MF and SS comprise a group of disorders that fall under the World Health Organization-European Organization for Research and Treatment of Cancer (WHO‑EORTC) classification of cutaneous lymphomas.¹ Cutaneous lymphomas include not only MF/SS, but also the primary cutaneous CD30⁺ lymphoproliferative disorders, the subcutaneous panniculitic‑like T‑cell lymphomas, NK/T‑cell lymphoma of the skin, primary cutaneous peripheral T‑cell lymphoma unspecified, and cutaneous gamma/delta T‑cell lymphoma (a provisional diagnosis).

MF/SS is a rare disease, with the incidence of MF in the United States, according to the National Institutes of Health, at 3.6 cases per million people per year, and SS a small fraction of that.²

CTCL can present with a myriad of clinical manifestations.³ It is characterized based on its manifestation in skin and is classified as T1-T4. Examples of each classification are shown in the slide.

• T1 skin disease includes either patches or plaques involving < 10% of the skin surface area.
• T2 includes patches or plaques involving ≥ 10% of the skin surface.
  • Patches and plaques may appear as psoriasiform lesions and may be hyper- or hypopigmented.
• T3 includes cutaneous tumors (≥ 1 tumor).
  • Tumors may appear as single small lesions or large ulcerating lesions.
• T4 is generalized erythroderma.
  • Erythroderma may involve multiple body areas or the entire skin surface area. Often, patients with erythroderma have flaking of the skin or exfoliation and thickening of the skin on the palms and the soles.

This slide also shows the characteristic skin biopsy of MF. Typically, one finds malignant T-cells within the epidermis of the skin in round aggregates called Pautrier microabcesses. These malignant cells can penetrate into the dermis as well.

The Sézary cell shown on the slide has is a T lymphocyte with a hyperconvoluted nucleus. These cells are circulating but may also be found in lymph nodes and other tissues.

The 10-year survival of patients with T1 skin disease is similar to that for the general population. The survival rate relative to the general population tends to decrease with the severity of disease: For those with more extensive patch and plaque disease (T2), the relative10-year survival rate is 67%; and for those with T3 disease, it decreases to 39%. Patents with T4 disease have a survival rate of 41% compared with the general population.

This slide outlines the staging system for cutaneous T‑cell lymphoma based on disease site: skin (T), nodule (N), visceral (M), and blood (B) (TNMB).^4-6 We have already discussed staging based on cutaneous measures. Nodal and visceral involvement is staged similarly to other cancers; that method is outlined on this slide. Staging for cutaneous T‑cell lymphomas also takes into account blood involvement as a separate parameter.

Blood involvement is the absolute number of circulating atypical cells or the percentage of peripheral blood lymphocytes that are atypical. As with the TNM classification, disease severity increases as the classification increases:

• B0: No significant blood involvement.
• B1: Blood involvement < 1000 malignant tumor cells per microliter.
• B2: Extensive blood involvement > 1000 malignant tumor cells per microliter of blood; these cells are typically CD4⁺ and CD26^-.

Combining the disease severity in all compartments provides the overall staging score for patients.⁴ Patients with stage IA or IB disease have only skin involvement, with patches, papules, or plaques (IA, < 10%, IB, ≥ 10%) and no lymph node involvement, no visceral disease, and no or limited blood involvement, up to level B1.

Stage IIA is similar to stage I, except with nodal involvement. Stage IIB is tumor-stage disease, with ≥ 1 tumors that are ≥ 1 cm diameter; nodal, visceral, and blood involvement is similar to stage IIA.

Stage III is erythrodermic disease and is defined by a confluence of erythroderma covering more than 80% of the body surface. Without blood involvement, this would be stage IIIA disease. If there is blood involvement in the setting of erythroderma, the disease is categorized as stage IIIB.

Stage IV disease has either extensive lymph node involvement or visceral disease. Stage IVA₁ disease is associated with extensive blood involvement but limited lymph node involvement. Stage IVA₂ disease is associated with more extensive lymph node involvement; stage IVB disease also includes visceral involvement.

