anti-CCR4 Monoclonal Antibody Research Articles

Real-life efficacy of immunotherapy for Sézary syndrome: a multicenter observational cohort study

Sézary syndrome is an extremely rare and fatal cutaneous T-cell lymphoma (CTCL). Mogamulizumab, an anti-CCR4 monoclonal antibody, has recently been associated with increased progression-free survival in a randomized clinical trial in CTCL. We aimed to evaluate OS and prognostic factors in Sézary syndrome, including treatment with mogamulizumab, in a real-life setting. Data from patients with Sézary (ISCL/EORTC stage IV) and pre-Sézary (stage IIIB) syndrome diagnosed from 2000 to 2020 were obtained from 24 centers in Europe. Age, disease stage, plasma lactate dehydrogenases levels, blood eosinophilia at diagnosis, large-cell transformation and treatment received were analyzed in a multivariable Cox proportional hazard ratio model. This study has been registered in ClinicalTrials (SURPASSe01 study: NCT05206045). Three hundred and thirty-nine patients were included (58% men, median age at diagnosis of 70 years, Q1-Q3, 61-79): 33 pre-Sézary (9.7% of 339), 296Sézary syndrome (87.3%), of whom 10 (2.9%) had large-cell transformation. One hundred and ten patients received mogamulizumab. Median follow-up was 58 months (95% confidence interval [CI], 53-68). OS was 46.5% (95% CI, 40.6%-53.3%) at 5 years. Multivariable analysis showed that age ≥ 80 versus <50 (HR: 4.9, 95% CI, 2.1-11.2, p=0.001), and large-cell transformation (HR: 2.8, 95% CI, 1.6-5.1, p=0.001) were independent and significant factors associated with reduced OS. Mogamulizumab treatment was significantly associated with decreased mortality (HR: 0.34, 95% CI, 0.15-0.80, p=0.013). Treatment with mogamulizumab was significantly and independently associated with decreased mortality in Sézary syndrome. French Society of Dermatology, Swiss National Science Foundation (IZLIZ3_200253/1) and SKINTEGRITY.CH collaborative research program.

Abstract 5171: CD39, CD73 and CD38 as potential biomarkers for monitoring the response to mogamulizumab in Sézary syndrome

Abstract We demonstrated aberrant expression of CD39 or CD73 and low expression of CD38 in circulating and skin-homing CD4+ T cells in patients with Sézary syndrome (SS), an erythrodermic cutaneous T-cell lymphoma (CTCL) with a leukemic component. The anti-CCR4 monoclonal antibody Mogamulizumab (Moga) has been shown to increase progression-free survival in patients with advanced SS. Here, we longitudinally explored the modulation of the expression of CD39, CD73 and CD38 in circulating CD4+ T cells from SS patients under treatment with Moga. Eight patients with relapsed/refractory SS were included in the study and prospectively followed up for two years (median duration of treatment 9,5 months, range 5-28 months). Seven out of eight (87,5%) patients showed early complete response in the blood and partial (5/7, 71,4%) or near complete response (2/7, 28,6%) in the skin. One patient (12,5%) showed no blood or skin response to the treatment. Flow cytometry analysis highlighted that the clinical response was accompanied by a rapid and remarkable increase in CD38 expression in the residual circulating CD4+ T cells, as well as in CD8+ T cells. Moreover, in six patients carrying the homozygous G/G or heterozygous A/G ENTPD1 SNP rs10748643 genotypes, permissive to CD39 overexpression in T cells, the increased CD38 expression was paralleled by rapid reduction/loss of CD39. Notably, in one patient carrying the A/A genotype, characterized by low CD39 and high CD73 expression at the baseline, response to treatment was characterized by reduction of CD73 expression. The only one patient with A/A genotype who didn’t respond to Moga showed no modulation of CD38 or CD39 expression, while CD73 expression increased. Noteworthy, Moga increases the expression of CD38 in responding patients, and influences the expression of CD39 only in patients with the permissive CD39 genotypes (G/G; A/G), but not in those with the A/A genotype. Two patients showing initial response to Moga experienced skin progression during treatment, which was associated with a significant increase of CD39 and simultaneous decrease of CD38 in residual circulating CD4+ T cells, although there was no evidence of blood relapse. These preliminary results suggest that partial or complete responses to Moga is paralleled by reduced CD39 and/or CD73 expression and increased CD38 expression. Instead, an opposite modulation of these markers is associated with disease progression hinting at the potential clinical utility of CD38, CD39 and CD73 as markers to monitor patients' response to Moga therapy. Citation Format: Yuliya Yakymiv, Sara Marchisio, Erika Ortolan, Verdiana Pullano, Chiara Leso, Rebecca Senetta, Lorenzo Marega, Gabriele Roccuzzo, Pietro Quaglino, Ada Funaro. CD39, CD73 and CD38 as potential biomarkers for monitoring the response to mogamulizumab in Sézary syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5171.

