REVIEW URRENT C OPINION
Experimental treatment strategies in primary cutaneous T-cell lymphomas Sima Rozati and Youn H. Kim
Purpose of review Cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of malignancies derived from skin-homing or resident T cells. Effective treatments are limited, thus new therapies are in development to address the unmet medical need. Recent findings Recent studies uncovering the genetic alteration in cutaneous T-cell lymphoma have enhanced our understanding of the importance of the T-cell activation/survival pathways, dysregulated immune system, and the relevance of chromatin modification in the pathogenesis of CTCL. New advances in cancer immunomodulation such as with PD1/PD-L1 inhibitors and novel targeted antitumor therapies such as brentuximab vedotin and mogamulizumab as well as potential combination strategies are promising for improving clinical efficacy with manageable toxicity profile. Summary All these new therapeutic approaches have resulted in broadening the treatment landscape and a potential paradigm shift in the management of CTCL. Keywords cancer immunotherapy, cutaneous T-cell lymphoma, targeted cancer therapy
INTRODUCTION Cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of malignancies derived from skin-homing or skin-resident T cells. The most common subtypes are mycosis fungoides, and Se´zary syndrome [1], which account for approximately 70–75% of CTCL [2]. Treatment options include skin-directed and/or systemic therapies [3]. The overall response rate of most available systemic therapies ranges from 30 to 40%; relapse is common and difficult to treat [4]. CTCLs have a more indolent course compared with the systemic TCLs. Moreover, aggressive multiagent chemotherapy approaches used in systemic TCLs have failed to result in meaningful clinical benefit in CTCL. In fact, response duration of such treatments is shortlived and the immunosuppressive and cytotoxic side-effect outweighs their potential mild benefits. Therefore, novel treatment approaches, such as cancer immunotherapy, epigenetic modulation, and other targeted therapies, have resulted in newer options and approaches in the management of this heterogeneous and often debilitating disease. www.co-oncology.com
GENOMIC LANDSCAPE IN CUTANEOUS TCELL LYMPHOMA Up to very recently there have been very limited genomic studies investigating mutational status in CTCL [5–8]. Recently, several groups have performed whole-genome or exome sequencing in addition to other sequencing techniques to investigate the genomic alterations in CTCL as well as identifying new biomarkers for diagnosis or potential targets for therapy. Ungewickell et al. performed whole-exome sequencing on 11 mycosis fungoides and Se´zary syndrome samples each paired with a healthy donor sample to identify somatic genetic alterations associated with these malignancies. MLL3 (26%) and TP53 (13%), both tumor suppressors, were Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA Correspondence to Sima Rozati, MD, Department of Dermatology, 450 Broadway, Pavilion B, 4th floor, Redwood city, CA 94063, USA. Tel: +1 650 721 7193; e-mail: [email protected] Curr Opin Oncol 2016, 28:166–171 DOI:10.1097/CCO.0000000000000272 Volume 28 Number 2 March 2016
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Treatment in cutaneous T-cell lymphoma Rozati and Kim
KEY POINTS Aggressive multiagent chemotherapy approaches used in systemic TCLs have failed to result in meaningful clinical benefit in CTCL. Newer immune-modulators such as anti-PD1/PD-L1 and novel targeted antitumor therapies, such as brentuximab vedotin, mogamulizumab, and antiKIR3DL2, are promising for subsets of CTCL patients. Our new understanding of the genomic landscape in CTCL will guide the development of treatment options and allow us to provide personalized, precision medicine.
identified as the most frequently mutated genes, while they noted previously described gain-of-function mutations such as KRAS and PLCG1 [6,9]. In 38% of the mycosis fungoides/Se´zary syndrome samples examined, there were recurrent alterations in the TNFR2-related pathway, resulting in enhanced NF-kB signaling, in addition to other genes regulating T-cell survival and proliferation. They also found in two patients a large deletion on chromosome 2 involving the functionally antagonistic surface receptors CTLA4 and CD28, fusing the extracellular portion of the inhibitory CTLA4 protein to the coactivating cytoplasmic tail of CD28, speculating that this fusion could be responsible for immune evasion and enhanced lymphoma cell proliferation in a subset of patients with mycosis fungoides and Se´zary syndrome [10 ]. Choi et al. [11 ] studied somatic single-nucleotide variants (SSNV) and somatic copy number variants (SCNV) in 40 cases of CTCL with stage IVA1-B and found genes with mutational status including TP53, DNMT3A, FAS, NFKB2, ARID1A, ZEB1, and CDKN2A. They demonstrated frequent deletions and damaging of SSNVs in chromatin-modifying genes ARID1A, CTCF, and DNMT3A. Some of their identified gene mutations such as CD28, DNMT3A, and RHOA, STAT5B and ZEB1 are seen in systemic Tcell lymphomas suggesting common pathway in the malignant transformation of mature T cells. Wang et al. [12] assessed somatic mutation, DNA copy number, and gene expression profiles in 37 Se´zary syndrome patients and demonstrated the most frequently mutated genes in their combined cohort were TP53 (24%), PLCG1 (18%), CARD11 (15%), ARID1A (10%), FAS (10%), CC chemokine receptor 4 (CCR4, 7%), RHOA (7%), and TNFRSF1B (6%). Da Silva Almeida et al. [13 ] performed wholeexome sequencing of tumor-normal sample pairs from 25 patients with Se´zary syndrome, eight &&
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patients with mycosis fungoides and nine patients with other CTCLs. They found recurrent deletions involving tumor-suppressor genes in TP53 (52%), RB1 (16%), PTEN (20%), and CDKN1B (20%) in Se´zary syndrome samples. Moreover, they observed focal chromosome deletions encompassing the DNMT3A locus of this epigenetic tumorsuppressor gene in 20% of the Se´zary syndrome samples. Additionally, they identified mutations resulting loss of function epigenetic regulators including TET2, CREBBP a histone acetyltransferase, MLL3 (KMT2C) histone H3 lysine 4 methyltransferase and other chromatin remodeling complexes [13 ]. Among other gene alterations, they identified three point mutations in Se´zary syndrome in PLCG1, an oncogene described as carrying gain-of-function mutations in CTCL [9]. Finally, they report alteration in TNFR2, as described by Khavari and colleagues, and CARD11, as described by Wang, leading to NFkB activation. These elaborate studies differ in their sample size, subtypes of CTCL and methodological techniques. Nevertheless, they demonstrate common mutations in tumor suppressors such as TP53 and oncogenes such as PLCG1, as well as mutations in key regulators leading to activation of the NF-kB pathway (TNFR2 and CARD11), the latter suggesting potential treatment benefits with bortezomib or other proteasome inhibitors in a subset of CTCL. Functional relevant mutations in chromatin modifying genes (MLL3, DNMT3A) could explain the clinical activity of histone deacetylase (HDAC) inhibitors in this disease. Genomic alterations in key elements of the immune system (CD28, CTLA-4) described in these studies support a potential relevance for immune checkpoint blockade strategy in CTCL [11 ]. &&
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CANCER IMMUNOTHERAPY There is mounting evidence that immune evasion is an important part of mycosis fungoides/Se´zary syndrome pathogenesis as they show features of immunomodulating regulatory T cells resulting in immune evasion and thus allowing clonal T-cell expansion [14,15]. Therefore, T-cell immunity is critical for meaningful antitumor response [16]. Tumor-infiltrating CD8þ T cells have been associated with improved survival and therapies which augment T-cell function are effective in mycosis fungoides/Se´zary syndrome [17]. Moreover, reports of 9p24.1/PD-L2 translocation, recurrent SSNV in CD28 [11 ], or CTLA4–CD28 fusion [10 ] in mycosis fungoides/Se´zary syndrome support a genomic basis for immune evasion.