Outcomes for advanced‑stage MF and SS depend on a number of factors.⁷ The data in this slide are based on an international retrospective review of patient survival with MF and SS. OS based on clinical stage is shown in the left graph. As expected, patients with stage IV disease showed a lower OS than those with stage III or IIB disease.

OS by risk group is shown on the right. The prognostic factors associated with poor OS include advanced‑stage disease, elevated LDH, aged older than 60 years, and the presence of large‑cell transformation (LCT) in the skin. The OS was dependent on the total number of risk factors: Patients with 0 or 1 risk factor had a significantly higher 5-year predicted OS—67.8%—than those with more risk factors. Patients with > 1 risk factor had worse outcomes: Intermediate-risk patients (2 variables) had a 5-year OS of 43.5%, and high-risk patients (3-4 variables) had an OS of 27.6% (P low vs high risk < .001). It is important to note that these factors are easy for us to employ in our clinical assessment of the patient, so this model is very useful.

This slide describes the landscape of the treatment of CTCL.⁸ MF is an immunologically responsive disease, and patients often receive multiple therapies over the course of their lifetime. Although the FDA has approved multiple agents, there remains an unmet need for additional therapies, because many patients progress beyond available treatments.

Unlike other cancers, stable disease in MF and SS is a meaningful endpoint, because many of our patients are symptomatic from itching and poor skin integument, frequent infections (including systemic infections and fever and chills), and cosmetic issues. If we can achieve stable disease with a therapy, then that will have a significant positive impact for the patient’s quality of life.

Infections are a major cause of morbidity and mortality in these patients, not only because of poor skin integument but also because of the immunosuppressive effect of both the underlying disease and various systemic therapies.

Most of our patients with CTCL will experience progression of their disease over time. The graph on this slide demonstrates that very early-stage patients have an approximately 20% risk of progression, whereas patients who have more advanced (T3 or T4) disease almost uniformly undergo stagewise progression of their disease over time.

With the next several slides, I describe the clinical skin presentations in the individual stages of CTCL.

Patch/plaque disease, which is associated with stage IA, IB, and IIA, can have a number of different clinical manifestations.^9,10 Patches are generally flat lesions, whereas plaques are raised or scaling. Some of these can be mistaken for a drug rash, contact dermatitis, or psoriasis. The skin lesions may be hyper- or hypopigmented, or they may be erythematous. The distribution of these lesions is not random, in that many patients exhibit disease in non−sun‑exposed areas of their trunk.¹¹ As the disease progresses, however, it may involve other areas that are sun-exposed.

Many of our patients will have received topical steroids before being referred for evaluation—it is important to remember that a diagnostic biopsy should be done when the patient is not receiving topical steroids, if possible.¹² The differential diagnosis for these rashes is broad, and because of this, many of our patients have been misdiagnosed—some for years—before they were presented for a diagnostic skin biopsy.

It is important to quantitate the degree of involvement of the skin as < 10% or ≥ 10% of the body surface area.¹³ At my institution, we generally use the palm of the hand to estimate 1%; this allows us to quickly obtain a gross estimate of the total skin involvement of the patient.

Tumor‑stage disease T3, which is associated with stage IIB, is manifested by ≥ 1 nodular lesions, each > 1 cm.⁹ These lesions may ulcerate; if one does a biopsy on one of these lesions, it is important to sample an area that is not ulcerative to avoid necrotic cells, which will not give accurate representation of the disease.

In tumor‑stage disease, one looks for the presence of large atypical convoluted cells in the biopsy in order to make a diagnosis of LCT.

One should also perform a histopathologic analysis and clonality studies of both T-cells and B-cells to differentiate between CTCLs and cutaneous B‑cell lymphomas.

