Point of Pure Return: Denileukin Diftitox-cxdl for Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma (CTCL) remains a difficult-to-treat lymphoma with limited curative options and a lack of effective therapy.¹ The most common types of CTCL include mycosis fungoides (MF) and Sézary syndrome, with MF comprising about 60% of new cases.² In general, CTCL is an indolent disease, and progression happens slowly over time.³ Patients often endure through many lines of therapy and experience reduced quality of life with a prolonged disease course.⁴

The treatment landscape of relapsed or refractory (R/R) CTCL remains diverse, with no single therapy demonstrating clear superiority over others.⁵ Treatment selection is dependent on toxicity profile as well as treatment goals made based on short- and long-term goals.⁵ One such option in this patient population is denileukin diftitox-cxdl (DD; Lymphir; Citius Pharmaceuticals, Inc), which was approved by the FDA in August 2024.⁶ This medication was originally approved by the FDA in 1999.⁷ The agent’s predecessor, denileukin diftitox (Ontak; Eisai), was withdrawn from the US market by the manufacturer in 2014, citing production issues.⁸

Since then, DD has been reformulated with increased purity and bioavailability, providing a much-needed alternative in the arsenal for the management of R/R CTCL.⁹ The mechanism of DD relies on the fusion protein interleukin-2 (IL-2) binding to the IL-2 receptor, and the diphtheria toxins are released into the cell, inhibiting protein synthesis and driving cell death.¹⁰ In preclinical studies, DD has shown antitumor activity against IL-2–expressing tumors, such as CTCL.¹⁰

Although the National Comprehensive Cancer Network (NCCN) guidelines include multiple treatment options for patients with R/R CTCL, including acitretin, bexarotene, brentuximab vedotin, gemcitabine, histone deacetylase inhibitors, interferon alfa, liposomal doxorubicin, mogamulizumab, pembrolizumab, and pralatrexate, DD is listed as a preferred systemic therapy option for stage IIB (generalized tumor disease) and as an option under “useful in certain circumstances" for stage IB-IIA, stage IIB (limited) and stage III disease.¹¹

A phase 2 study from Japan showed the efficacy and safety of DD in patients with R/R peripheral T-cell lymphoma or CTCL, leading to its approval in 2021.¹² Here we discuss the recent outcomes of the Study 302 trial (NCT01871727), which supported the approval of the reformulated DD in the United States.⁹

Study 302 Trial Overview

Study 302 was a phase 3, multicenter, open-label, single-arm trial examining the efficacy and safety of DD in patients with relapsed/refractory cutaneous T-cell lymphoma.⁹ The trial included sites across the US and Australia. Eligible patients included patients with stage IA-IVA CTCL, excluding patients with visceral disease. Patients with previous DD use or topical corticosteroids within 1 day of initial therapy were excluded from the trial. The analysis was conducted on patients with stage IA-IIIB to align with the historical reference DD. Patients received DD at 9 µg/kg for 5 consecutive days intravenously (IV) over 60 minutes every 21 days. In the main study, the treatment was continued for up to 8 cycles, and patients could receive more than 8 cycles at the discretion of the treating physician. Premedication with acetaminophen, diphenhydramine, antiemetics, and hydration was administered before the infusion for cycles 1 through 3 and was optional for cycle 4 and onward.

Results

A total of 69 patients were included in the analysis, with a majority of patients (95%) having MF and 56.5% with advanced stage IIB-IIIB disease. Many of the patients were heavily pretreated with 4 median prior lines of therapy, including but not limited to brentuximab, mogamulizumab, HDAC inhibitors, and systemic retinoids.

At the data cutoff period, defined as having completed cycle 8 or being off treatment and having at least 1 documented partial response or better, the objective response rate was 36.2%, and 8.7% achieved a complete response (Table 1). The median time to response was 1.4 months (range, 0.7-2.1 months), and the median duration of response was 6.47 months (range, 3-23.5 months). Patients received a median number of 6 cycles (range, 1-42 cycles) (Table 1). The median progression-free survival and overall survival were not estimable. There were observable improvements in patients’ skin manifestations: 84.4% showed a reduction in skin tumor burden; 12.5% achieved complete skin lesion clearance

[TABLE 1]

Adverse Events

DD had an expected safety profile with the most common adverse events (AEs) including nausea (43.5%), hepatotoxicity (36.2%), infusion reactions (73.9%), and capillary leak syndrome (CLS; 20.3%). CLS was observed in 20.3% of patients in the trial, with grade 1 at 2.9%, grade 2 at 11.6%, and grade 3 or higher at 5.8%; the median onset was 6.5 days (Table 2). Inpatient hospitalization or prolongation of existing hospitalization was seen in 37.7% of patients. The drug label includes a boxed warning for CLS, which occurred most during the first 2 cycles with a median duration of 14 days (range, 2-40 days).

Most AEs occurred during the first 2 cycles, and patients were able to continue therapy at full dose after restarting. Overall, 42% of patients underwent drug modification, 11.6% of patients discontinued treatment, and 37.7% of patients either had their dose reduced or temporarily held.

[TABLE 2]

Discussion

The return of DD to market unlocks another treatment option for patients with R/R CTCL. The overall response rate of 36% observed in this trial matches the historical response rates of the original DD trial (44%).¹³ To contextualize this in the current treatment landscape, the response rate of DD is comparable to that of other medications in this line of therapy, such as pralatrexate (40.7%), gemcitabine (51%), romidepsin (34%), brentuximab vedotin (53%), and mogamulizumab (28%).^14-18 A majority of patients (84%) reported marked improvement in skin tumor burden, with 12.5% of patients experiencing 100% skin lesion clearance, which shows the clinical impact of the medication.⁹ While the selection of medications largely depends on patient factors and adverse effects, the one benefit to DD is that it is not myelosuppressive and may be beneficial in patients where cumulative marrow toxicity is a concern.¹³

DD has a unique toxicity profile of CLS, hepatotoxicity, and vision impairment, which were consistent with historical DD trials.^19,20 CLS was assessed with serum albumin levels and vigilant monitoring of weight, edema, and blood pressure. The rate of CLS with the new DD formulation was 20.3%, with most events being grade 1 (2.9%) or 2 (11.6%), and the median onset was 6.5 days. The discontinuation rate due to adverse events was 7.2%, indicating a tolerable treatment profile. The incidence of infusion reactions (74%) with the new formulation is comparable to that of the historical DD formulation (70%).²¹ With the historical DD, some clinical trials used dexamethasone premedication to mitigate infusion reactions.²¹ The package insert for the new DD formulation lists dexamethasone as a premedication for at least 3 cycles if a grade 2 or greater reaction occurs, and patients should be monitored to ensure safe administration.²² 

For operational considerations, DD can be administered in an infusion clinic setting. The dose for the new formulation of DD is 9 µg/kg/day, with dose adjustments of 50% for toxicities, per the package label.²² Pharmacists can be vigilant in screening for appropriate candidates for DD therapy based on comorbidities, ensuring patients have adequate premedications, especially if patients have prior infusion reactions, and monitoring albumin levels and signs and symptoms of CLS.

Conclusion

DD offers a novel mechanism of action in a treatment landscape with many treatment options. Given its distinct toxicity profile, including CLS and infusion reactions, the adverse effects were manageable in the clinical trial. As a noncumulative, nonmyelosuppressive option, DD may be beneficial in heavily pretreated patients. Pharmacists play a vital role in assisting patients and providers in maximizing the safety and monitoring of DD therapy. With the new formulation of DD, a treatment option has expanded once again for R/R CTCL as work continues to bridge the gap of quality of life and disease management for CTCL patients.

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