New data from the MAVORIC (Mogamulizumab anti-CCR4 Antibody Versus ComparatOR In CTCL; NCT01728805) trial evaluating the response to treatment with mogamulizumab-kpkc (Poteligeo®; Kyowa Kirin; previously known as KW-0761) in adults with mycosis fungoides (MF) or Sézary syndrome (SS) offers insight novel based on the extent of blood involvement at baseline.

Mycosis fungoides and Sézary syndrome are the most common subtypes of cutaneous T-cell lymphoma.[1] Most people with CTCL have MF (50%-70%), with some (~12%) experiencing rapid progression (or disease worsening) to advanced-stage MF.[2][3] In the early stages, many people only experience skin symptoms, which may include redness, rashes, and smaller patches.[3] If skin symptoms progress, larger areas of the skin will be affected with more intense redness, scaling, and lesions.[1] In some people, CTCL can spread to other parts of the body such as the blood and lymph nodes.[7] SS is a rare (~3%), a serious form of CTCL that affects the skin and blood with the most noticeable symptom being a red, itchy rash covering large portions of the body. [8][9] Sometimes, it can spread to the lymph nodes and internal organs.[8][9]

Mogamulizumab is a humanized monoclonal antibody that recruits the body’s own immune cells to kill CCR4+ (CC chemokine receptor 4) malignant T-cells. [7][8] CCR4 is overexpressed in Sézary syndrome and in mycosis fungoides at all stages.[9][10] Mogamulizumab was produced using Kyowa Kirin’s proprietary POTELLIGENT® technology platform, which is associated with enhanced antibody-dependent cellular cytotoxicity.[11]

Post-hoc analysis
The post-hoc analysis of the study, published in the Journal of the European Academy of Dermatology and Venereology, showed that patients with higher levels of blood involvement in MF or SS saw improved outcomes when treated with mogamulizumab compared to vorinostat (Zolinza®; Merck & Co).[12]

The published findings reinforce the importance of identifying and closely monitoring the blood in MF or SS to ensure treatment is tailored as the disease evolves. These findings are important because studies have shown that I=increasing blood tumor burden is associated with poorer prognosis for both MF and SS [13] Furthermore, while relatively common in more advanced diseases, blood involvement may be present in up to 20% of less advanced cases [14] and finally, 1 in 3 patients with MF, the most common CTCL subtype, will experience progression within the skin or to other areas, including blood.[13][15]

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Complex treartment
“Managing any type of cutaneous T-cell lymphoma can be complex as the initial presentation and treatment is focused on the skin but the disease can travel into the blood,” explained the study author Lauren C. Pinter-Brown MD, FACP, Chao Family Comprehensive Cancer Center, University of California, Irvine.

“This latest analysis shows the need to be vigilant in monitoring a patient’s blood so that the appropriate treatment can be used in patients with blood involvement to help improve outcomes,” she added.

Trial
The MAVORIC trial is a pivotal open-label, international, Phase 3, randomized controlled trial that evaluated the safety and efficacy of mogamulizumab versus standard-of-care vorinostat in patients with previously treated MF or SS, the two most common types of cutaneous T-cell lymphoma (CTCL).

It is the largest randomized study to compare systemic therapies in these subtypes of CTCL, a rare form of non-Hodgkin’s lymphoma that can affect the skin, blood, lymph nodes and internal organs. The trial included CTCL patients at varying blood classification stages from those with no blood involvement (B0) to intermediate (B1) to the most severe patients (B2).[16] Blood involvement can occur in both SS and MF, especially in advanced disease, although it may also occur in early stages.[17]

The analysis showed that investigator-assessed progression-free survival (PFS) was significantly longer for patients treated with mogamulizumab compared to vorinostat, at 7.7 months and 3.1 months, respectively (P<0.0001). When data were stratified by blood classification, PFS was found to be significantly longer for mogamulizumab compared to vorinostat in patients with any blood involvement (B1 and B2 levels).[12]

Overall response rate (ORR) was also higher with mogamulizumab than with vorinostat in the overall trial population (28.0% vs 4.8%, respectively; P < 0.0001) and significantly so for those with the highest level of blood involvement (B2: 37.4% vs 3.2%; P < 0.0001). Additionally, the difference in time-to-next-treatment was significantly longer for patients treated with mogamulizumab versus vorinostat with B1 (12.63 vs 3.07 months, P=0.0018) and B2 (13.07 vs 3.53 months, P<0.0001) level blood involvement.[12]