The differential diagnosis is broad for cutaneous tumors, including pseudolymphomas of B-cells, various kinds of T‑cell lymphomas involving the skin, and lymphocytoma cutis in patients who have acute lymphocytic leukemia. In addition, metastatic tumors from other cancers can also be present in the skin.

This slide shows tissue from a skin biopsy from a patient with tumor‑stage MF. Extensive involvement of the deep dermis with these infiltrating malignant T-cells is evident.

Erythrodermic disease (T4) is characterized by involvement of ≥ 80% of the body surface area with diffuse erythema and is indicative of stage III CTCL.^9,14 Lesions may be either flat or raised, and they may present with scaling or exfoliation of the skin. Patients with erythrodermic disease may have hair loss in affected areas and characteristic hyperkeratosis on their palms and the soles of their feet.

A diagnosis of SS—an aggressive variant of erythrodermic disease—can be very difficult to confirm by skin biopsy alone. As noted previously, patients referred for evaluation may be using topical steroids that can affect the infiltrate in the skin, and the biopsy may not be accurate. Patients may require multiple samplings before a diagnostic biopsy is obtained. Immunophenotyping of the lesion is important to determine whether there are clonal T‑cell receptor rearrangements in these patients. Atopic dermatitis and psoriasis can present with similar clinical findings.

SS is a systemic disease characterized not only by erythroderma on the skin but also by circulating neoplastic cells, as demonstrated on this slide.¹⁵ These Sézary cells typically are larger than normal lymphocytes and have a hyperconvoluted or flowerlike nucleus. Patients may present with exfoliative erythroderma, loss of hair, extensive itching, and thickening of the palms and soles. There is a high incidence of infection with SS due to the extent of skin involvement and skin cracking and fissuring.

Sézary cells are circulating atypical lymphocytes that are typically CD4⁺ helper T-cells that often express CD5 and may lose other antigens, such as CD7. These cells should be evaluated for markers such as CD2, CD25,CD30, CD45, CD52, and CD158.

The International Society for Cutaneous Lymphoma (ISCL)–recommended staging evaluation for CTCL is shown on this slide.⁴

Patients should undergo a physical examination to determine the presence of enlarged peripheral lymph nodes (> 1.5 cm) and/or organ involvement, as well as CT or PET scans of the chest, abdomen, pelvis, and neck. Patients who have limited stage IA disease with no palpable lymph nodes should have an initial CT scan to determine whether they also have systemic involvement.

If a patient has any lymph nodes > 1.5 cm, a biopsy is recommended if the node is peripheral and accessible. Excisional biopsy is preferred over core needle biopsy; fine needle aspiration is not recommended.

Immunophenotyping of sample cells should be extensive to rule out other types of lymphoma. It should include T-cell markers such as CD2, CD3, CD4, CD5, CD7, and CD8, as well as B‑cell markers such as CD20, CD26, and CD30. Molecular genetics studies should be performed, including an analysis of T‑cell receptor rearrangement or, in patients with circulating Sézary cells, V-beta by flow cytometry.

Bone marrow biopsy is not routinely recommended for patients with MF, except for patients who have extensive blood involvement (B2) or patients who have underlying hematologic abnormalities that might suggest a secondary process, such as myelodysplastic syndrome.

Let’s discuss a few cases. The first is a typical patient with tumor‑stage MF. DT is a 67‑year‑old man who presented with extensive infiltrated plaques. He was initially diagnosed with psoriasis and treated with topical steroids and ultraviolet B-light therapy, with some response. Over the following 2 years, his lesions progressed and he rapidly developed several cutaneous tumors, some ulcerating, as shown in the slide.

The patient underwent a tumor biopsy. As shown on this slide, the biopsy revealed extensive tumor‑stage MF with epidermotropism and deep dermal infiltration. An immunophenotypic analysis of the tumor showed that the malignant cells were CD4⁺, CD7^-, and CD26^-, and 20% of the tumor cells staining positive for CD30. Flow cytometry of the peripheral blood showed no evidence of circulating cells. T‑cell receptor rearrangement in the skin showed a dominant clone. LDH was elevated at 430 U/L. The PET scan showed an uptake with SUVs ranging from 5-7 in axillary and inguinal nodes and in skin lesions.

