Long-Term Outcomes with Mogamulizumab Alone or in Combination with Other Therapies for the Treatment of Cutaneous T-Cell Lymphoma

Background:

Mogamulizumab (moga) is an anti-CCR4 monoclonal antibody approved for mycosis fungoides (MF) and Sézary syndrome (SS). The safety and efficacy of moga combination with other systemic agents (combotx), and the role of retreatment with moga, have yet to be defined. The purpose of this study include 1. to assess long-term outcomes with moga including in a real-world setting 2. to evaluate the impact of moga-associated rash (MAR) 3. to assess the outcomes with combotx. 4. to describe moga retreatment experience.

Methods:

This retrospective study included patients with MF or SS from our multidisciplinary cutaneous lymphoma clinic treated with at least one dose of moga from 2009 to 2022. Combotx were defined as the intended use of concurrent or sequential treatment(s) to augment or prolong clinical response and/or as a supportive therapy for MAR. Methotrexate (MTX) was used sequentially to either address MAR or as a maintenance strategy post-moga once blood CR was achieved. Oral retinoids (used sequentially) or TSEBT (used either concurrently or sequentially) were used to augment skin compartmental response. Time to next treatment (TTNT) was defined as the interval between moga initiation and the start of the next lymphoma-specific therapy. Systemic steroids (used for MAR) were not considered lymphoma-specific therapies and therefore were excluded from the TTNT calculation. Molecular testing was performed using T-cell receptor (TCR) next generation sequencing (NGS) to help distinguish CTCL from MAR as the primary process.

Results:

65 patients were included: MF=16, SS=49. Median age was 68 (range 26-90). Most patients were heavily pretreated and with advanced disease. Median follow-up was 42 months (range 1.3-148). Overall, median TTNT was 15 months (95% CI 10-23), PFS 25 months (95% CI 15-39), OS 127 months (95% CI 45-135).

Combotx was used in 21 (32%) patients. ORR was higher with combotx (95% vs 45%, p<0.0001). Combotx led to significant improvement in the rate of response lasting ≥ 12 months (ORR12) (90% vs 55%, p=0.03), TTNT (38 vs 10 months, p=0.0018) and PFS (39 vs 19 months, p=0.0406).

MAR occurred in 32 (49%) patients (MAR+). ORR was 91% in MAR+ vs 33 % without MAR (MAR-). MAR+ had significant improvement in ORR12 (86% vs 36%, p=0.0037), TTNT (30 vs 7.5 months, p<0.0001) and PFS (30 vs 11.5 months, p=0.0032). Moga exposure was similar between MAR+ and MAR- and responders vs non-responders. Subanalysis of outcomes in patients that experienced MAR that were treated with moga monotherapy (44%) vs. combotx (56%) showed that patients treated with combotx had a trend for better response rates (100% vs. 78%, p=0.07), complete response (CR) rates (61% vs. 29%, p=0.09) and TTNT (38 vs. 23 moths, p=0.34).

Ten patients have been retreated with moga; six patients have received two total moga courses, three received three, and one received four. Most common reason for moga retreatment was increase in blood Sézary burden. During the second moga course, 3/10 had global CR, 4/10 partial response (PR), 2/10 stable disease (SD), and 1/10 progressive disease (PD). Five out of 10 patients received combotx, with 3/5 MTX, 1/5 MTX + TSEBT, and 1/5 acitretin. Three out of 10 patients had grade (GR) 3 MAR, with 2/3 CR and 1/3 PR. Out of the 3 patients that received a third course of moga, 1/3 had PD and 1/3 SD, 1/3 response could not be assessed. 2/3 had GR 3 MAR. All received combotx (2/3 with MTX and 1/3 with TSEBT). One achieved global PR to the first two courses but had PD after the third. Her CCR4 expression by flow during her third moga course was initially 15%, but at the time of PD was 0%. Noticeably, molecular studies right before PD showed a new CCR4 L21V resistant mutation. The only patient that received a fourth treatment course had global CR with 100% clearance of blood Sézary burden with one single dose. He continued maintenance MTX 15 mg PO weekly. This patient had GR 3 MAR during the first three courses and GR 1 during his fourth course.

Of the 10 patients that received >1 course of moga, 7 had MAR during their initial moga course (1 patient with GR 1, 1 with GR 2, 5 with GR 3). Three out of seven patients had similar MAR severity during subsequent courses.

Conclusion:

Our study supports promising survival and durable responses with moga. Patients with MAR or treated with combotx had better outcomes. Retreatment with moga was well tolerated, even in patients with prior MAR. Prospective studies are needed to assess outcomes with combotx and moga retreatment.

Khodadoust:CRISPR Therapeutics: Research Funding; Nutcracker Therapeutics: Research Funding. Kim:Pfizer/Seattle Genetics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Soligenix: Research Funding; Trillium: Research Funding; Innate-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Kirin Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Elorac: Research Funding; Eisai: Research Funding; DrenBio: Research Funding; CRISPR Therapeutics: Research Funding; Portola/Alexion Pharma: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees.