The C-C chemokine receptor 4 (CCR4) is predominantly expressed in type 2 helper T (Th2) cells and regulatory T (Treg) cells.1 Under physiologic conditions and in response to its ligands, CCL17 (TARC) and CCL22 (MDC), CCR4 promotes T-cell migration to the skin.2 Of note, CCR4 is highly expressed in mature T-cell neoplasms, such as adult T-cell leukemia/lymphoma and cutaneous T-cell lymphomas, and therefore provides an attractive therapeutic target.3
Poor Prognosis for These Cutaneous Lymphomas
Cutaneous T-cell lymphomas are a heterogeneous group of non-Hodgkin lymphomas with clonal proliferation of skin-homing T cells. The two most common variants of cutaneous T-cell lymphomas are mycosis fungoides (presenting with cutaneous patches, plaques, tumors, and/or erythroderma) and the erythrodermic and leukemic variant Sézary syndrome. Advanced, treatment-refractory, and/or transformed stages of cutaneous T-cell lymphomas have a poor prognosis.4 There is no cure, and current treatments for progressive disease using U.S. Food and Drug Administration (FDA)-approved agents achieve response rates of only ~30%, and responses are of short duration.
A recent retrospective analysis of systemic therapies evaluating nearly 200 patients revealed a median time to next treatment of 3.9 months, with few durable responses seen among patients initiating single-agent or multiagent chemotherapy compared with biologic therapies, such as interferon-alpha (time to next treatment = 8.7 months, P < .00001) and histone deacetylase (HDAC) inhibitors (time to next treatment = 4.5 months, P = .01).5 The majority of patients, however, will need an alternative therapy within 1 year after treatment initiation, and treatment decisions must take into account patients’ disease, comorbidities, treatment availability, therapeutic toxicities, and quality of life.
New Kid on the Block
Mogamulizumab (Poteligeo) is a defucosylated, humanized anti-CCR4 monoclonal antibody that depletes CCR4-expressing cells by enhanced antibody-dependent, cell-mediated cytotoxicity. Data from a translational study leveraging a phase I/II trial of mogamulizumab in cutaneous T-cell lymphomas have shown that it reduces the numbers of CCR4-positive malignant T cells and CCR4-positive Treg cells in the peripheral blood of patients with cutaneous T-cell lymphomas.6
As reviewed in this issue of The ASCO Post, and as reported in The Lancet Oncology, Kim et al7 investigated the clinical efficacy of mogamulizumab in patients with mycosis fungoides and Sézary syndrome in the MAVORIC trial, based on encouraging results and a favorable toxicity profile seen in the same disease population in phase I/II trials. In this open-label, randomized, controlled phase III trial, the efficacy and safety of mogamulizumab given weekly for the first month (intravenously at 1 mg/kg) and bimonthly thereafter were compared with those of standard treatment with vorinostat (Zolinza; 400 mg daily), an oral HDAC inhibitor that was approved by the FDA for treatment of relapsed or refractory mycosis fungoides or Sézary syndrome in 2006.
CCR4 gain-of-function mutations determine sensitivity to mogamulizumab and are associated with superior outcome.— Christiane Querfeld, MD, PhD
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In total, 372 patients with relapsed or refractory mycosis fungoides and Sézary syndrome were randomly assigned 1:1 to receive mogamulizumab (n = 186) or vorinostat (n = 186). Mogamulizumab was superior to vorinostat for most endpoints. The estimated median progression-free survival was 7.6 months (95% confidence interval [CI] = 5.6–10.2 months) for those treated with mogamulizumab, compared with 3.1 months (95% CI = 2.8–4.0 months) in the vorinostat arm (hazard ratio = 0.53, 95% CI = 0.41–0.69). The investigator-assessed proportion of patients achieving an overall response was also higher with mogamulizumab than with vorinostat (28% vs 5%, P < .001). The difference in overall response rates between mogamulizumab and vorinostat was greater in patients with Sézary syndrome (37% vs 2.3%). Of the 186 patients randomly assigned to vorinostat, 136 patients crossed over to mogamulizumab treatment because of disease progression (80%) or intolerable toxicities (20%).