New Molecular and Biological Markers in Cutaneous T Cell Lymphoma: Therapeutic Implications.

Cutaneous T cell lymphomas (CTCLs) exhibit a wide variety of clinical features, histologic characteristics, and genetic drivers. We review novel molecular findings that inform our understanding of the pathogenesis of CTCL, with a focus on the tumor microenvironment (TME). There is increasing evidence challenging the model of TCM:mycosis fungoides (MF) and TEM:Sézary syndrome (SS) phenotype. Phylogenetic analysis performed using whole-exome sequencing (WES) raises the possibility that MF can arise without a common ancestral T cell clone. The detection of ultraviolet (UV) marker signature 7 mutations in the blood of patients with SS raises questions about the role of UV exposure in CTCL pathogenesis. There is also increasing interest on the role of the TME in CTCL. Existing therapies such as the RXR retinoid bexarotene and the anti-CCR4 monoclonal antibody mogamulizumab may act through the CTCL TME by impacting the CCL22:CCR4 axis, while cancer-associated fibroblasts (CAFs) in the CTCL TME contribute to drug resistance, as well as a Th2 milieu and tumor growth via secretion of pro-tumorigenic cytokines. Staphylococcus aureus (SA) is a frequent cause of morbidity among CTCL patients. SA may positively select for malignant T cells through adaptive downregulation of alpha-toxin surface receptors and promotion of tumor growth via upregulation of the JAK/STAT pathway. Recent molecular advancements have contributed to our understanding of the pathogenesis of CTCL and shed light into the potential mechanisms of existing therapies. Further understanding of the CTCL TME may fuel the discovery of novel therapies for CTCL.

Mogamulizumab-Associated Rash (MAR) Correlates with Longer Progression Free Survival in Cutaneous T Cell Lymphoma (CTCL)

Background: Mogamulizumab-kpkc (mogamulizumab) is an anti-CCR4 monoclonal antibody approved for relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS). In the Phase III MAVORIC trial comparing mogamulizumab to vorinostat, mogamulizumab-associated rash (MAR) was reported in 25% of patients (pts) and was more common in responders than in non-responders. Since then, several small case series have suggested that MAR is associated with response to the drug and prolonged remission. Methods: We collected retrospective data from 8 academic centers on pts diagnosed with CTCL as defined by 2018 WHO-EORTC classification, who received at least one dose of mogamulizumab from 1/1/2000 to 1/31/2022. Primary endpoints were PFS and overall survival (OS) as calculated by Kaplan-Meier, compared with log rank test. Secondary endpoint was response to mogamulizumab in accordance with ISCL/EORTC 2011 criteria. MAR was graded with NCI CTCAE version 5.0. Categorical variables were compared between groups using Fisher test. Quantitative variables are presented with means and standard deviation or median and interquartile range (IQR). Univariate analysis was performed to calculate the hazard ratios (HR) for PFS. Results: A total of 159 pts were included in analysis: 80 (50%) pts had a diagnosis of MF, 67 (42%) had SS, and 11 (7%) had other CTCLs. Median age was 70 (IQR 59.5-76), 65 (41%) were female, 124 (78%) were non-Hispanic Caucasian, 22 (14%) were Black. Median of prior lines of therapy was 3 (0-14). ECOG was 0-1 in 80% of pts at start of mogamulizumab. Majority of pts (70%, n=111) had advanced stage disease (Stage III or IV). Extranodal disease other than skin was present in 111 (70%) and LDH was elevated in 80 (50%) of pts. MAR occurred in 72 (45%) pts. Majority of rash was grade 1-2 (76%, n=55) but 14% (n=10) developed grade 3 rash. Median time to onset was 3.7 months (mo) (IQR 2.1, 7.6) and median time to resolution was 4.3 mo (IQR 1.4, 7.5). Skin biopsy was obtained in 51 of 72 pts who developed MAR. Histologic patterns ranged from spongiotic/psoriasiform (40%, n=29), interface (19%, n=14), lichenoid (28%, n=20), granulomatous (7%, n=5) or a combination of patterns. Location of rash occurred in extremities (78%, n=56), trunk (69%, n=50), face/scalp (39%, n=28), buttocks/groin (8%, n=6) or combination of places. Of the pts who developed MAR, 24 (33%) were treated with topical steroids, 13 (18%) with systemic steroids, 16 (42%) with both topical and systemic steroids and 12 (17%) with other therapies, while 4 (6%) did not receive any treatment. Median follow up was 20.9 mo, IQR: (12.0, 38.4). Median PFS was 30.5 mo (95% CI: 27.0 mo to not reached) for pts who developed MAR vs. 8.6 mo (95% CI: 5.7-20.9) for those who did not (HR=0.38, 95% CI: 0.24-0.62, p<0.0001). Three-year OS for pts with MAR vs. those without was 84% vs 55% (HR 0.3, 95% CI: 0.14-0.63, p=0.0008). Complete remission (CR) was higher in pts with MAR (64%; n=46) than those who did not develop MAR (26%; n=23). Overall response rate (ORR) was also higher in those with MAR vs those without, 85% (n=61) vs. 54% (n=47), p<0.0001. Odds ratio of CR in pts with MAR was 4.64 (95% CI: 2.37-10.25), p<0.0001. CR and partial remission (PR) in the blood were the most predictive of longer PFS on univariate analysis with HR of 0.05 (95% CI: 0.02, 0.14, p<0.001) and 0.07 (95% CI: 0.03, 0.20, p<0.001), respectively. Advanced stage CTCL at the start of mogamulizumab was also associated with improved PFS compared with early stage, HR 0.61 (95% CI: 0.37, 1.00), p=0.05. At last follow-up, mogamulizumab had been discontinued in 114 pts due to rash (n=38), immune event (n=2), progression (n=56) or other adverse outcome (n=22). Mogamulizumab was held in 40 pts with drug rash. Of the pts who permanently discontinued mogamulizumab due to rash, 16 of 38 pts (42%) remain off systemic therapy at last follow up with ongoing response; median time off of systemic therapy for these pts was 7.8 mo (IQR: 6.1, 16.5). Conclusions: The development of MAR in patients with CTCL is associated with higher rates of CR and ORR and significantly longer PFS and OS. CR/PR response in blood were associated with improved PFS. Additionally, 40% of patients who developed MAR and discontinued mogamulizumab had ongoing responses without additional systemic therapy. Rash may be a surrogate marker of favorable outcome with mogamulizumab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CCR7 alterations associated with inferior outcome of adult T-cell leukemia/lymphoma under mogamulizumab treatment.