Over the first 12 cycles of treatment, 81 patients treated with mogamulizumab (43.5%) had a ≥50% improvement in skin response (modified Severity-Weighted Assessment Tool), versus 41 patients (22.0%) with vorinostat. In the mogamulizumab arm, complete or partial skin responses occurred more often among patients with B1 (14/31 [45.2%]) and B2 (51/91 [56.0%]) level blood involvement, compared to B0 (16/64 [25.0%]). Additionally, 16/91 (17.6%) mogamulizumab-treated patients with B2 level blood involvement had a 100% improvement compared to 3/93 (3.2%) patients treated with vorinostat.[1] Drug-related treatment-emergent adverse events were similar in patients regardless of blood involvement.[12]

“Insights from this MAVORIC analysis drive home the importance of identifying and closely monitoring for blood involvement in patients with either MF or SS, to ensure treatment approaches are tailored as the disease evolves,” said Eslie Dennis, M.D., SVP, Chief Medical Officer at Kyowa Kirin Inc.

“These data demonstrate mogamulizumab provides benefit over vorinostat in all patients with this rare cancer, particularly for patients with blood involvement who are thought to have a worse prognosis.”

In the United States mogamulizumab is approved by the US Food and Drug Administration for intravenous infusion indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy.

Clinical trial
Study of KW-0761 Versus Vorinostat in Relapsed/Refractory CTCL – NCT01728805

Highlights of Prescribing Information
Mogamulizumab-kpkc (Poteligeo®; Kyowa Kirin) [Prescribing Information]]
Vorinostat (Zolinza®; Merck & Co) [Prescribing Information]

References
[1] Cutaneous T-Cell Lymphoma. Leukemia & Lymphoma Society. Online. Last accessed on July 21, 2021. [Article]
[2] Talpur R, Singh L, Daulat S, et al. Long-term Outcomes of 1,263 Patients with Mycosis Fungoides and Sezary Syndrome from 1982 to 2009. Clin Can Res. 2012;18(18):5051-5060. doi:10.1158/1078-0432.ccr-12-0604.
[3] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) – Primary Cutaneous Lymphomas. Online. Last accessed on July 21, 2021 [Guideline]
[4] Pulitzer M. Cutaneous T-cell Lymphoma. Clin in Laboratory Med. 2017;37(3):527-546. doi:10.1016/j.cll.2017.06.006.
[5] Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood. 2019;133(16):1703-1714. doi:10.1182/blood-2018-11-881268
[6] Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110(6):1713-1722. doi:10.1182/blood-2007-03-055749.
[7] Mogamulizumab-kpkc (Poteligeo®; Kyowa Kirin Inc., Bedminster, NJ USA). Prescribing information.
[8] Ishida T, Iida S, Akatsuka Y, et al. The CC chemokine receptor 4 as a novel-specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma. Clin Cancer Res. 2004;10:7529-7539.
[9] Ferenczi K, Fuhlbrigge RC, Pinkus J, et al. Increased CCR4 expression in cutaneous T cell lymphoma. J Invest Dermatol. 2002;119:1405-1410.
[10] Kallinich T, Muche JM, Qin S, et al. Chemokine receptor expression on neoplastic and reactive T cells in the skin at different stages of mycosis fungoides. J Invest Dermatol. 2003;121:1045-1052.
[11] National Cancer Institute. Mogamulizamab. Dictionaries. Online. last accessed on July 21, 2021. [Article]  .
[12] R. Cowan, J.J. Scarisbrick et al. Efficacy and safety of mogamulizumab by patient baseline blood tumour burden: a post hoc analysis of the MAVORIC trial. Journal of the European Academy of Dermatology and Venerology. 2021. doi:10.1111/jdv.17523
[13] Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol. 2010;28(31):4730-4739.
[14] Scarisbrick JJ, Quaglino P, Prince HM, et al. The PROCLIPI international registry of early-stage mycosis fungoides identifies substantial diagnostic delay in most patients. Br J Dermatol. 2019;181:350–357.
[15] Amorim GM, Niemeyer-Corbellini JP, Quintella DC, Cuzzi T, Ramos-E-Silva M. Clinical and epidemiological profile of patients with early stage mycosis fungoides. An Bras Dermatol. 2018;93(4):546-552.
[16] Kim YH, Bagot M, Pinter-Brown L, et al. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018;19(9):1192-1204.
[17] Scarisbrick JJ, Hodak E, Bagot M, et al. Blood classification and blood response criteria in mycosis fungoides and Sézary syndrome using flow cytometry: recommendations from the EORTC cutaneous lymphoma task force. Eur J Cancer. 2018;93:47-56. doi:10.1016/j.ejca.2018.01.076

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