecular characteristics, intracellular signalling pathways, and interactions with the tumour microenvironment in MF/SS, which continue to unveil new potential therapeutic targets.

Mogamulizumab and magrolimab

During the development of the study, a phase Ib/II clinical trial (NCT04541017) is being conducted to identify the optimal dose, as well as any potential benefits and/or side effects of administering Hu5F9-G4 (magrolimab) in combination with mogamulizumab for treating patients with stage IB-IV MF or SS that have relapsed or are refractory to treatment. Magrolimab is a monoclonal antibody that blocks CD47, a “don’t-eat-me” signal often overexpressed on cancer cells. By inhibiting CD47, magrolimab promotes macrophage-mediated phagocytosis of tumour cells.

Patients receive either the combination therapy or mogamulizumab alone every 28 days for up to 12 cycles. Follow-up is necessary for up to 2 years after completion of study treatment [40].

Programmed cell death protein 1: pembrolizumab and nivolumab

Immune checkpoint antibodies targeting programmed cell death protein 1 (PD-1) function by engaging inhibitory PD-1 molecules expressed on exhausted T cells. Notably, PD-1 is also expressed on malignant T cells in MF and SS. In a phase II trial, 24 patients with refractory MF/SS were treated with pembrolizumab, an anti-PD-1 monoclonal antibody, at a dose of 2 mg/kg every 3 weeks for up to 24 months. The treatment resulted in the ORR of 38%, with 9 patients responding, including 2 who achieved CRR [41]. Further studies have been conducted with nivolumab, another agent targeting PD-1. A phase I trial consisting of 13 patients with MF revealed the ORR of 15%. There are also case reports signifying a favourable response in refractory SS patients [42]. Current research is exploring the combination of PD-1 inhibitors with other therapeutic agents, such as IFN-γ, in order to ascertain the potential synergistic effects.

Alemtuzumab

Alemtuzumab, denoted as a humanized IgG1 monoclonal antibody, specifically binds to the CD52 antigen, which is ubiquitously present on B-cells, T-cells, and monocytes. A phase II trial assessing 22 patients with advanced-stage MF/SS, indicated the ORR of 55% and CRR of 32%. Alemtuzumab was administered using a rapidly escalating initial dosing regimen, followed by a maintenance dose of 30 mg three times per week for up to 12 weeks [43].

Given the inherent proclivity for infectious adversities, an alternative protocol employing 10 mg maximum per administration of alemtuzumab s.c. was appraised in 14 SS patients. 85.7% (12/14) of patients showed ORR, including 21.4% (3) with CRR [44].

SIRPαFc

CD47, a prevalent glycoprotein, acts to inhibit macrophage phagocytosis through its interaction with the macrophage-bound SIRP-α. It is noteworthy that Sézary cells exhibit an enhanced expression of CD47. Experimental studies (NCT02890368) have introduced a decoy receptor, TTI-621 (secreting CD47 blocker signal regulatory protein a-SIRPαFc), via administration in SS patients, resulting in a significant reduction in circulating Sézary cells. TTI-621 was injected intralesionally in a dose-escalation study (cohorts 1–5: 1 mg, 3 mg, or 10 mg single dose, or three 10 mg doses weekly for 1–2 weeks) and in expansion cohorts (cohorts 6–9: 2-week induction at the maximum tolerated dose, with optional weekly continuation) [45].

Systemic TLR-agonists

In the realm of MF/SS therapeutic investigations, systemic deployment of TLR-agonists has been subjected to limited trials. The utilization of cytosine-guanine oligodeoxynucleotides (CpG-ODN), potent binders of TLR-9, facilitates the activation of plasmacytoid DCs. Within a phase I trial, clinical advanced refractory MF/SS patients were subcutaneously treated with escalating CpG-ODN doses yielded the ORR of 32%. Notably, as the study did not ascend to the maximal tolerable dose threshold, these initial findings suggest a potential therapeutic efficacy and warrant further exploration [46].