Adult T-cell leukemia/lymphoma (ATL) patients have a very poor prognosis. The humanized anti-CCR4 therapeutic monoclonal antibody, mogamulizumab, is a key agent for ATL treatment. Our previous integrated molecular analysis demonstrated that among all the driver genes in ATL, CCR7 gene alterations were significantly associated with clinical response to mogamulizumab. Accordingly, here we investigated the detailed clinical impact of CCR7 alterations in a larger cohort of ATL patients. These CCR7 alterations, most of which lead to C-terminus truncations, were observed in 27 of 223 patients (12%). For patients receiving mogamulizumab but not allogeneic hematopoietic stem cell transplantation (HSCT), CCR7 alterations were significantly associated with worse survival (median survival from the first dose of mogamulizumab of 0.7years for 12 patients with CCR7 alterations vs. 1.6years for 72 patients without, p=0.020). On the other hand, the presence or absence of CCR7 alterations had no significant impact on survival in the entire cohort (median overall survival of 1.4 and 1.8years, respectively, p=0.901), or on the survival of patients receiving allogeneic HSCT (median survival from the day of transplantation of 0.9years for 6 patients with CCR7 alterations and 1.4years for 48 without, p=0.543). Multivariate analysis indicated that patients with CCR4 alterations but lacking CCR7 alterations (n=20) had significantly better survival after receiving mogamulizumab-containing treatments (hazard ratio for survival, 0.437, 95% confidence interval, 0.192-0.994). This study contributes to the establishment of precision medicine for ATL.

A novel mouse model of cutaneous T-cell lymphoma revealed the combined effect of mogamulizumab with psoralen and ultraviolet a therapy.

Mycosis fungoides (MF) is a subtype of cutaneous T-cell lymphoma (CTCL). Topical or systemic treatment with psoralen, such as 8-methoxypsoralen (8-MOP), followed by ultraviolet A (UVA) irradiation (PUVA therapy) is an effective phototherapy for early-stage MF. However, the efficacy of PUVA therapy for advanced-stage MF is not satisfactory, and the ideal combination partner for PUVA therapy has not yet been found. In this study, we developed a new mouse model of CTCL in which efficacy of PUVA was detected and further evaluated the efficacy of combination treatment of PUVA and mogamulizumab, an anti-CCR4 monoclonal antibody. Cytotoxicity of PUVA therapy against HH cells, a CTCL cell line, was observed in vitro. The cytotoxicity was dependent on both 8-MOP and UVA. Using HH cells, we developed a mouse model in which HH cells were subcutaneously inoculated in the ear. In this model, PUVA therapy suppressed tumour growth with statistical significance, while 8-MOP or UVA alone did not. Combination therapy of PUVA and mogamulizumab showed greater antitumor activity than either monotherapy with statistical significance. In the histological analysis of the tumour tissue, PUVA accelerated tumour necrosis and then induced the infiltration inflammatory cells in the necrotic area, suggesting that these cells served as effector cells for mogamulizumab. This combination therapy is expected to be a beneficial option for CTCL therapy.