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IMMUNE CHECKPOINT BLOCKADE (ANTIPD-1 mAb)
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
PD-1, programmed cell death 1 receptor, is an immune-checkpoint molecule expressed by T cells. When bound to its ligands, it negatively regulates Tcell effector functions. The PD-1 pathway functions to limit unwanted or excessive immune responses, including autoimmune reactions as part of the adaptive phase of the immune system. Current data suggest that the PD-1, PD-L1/PD-L2 may play a significant role in preventing immune-driven eradication of mycosis fungoides/Se´zary syndrome tumor population. Samimi et al. showed expression of PD-1 and PD-L1 expression in various morphological subsets of mycosis fungoides [18] as well as on tumor cells circulating in the peripheral blood of Se´zary syndrome patients [19]. Pembrolizumab (MK-3475) is a humanized immunoglobulin G4 mAb which binds the PD-1 receptor, thus inhibiting the interaction with its ligands, PD-L1 and PD-L2. Fatigue and skin eruption are the most common immune-related adverse events. Other organspecific events such pneumonitis, colitis, endocrine, and hepatic toxicities reported with CTLA-4 blocking agents are less frequently described in clinical trials with anti-PD-1/PD-L1 agents. A clear knowledge of the toxicities of these agents is vital to achieving their safe delivery outside of clinical trials [20]. Currently, a multicentered, open-labeled, nonrandomized phase II clinical trial of pembrolizumab in stage IB–IVB mycosis fungoides/Se´zary syndrome is ongoing (NCT02243579). The clinical and correlative data from this study may guide rational combination strategies in CTCL.
Allogeneic hematopoietic stem cell transplantation (allogeneic HSCT) can result in sustained remissions suggesting immune response to tumor may be curative by immune-mediated graft versus lymphoma [25,26]. Duvic et al. [27] have reported their experience with total skin electron beam and nonmyeloablative allogenic HSCT including 19 patients with mycosis fungoides or Se´zary syndrome. They reported overall survival 79% and progression-free survival 53% at 2 years. Of note, 67% of the patients suffered from acute graft versus host disease and chronic graft versus host disease. Duarte et al. [28] demonstrated a progression-free survival of 30% and overall survival of 44% in their extended analysis of 60 patients with mycosis fungoides or Se´zary syndrome at 7 years post-HSCT (27% received myeloablative conditioning regimen). Despite the difference in nonmyeloablative conditioning regimens used in the several reported case series the progression-free survival and overall survival after HSCT have been similar at the different centers. Hence, HSCT can be considered in high-risk patients with advanced or refractory mycosis fungoides/Se´zary syndrome. Weng et al. [25] demonstrated determination of clinically meaningful molecular remission and monitoring minimal residual disease by high-through put sequencing of TCRB allows to optimize the management of these patients after transplant. Longer follow-up to better assess posttransplant complication issues and management are required but these studies also undermine the rationales for developing new immunotherapy approaches.
RESIQUIMOD Another promising approach to utilizing immunotherapy in CTCL is Toll-like receptor agonists, which stimulate the innate immune system for the induction of an antitumor response by enhancement of production of cytokines such as IFN-a and IFN-g, and IL-12 [21] as well as activation of plasmacytoid predendritic cells [22,23]. In a phase I open-label clinical trial with topical resiquimod 0.03% and 0.06% gel, a Toll-like receptor 7/8 agonist, target lesions of 12 patients with stage IA–IIA CTCL were treated. In 75% of patients treated lesions significantly improved and 30% had clearing of all treated lesions. Resiquimod also induced regression of untreated lesions suggesting enhanced systemic antitumor activity [24]. With adverse events being primarily limited to local skin irritation, topical resiquimod gel can be considered a good skin-directed therapy in early stage mycosis fungoides. 168
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NOVEL TARGETED ANTITUMOR THERAPIES There are many novel targeted antitumor therapies coming down the pipeline. Here, we summarize therapies with more clinical evidence in CTCL at this time.
ANTI-KIR3DL2 mAb (IPH4102) KIR3DL2 (CD158) is a killer-cell immunoglobulinlike receptor that binds to its cognate HLA-class I ligands negatively modulating immune cell function. This receptor is consistently expressed across most CTCL subtypes [29] but found only on a small subset of NK-cells and CD8þT cells [30,31]. IPH4102 is a first-in-class humanized IgG1 mAb that binds to KIR3DL2-expressing tumor cells. In preclinical studies including xenograft mouse models, IPH4102 was suggested to recruit human NK cells Volume 28 Number 2 March 2016
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Treatment in cutaneous T-cell lymphoma Rozati and Kim
and macrophages to kill KIR3DL2þ tumor cells via antibody-dependent cell cytotoxicity and antibodydependent cell phagocytosis, respectively [32]. The safety and potential efficacy of this targeted immunotherapy is to be investigated in an upcoming phase I multicenter clinical trial in CTCL (NCT02593045).
BRENTUXIMAB VEDOTIN Brentuximab vedotin is an anti-CD30 mAb conjugated with monomethyl auristatin E by a proteasecleavable linker [33,34]. CD30 is highly expressed on the surface of primary cutaneous anaplastic large-cell lymphoma (pcALCL) and subtypes of lymphomatoid papulosis and is variably expressed in mycosis fungoides morphological subtypes including large cell transformed mycosis fungoides. The results of two phase II clinical trials in CTCL have been recently published. In the phase II study of brentuximab vedotin in mycosis fungoides or Se´zary syndrome, by Kim et al. [35 ], among the 30 evaluable patients, the overall global response was 70%. CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30 maximum expression of 13% (range, 0–100%); those with less than 5% CD30 expression had lower likelihood of global response than those with higher than 5% CD30 expression. They demonstrated that CD163þ M2-type tumorassociated macrophages were abundant suggesting that brentuximab vedotin may target these macrophages in addition to the malignant T cells and disrupt their tumor-promoting function as well as the possibility that these CD30 coexpressing macrophages may offer an additional source of monomethyl auristatin E to the nearby malignant T cells. In the other phase II open-label trial in patients with CD30 lymphoproliferative disorder or CD30 mycosis fungoides/Se´zary syndrome by Duvic et al. [36 ], of the 48 evaluable patients, the overall response was 73%, with a CR rate of 35%. Median time to response was 12 weeks, and duration of response was 32 weeks (range, 3–93 weeks). All patients with lymphomatoid papulosis or pcALCL responded. In both clinical trials, brentuximab vedotin was relatively well tolerated with most adverse events being manageable. Most common adverse event was peripheral neuropathy although it was reversible with dose reduction or discontinuation of the drug; some experienced irreversible neuropathy. Therefore, the authors concluded that the risk for peripheral neuropathy must be carefully assessed and monitored while the patient is receiving therapy. &
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MOGAMULIZUMAB (KW-0761, ANTI-CC CHEMOKINE RECEPTOR 4 mAb) CCR4 is a selective marker of the Th2 phenotype [37]. The interplay between CCR4 and its ligands facilitates the cross talk between malignant T-cell and its microenvironment as well as distant organ involvement. Mogamulizumab (KW-0761) is a defucosylated, humanized anti-CCR4 mAb that stimulates antibody-dependent cell-mediated cytotoxicity [38]. A phase 1/2 open-label multicenter randomized clinical trial demonstrated overall response of 47.1% for Se´zary syndrome patients and 28.6% in mycosis fungoides patients. Interestingly, mogamulizumab therapy resulted in a dramatic clearance of malignant cells as measured by flow cytometry in 18 of 19 patients with blood involvement [39]. Based on the results of this study, a phase 3 randomized trial comparing mogamulizumab versus vorinostat in patients with relapsed or refractory mycosis fungoides or Se´zary syndrome with respect to efficacy, safety, and quality of life is ongoing (NCT01728805).
IMPROVED USE OF ESTABLISHED THERAPIES The uses of standard therapies such as total skin electron beam radiation and HDAC inhibitors have been modified over the years to minimize their toxicity profile and/or lengthen duration of response, as discussed below.
LOW-DOSE TOTAL SKIN ELECTRON BEAM TREATMENT Total skin electron beam radiation (TSEBT) is administered in different doses but 36 Gy has been considered standard of therapy. Temporary loss of nails and possible permanent alopecia are reported with this dose of TSEBT in addition to common adverse events such as erythema and desquamation. Many of the toxicities are dose dependent. Furthermore, given the risk of skin atrophy, xerosis, and pigmentation changes more than two courses of 36 Gy TSEBT is not recommended [40]. Recent new data pooled from three phase II clinical trials using low-dose (12 Gy) TSEBT in mycosis fungoides patients with stage IB–IIIA revealed that this dose can result in rapid reduction of disease burden with response rates exceeding 88%, with a more favorable toxicity profile compared with highdose TSEBT. Other advantages are the shorter treatment period and the possibility to treat patients multiple times with this regimen [41 ], as well as in combination with immune-modulatory agents to prolong clinical benefits.
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EPIGENETIC THERAPIES Our understanding of epigenetic modifications in cancer progression and therapy in the past decade has resulted in novel approaches to cancer therapy. HDAC inhibitors increase the acetylation of the histone lysine residues in the nucleosome as well as acetylation of nonhistone proteins leading to chromatin accessibility to transcription factors [42]. There are multiple classes of HDAC inhibitors grouped based on their specificity to different types of HDACs [43]. Vorinostat (Zolinda) is a hydroxamic acid derivatives pan-HDAC inhibitor that was approved by the United States Food and Drug Administration in October 2006 for the treatment of CTCL. Romidepsin (F228 or desipeptide) is a potent bicyclic class I HDAC inhibitor and to a lesser extent a class II HDAC inhibitor. Romidepsin was approved by the United States Food and Drug Administration in November 2009 for the treatment of CTCL patients on the basis of two phase II, single arm, open label clinical trials showing an overall response rate of 34–35% with a complete response of 6% in relapsed/refractory CTCL patients [44,45]. Most common side-effects of HDAC inhibitors are fatigue, nausea, vomiting, and thrombocytopenia. The use of HDAC inhibitors is well documented but their use in combination with other agents is experimental in CTCL [46]. Additionally, a phase II, multicenter, openlabel, randomized clinical trial with suberohydroxamic acid phenyl ester that is a novel HDAC inhibitor designed for topical application for early stage CTCL lesions is on going (NCT02213861).