Before discussing treatment options for this patient, I’d like to present another case scenario illustrating some of the diversity of presentation in MF/SS.

Our second patient is an 85‑year‑old woman who presented with a skin rash and pruritus that had lasted for 4 months. On examination, she was found to have erythroderma involving nearly 100% of her body surface area, with mild exfoliation of the skin over the trunk and extremities and fissures on the palms and soles, as shown in the slide. She reported that she felt “cold all the time” but had had no fever. She was using topical steroids, with no relief; itching related to the rash was preventing her from sleeping.

A skin biopsy of this patient showed epidermotropism with extensive involvement of the skin and a deep dermal infiltrate, both of which suggested MF. The complete blood count showed a white cell count of 4.9 x 10⁹/L, and flow cytometry showed that 18% of the lymphocytes were CD2⁺, CD4⁺, CD5⁺, and CD7^-, all of which is consistent with SS. A molecular analysis revealed T‑cell receptor rearrangements. The CT scan showed axillary and inguinal adenopathy with nodes measuring ≤ 2 cm. The blood smear seen in this slide shows large, atypical cells with hyperconvoluted nuclei.

These 2 patients have clearly different manifestations of the disease. What is the therapeutic algorithm for each of these patients?

We should start by discussing skin‑directed therapies.^9,16 All of our patients, regardless of the stage of their disease, have skin manifestations requiring palliation. Almost all will receive 1 or more of these skin‑directed therapies.

These therapies include topical steroids, topical retinoids, local radiation to the skin, and various forms of phototherapy. Other agents that may be considered include mechlorethamine (topical nitrogen mustard), topical imiquimod, or topical carmustine, although these are used less frequently. In addition, patients may receive a combinations of topical therapies with ultraviolet light or, in some cases, total skin electron beam therapy.

We may start with single‑modality therapy, but we can also employ combination therapies.^9,16 Many of the combinations that we use are shown in this slide.

We often combine a skin‑directed therapy with a systemic therapy using agents such as interferon or oral retinoids combined with phototherapy or with EBT.

We may use photopheresis for patients—particularly those with erythroderma—and we may combine photopheresis with interferon, retinoids, or a combination of both interferon and retinoids. We try to exploit these biologic therapies early in the course of our treatment of these patients, because MF is a biologically responsive disease. Many of these therapies are not immunosuppressive and have the dual benefit of clearing the skin and preserving the patient’s immune system.

We should consider systemic options when patients move beyond topical modalities and have more advanced disease.^9,16-18 For example, patients with extensive patch/plaque disease that does not respond to topical modalities often need to move on to systemic therapies. Systemic options are also important for patients with tumor‑stage disease and for patients with erythroderma and SS who have not achieved stable disease or remission with the various topical and biologic modalities.

Systemic therapies based on the level of evidence are shown here. They include: brentuximab vedotin, which targets the CD30 receptor; bexarotene, which targets the retinoid X receptor (RXR); photopheresis; interferons alpha and gamma; methotrexate, either orally or subcutaneously administered; mogamulizumab, an agent that targets the chemokine receptor CCR4; and romidepsin or vorinostat, both of which are histone deacetylase inhibitors.

Patients who experience LCT may be candidates for a more aggressive approach, which also includes brentuximab vedotin, as well as gemcitabine; liposomal doxorubicin; pralatrexate (a methotrexate analogue); and/or romidepsin.

In many patients, the disease progresses beyond the efficacy of first-line and second-line therapies and requires other treatments. Systemic therapies for relapsed/refractory disease include agents that we use with other hematologic malignancies, including alemtuzumab,¹⁹ chlorambucil,⁹ cyclophosphamide,⁹ etoposide,²⁰ pentostatin,²¹ bortezomib,²² temozolomide,²³ and pembrolizumab.²⁴ We should note, however, that the evidence for pembrolizumab in CTCL is limited to small phase II studies.

