FDA Accepts BLA Resubmission for Denileukin Diftitox in Relapsed/Refractory Cutaneous T-Cell Lymphoma

Key Takeaways

  • The FDA accepted the resubmission of the BLA for denileukin diftitox-cxdl for relapsed/refractory CTCL.
  • The pivotal phase 3 Study 302 showed an ORR of 36.2% by independent review and 42.3% by investigator assessment.


The FDA has accepted the resubmission of the biologics license application (BLA) seeking the approval of denileukin diftitox-cxdl (Lymphir), an interleukin-2–based immunotherapy, for the treatment of patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL) following at least 1 prior systemic therapy.1

The BLA is supported by data from the pivotal phase 3 Study 302 trial (E7777-G000-302; NCT01871727) in which denileukin diftitox led to an independent review committee–assessed objective response rate (ORR) of 36.2% (n = 25/69; 95% CI, 25.0%-48.7%). The ORR according to investigator assessment was 42.3% (n = 30/71; 95% CI, 30.6%-54.6%).2

“The acceptance of the BLA resubmission reflects the completeness of our response to the enhanced product testing and additional controls highlighted by the FDA in their July 2023 complete response letter [CRL]. No concerns relating to safety or efficacy were noted in the letter, and we remain confident in the robustness of the clinical data package included with the initial BLA submission,” Leonard Mazur, chairman and chief executive officer of Citius, said in a news release.

On February 14, 2024, Citius Pharmaceuticals resubmitted the BLA for denileukin diftitox after discussions with the FDA regarding the agency’s CRL.3 The CRL, which was issued on July 29, 2023, mandated Citius provide enhanced product testing and additional controls. No concerns were made pertaining to safety or efficacy included in the data submission package for the BLA or the proposed prescribing information.4

With the resubmission, Citius believes it has shown proof of enhanced product testing and additional manufacturing controls requested in the CRL.1

Study 302 enrolled patients with relapsed or refractory stage I to IV, CD25-positive CTCL. Eligibility criteria required patients to have an ECOG performance status of 0 to 2, adequate organ function, and prior exposure to at least 1 CTCL therapy excluding denileukin diftitox.5

In accordance with the data from the lead-in portion of the study, patients received denileukin diftitox once daily at 9 μg/kg over a 60-minute infusion for the first 5 days of every 21-day cycle for up to 8 cycles.

The primary end point was ORR. Secondary end points included duration of response (DOR), time to response (TTR), skin response, duration of skin response, safety, and tolerability. Exploratory end points included progression-free survival, time to progression, pruritus improvement, and quality of life.

A total of 69 patients received the agent at 9 μg/kg and were assessed as part of the primary efficacy analysis set. The median age of this population was 64.0 years (range, 28-87); 50.7% of patients were younger than 65 years of age. Most patients were male (65.2%), White (72.5%), and had mycosis fungoides (95.7%). Regarding CTCL disease stage, 7.2% had stage IA disease, 23.2% had stage IB to IIA disease, 34.8% had stage IIB disease, 11.6% had stage IIIA disease, and 10.1% had stage IIIB disease. The median number of prior lines of therapy was 4. Seventeen percent of patients had received 8 or more prior lines of therapy.

In the primary efficacy population, the ORRs among patients with stage IA/IB/IIA (n = 30), IIB (n = 24), and IIIA/IIIB (n = 15) disease were 36.7% (95% CI, 19.9%-56.1%), 45.8% (95% CI, 25.6%-67.2%), and 20.0% (95% CI, 4.3%-48.1%), respectively. The respective clinical benefit rates were 60.0% (95% CI, 40.6%-77.3%), 54.2% (955 CI, 32.8%-74.4%), and 20.0% (95% CI, 4.3%-48.1%). The overall median DOR was 6.47 months, and the median TTR was 1.41 months (range, 0.7-5.6).

Of 64 evaluable patients, 84.4% experienced a reduction in skin tumor burden. Moreover, 48.4% experienced a maximum reduction of at least 50% compared with baseline, and 12.5% achieved a complete response.

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 98.6% of patients. Serious TEAEs occurred in 37.7% of patients. TEAEs leading to treatment discontinuation, reduction, and interruption were reported in 11.6%, 4.3%, and 37.7% of patients, respectively. No fatal serious TEAEs occurred.

The most frequent TEAEs that occurred included nausea (any grade, 43.5%; grade ≥3, 1.4%), fatigue (31.9%; 0%), increased alanine aminotransferase (27.5%; 8.7%), chills (27.5%; 1.4%), peripheral edema (27.5%; 1.4%), increased aspartate aminotransferase (26.1%; 4.3%), infusion-related reaction (24.6%; 5.8%), headache (23.2%; 0%), diarrhea (18.8%; 0%), pruritus (18.8%; 5.8%), capillary leak syndrome (17.4%; 5.8%), pyrexia (15.9%; 1.4%), hypoalbuminemia (14.5%; 0%), reduced appetite (13.0%; 1.4%), and constipation (11.6%; 0%).

“We believe there remains a critical unmet need for an additional viable treatment option for patients with relapsed or refractory CTCL as current therapies are non-curative. We are grateful for the FDA’s vital support for rare disease drug development as we work to expand treatment options for patients with CTCL. We look forward to the FDA’s decision and the potential benefit [denileukin diftitox] may provide patients with relapsed or refractory CTCL,” Mazur concluded.1


  1. Citius Pharmaceuticals announces FDA acceptance of the BLA resubmission of LYMPHIR (denileukin diftitox) for the treatment of adults with relapsed or refractory cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals. March 18, 2024. Accessed March 18, 2024.
  2. Citius Pharmaceuticals reports topline data from the pivotal phase 3 study of cancer immunotherapy I/ONTAK (E7777) for the treatment of persistent or recurrent cutaneous T-cell lymphoma (CTCL) in support of BLA submission. News release. Citius Pharmaceuticals. April 6, 2022. Accessed March 18, 2024.
  3. Citius Pharmaceuticals resubmits the biologics license application of Lymphir (denileukin diftitox) for the treatment of adults with relapsed or refractory cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals, Inc. February 14, 2024. Accessed February 14, 2024.
  4. Citius Pharmaceuticals, Inc. receives a complete response letter from the US Food and Drug Administration (FDA) for Lymphir (denileukin diftitox) for the treatment of patients with relapsed or refractory cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals. July 29, 2023. Accessed March 18, 2024.
  5. Foss FM, Kim YH, Prince HMM, et al. Efficacy and safety of E7777 (improved purity denileukin diftitox [Ontak]) in patients with relapsed or refractory cutaneous T-cell lymphoma: results from pivotal study 302. Blood. 2022;140(suppl 1):1491-1492. doi:10.1182/blood-2022-166916
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