The most common treatment-related side effects were grade 1/2 in both arms and consisted of infusion-related reactions (32%), diarrhea (23%), and fatigue (22%) in the mogamulizumab-treated population, whereas diarrhea (57%), nausea (41%), and fatigue (32%) were the most common side effects in the vorinostat-treated population. Serious grade 3/4 adverse events were infrequent in the mogamulizumab group and consisted of pyrexia in 8 patients (4%) and cellulitis in 5 patients (3%).
Data from Ni et al have shown that treatment with mogamulizumab causes dramatic decreases in cell numbers and CCR4 expression levels in both malignant T cells and Treg cells in peripheral blood samples of patients with mycosis fungoides or Sézary syndrome.6 Treg cells suppress immune reactions, including autoimmunity and antitumor immunity. The high incidence of infusion-related rashes with anti-CCR4 (mogamulizumab) is not fully elucidated but may be caused by depleting Tregs and the abrogation of their immunosuppressive properties. In adult T-cell leukemia/lymphoma, the onset of skin rash was coincident with effector Treg cell (CD45RA-FoxP3+CCR4+) depletion from the peripheral blood, whereas adult T-cell leukemia/lymphoma relapses were coincident with effector Treg recovery.8
Closing Thoughts
Mogamulizumab is active in cutaneous T-cell lymphomas with a good safety profile, and patients with Sézary syndrome appear to have a more profound benefit from this agent, including symptom relief. It is now approved by the FDA for treatment of patients with relapsed or refractory mycosis fungoides or Sézary syndrome who failed to respond to at least one systemic therapy. The response rates and duration of response suggest a modest advance as a single agent, but it offers vast unexplored possibilities in combination with biologic/immunomodulatory agents. The phase III trial results also confirm that vorinostat, although approved by the FDA, has low real-world durable responses and compliance because of poor tolerance.
CCR4 targeting is an exciting and new therapeutic approach in cutaneous T-cell lymphomas.— Christiane Querfeld, MD, PhD
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CCR4 targeting is an exciting and new therapeutic approach in cutaneous T-cell lymphomas. Genomic profiling analysis of circulating CD4-positive CD26-negative T cells from 37 patients with Sézary syndrome revealed activating CCR4 mutations in nearly one-third of patients; it would be interesting to explore whether these mutations have an effect on the outcome of mogamulizumab treatment in cutaneous T-cell lymphomas.9 In patients with adult T-cell leukemia/lymphoma, CCR4 gain-of-function mutations determine sensitivity to mogamulizumab and are associated with superior outcome.10 ■
Dr. Querfeld is Chief, Division of Dermatology and Director, Cutaneous Lymphoma Program, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, California.
DISCLOSURE: Dr. Querfeld has received honoraria from Kyowa Pharmaceutical, MiRagen, and Medivir; has been a consultant/advisor to MiRagen, Actelion Pharmaceuticals, Medivir, Bioniz Therapeutics, Kyowa Pharmaceutical, Trillium; has received funding from Celgene; and travel/acommodations/expenses from Trillium.
REFERENCES
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2. Campbell JJ, O’Connell DJ, Wurbel MA: Cutting edge: Chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions. J Immunol 178:3358-3362, 2007.
3. Yoshie O, Matsushima K: CCR4 and its ligands: From bench to bedside. Int Immunol 27:11-20, 2015.
4. Rubio-Gonzalez B, et al: Clinical manifestations and pathogenesis of cutaneous lymphomas. Br J Haematol 176:16-36, 2017.
5. Hughes CF, et al: Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome. Blood 125:71-81, 2015.
6. Ni X, Langridge T, Duvic M: Depletion of regulatory T cells by targeting CC chemokine receptor type 4 with mogamulizumab. Oncoimmunology 4:e1011524, 2015.
7. Kim YH, et al: Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC). Lancet Oncol 19:1192-1204, 2018.
8. Ureshino H, et al: Effector regulatory T cells reflect the equilibrium between antitumor immunity and autoimmunity in adult T-cell leukemia. Cancer Immunol Res 4:644-649, 2016.
9. Wang L, et al: Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat Genet 47:1426-1434, 2015.
10. Sakamoto Y, et al: CCR4 mutations associated with superior outcome of adult T-cell leukemia/lymphoma under mogamulizumab treatment. Blood 132:758-761, 2018.