CONCLUSION CTCL is overall a debilitating, noncurative disease where current therapies do not provide reliable and/ or durable clinical responses. Moreover, patients with advanced stage mycosis fungoides/Se´zary syndrome or aggressive subtype of CTCL have a significantly compromised life expectancy, often associated with local tissue and systemic immune suppression. Thus, development of treatments that can improve not only the clinical efficacy but also provide acceptable tolerability is central to advancing the clinical management and outcome in CTCL. Current and upcoming cancer immune-modulators such as PD-1, PD-L1/PD-L2 inhibitors are promising treatment approaches that restore and augment antitumor immune response. Newer targeted antitumor therapies such as brentuximab vedotin, mogamulizumab, and anti-KIR3DL2 are promising for subsets of CTCL patients. Currently, allogeneic
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HSCT is the only potential curative therapy in those with advanced or aggressive disease. Finally, these new or established therapies used in combination can target multiple molecules or pathways thus optimizing clinical efficacy while keeping toxicity profile at a manageable level. Our new understanding of the genomic landscape in CTCL will guide the development of novel treatment options and allow us to provide the most personalized, precision medicine. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sezary 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; 110:1713–1722. 2. Bradford PT, Devesa SS, Anderson WF, Toro JR. Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases. Blood 2009; 113:5064–5073. 3. Guenova E, Hoetzenecker W, Rozati S, et al. Novel therapies for cutaneous Tcell lymphoma: what does the future hold? Expert Opin Investig Drugs 2014; 23:457–467. 4. Kim YH, Liu HL, Mraz-Gernhard S, et al. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol 2003; 139:857–866. 5. Espinet B, Salido M, Pujol RM, et al. Genetic characterization of Se´zary’s syndrome by conventional cytogenetics and cross-species color banding fluorescent in situhybridization. Haematologica 2004; 89:165–173. 6. Kiessling MK, Oberholzer PA, Mondal C, et al. High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade. Blood 2011; 117:2433–2440. 7. Lin WM, Lewis JM, Filler RB, et al. Characterization of the DNA copy-number genome in the blood of cutaneous T-cell lymphoma patients. J Invest Dermatol 2012; 132:188–197. 8. Maj J, Jankowska-Konsur A, Plomer-Niezgoda E, et al. Altered expression of Bcl-2, c-Myc, H-Ras, K-Ras, and N-Ras does not influence the course of mycosis fungoides. Arch Med Sci 2013; 9:895–898. 9. Vaque´ JP, Go´mez-Lo´pez G, Monsa´lvez V, et al. PLCG1 mutations in cutaneous T-cell lymphomas. Blood 2014; 123:2034–2043. 10. Ungewickell A, Bhaduri A, Rios E, et al. Genomic analysis of mycosis && fungoides and Se´zary syndrome identifies recurrent alterations in TNFR2. Nat Genet 2015; 47:1056–1060. These studies demonstrate important pathways involved in mycosis fungoides/ Se´zary syndrome, which can guide novel targeted therapies as well as potential diagnostic and prognostic markers. 11. Choi J, Goh G, Walradt T, et al. Genomic landscape of cutaneous T cell && lymphoma. Nat Genet 2015; 47:1011–1019. These studies demonstrate important pathways involved in mycosis fungoides/ Se´zary syndrome, which can guide novel targeted therapies as well as potential diagnostic and prognostic markers. 12. Wang L, Ni X, Covington KR, et al. Genomic profiling of Se´zary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat Genet 2015; 47:1426–1434.
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Treatment in cutaneous T-cell lymphoma Rozati and Kim 13. da Silva Almeida AC, Abate F, Khiabanian H, et al. The mutational landscape of cutaneous T cell lymphoma and Se´zary syndrome. Nat Genet 2015; 47:1465–1470. These studies demonstrate important pathways involved in mycosis fungoides/ Se´zary syndrome, which can guide novel targeted therapies as well as potential diagnostic and prognostic markers. 14. Abraham RM, Zhang Q, Odum N, Wasik MA. The role of cytokine signaling in the pathogenesis of cutaneous T-cell lymphoma. Cancer Biol Ther 2011; 12:1019–1022. 15. Wysocka M, Zaki MH, French LE, et al. Se´zary syndrome patients demonstrate a defect in dendritic cell populations: effects of CD40 ligand and treatment with GM-CSF on dendritic cell numbers and the production of cytokines. Blood 2002; 100:3287–3294. 16. Berger CL, Tigelaar R, Cohen J, et al. Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. Blood 2005; 105:1640–1647. 17. Hoppe RT, Medeiros LJ, Warnke RA, Wood GS. CD8-positive tumor-infiltrating lymphocytes influence the long-term survival of patients with mycosis fungoides. J Am Acad Dermatol 1995; 32:448–453. 18. Kantekure K, Yang Y, Raghunath P, et al. Expression patterns of the immunosuppressive proteins PD-1/CD279 and PD-L1/CD274 at different stages of cutaneous T-cell lymphoma/mycosis fungoides. Am J Dermatopathol 2012; 34:126–128. 19. Samimi S, Benoit B, Evans K, et al. Increased programmed death-1 expression on CD4þ T cells in cutaneous T-cell lymphoma: implications for immune suppression. Arch Dermatol 2010; 146:1382–1388. 20. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 2015; 26:2375–2391. 21. Huen AO, Rook AH. Toll receptor agonist therapy of skin cancer and cutaneous T-cell lymphoma. Curr Opin Oncol 2014; 26:237–244. 22. Urosevic M, Dummer R, Conrad C, et al. Disease-independent skin recruitment and activation of plasmacytoid predendritic cells following imiquimod treatment. J Natl Cancer Inst 2005; 97:1143–1153. 23. Kim YH, Gratzinger D, Harrison C, et al. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood 2012; 119:355–363. 24. Rook AH, Gelfand JC, Wysocka M, et al. Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma. Blood 2015; 126:1452–1461. 25. Weng WK, Armstrong R, Arai S, et al. Minimal residual disease monitoring with high-throughput sequencing of T cell receptors in cutaneous T cell lymphoma. Sci Transl Med 2013; 5:214ra171. 26. Hosing C, Bassett R, Dabaja B, et al. Allogeneic stem-cell transplantation in patients with cutaneous lymphoma: updated results from a single institution. Ann Oncol 2015; 26:2490–2495. 27. Duvic M, Donato M, Dabaja B, et al. Total skin electron beam and nonmyeloablative allogeneic hematopoietic stem-cell transplantation in advanced mycosis fungoides and Sezary syndrome. J Clin Oncol 2010; 28:2365–2372. 28. Duarte RF, Boumendil A, Onida F, et al. Long-term outcome of allogeneic hematopoietic cell transplantation for patients with mycosis fungoides and Se´zary syndrome: a European society for blood and marrow transplantation lymphoma working party extended analysis. J Clin Oncol 2014; 32:3347–3348. 29. Sako N, Schiavon V, Bounfour T, et al. Membrane expression of NK receptors CD160 and CD158k contributes to delineate a unique CD4þ T-lymphocyte subset in normal and mycosis fungoides skin. Cytometry A 2014; 85:869–882.
