Novel Agents Gain Ground as CTCL Treatment Landscape Evolves

Pamela Allen, MD, MSc

Treating patients with cutaneous T-cell lymphoma (CTCL) is complex and can sometimes feel like navigating a maze with too many paths, but novel therapies for this patient population are helping to create straightforward management strategies, according to Pamela Allen, MD, MSc.

Leading the way for novel therapies in this setting are the antibody-drug conjugate brentuximab vedotin (Adcetris®; Seagen) and afucosylated monoclonal antibody mogamulizumab (Poteligeo®; Kyowa Kirin), which both were approved by the FDA.^1,2

“Historically, the response rates for single-agent therapy in CTCL, particularly in the advanced stage, has been pretty poor,” Allen said in an interview with the SOHO Daily News. “We have started working more on trying to improve the standard treatment for patients with some of these novel agents. [Therapies] like brentuximab vedotin and mogamulizumab have far superior efficacy than what we’ve seen from prior standard treatments.” Allen is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, Georgia.

At the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022), Allen’s presentation “Integrating Novel Agents into the Management of Cutaneous T-Cell Lymphoma” will focus on these 2 novel agents, as well as others that are being evaluated in clinical trials that have marked a turning point in treating patients with CTCL.

“As we learn more about the disease biology, we’re starting to develop more novel therapies,” she said. “Moreover, as we start pushing to add CTCL cohorts to studies that are broadly looking at lymphomas or T-cell lymphomas, like peripheral T-cell lymphomas, then we learn that some of the agents that work in other diseases actually do work in [the CTCL] setting, as well.”

Helping Patients With Either Mycosis Fungoides or Sézary Syndrome

Historically, patients with CTCL would be given other treatments that were active in B-cell lymphomas, but this approach lacked effective T-cell targeting therapies in place of rituximab (Rituxan®; Genentech, Biogen).³ Now mogamulizumab can fill this gap and help relapsed or refractory patients with either mycosis fungoides (MF) or Sézary syndrome (SS) CTCL. This is already a significant help for clinicians, as MF is the most common form of CTCL but makes up less than 1% of the total non-Hodgkin lymphoma cases they will see.⁴ Moreover, research has shown that SS and MF are closely related, allowing for 1 novel therapy to effectively help patients with CTCL.

Patients with MF are often diagnosed at stage IA-II, MF. Clinicians have determined that observation or local therapy alone are reasonable first steps for patients that include topical steroids, topical chemotherapy (mechlorethamine), immunomodulators (imiquimod), radiation, or phototherapy, usually at the direction of a dermatologist.^5,6

For patients with early stage MF, their 5-year disease-specific survival approaches 90% vs 30% to 50% for patients with advanced disease.⁵ In comparison, patients with SS who have less than 1000 Sézary cells/μL have a median overall survival (OS) of 7.6 years, but patients with 10,000 cells/μL or more can see their median OS decrease to 2.1 years.⁷

CD30-Positive Mycosis Fungoides

To address patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma, the international open-label, randomized, multicenter phase 3 ALCANZA trial (NCT01578499) looked at 128 patients in the intent-to-treat population either on 1.8 mg/kg intravenous brentuximab vedotin or physician’s choice of therapy.⁸ Intravenous brentuximab vedotin was given once every 3 weeks (n = 64) for up to 16.3-week cycles compared with the physician’s choice of oral methotrexate at 5 to 50 mg given once per week or 300 mg/m² of oral bexarotene (n = 64) given once per day for up to 48 weeks.

Investigators found that after a median follow-up of 22.9 months (95% CI, 18.4-26.1 months), 56.3% achieved an objective global response that lasted at least 4 months on brentuximab vedotin vs 12.5% of patients on physician’s choice (95% CI, 29.1%-58.4%; P < .0001). Objective global response that lasted at least 4 months favoring brentuximab vedotin over physician’s choice therapy continued in the MF subgroup at 50% vs 10%, respectively.

Moreover, 67% of patients in the overall brentuximab vedotin group had an objective response compared with the physician’s choice group at 20% (P < .0001), with 65% of patients in the MF group achieving an ORR, as well, with 5 patients having a complete response. Two patients with stage IVA disease on the study also had a complete response.

Among the most frequently reported treatment-emergent adverse events (TEAEs), peripheral sensory neuropathy was the most frequent in the brentuximab vedotin group, with 45% of patients experiencing any-grade peripheral sensory neuropathy and 5% experiencing grade 3 peripheral sensory neuropathy. Other common TEAEs in the brentuximab vedotin group at any grade included nausea (36%), diarrhea (29%), fatigue (29%), and vomiting (17%). Looking at all AEs, the investigators found that peripheral neuropathy was reported in 67% of patients in the treatment group, with most patients experiencing grade 2 peripheral neuropathy.

“We [must] remember brentuximab vedotin wasn’t really studied in SS, so that’s a situation where I tend to not to use it,” Allen said. “For patients with tumor stage disease, if it’s a low-risk tumor stage disease—like patients with lymphomatoid papulosis or primary cutaneous anaplastic large cell lymphoma—they have excellent long-term responses. But with mycosis fungoides, it’s hard to predict who is going to have a long-term response and who is not.”

In the SS setting, Allen says this is where clinicians have made the most progress for patients with CTCL, with mogamulizumab showing the most benefit for patients with SS. Mogamulizumab is a treatment Allen frequently uses, and most patients with SS will be treated with it at some point, she explained. Moreover, she will often start with mogamulizumab if the patient has a higher disease burden.