Mogamulizumab induces long-term immune restoration and reshapes tumour heterogeneity in Sézary syndrome.

Mogamulizumab, an anti-CCR4 monoclonal antibody, has been shown to increase progression-free survival in cutaneous T-cell lymphoma. We hypothesized that besides the targeted depletion of Sézary cells (SCs), mogamulizumab may reshape the immune tumour microenvironment. Both malignant and benign compartments from 26 patients with B2 stage Sézary syndrome before mogamulizumab initiation were prospectively analysed using KIR3DL2 and TCRVβ markers, serological markers and molecular assessments of clonality. Prior to mogamulizumab, the benign subset of CD4+ T cells displayed exhausted phenotypes, with an increased gradient in programmed death-1, TIGIT, DNAM-1, CD27, CD28 and CD70 expression from age-matched controls to patients' benign CD4+ T cells and to SCs. All patients presented SCs with heterogeneous phenotypes, and differential expression of individual markers was found within distinct malignant subsets. Early complete blood response was observed in 17 of 26 patients and was associated with higher baseline CCR4 expression. A drastic decrease in benign T cells and activated regulatory T-cell counts was observed during the first 4 weeks. Long-term follow-up revealed the emergence of an immune restoration involving CD8+ and naive and stem memory CD4+ T cells, with almost complete disappearance of exhausted lymphocytes. Development of resistance or tumour escape to mogamulizumab was associated with the emergence of CCR4- SCs in blood and skin, displaying significant changes in their heterogeneity patterns, and not explained only by mutations within CCR4 coding regions. Mogamulizumab likely contributes to the restoration of efficient immunity and reshapes not only the malignant lymphocyte subset but also the benign subset. These results have potential implications for optimal therapeutic sequences and/or combinations. What is already known about this topic? Management of Sézary syndrome (SS) involves successive therapies that participate as cause and consequence in the emergence of resistant clones, on a background of immunodeficiency. We and others have reported the complex and dynamic heterogeneity of Sézary cells (SCs) during disease progression. Mogamulizumab therapy, by targeting the skin-homing receptor CCR4, mainly expressed by SCs, has been shown to increase progression-free survival in patients with SS. What does this study add? Using multicolour flow cytometry, we provide quantification of CCR4 and immune checkpoint molecules on malignant SCs and benign CD4+ T cells from patients with SS, separated using KIR3DL2 and TCRVβ expression. Mogamulizumab is not only aimed at eradicating malignant SCs but potentially contributes to the restoration of efficient immunity. Tumour escape is associated with the emergence of CCR4- SCs, not explained only by mutations within CCR4 coding regions.

Development of a Novel Anti-Mouse CCR4 Monoclonal Antibody (C4Mab-1) by N-Terminal Peptide Immunization.

The CC chemokine receptor type-4 (CCR4) belongs to the G-protein-coupled receptor superfamily, expressed on the cell surface of T cells and its malignancy. Two CCR4 ligands (CCL17 and CCL22) bind to CCR4 that mediate physiological and pathological functions of T cell immune responses. Anti-CCR4 monoclonal antibody (mAb) mogamulizumab is approved for adult T cell leukemia/lymphoma and cutaneous T cell lymphomas. In addition, mogamulizumab can deplete regulatory T cells, implying the application to solid tumors as an immunomodulator. Therefore, the development of sensitive mAbs for CCR4 has been desired for basic research, diagnosis, and therapy. In this study, a specific, and sensitive anti-mouse CCR4 (mCCR4) mAb, C4Mab-1 (rat IgG1, kappa), was established using N-terminal peptide immunization. C4Mab-1 reacted with mCCR4-overexpressed Chinese hamster ovary (CHO)-K1 cells, P388 (mouse lymphoid neoplasm), and J774-1 (mouse macrophage-like) cells in flow cytometry. Kinetic analyses using flow cytometry showed that KDs of C4Mab-1 for CHO/mCCR4, P388, and J774-1 cells were 4.2 × 10-9 M, 5.4 × 10-7 M, and 1.1 × 10-6 M, respectively. C4Mab-1 could be a valuable tool for elucidating mCCR4-related biological responses.

Depletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab

Regulatory T (Treg) cells are important negative regulators of immune homeostasis, but in cancers they tone down the anti-tumor immune response. They are distinguished by high expression levels of the chemokine receptor CCR4, hence their targeting by the anti-CCR4 monoclonal antibody mogamulizumab holds therapeutic promise. Here we show that despite a significant reduction in peripheral effector Treg cells, clinical responses are minimal in a cohort of patients with advanced CCR4-negative solid cancer in a phase Ib study (NCT01929486). Comprehensive immune-monitoring reveals that the abundance of CCR4-expressing central memory CD8+ T cells that are known to play roles in the antitumor immune response is reduced. In long survivors, characterised by lower CCR4 expression in their central memory CD8+ T cells possessed and/or NK cells with an exhausted phenotype, cell numbers are eventually maintained. Our study thus shows that mogamulizumab doses that are currently administered to patients in clinical studies may not differentiate between targeting effector Treg cells and central memory CD8+ T cells, and dosage refinement might be necessary to avoid depletion of effector components during immune therapy.

Tre-P-11 - Is mogamulizumab-induced alopecia areata associated with favorable outcomes in Sézary syndrome?

Introduction: Mogamulizumab (moga), an anti-CCR4 monoclonal antibody, is approved in cutaneous T-cell lymphomas (CTCL). Moga immune-related adverse events (IrAE) have been described, and we report the first case series of alopecia areata (AA) following the administration of moga.

Tre-O2-04 - Mogamulizumab induces long term immune restoration and reshapes tumoral heterogeneity in Sézary syndrome

Mogamulizumab, an anti-CCR4 monoclonal antibody, has shown to increase progression-free survival in cutaneous T-cell lymphoma. We hypothesized that, besides the targeted depletion of Sézary cells (SCs), mogamulizumab may contribute to immunological changes, improving clinical response. We also explored potential phenotypic changes of SCs during treatment, potentially resulting in resistance/tumor escape to therapy. We have prospectively followed 26 SS patients with B2 stage before mogamulizumab initiation. We performed extended phenotypic characterization of malignant and benign compartments, using KIR3DL2, TCRVb and/or CD26 markers, every month, up to one year. Prior to mogamulizumab, the non-malignant (benign) subset of CD4+ T-cells displayed exhausted phenotypes. When comparing SCs, benign and controls CD4+ T cells, our data showed a gradient of PD1, TIGIT, DNAM, CD27, CD28 and CD70 expression. All patients presented SCs with heterogeneous surface phenotypes and differential expression of individual markers were found within distinct malignant subsets. An early complete blood response was observed in 17/26 patients and was associated to a higher baseline CCR4 expression on SCs. A drastic decrease in benign T-cells and activated Treg absolute counts was observed during the first 4 weeks. Long-term follow-up revealed the emergence of an immune restoration involving CD8+ and naive and TSCM CD4+ subsets, concomitant with almost complete disappearance of exhausted T lymphocytes. Finally, the development of resistance/tumor escape to mogamulizumab therapy allowed us to longitudinally follow phenotypic characteristics of SCs and revealed the emergence of CCR4–SCs displaying significant changes in their heterogeneity patterns. In conclusion, mogamulizumab is not only aimed at eradicating malignant-cells but is likely contributing to the restoration of an efficient immunity. This is of importance as a competent immune status is required for effective anti-infectious and anti-tumoral responses as well as for the efficacy of further immunotherapies.

Tre-P-13 - Mogamulizumab in a patient with Sézary syndrome and severe atopic dermatitis

Introduction: The chemokine receptor type 4 (CCR4) is involved in both Sézary syndrome (SS) and atopic dermatitis (AD) pathophysiology. Mogamulizumab (Moga), an anti-CCR4 monoclonal antibody, is labeled for the treatment of SS. We describe a patient for whom Moga had a benefit in both SS and AD.

Quality of life in patients with mycosis fungoides and Sézary syndrome undergoing low-dose total skin electron beam therapy with or without maintenance therapy

Quality of life in patients with mycosis fungoides and Sézary syndrome undergoing low-dose total skin electron beam therapy with or without maintenance therapy

Quality of Life Effect of the Anti-CCR4 Monoclonal Antibody Mogamulizumab Versus Vorinostat in Patients With Cutaneous T-cell Lymphoma