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30. Moretta A, Moretta L. HLA class I specific inhibitory receptors. Curr Opin Immunol 1997; 9:694–701. 31. Moins-Teisserenc H, Daubord M, Clave E, et al. CD158k is a reliable marker for diagnosis of Se´zary syndrome and reveals an unprecedented heterogeneity of circulating malignant cells. J Invest Dermatol 2015; 135:247–257. 32. Sicard H, Bonnafous C, Morel A, et al. A novel targeted immunotherapy for CTCL is on its way: Anti-KIR3DL2 mAb IPH4102 is potent and safe in nonclinical studies. Oncoimmunology 2015; 4:e1022306. 33. Younes A, Yasothan U, Kirkpatrick P. Brentuximab vedotin. Nat Rev Drug Discov 2012; 11:19–20. 34. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood 2003; 102:1458–1465. 35. Kim YH, Tavallaee M, Sundram U, et al. Phase II investigator-initiated study of & brentuximab vedotin in mycosis fungoides and se´zary syndrome with variable cd30 expression level: a multi-institution collaborative project. J Clin Oncol 2015; 33:3750–3758. These studies contain relevant information about the therapy, dosing, and potential side-effects. 36. Duvic M, Tetzlaff MT, Gangar P, et al. Results of a phase II trial of brentuximab & vedotin for CD30þ cutaneous t-cell lymphoma and lymphomatoid papulosis. J Clin Oncol 2015; 33:3759–3765. These studies contain relevant information about the therapy, dosing, and potential side-effects. 37. D’Ambrosio D, Iellem A, Bonecchi R, et al. Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J Immunol 1998; 161:5111–5115. 38. Wilcox RA. Mogamulizumab: 2 birds, 1 stone. Blood 2015; 125:1847–1848. 39. Duvic M, Pinter-Brown LC, Foss FM, et al. Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood 2015; 125:1883–1889. 40. Becker M, Hoppe RT, Knox SJ. Multiple courses of high-dose total skin electron beam therapy in the management of mycosis fungoides. Int J Radiat Oncol Biol Phys 1995; 32:1445–1449. 41. Hoppe RT, Harrison C, Tavallaee M, et al. Low-dose total skin electron beam & therapy as an effective modality to reduce disease burden in patients with mycosis fungoides: results of a pooled analysis from 3 phase-II clinical trials. J Am Acad Dermatol 2015; 72:286–292. These studies contain relevant information about the therapy, dosing, and potential side-effects. 42. Jones PA. At the tipping point for epigenetic therapies in cancer. J Clin Invest 2014; 124:14–16. 43. Prince HM, Dickinson M. Romidepsin for cutaneous T-cell lymphoma. Clin Cancer Res 2012; 18:3509–3515. 44. Piekarz RL, Frye R, Turner M, et al. Phase II multiinstitutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 2009; 27:5410–5417. 45. Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 2010; 28:4485–4491. 46. Rozati S, Cheng PF, Widmer DS, et al. Romidepsin and azacitidine synergize in their epigenetic modulatory effects to induce apoptosis in CTCL. Clin Cancer Res 2015.
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Experimental treatment strategies in primary cutaneous T-cell lymphomas Sima Rozati and Youn H. Kim
Purpose of review Cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of malignancies derived from skin-homing or resident T cells. Effective treatments are limited, thus new therapies are in development to address the unmet medical need. Recent findings Recent studies uncovering the genetic alteration in cutaneous T-cell lymphoma have enhanced our understanding of the importance of the T-cell activation/survival pathways, dysregulated immune system, and the relevance of chromatin modification in the pathogenesis of CTCL. New advances in cancer immunomodulation such as with PD1/PD-L1 inhibitors and novel targeted antitumor therapies such as brentuximab vedotin and mogamulizumab as well as potential combination strategies are promising for improving clinical efficacy with manageable toxicity profile. Summary All these new therapeutic approaches have resulted in broadening the treatment landscape and a potential paradigm shift in the management of CTCL. Keywords cancer immunotherapy, cutaneous T-cell lymphoma, targeted cancer therapy
INTRODUCTION Cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of malignancies derived from skin-homing or skin-resident T cells. The most common subtypes are mycosis fungoides, and Se´zary syndrome [1], which account for approximately 70–75% of CTCL [2]. Treatment options include skin-directed and/or systemic therapies [3]. The overall response rate of most available systemic therapies ranges from 30 to 40%; relapse is common and difficult to treat [4]. CTCLs have a more indolent course compared with the systemic TCLs. Moreover, aggressive multiagent chemotherapy approaches used in systemic TCLs have failed to result in meaningful clinical benefit in CTCL. In fact, response duration of such treatments is shortlived and the immunosuppressive and cytotoxic side-effect outweighs their potential mild benefits. Therefore, novel treatment approaches, such as cancer immunotherapy, epigenetic modulation, and other targeted therapies, have resulted in newer options and approaches in the management of this heterogeneous and often debilitating disease. www.co-oncology.com
GENOMIC LANDSCAPE IN CUTANEOUS TCELL LYMPHOMA Up to very recently there have been very limited genomic studies investigating mutational status in CTCL [5–8]. Recently, several groups have performed whole-genome or exome sequencing in addition to other sequencing techniques to investigate the genomic alterations in CTCL as well as identifying new biomarkers for diagnosis or potential targets for therapy. Ungewickell et al. performed whole-exome sequencing on 11 mycosis fungoides and Se´zary syndrome samples each paired with a healthy donor sample to identify somatic genetic alterations associated with these malignancies. MLL3 (26%) and TP53 (13%), both tumor suppressors, were Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA Correspondence to Sima Rozati, MD, Department of Dermatology, 450 Broadway, Pavilion B, 4th floor, Redwood city, CA 94063, USA. Tel: +1 650 721 7193; e-mail: [email protected] Curr Opin Oncol 2016, 28:166–171 DOI:10.1097/CCO.0000000000000272 Volume 28 Number 2 March 2016
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KEY POINTS Aggressive multiagent chemotherapy approaches used in systemic TCLs have failed to result in meaningful clinical benefit in CTCL. Newer immune-modulators such as anti-PD1/PD-L1 and novel targeted antitumor therapies, such as brentuximab vedotin, mogamulizumab, and antiKIR3DL2, are promising for subsets of CTCL patients. Our new understanding of the genomic landscape in CTCL will guide the development of treatment options and allow us to provide personalized, precision medicine.