In patients who have erythrodermic disease or SS, we choose treatment modalities based on the degree of disease burden.^9,16-18 Patients with low or limited disease burden in the skin or blood are often treated using combination strategies, including a skin‑directed therapy (photopheresis or UVB therapy) with or without retinoids, interferon, or other systemic agents. We also use biologic therapies until they have been fully exploited.

For patients with a higher disease burden and extensive blood involvement, we may start by using more aggressive treatments early on. Two agents have shown activity in patients with a high disease burden: the histone deacetylase inhibitor romidepsin and the chimeric antibody mogamulizumab, which targets the CCR4 receptor. Both of these have been effective, in particular, at clearing circulating malignant cells in patients with SS.

The FDA-approved agents for relapsed/refractory CTCL are shown on this slide. Romidepsin, a histone deacetylase inhibitor, is indicated for patients with CTCL who have previously received systemic therapy.²⁵ The pivotal trial supporting approval of this agent included 96 patients with an ORR of 34% and a mean duration of response (DoR) of 15 months. A supportive study that included more advanced‑stage patients was also conducted (N = 71). These patients had an ORR of 35% and a mean DoR of 11 months.

Denileukin diftitox is a fusion protein targeting the interleukin‑2 receptor CD25 and is approved for patients with relapsed/refractory CTCL whose cells express CD25.²⁶ In a pivotal trial in 71 patients, the ORR was 30%, but the mean DoR was only 4 months.

Bexarotene, an oral agent targeting RXR, is approved for patients with advanced MF and SS.²⁷ In a pivotal trial in 62 patients, the ORR was 32% and the mean DoR was more than 5 months.

Vorinostat, an oral histone deacetylase inhibitor, was approved based on the results of a pivotal trial in 74 patients who had an ORR of 30% and a mean DoR > 6 months.²⁸ A supportive trial of 33 patients showed a lower ORR (24%) with a mean DoR of 3.5 months.

Brentuximab vedotin was approved based on the results of a trial in patients with CD30⁺ CTCL randomized to either brentuximab vedotin or physician’s choice (methotrexate or bexarotene).²⁹ The 64 patients randomized to brentuximab vedotin had an ORR of 67% and a considerable mean PFS of 17 months.

Mogamulizumab was approved based on the results of a study in patients with relapsed/refractory disease who had been randomized to mogamulizumab or vorinostat (N = 372).³⁰ The patients receiving mogamulizumab showed an ORR of 28% with a DoR of 14 months.

Now let’s take a closer look at our first case: a patient with advanced progressive tumor‑stage MF who presented with patches and plaques and whose disease progressed to cutaneous tumors. Because this patient’s malignant cells expressed CD30, brentuximab vedotin²⁹—which targets CD30 receptors expressed on activated B-cells and T-cells in a number of different malignancies, including CTCL, anaplastic large‑cell lymphoma (ALCL), and Hodgkin disease—was considered an appropriate therapy.

Brentuximab vedotin is a chimeric antibody conjugated to monomethyl auristatin E, the cytotoxic moiety. This drug is given by IV infusion every 3 weeks.

In a trial of this drug in patients with systemic ALCL, the ORR was 86%, and 57% of these patients achieved a complete clinical response.

Brentuximab vedotin was studied in patients with CTCL in the ALCANZA trial, in which patients with CD30⁺ MF or primary cutaneous ALCL were randomized 1:1 to brentuximab vedotin (n = 64) or the investigator’s choice (n = 64) of methotrexate or bexarotene.³¹ Patients with MF had to have previously received ≥ 1 systemic therapy.

Patients were treated for 48 weeks, then followed every 12 weeks for 2 years and then every 6 months. The primary endpoint of the study was an objective global response lasting ≥ 4 months (ORR4). Secondary endpoints were CR, PFS, and several quality-of-life endpoints.

Baseline characteristics, both demographics and disease related, were well matched between the 2 arms.³¹ The median number of prior therapies was 3-4, and the median number of systemic therapies was 2 in each arm.

These graphics show the clinical benefit in skin and quality-of-life indices.³¹ As seen in the waterfall plots, many of the patients in the brentuximab vedotin arm showed improvement in their skin lesions, and some had a CR. Patients in the physician’s choice arm also experienced benefit, but less than with brentuximab vedotin.

Changes in skin symptoms were measured by the quality-of-life assessment tool Skindex. Patients who received brentuximab vedotin had a significantly greater mean change in overall Skindex score compared with those in the comparator arm (-27.92 vs -8.62, P < .0001).

This trial showed a correlation between CD30 expression and clinical response to brentuximab vedotin in patients with MF.³² There was a high degree of CD30 expression in many of the patients, and the level of CD30 expression predicted clinical response. Even in patients with low-level CD30 expression, however, a meaningful clinical response was observed. Thus, it appears in this trial that patients with both high and low levels of CD30 expression responded to brentuximab vedotin.

A fairly consistent percentage of patients achieved the primary endpoint of ORR4 across the MF disease spectrum.³¹ Of note, patients with stage IVB disease achieved a slightly lower response rate; however, there were very few patients in this subgroup (n = 7). Patients with primary cutaneous ALCL also achieved a very high ORR.

ORR4 was higher for patients in the brentuximab vedotin cohort compared with patients treated with methotrexate or bexarotene, whether there was only skin involvement or extracutaneous disease. Patients with only skin involvement had a high response rate (89%) with brentuximab vedotin. The rate was lower, but still meaningful, for patients with extracutaneous disease (57%).

As seen in this slide, the mean PFS was significantly longer in patients treated with brentuximab vedotin compared with other agents: 16.7 months vs 3.5 months (P < .001).³¹

As shown in this slide, adverse events varied with brentuximab vedotin vs physician’s choice.³¹ Peripheral neuropathy is a known toxicity related to brentuximab vedotin. In this trial, a significantly increased incidence of peripheral neuropathy was seen in the brentuximab vedotin arm compared with the physician’s choice arm. However, the incidence of other adverse events was very low and similar between the 2 arms. Overall, these regimens were relatively well tolerated.

In my institution, we have established a scoring system for peripheral neuropathy that we borrowed from our neurology colleagues to use with our patients treated with brentuximab vedotin. Patients graded their neuropathy at every visit. The items they assessed included being able to pick up a penny from the floor and button their shirt and whether there is any instability of gait or weakness of arms or legs. This gives a general assessment of their impairment. In addition, we keep track of any supportive medications that are necessary to control peripheral neuropathy, such as gabapentin.

Many of our patients can tolerate brentuximab vedotin without experiencing significant neuropathy. If they are symptomatic, and we feel it’s important to continue treatment based on response, we may reduce the dose of brentuximab vedotin or increase the dosing interval. Many of the patients whom we treat, however, find that a low dose of gabapentin is helpful for reducing the paresthesia associated with brentuximab vedotin.

Now let’s revisit our patient with advanced progressive CD30+ tumor‑stage MF.

This patient was initially treated with radiation for his ulcerating tumor lesions. I often ask my radiation therapy colleagues to evaluate the patient’s skin and radiate areas that are either rapidly enlarging or ulcerating. Some patients with long-standing MF often have infections, so I also treat these patients with an oral antibiotic. It is important to note that S aureus colonies have been found in many of these patients. Given that S aureus can stimulate an immune response, treatments should be designed to target this organism. Indeed, studies have shown that targeting S aureus results in significant improvement in the skin of these patients.

After radiation, my choice of systemic therapy choice for this patient was brentuximab vedotin. As we discussed, brentuximab vedotin should be highly effective for this patient because of its favorable toxicity profile compared with most chemotherapy regimens. The patient received brentuximab vedotin, and over the first 3 or 4 months of treatment, most of the tumors resolved. The patient remained on brentuximab vedotin for 14 months and had a clinical complete remission.