BackgroundSézary syndrome (SS) and mycosis fungoides (MF), 2 types of cutaneous T-cell lymphoma, cause significant morbidity and adversely affect patients’ quality of life (QoL). The present study assessed the QoL measurement changes in patients receiving mogamulizumab versus vorinostat. Patients and MethodsA multicenter phase III trial was conducted of patients with stage IB-IV MF/SS with ≥ 1 failed systemic therapy. The QoL measures included Skindex-29 and the Functional Assessment of Cancer Therapy–General. The symptoms, function, and QoL subdomains were longitudinally modeled using mixed models with prespecified covariates. Meaningful change thresholds (MCTs) were defined using distribution-based methods. The categorical changes by group over time and the time to clinically meaningful worsening were analyzed. ResultsOf the 372 randomized patients, mogamulizumab demonstrated improvement in Skindex-29 symptoms (cycles 3, 5, and 7; P < .05) and functional (cycles 3 and 5; P < .05) scales. A significantly greater proportion of mogamulizumab-treated patients improved by MCTs or more from baseline in the Skindex-29 symptoms domain (cycles 3, 5, 7, and 11) and functioning domain (cycle 5). Significant differences in the Functional Assessment of Cancer Therapy–General physical well-being (cycles 1, 3, and 5; P < .05) were observed in favor of mogamulizumab and a greater proportion of patients had declined by MCTs or more at cycles 1, 3, 5, and 7 with vorinostat treatment. The median time to symptom worsening using Skindex-29 was 27.4 months for mogamulizumab versus 6.6 months for vorinostat. In the patients with SS, the time to worsening favored mogamulizumab (P < .005) for all Skindex-29 domains. The time to worsening was similar for the 2 MF treatment arms. ConclusionThe symptoms, function, and overall QoL of patients with MF/SS favored mogamulizumab over vorinostat across all time points. Patients with the greatest symptom burden and functional impairment derived the most QoL benefit from mogamulizumab.

Robust CD8+ T-cell proliferation and diversification after mogamulizumab in patients with adult T-cell leukemia-lymphoma

AbstractSkin-related adverse events (AEs) occur frequently in adult T-cell leukemia-lymphoma (ATL) patients treated with mogamulizumab, a humanized anti-CCR4 monoclonal antibody. This study was undertaken to elucidate the mechanisms of mogamulizumab-induced skin-related AEs. We analyzed the T-cell receptor β chain repertoire in ATL patients' peripheral blood mononuclear cells (PBMCs) before and after mogamulizumab. Skin-related AEs were present in 16 patients and were absent in 8 patients. Additionally, we included 11 patients before and after chemotherapy without mogamulizumab. Immune-related gene expression in PBMCs before and after mogamulizumab was also assessed (n = 24). Mogamulizumab treatment resulted in CCR4+ T-cell depletion, and the consequent lymphopenia provoked homeostatic CD8+ T-cell proliferation, as evidenced by increased expressions of CD8B and CD8A, which were significantly greater in patients with skin-related AEs than in those without them. We hypothesize that proliferation is driven by the engagement of self-antigens, including skin-related antigens, in the face of regulatory T-cell depletion. Together with the observed activated antigen presentation function, this resulted in T-cell diversification that was significantly greater in patients with skin-related AEs than in those without. We found that the CD8+ T cells that proliferated and diversified after mogamulizumab treatment were almost entirely newly emerged clones. There was an inverse relationship between the degree of CCR4+ T-cell depletion and increased CD8+ T-cell proliferation and diversification. Thus, lymphocyte-depleting mogamulizumab treatment provokes homeostatic CD8+ T-cell proliferation predominantly of newly emerging clones, some of which could have important roles in the pathogenesis of mogamulizumab-induced skin-related AEs.

A Prospective Cohort of Black Patients with Mycosis Fungoides and Sézary Syndrome: Subset Analysis of the Mavoric Trial