identified as the most frequently mutated genes, while they noted previously described gain-of-function mutations such as KRAS and PLCG1 [6,9]. In 38% of the mycosis fungoides/Se´zary syndrome samples examined, there were recurrent alterations in the TNFR2-related pathway, resulting in enhanced NF-kB signaling, in addition to other genes regulating T-cell survival and proliferation. They also found in two patients a large deletion on chromosome 2 involving the functionally antagonistic surface receptors CTLA4 and CD28, fusing the extracellular portion of the inhibitory CTLA4 protein to the coactivating cytoplasmic tail of CD28, speculating that this fusion could be responsible for immune evasion and enhanced lymphoma cell proliferation in a subset of patients with mycosis fungoides and Se´zary syndrome [10 ]. Choi et al. [11 ] studied somatic single-nucleotide variants (SSNV) and somatic copy number variants (SCNV) in 40 cases of CTCL with stage IVA1-B and found genes with mutational status including TP53, DNMT3A, FAS, NFKB2, ARID1A, ZEB1, and CDKN2A. They demonstrated frequent deletions and damaging of SSNVs in chromatin-modifying genes ARID1A, CTCF, and DNMT3A. Some of their identified gene mutations such as CD28, DNMT3A, and RHOA, STAT5B and ZEB1 are seen in systemic Tcell lymphomas suggesting common pathway in the malignant transformation of mature T cells. Wang et al. [12] assessed somatic mutation, DNA copy number, and gene expression profiles in 37 Se´zary syndrome patients and demonstrated the most frequently mutated genes in their combined cohort were TP53 (24%), PLCG1 (18%), CARD11 (15%), ARID1A (10%), FAS (10%), CC chemokine receptor 4 (CCR4, 7%), RHOA (7%), and TNFRSF1B (6%). Da Silva Almeida et al. [13 ] performed wholeexome sequencing of tumor-normal sample pairs from 25 patients with Se´zary syndrome, eight &&
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patients with mycosis fungoides and nine patients with other CTCLs. They found recurrent deletions involving tumor-suppressor genes in TP53 (52%), RB1 (16%), PTEN (20%), and CDKN1B (20%) in Se´zary syndrome samples. Moreover, they observed focal chromosome deletions encompassing the DNMT3A locus of this epigenetic tumorsuppressor gene in 20% of the Se´zary syndrome samples. Additionally, they identified mutations resulting loss of function epigenetic regulators including TET2, CREBBP a histone acetyltransferase, MLL3 (KMT2C) histone H3 lysine 4 methyltransferase and other chromatin remodeling complexes [13 ]. Among other gene alterations, they identified three point mutations in Se´zary syndrome in PLCG1, an oncogene described as carrying gain-of-function mutations in CTCL [9]. Finally, they report alteration in TNFR2, as described by Khavari and colleagues, and CARD11, as described by Wang, leading to NFkB activation. These elaborate studies differ in their sample size, subtypes of CTCL and methodological techniques. Nevertheless, they demonstrate common mutations in tumor suppressors such as TP53 and oncogenes such as PLCG1, as well as mutations in key regulators leading to activation of the NF-kB pathway (TNFR2 and CARD11), the latter suggesting potential treatment benefits with bortezomib or other proteasome inhibitors in a subset of CTCL. Functional relevant mutations in chromatin modifying genes (MLL3, DNMT3A) could explain the clinical activity of histone deacetylase (HDAC) inhibitors in this disease. Genomic alterations in key elements of the immune system (CD28, CTLA-4) described in these studies support a potential relevance for immune checkpoint blockade strategy in CTCL [11 ]. &&
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CANCER IMMUNOTHERAPY There is mounting evidence that immune evasion is an important part of mycosis fungoides/Se´zary syndrome pathogenesis as they show features of immunomodulating regulatory T cells resulting in immune evasion and thus allowing clonal T-cell expansion [14,15]. Therefore, T-cell immunity is critical for meaningful antitumor response [16]. Tumor-infiltrating CD8þ T cells have been associated with improved survival and therapies which augment T-cell function are effective in mycosis fungoides/Se´zary syndrome [17]. Moreover, reports of 9p24.1/PD-L2 translocation, recurrent SSNV in CD28 [11 ], or CTLA4–CD28 fusion [10 ] in mycosis fungoides/Se´zary syndrome support a genomic basis for immune evasion.
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IMMUNE CHECKPOINT BLOCKADE (ANTIPD-1 mAb)
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
PD-1, programmed cell death 1 receptor, is an immune-checkpoint molecule expressed by T cells. When bound to its ligands, it negatively regulates Tcell effector functions. The PD-1 pathway functions to limit unwanted or excessive immune responses, including autoimmune reactions as part of the adaptive phase of the immune system. Current data suggest that the PD-1, PD-L1/PD-L2 may play a significant role in preventing immune-driven eradication of mycosis fungoides/Se´zary syndrome tumor population. Samimi et al. showed expression of PD-1 and PD-L1 expression in various morphological subsets of mycosis fungoides [18] as well as on tumor cells circulating in the peripheral blood of Se´zary syndrome patients [19]. Pembrolizumab (MK-3475) is a humanized immunoglobulin G4 mAb which binds the PD-1 receptor, thus inhibiting the interaction with its ligands, PD-L1 and PD-L2. Fatigue and skin eruption are the most common immune-related adverse events. Other organspecific events such pneumonitis, colitis, endocrine, and hepatic toxicities reported with CTLA-4 blocking agents are less frequently described in clinical trials with anti-PD-1/PD-L1 agents. A clear knowledge of the toxicities of these agents is vital to achieving their safe delivery outside of clinical trials [20]. Currently, a multicentered, open-labeled, nonrandomized phase II clinical trial of pembrolizumab in stage IB–IVB mycosis fungoides/Se´zary syndrome is ongoing (NCT02243579). The clinical and correlative data from this study may guide rational combination strategies in CTCL.