Results from the phase 3 MAVORIC study (NCT01728805) showed that mogamulizumab had a significant PFS increase over the chemotherapy vorinostat (Zolinza®; Merck) in both the MF and SS settings.⁹ Overall, the study looked at 372 patients assigned to either receive 1 mg/kg of mogamulizumab intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles (n = 186) or 400 mg of daily vorinostat (n = 186).

Clinicians found that treatment with mogamulizumab had a superior investigator-assessed PFS at a median of 7.7 months (95% CI, 5.7-10.3 months) compared with 3.1 months (95% CI, 5.7-10.3 months) in the chemotherapy group (HR, 0.53; 95% CI, 0.41-0.69; P < .0001). Forty-one of the 81 patients with SS in the mogamulizumab arm had PFS events, with a hazard ratio of 0.32 (95% CI, 0.21-0.49) favoring the treatment drug.

Secondary end points of the study included overall response by global assessment, and the investigators found that 28% (95% CI, 21.65-35%) of patients in the mogamulizumab arm had an overall response compared with 5% (95% CI, 2.2%-9%) in the vorinostat arm. In the subgroup analysis, patients with SS had the best overall response, with 37% of patients on mogamulizumab compared with 7% on vorinostat. Moreover, 21% of patients with MF had an overall response with mogamulizumab vs 7% in the chemotherapy arm. It was also notable that patients with SS had a longer median duration of response at 17.3 months (range, 9.4-19.9 months) compared with 6.9 months (range, 6.9-6.9 months) in the chemotherapy arm.

The most common TEAEs of any grade for patients on mogamulizumab included infusion-related reactions (32%), drug rash (20%), diarrhea (23%), and fatigue (22%). Grade 3 to 4 AEs were seen in 41% of patients in the mogamulizumab group, and serious AEs of any cause were reported in 38% in the treatment arm. The most frequently reported serious AEs of any cause were pyrexia (4%) and cellulitis (3%).

However, other treatments, such as extracorporeal photopheresis (ECP), remain important to use with the novel therapies in a maintenance role. “ECP is a little slower to kick-start the response; it can take a few months to get a response going,” Allen said. “ECP works better either as an adjunct to something else or in patients who are a little lower risk, or you can start with mogamulizumab and follow-up with ECP maintenance.”

Better Biological Understanding of CTCL Evolves Treatment

More research into the biology of CTCL has provided clinicians with novel targets and different avenues of treatment, according to Allen. In the case of brentuximab vedotin, the antibody-drug conjugate targets tumor cells that express the CD30 antigen.

“We know that if we do multiple biopsies, and every single one of them is less than 5%, then brentuximab vedotin is unlikely to work,” Allen said. “If you have at least 1 lesion that has some CD30, there’s not strong evidence that a great amount of CD30 vs a lesser amount of CD30 makes a difference. So if you have some CD30 in at least 1 lesion, then it makes sense to use brentuximab vedotin.”

Brentuximab vedotin isn’t the only novel agent targeting disease with CD30 expression. Currently, a phase 2 study (NCT04101331) of the novel tetravalent bispecific chimeric (antihuman CD30× antihuman CD16A) recombinant antibody construct, AFM13, is investigating the monotherapy’s efficacy for patients with CD30-positive malignancies.¹⁰

In this study, patients with peripheral T-cell lymphoma or transformed MF with CD30, and who have relapsed after an earlier treatment or have refractory disease, have been enrolled into the study. Participants will be assigned to 1 of 3 cohorts, depending on their disease type and level of CD30 expression, with each cohort receiving 200 mg of AFM13 per infusion. The primary end point of the study is to assess the efficacy of AFM13 based on objective responses to the monotherapy, with secondary end points looking at safety, immunogenicity of AFM13, and the concentration of AFM13 in the blood.

The study is closed to accrual and underway, but research into other biomarkers is ongoing as targets for SF disease are being discussed. These include the use of reverse transcription–polymerase chain reaction (RT-PCR) that allow clinicians to measure the amount of specific RNA in patients.11

For patients with SF, research has shown that the use of PCR and RT-PCR is important to early diagnosis of SF by identifying 5 biomarkers: PL53, TWIST1, CD158k, KIR3DL2, and NKp46. By identifying the TWIST1 protein, investigators believe they can find a way to target or inhibit this, as the protein blocks p53 and inhibits c-MYC–induced apoptosis, which is believed to promote the progression of solid tumors. However, further studies are needed to see where these targets can go for patients with SF.

In the interim, some aspects of patient care won’t change, including making sure you talk with your patient through what they can expect and what the therapy you chose for them will bring to the table. “You also [must] think about the goals of therapy,” Allen said. “Is this a young patient, [whom] you want to get to an allogeneic transplant, and you’re going for a cure? In that population, you might be willing to accept a little more toxicity vs an older patient with multiple comorbidities. And in that population, you want to do as little as possible, because you want therapy to be as tolerable as possible over the long term, and you don’t want the treatment to be worse than the disease.”

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_{8. Prince HM, Kim YH, Horwitz SM, et al; ALCANZA Study Group. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017;390(10094):555-566. doi:10.1016/S0140-6736(17)31266-7}

_{9. Kim YH, Bagot M, Pinter-Brown L, et al; MAVORIC Investigators. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018;19(9):1192-1204. doi:10.1016/S1470-2045(18)30379-6}

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