Let’s now return to our second case: a patient who presented with diffuse erythroderma with blood involvement.

This patient was initially treated with extracorporeal photopheresis (ECP) with minimal response. Therefore, we added other agents: bexarotene first, then interferon, and then combination therapy with bexarotene, interferon, and photopheresis.

This patient had a modest response but continued to have erythroderma and extensive pruritus. More importantly, tumor markers such as LDH started rising. This patient had progressed from MF with low disease burden into the higher disease burden category. Therefore, it was important to treat this patient with a more definitive therapy, such as romidepsin or mogamulizumab.

Mogamulizumab is a humanized monoclonal antibody that binds to the CCR4 receptor, which is a chemokine receptor that is highly expressed on the surface of T-cells in mature T-cell neoplasms such as CTCL. Mogamulizumab stimulates cell death by means of antibody‐dependent, cell‐mediated cytotoxicity.³³ CCR4 is expressed to varying degrees in patients with plaque‑stage and tumor‑stage MF and SS.

The graphic on the right of the slide shows that the extent of disease correlates with the level of CCR4 expression. Patients with SS often have high CCR4 expression; this marker is not expressed in nonmalignant skin disorders such as psoriasis. Mogamulizumab is approved by the FDA for patients with relapsed/refractory MF and SS who have received ≥ 1 previous systemic therapy.³⁰

Mogamulizumab was approved based on the results of a multicenter, international, open-label trial in 372 patients with MF or SS who had experienced failure on ≥ 1 previous systemic therapy.³² These patients were randomized 1:1 to received mogamulizumab IV or oral vorinostat. Patients received oral vorinostat 400 mg daily (the approved dose) or mogamulizumab 1 mg/kg IV every week for the first 4 weeks and then every other week. Patients were followed until they experienced disease progression or intolerable toxicity. Patients randomized to the vorinostat arm were allowed to crossover to mogamulizumab if they experienced progressive disease or toxicity.

The ORR by global assessment—which took into consideration the involvement of skin, lymph nodes, and blood—is shown here.³² The ORR for the mogamulizumab arm was significantly higher than that seen with vorinostat (28% vs 5%; P < .0001).

There were differences in response to mogamulizumab based on the clinical stage of the disease: 21% of patients with MF had a clinical response compared with 36% of those with SS. Patients with early patch or plaque disease had more modest response rates compared with those with erythroderma or stage IV disease.

The mean DoR for the mogamulizumab arm was 14 months vs 9 months with vorinostat, and the mean DoR for those with SS was 17 months vs 7 months, respectively. The mean DoR for vorinostat was inferior to that of mogamulizumab for patients in all disease categories.

The waterfall plots seen in this slide show that many more patients responded to mogamulizumab compared with vorinostat. This included patients with complete and partial responses, as well as patients with disease stabilization.^34,35

There was also a difference in ORR among body compartments, as seen in the table. Patients with disease in the skin had a 42% ORR with mogamulizumab vs 16% with vorinostat. The difference was even more striking in patients with disease in the blood, who exhibited an ORR of 68% with mogamulizumab vs 19% with vorinostat and a CR of 44% vs 4%, respectively. Among patients with disease in the lymph nodes, however, the ORR was much lower at 17% vs 4%, respectively. There were no responses to mogamulizumab or vorinostat in visceral disease.

Patients treated with mogamulizumab (shown in the top curve) had a median PFS of 7.7 months vs 3.1 months for those on vorinostat; this difference is highly significant (P < .0001).³²

Patient‑reported outcomes focused on symptomatic improvement with these 2 therapies.³² Patients treated with mogamulizumab showed greater improvement in the Skindex-29 symptoms scale vs vorinostat and maintained those improvements far longer, with the time to symptom worsening being 7 months for vorinostat vs 27 months for mogamulizumab.

These slides compare treatment‑emergent adverse events occurring in > 20% of patients in treatment either group.^32,36 Two key events seen in the mogamulizumab cohort were infusion‑related reactions and drug eruption; the drug caused additional skin eruptions in these patients. With vorinostat, there was a higher incidence of diarrhea, fatigue, nausea, and thrombocytopenia, which are known side effects of this drug. No unexpected adverse events were seen in this clinical trial.

In our clinical practice, when we see patients with infusion‑related reactions related to mogamulizumab, we either slow or stop the infusion then administer corticosteroids then try to continue the infusion. This is similar to what we do when there are infusion reactions with rituximab.

In patients who have experienced drug eruption, it is important to distinguish a drug eruption from a flaring of skin disease; however, it is often difficult to make that distinction.

In many patients with SS with extensive skin involvement, mogamulizumab will target some of the skin disease. In this case, a cytokine release syndrome may develop, causing an increase in skin itching, skin swelling, and erythema. We manage this either with topical steroids or, in some cases, with a short course of systemic steroids. In almost all instances, we are able to administer the drug again within a week or 2 once the cutaneous symptoms are under control.

One way to make a distinction between drug eruption and flaring of the underlying skin disease is by obtaining a skin biopsy, which we have performed in a number of our patients. Management remains the same: topical or systemic corticosteroids.

Let’s return to our patient with erythroderma who is being treated with ECP plus biologic therapy and is experiencing worsening symptoms—increasing itching and elevated LDH. Clearly another treatment is required for this patient.

My recommendation for this patient would be mogamulizumab, but one might also consider romidepsin in this setting. Both have been shown to be quite effective for these patients.

One way one might choose between these 2 drugs is through the adverse event profile: Patients receiving romidepsin have significant nausea, change in taste, and fatigue. As we saw previously, the toxicities associated with mogamulizumab include infusion reactions and skin flares. These usually occur at the beginning of therapy. The drug is relatively well tolerated over the remaining course of therapy—which is another reason that I elected to treat this patient with mogamulizumab.

After this patient received mogamulizumab, she had a skin flare and was treated with topical steroids and a few doses of prednisone. The skin flare resolved within 2 weeks, and she continued therapy. She had a clinical CR in her skin disease and clearing of malignant cells in her blood. She remains on mogamulizumab at this time. This therapy has been very effective for this patient.

The frontier for CTCL therapy includes a number of different agents that are currently in clinical trials targeting various disease pathways.

E7777 is a reformulation of denileukin diftitox, the interleukin‑2 diphtheria toxin fusion protein molecule, with improved purity and an increased percentage of active protein monomer species. An ongoing phase II clinical trial is underway to seek approval for this agent in patients with CD25+ MF.³⁷

Cobomarsen is a microRNA inhibitor that has shown activity in early studies in patients with MF.^38-40

ASTX‑660 is an XIAP inhibitor (another novel mechanism of action). This agent has shown activity in early clinical trials, with a preliminary result of 12% ORR in the CTCL cohort of a phase II study.⁴¹ Like many of the treatments that we use, it is associated with an initial flare of disease before the disease resolves.⁴²

Lacutamab (IPH4102) is a humanized anti‑KIR3DL2 monoclonal antibody targeting a KIR receptor that is expressed in patients with MF and SS.^43,44

There is some limited experience with checkpoint inhibitors, including pembrolizumab and nivolumab. Studies of these drugs have been very limited and have yielded response rates in the range of approximately 20% to 30%.^45-47

The PI3 kinase inhibitors have shown activity in patients with MF. Evidence of their activity was demonstrated in a trial of duvelisib in patients with CTCL.^48,49

Finally, a number of CAR T‑cell constructs are currently in clinical trials, including one that targets CD30.⁴⁸

So there are many different mechanisms that may be exploited as new therapies are developed for CTCL and we hope will show benefit for patients with this disease.