Allogeneic hematopoietic stem cell transplantation (allogeneic HSCT) can result in sustained remissions suggesting immune response to tumor may be curative by immune-mediated graft versus lymphoma [25,26]. Duvic et al. [27] have reported their experience with total skin electron beam and nonmyeloablative allogenic HSCT including 19 patients with mycosis fungoides or Se´zary syndrome. They reported overall survival 79% and progression-free survival 53% at 2 years. Of note, 67% of the patients suffered from acute graft versus host disease and chronic graft versus host disease. Duarte et al. [28] demonstrated a progression-free survival of 30% and overall survival of 44% in their extended analysis of 60 patients with mycosis fungoides or Se´zary syndrome at 7 years post-HSCT (27% received myeloablative conditioning regimen). Despite the difference in nonmyeloablative conditioning regimens used in the several reported case series the progression-free survival and overall survival after HSCT have been similar at the different centers. Hence, HSCT can be considered in high-risk patients with advanced or refractory mycosis fungoides/Se´zary syndrome. Weng et al. [25] demonstrated determination of clinically meaningful molecular remission and monitoring minimal residual disease by high-through put sequencing of TCRB allows to optimize the management of these patients after transplant. Longer follow-up to better assess posttransplant complication issues and management are required but these studies also undermine the rationales for developing new immunotherapy approaches.
RESIQUIMOD Another promising approach to utilizing immunotherapy in CTCL is Toll-like receptor agonists, which stimulate the innate immune system for the induction of an antitumor response by enhancement of production of cytokines such as IFN-a and IFN-g, and IL-12 [21] as well as activation of plasmacytoid predendritic cells [22,23]. In a phase I open-label clinical trial with topical resiquimod 0.03% and 0.06% gel, a Toll-like receptor 7/8 agonist, target lesions of 12 patients with stage IA–IIA CTCL were treated. In 75% of patients treated lesions significantly improved and 30% had clearing of all treated lesions. Resiquimod also induced regression of untreated lesions suggesting enhanced systemic antitumor activity [24]. With adverse events being primarily limited to local skin irritation, topical resiquimod gel can be considered a good skin-directed therapy in early stage mycosis fungoides. 168
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NOVEL TARGETED ANTITUMOR THERAPIES There are many novel targeted antitumor therapies coming down the pipeline. Here, we summarize therapies with more clinical evidence in CTCL at this time.
ANTI-KIR3DL2 mAb (IPH4102) KIR3DL2 (CD158) is a killer-cell immunoglobulinlike receptor that binds to its cognate HLA-class I ligands negatively modulating immune cell function. This receptor is consistently expressed across most CTCL subtypes [29] but found only on a small subset of NK-cells and CD8þT cells [30,31]. IPH4102 is a first-in-class humanized IgG1 mAb that binds to KIR3DL2-expressing tumor cells. In preclinical studies including xenograft mouse models, IPH4102 was suggested to recruit human NK cells Volume 28 Number 2 March 2016
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and macrophages to kill KIR3DL2þ tumor cells via antibody-dependent cell cytotoxicity and antibodydependent cell phagocytosis, respectively [32]. The safety and potential efficacy of this targeted immunotherapy is to be investigated in an upcoming phase I multicenter clinical trial in CTCL (NCT02593045).
BRENTUXIMAB VEDOTIN Brentuximab vedotin is an anti-CD30 mAb conjugated with monomethyl auristatin E by a proteasecleavable linker [33,34]. CD30 is highly expressed on the surface of primary cutaneous anaplastic large-cell lymphoma (pcALCL) and subtypes of lymphomatoid papulosis and is variably expressed in mycosis fungoides morphological subtypes including large cell transformed mycosis fungoides. The results of two phase II clinical trials in CTCL have been recently published. In the phase II study of brentuximab vedotin in mycosis fungoides or Se´zary syndrome, by Kim et al. [35 ], among the 30 evaluable patients, the overall global response was 70%. CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30 maximum expression of 13% (range, 0–100%); those with less than 5% CD30 expression had lower likelihood of global response than those with higher than 5% CD30 expression. They demonstrated that CD163þ M2-type tumorassociated macrophages were abundant suggesting that brentuximab vedotin may target these macrophages in addition to the malignant T cells and disrupt their tumor-promoting function as well as the possibility that these CD30 coexpressing macrophages may offer an additional source of monomethyl auristatin E to the nearby malignant T cells. In the other phase II open-label trial in patients with CD30 lymphoproliferative disorder or CD30 mycosis fungoides/Se´zary syndrome by Duvic et al. [36 ], of the 48 evaluable patients, the overall response was 73%, with a CR rate of 35%. Median time to response was 12 weeks, and duration of response was 32 weeks (range, 3–93 weeks). All patients with lymphomatoid papulosis or pcALCL responded. In both clinical trials, brentuximab vedotin was relatively well tolerated with most adverse events being manageable. Most common adverse event was peripheral neuropathy although it was reversible with dose reduction or discontinuation of the drug; some experienced irreversible neuropathy. Therefore, the authors concluded that the risk for peripheral neuropathy must be carefully assessed and monitored while the patient is receiving therapy. &
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MOGAMULIZUMAB (KW-0761, ANTI-CC CHEMOKINE RECEPTOR 4 mAb) CCR4 is a selective marker of the Th2 phenotype [37]. The interplay between CCR4 and its ligands facilitates the cross talk between malignant T-cell and its microenvironment as well as distant organ involvement. Mogamulizumab (KW-0761) is a defucosylated, humanized anti-CCR4 mAb that stimulates antibody-dependent cell-mediated cytotoxicity [38]. A phase 1/2 open-label multicenter randomized clinical trial demonstrated overall response of 47.1% for Se´zary syndrome patients and 28.6% in mycosis fungoides patients. Interestingly, mogamulizumab therapy resulted in a dramatic clearance of malignant cells as measured by flow cytometry in 18 of 19 patients with blood involvement [39]. Based on the results of this study, a phase 3 randomized trial comparing mogamulizumab versus vorinostat in patients with relapsed or refractory mycosis fungoides or Se´zary syndrome with respect to efficacy, safety, and quality of life is ongoing (NCT01728805).
IMPROVED USE OF ESTABLISHED THERAPIES The uses of standard therapies such as total skin electron beam radiation and HDAC inhibitors have been modified over the years to minimize their toxicity profile and/or lengthen duration of response, as discussed below.