Introduction: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common types of cutaneous T-cell lymphoma (CTCL). Incidence rates for CTCL are higher in blacks than Caucasians (9.0 vs 6.4 cases per million persons). Retrospective studies suggest that black patients with CTCL present with younger age at diagnosis, lower male to female ratio, higher cutaneous disease burden, and inferior survival (Nath S, et al. Clin Lym Myel Leuk 2014). Prospective data on treatment outcomes in this patient subset are rare. Mogamulizumab, an anti-CCR4 monoclonal antibody, was recently FDA approved for relapsed/refractory (R/R) MF and SS with improved response rates and progression-free survival (PFS) vs comparator vorinostat. Here we report the clinical characteristics and outcomes of black patients treated in the MAVORIC trial with a specific focus on responses to mogamulizumab. Methods: The MAVORIC trial was an international, open-label, randomized phase 3 trial comparing mogamulizumab vs vorinostat in R/R MF/SS. Complete study design and results were recently published (Kim YH, et al. Lancet Oncol 2018). Patients were randomized 1:1 and stratified by both clinical stage (IB-II vs III-IV) and disease type (MF vs SS). The primary endpoint was PFS, based on investigator assessment. Key secondary endpoints included overall response rate (ORR), duration of response, response by compartment (blood, skin, nodal, and visceral). We conducted a subset analysis on black vs non-black patients who were enrolled in the intention-to-treat population (ITT). Results: 372 patients were enrolled of which 37 (10%) self-identified as black. Compared to non-black patients (N=335), the median age was younger (53 vs 66 years). Twenty-one (56.8%) were male, similar to 58.2% in non-black patients. Skin stage distribution in the black patients was: T1, N=0; T2, N=18 (48.6%); T3, N=4 (10.8%); and T4, N=15 (40.5%). Twenty-seven (73%) had blood involvement and 32 (86.5%) had lymphadenopathy. A greater fraction of the randomized black patients had MF compared to non-black (73% vs 52.8%); the opposite was true for SS (27% vs 47.2%). More black patients were randomized to mogamulizumab (N=24) than vorinostat (N=13). Median exposure to mogamulizumab was 170 days for all populations analyzed (black, non-black, and ITT). Instead median exposure to vorinostat was longer in black vs non-black patients (105 vs 83 days), and in blacks vs ITT (105 vs 84 days). Nearly two thirds (61.5%) of black patients randomized to vorinostat crossed over to mogamulizumab, slightly less than in the ITT population (73%). Median follow-up for black patients and for the entire MAVORIC cohort were 20.8 months and 17 months, respectively. In the ITT cohort, PFS was superior in patients randomized to mogamulizumab vs vorinostat (7.7 vs 3.1 months; HR 0.53; P&lt;0.0001) (Kim YH, et al. Lancet Oncol 2018). In ad-hoc investigator assessed subgroup analyses, PFS also favored mogamulizumab over vorinostat in black patients [7.57 vs 3.9 months, respectively; HR 0.81; (95% CI 0.33-1.96)]. Additionally, by both investigator assessment and independent review, ORR to mogamulizumab was comparable to non-black patients. Similarly, mogamulizumab in black patients was superior to vorinostat in terms of responses by compartment with a confirmed response rate of 72.2% vs 11.1%, respectively in the blood, and a confirmed response rate of 41.7% vs 7.7%, respectively in the skin. Responses by compartment to mogamulizumab in non-black patients were similar (66% for blood and 42% for skin). There were fewer nodal responses in black patients (9.1%) compared with non-black patients (16.7%). When analyzed by disease subtype, higher ORR were seen in black patients randomized to mogamulizumab than to vorinostat for both MF (33.3% vs 11.1%, respectively) and SS (16.7% vs 0%, respectively). There were no differences in safety signals in black patients vs non-black. There was a slightly higher rate of infusion reactions 41.7% vs 31.9%. The rate of drug eruptions was similar, 25% vs 24.4%. Conclusion: These results support mogamulizumab as an effective treatment for MF/SS in black patients with similar PFS and ORR, including by disease compartments (blood and skin) and responses by disease type (MF or SS), as non-black patients. Safety signals for black vs non-black patients were similar with mogamulizumab, including drug eruptions. Figure Disclosures Porcu: Viracta: Honoraria, Other: Scientific Board, Research Funding; Kyowa: Honoraria, Other: Scientific Board, Research Funding; Innate Pharma: Honoraria, Other: Scientific Board, Research Funding; Daiichi: Research Funding; BeiGene: Other: Scientific Board, Research Funding; Incyte: Research Funding; Spectrum: Consultancy; ADCT: Research Funding.

Improved Overall Survival Among Newly Diagnosed Aggressive Adult T-Cell Leukemia/Lymphoma Patients Treated with Mogamulizumab Plus EPOCH Compared to Mogamulizumab Plus Vcap-AMP-Vecp