NM-IL-12

Interleukin-12 (IL-12), mainly produced by monocytes and dendritic cells (DCs), activates NK cells and CD8+ T cells, promoting IFN-γ secretion. In MF/SS advanced-stage patients, particularly with SS, show marked Th1 immunity deficits, with reduced DCs and lower IFN-γ and IL-12 levels. Given the shift towards Th2 immunity, marked by increased IL-4, IL-13, and IL-5, IL-12’s ability to suppress T2 cytokine secretion in SS patients holds important scientific relevance [47]. Initial findings suggest that NM-IL-12 can be safely co-administered with low-dose TSEBT (12 Gy, 1 Gy per fraction over 3 weeks) in MF/SS patients. The ORR was 88% (29/33), with 9 CRR. Median time to response was 7.6 weeks [48].

Cobomarsen (MRG-106)

Imbalance of miRNA propels MF/SS, with heightened oncogenic miR-155 driving abnormal proliferation. Unravelling its gene interactions could refine therapies, restoring miRNA balance for effective CTCL intervention [49]. Cobomarsen (MRG-106), an oligonucleotide miR-155 inhibitor, underwent phase I for MF/SS. Involving 24 patients, MRG-106 was administered via subcutaneous/IV injection (300–900 mg/dose, weekly/biweekly) and intralesional injection (75 mg/dose). Positive outcomes were seen in 95% of subjects, improving lesions and skin via mSWAT scores [50]. Post-treatment MRG-106 reduced T cell clonality, and 50% of patients showed a 50% mSWAT reduction, especially after multiple cycles [51].

Enhanced KIR3DL

IPH4102 represents a novel monoclonal antibody that selectively targets killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2), a cell surface protein with notable expression in MF/SS, particularly in SS, effectively eliminating these cells through antibody-dependent cell cytotoxicity. In the context of a phase I trial targeting relapsed MF/SS, 44 patients were administered IPH4102, with no instances of dose-limiting toxicity observed. The agent’s favourable tolerance profile yielded a noteworthy ORR in 16 out of 44 patients [52]. Presently, ongoing multicohort phase II trials are underway to further show IPH4102’s therapeutic prospects.

PI3K, SYK/JAK inhibitors

Phosphatidylinositol 3-kinase (PI3K) orchestrates downstream oncogenic pathways. Its δ and γ isoforms, prominent in hematopoietic cells, offer targets for MF/SS. Tenalisib (RP6530), a pioneering dual PI3K δ/γ inhibitor at doses of 200–800 mg b.i.d. p.o. in 28-day cycles. Among 35 evaluable patients, the ORR was 45.7% (3 CRR, 13 PRR), with a median response duration of 4.9 months. Responding tumours showed reduced levels of CD30, IL-31, and IL-32a. A phase I/II combination study with romidepsin is currently ongoing [53]. Critical in MF/SS are the SYK and JAK pathways. A phase IIa study assessed cerdulatinib, a reversible ATP competitive inhibitor of SYK/JAK. Administered at 30 mg b.i.d., cerdulatinib yielded the ORR of 35%, diverging between MF (45%) and SS (17%) [54]. Cerdulatinib exhibited notable clinical efficacy and a favourable safety profile, warranting further exploration in ongoing trials.

BNZ-1

BNZ-1, a pegylated peptide antagonist, selectively engages the shared g-chain signalling receptor of interleukin-2 (IL-2), IL-9, and IL-15 cytokines. This interaction culminates in the disruption of downstream signalling cascades activated by these cytokines, yielding potential therapeutic implications for MF/SS patients. In a clinical trial, individuals with refractory MF/SS were subjected to weekly i.v. administrations of BNZ-1 at varied doses (0.5/1/2/4 mg/kg). Clinical responses were 1 CRR and 11 ORR (58%). Importantly, BNZ-1 exhibited favourable tolerability, underscoring its prospective utility as an innovative therapeutic approach for MF/SS management [55].