LOW-DOSE TOTAL SKIN ELECTRON BEAM TREATMENT Total skin electron beam radiation (TSEBT) is administered in different doses but 36 Gy has been considered standard of therapy. Temporary loss of nails and possible permanent alopecia are reported with this dose of TSEBT in addition to common adverse events such as erythema and desquamation. Many of the toxicities are dose dependent. Furthermore, given the risk of skin atrophy, xerosis, and pigmentation changes more than two courses of 36 Gy TSEBT is not recommended [40]. Recent new data pooled from three phase II clinical trials using low-dose (12 Gy) TSEBT in mycosis fungoides patients with stage IB–IIIA revealed that this dose can result in rapid reduction of disease burden with response rates exceeding 88%, with a more favorable toxicity profile compared with highdose TSEBT. Other advantages are the shorter treatment period and the possibility to treat patients multiple times with this regimen [41 ], as well as in combination with immune-modulatory agents to prolong clinical benefits.
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EPIGENETIC THERAPIES Our understanding of epigenetic modifications in cancer progression and therapy in the past decade has resulted in novel approaches to cancer therapy. HDAC inhibitors increase the acetylation of the histone lysine residues in the nucleosome as well as acetylation of nonhistone proteins leading to chromatin accessibility to transcription factors [42]. There are multiple classes of HDAC inhibitors grouped based on their specificity to different types of HDACs [43]. Vorinostat (Zolinda) is a hydroxamic acid derivatives pan-HDAC inhibitor that was approved by the United States Food and Drug Administration in October 2006 for the treatment of CTCL. Romidepsin (F228 or desipeptide) is a potent bicyclic class I HDAC inhibitor and to a lesser extent a class II HDAC inhibitor. Romidepsin was approved by the United States Food and Drug Administration in November 2009 for the treatment of CTCL patients on the basis of two phase II, single arm, open label clinical trials showing an overall response rate of 34–35% with a complete response of 6% in relapsed/refractory CTCL patients [44,45]. Most common side-effects of HDAC inhibitors are fatigue, nausea, vomiting, and thrombocytopenia. The use of HDAC inhibitors is well documented but their use in combination with other agents is experimental in CTCL [46]. Additionally, a phase II, multicenter, openlabel, randomized clinical trial with suberohydroxamic acid phenyl ester that is a novel HDAC inhibitor designed for topical application for early stage CTCL lesions is on going (NCT02213861).
CONCLUSION CTCL is overall a debilitating, noncurative disease where current therapies do not provide reliable and/ or durable clinical responses. Moreover, patients with advanced stage mycosis fungoides/Se´zary syndrome or aggressive subtype of CTCL have a significantly compromised life expectancy, often associated with local tissue and systemic immune suppression. Thus, development of treatments that can improve not only the clinical efficacy but also provide acceptable tolerability is central to advancing the clinical management and outcome in CTCL. Current and upcoming cancer immune-modulators such as PD-1, PD-L1/PD-L2 inhibitors are promising treatment approaches that restore and augment antitumor immune response. Newer targeted antitumor therapies such as brentuximab vedotin, mogamulizumab, and anti-KIR3DL2 are promising for subsets of CTCL patients. Currently, allogeneic
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HSCT is the only potential curative therapy in those with advanced or aggressive disease. Finally, these new or established therapies used in combination can target multiple molecules or pathways thus optimizing clinical efficacy while keeping toxicity profile at a manageable level. Our new understanding of the genomic landscape in CTCL will guide the development of novel treatment options and allow us to provide the most personalized, precision medicine. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
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30. Moretta A, Moretta L. HLA class I specific inhibitory receptors. Curr Opin Immunol 1997; 9:694–701. 31. Moins-Teisserenc H, Daubord M, Clave E, et al. CD158k is a reliable marker for diagnosis of Se´zary syndrome and reveals an unprecedented heterogeneity of circulating malignant cells. J Invest Dermatol 2015; 135:247–257. 32. Sicard H, Bonnafous C, Morel A, et al. A novel targeted immunotherapy for CTCL is on its way: Anti-KIR3DL2 mAb IPH4102 is potent and safe in nonclinical studies. Oncoimmunology 2015; 4:e1022306. 33. Younes A, Yasothan U, Kirkpatrick P. Brentuximab vedotin. Nat Rev Drug Discov 2012; 11:19–20. 34. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood 2003; 102:1458–1465. 35. Kim YH, Tavallaee M, Sundram U, et al. Phase II investigator-initiated study of & brentuximab vedotin in mycosis fungoides and se´zary syndrome with variable cd30 expression level: a multi-institution collaborative project. J Clin Oncol 2015; 33:3750–3758. These studies contain relevant information about the therapy, dosing, and potential side-effects. 36. Duvic M, Tetzlaff MT, Gangar P, et al. Results of a phase II trial of brentuximab & vedotin for CD30þ cutaneous t-cell lymphoma and lymphomatoid papulosis. J Clin Oncol 2015; 33:3759–3765. These studies contain relevant information about the therapy, dosing, and potential side-effects. 37. D’Ambrosio D, Iellem A, Bonecchi R, et al. Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J Immunol 1998; 161:5111–5115. 38. Wilcox RA. Mogamulizumab: 2 birds, 1 stone. Blood 2015; 125:1847–1848. 39. Duvic M, Pinter-Brown LC, Foss FM, et al. Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood 2015; 125:1883–1889. 40. Becker M, Hoppe RT, Knox SJ. Multiple courses of high-dose total skin electron beam therapy in the management of mycosis fungoides. Int J Radiat Oncol Biol Phys 1995; 32:1445–1449. 41. Hoppe RT, Harrison C, Tavallaee M, et al. Low-dose total skin electron beam & therapy as an effective modality to reduce disease burden in patients with mycosis fungoides: results of a pooled analysis from 3 phase-II clinical trials. J Am Acad Dermatol 2015; 72:286–292. These studies contain relevant information about the therapy, dosing, and potential side-effects. 42. Jones PA. At the tipping point for epigenetic therapies in cancer. J Clin Invest 2014; 124:14–16. 43. Prince HM, Dickinson M. Romidepsin for cutaneous T-cell lymphoma. Clin Cancer Res 2012; 18:3509–3515. 44. Piekarz RL, Frye R, Turner M, et al. Phase II multiinstitutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 2009; 27:5410–5417. 45. Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 2010; 28:4485–4491. 46. Rozati S, Cheng PF, Widmer DS, et al. Romidepsin and azacitidine synergize in their epigenetic modulatory effects to induce apoptosis in CTCL. Clin Cancer Res 2015.
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