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a rare and quite refractory peripheral T-cell lymphoma. The human T-lymphotropic virus type 1 (HTLV-1) retrovirus causes ATLL. Tax protein produced by HTLV-1 has oncogenic activities, and its peptides can be recognized as tumor antigens by the host immune system. Therefore, some immunological approaches to treat ATLL are effective. Mogamulizumab (Moga), an anti-CCR4 monoclonal antibody, and lenalidomide, an immunomodulator, have been recently approved for newly diagnosed and/or relapsed/refractory aggressive ATLL in Japan. However, to date, satisfactory treatment results have not been obtained with these drugs. Before approval of Moga and lenalidomide, VCAP-AMP-VECP (mLSG15) therapy was one of the standard combination chemotherapies for aggressive ATLL. A randomized phase II study comparing Moga plus mLSG15 and mLSG15 alone showed a higher %CR in Moga plus mLSG15 arm but no significant difference in overall survival (OS) between the two arms. In this study, we compared the outcomes of Moga plus EPOCH with those of Moga plus mLSG15. Methods: Aggressive ATLL patients, who were ineligible for hematopoietic stem cell transplantation (HSCT) and were newly diagnosed after June 2000 in our hospital, were retrospectively analyzed. Results: Table 1 summarizes the patient characteristics. Twenty-two patients were treated with Moga plus EPOCH, and 16 were treated with Moga plus mLSG15. There was no significant difference in gender and disease subtype between the groups. Moga-induced skin disorders, such as rash and erythema, were observed in 14 (64%) patients treated with Moga plus EPOCH group and 9 (56%) patients treated within Moga plus mLSG15; the difference was not significant. Figure 1 shows OS of both groups. There was no significant difference (P=0.3092), but a 30% risk reduction was observed in the Moga plus EPOCH group (hazard ratio [HR]: 0.6859, 95% confidence interval [CI]: 0.3165−1.430), though patients treated with Moga plus EPOCH were significantly older than those treated with Moga plus mLSG15 (Table 1). Figure 2 shows OS of patients with and without Moga-induced skin disorders in both groups. The OS of patients with skin disorders was significantly greater than that of those without skin disorders (P&lt;0.0001, HR: 0.2653, 95% CI: 0.05879−0.3628), as previously reported. Elevation of the Tax-specific cytotoxic T-lymphocytes (CTL) percentage was observed after occurrences of skin disorders in some patients. Representative data are shown in Figure 3. These data suggest that the combination chemotherapy regimen might be irrelevant for patients with Moga-induced skin disorders. Next, the OS of the Moga plus EPOCH group was compared with that of those treated with chemotherapy alone, such as mLSG15 and the CHOP-like regimen, as the historical control (Table 2). There was no statistical difference between the groups, but a 16% risk reduction was observed in the Moga plus EPOCH group (P=0.5885, HR: 0.8401, 95% CI: 0.4491−1.568) (Figure 4), though those treated with Moga plus EPOCH were significantly older than those treated with chemotherapy alone (Table 2). A 36% risk reduction in OS was observed in patients with Moga-induced skin disorders compared to those treated with chemotherapy alone (Figure 5). Conclusion: Improved OS was observed more frequently in the Moga plus EPOCH group than in the Moga plus mLSG15 group. However, to date, Moga plus chemotherapy has not shown a significant impact on OS for newly diagnosed aggressive ATLL patients in non-HSCT settings, except for patients with Moga-induced skin disorders. Elevation of the Tax-specific CTL percentage was observed in some patients with Moga-induced skin disorders. We previously reported in the 2014 ASH annual meeting that several aggressive ATLL patients, who obtained long-time survival using chemotherapy alone, had maintained Tax-specific CTLs for long periods. Therefore, it might be necessary to induce, up-regulate, and maintain ATLL-specific CTLs to obtain long-time survival. Moga is useful, but insufficient, for inducing such CTLs by suppressing regulatory T-cells. No effective method is available to activate an ATLL-specific cellular immune response. Further studies are urgently needed to establish effective methods for attaining ATLL-specific CTLs. Disclosures No relevant conflicts of interest to declare.

Anti-CCR4 Monoclonal Antibody (Mogamulizumab) and Total Skin Electron Beam Therapy (TSEB) in Patients With Stage IB-IIB Cutaneous T-Cell Lymphoma

Anti-CCR4 Monoclonal Antibody (Mogamulizumab) and Total Skin Electron Beam Therapy (TSEB) in Patients With Stage IB-IIB Cutaneous T-Cell Lymphoma

Cutaneous T-Cell Lymphoma: Optimizing Care in Patients Receiving Anti-CCR4 Monoclonal Antibody Mogamulizumab.

Cutaneous T-cell lymphoma (CTCL), including subtypes mycosis fungoides (MF) and Sézary syndrome (SS), represents a rare group of non-Hodgkin lymphomas. Mogamulizumab is a first-in-class monoclonal antibody that selectively binds to C-C chemokine receptor 4, which is overexpressed on the surface of tumor cells in T-cell malignancies, including MF/SS-type CTCL. This review identifies common diagnostic features of MF/SS, the efficacy and side effect profile of mogamulizumab, and practical management strategies for optimizing the nursing care of patients with MF/SS-type CTCL. Case studies are used to describe the role of mogamulizumab in CTCL and to review practical considerations when administering mogamulizumab to patients. Mogamulizumab is an effective treatment for adult patients with relapsed or refractory MF/SS-type CTCL who have received at least one prior systemic therapy. Infusion reactions and drug eruptions require prompt diagnosis and treatment.

Quality of Life in Cutaneous T-cell Lymphoma Patients Treated with the Anti-CCR4 Monoclonal Antibody Mogamulizumab versus Vorinostat: Results from MAVORIC

Quality of Life in Cutaneous T-cell Lymphoma Patients Treated with the Anti-CCR4 Monoclonal Antibody Mogamulizumab versus Vorinostat: Results from MAVORIC