Multidisciplinary Cutaneous Lymphoma Group–

Research in Cutaneous Lymphoma

Cutaneous Lymphoma Research Group
(Left to right) M. Peter Marinkovich, MD, Howard Chang, MD, PhD, Paul Khavari, MD, PhD,
Youn Kim, MD, Anthony Oro, MD, PhD

Investigative research in cutaneous lymphoma lead by our group is more active than ever before. Our research efforts are a successful product of multidisciplinary collaboration among key departments and research laboratories including Dermatology, Medical and Radiation Oncology, Surgical Pathology, Radiology, and Blood and Marrow Transplantation Services. We have built a critical mass of investigators who share an interest in cutaneous lymphomas. Our research activities are updated in this web page and will be divided into Clinical/Translational Research and Clinical Trials.

The Stanford Multidsciplinary Cutaneous Lymphoma team offers expert treatment for patients with cutaneous lymphomas, including mycosis fungoides, Sezary syndrome, CD30+ lymphoproliferative disorders (lymphomatoid papulosis and anaplastic large cell lymphoma), subcutaneous panniculitis-like T-cell lymphoma, gamma-delta T-cell lymphoma, CD8+ aggressive epidermotropic T-cell lymphoma, NK/T-cell lymphoma, other unspecified cutaneous peripheral T-cell lymphomas, and cutaneous B-cell lymphomas. Our physicians subspecialize in treating these types of cancers, and have extensive expertise in handling the most complicated cases. Care among specialists is tightly integrated.

Read more about the Stanford Cutaneous Lymphoma Program (pdf) More>>

Important Contributions to Science

Improvement in clinical staging and prognostic models in cutaneous lymphoma

Mycosis fungoides (MF) and Sézary syndrome (SS) comprise 60% of cutaneous lymphomas (CL) with very heterogeneous clinical presentation and outcome.  Median survival of early (I-IIA) vs. advanced stages (IIB-IV) of MF/SS is >15 vs. 2-5 yrs with 5-25% disease progression rate of early to advanced stages. I have partnered with other international experts in CL to establish the revised staging system in MF/SS and the new TNM system for the non-MF/SS CLs. These staging system in CLs are used in clinical management of CLs and guide the design of clinical trials. Furthermore, I have led the establishment of the CL International Consortium, CLIC, which will be the conduit for large-scale collaborative research for the development of improved prognostic models to augment the prognosticating power of the current clinical staging system. A federated Biobank with clinical annotation will be established to incorporate new biomarkers in the prognostic modeling and for future translational projects.

  1. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome of 525 patients with mycosis fungoides and Sézary syndrome: clinical prognostic factors and risk for disease progression.  Arch Dermatol  139:857-866, 2003.
  2. Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, Zackheim H, Duvic M, Estrach T, Wood G, Dummer R, Ranki A, Burg G, Heald P, Pittelkow M, Bernengo M-G, Sterry W, Laroche L, Trautinger F, Whittaker S.  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 110:1713-1722, 2007.
  3. Kim YH, Willemze R,  Pimpinelli N, Whittaker S, Olson EA, Ranki A, Dummer R, Hoppe RT.  TNM classification system for primary cutaneous lymphomas other than 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 110: 479-484, 2007.
  4. Scarisbrick JJ, Prince HM, Vermeer MH, Quaglino P, Horwitz S, Porcu P, Stadler R, Wood G, Beylot-Barry M, Pham-Ledard A, Foss F, Girardi M, Bagot M, Michel L, Battistella M, Guitart J, Kuzel TM, Martinez-Escala M, Estrach T, Papadavid E, Antoniou C, Rigopoulos D, Nikolaou V, Sugaya M, Miyagaki T, Gniadecki R, Saches J, Cury-Martins J, Miyashiro D, Servitje O, Muniesa C, Berti E, Onida F, Corti L, Hodak E, Amitay-Laish I, Ortiz-Romero P, Rodriguez-Peralto J, Knobler R, Porkert S, Bauer W, Pimpinelli N, Grandi V, Cowan R, Rook A, Kim E, Pileri A, Patrizi A, Pujol R, Wong H, Tyler K, Stranzenbach R, Querfeld C, Fava P, Maule M, Willemze R, Evison F, Morris S, Twigger R, Talpur R, Kim J, Ognibene G, Li S, Tavallaee M, Hoppe RT, Duvic M, Whittaker SJ, Kim YH.  Cutaneous Lymphoma International Consortium (CLIC) Study of Outcome in Advanced Stages of Mycosis Fungoides & Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model. J Clin Oncol, accepted for publication, June, 2015.

Deciphering the molecular pathogenesis in MF/SS and identification of actionable alterations

Molecular pathogenesis of cutaneous lymphomas remains largely unknown including MF and SS.  I have partnered with Khavari and Chang laboratories at Stanford (Department of Dermatology, Program in Epithelial Biology) to apply next generation sequencing tools to decipher the molecular drivers in MF and SS. We have one of the largest referral clinics for these rare disorders and have an established Biobank with thorough clinical annotation. These clinical samples were used to identify novel and/or recurrent aberrant pathways, oncogenes, or non-coding RNAs. We have discovered recurrent point mutations and genomic gains in TNFR2 and established its functional significance.  Additionally, we identified recurrent CTLA4-CD28 fusion and mutations in downstream signaling mediators. These aberrant findings will be targeted for potential therapeutic relevance.

  1. Lee CS, Ungewickell A, Bhaduri A, Qu K, Webster DE, Armstrong R, Weng WK, Aros CJ, Mah A, Chen RO, Lin M, Sundram U, Chang HY, Kretz M, Kim YH, Khavari PA.  Transcriptome sequencing in Sézary syndrome identifies Sézary cell and mycosis fungoides-associated lncRNAs and novel transcripts. Blood 120:3288-97, 2012.
  2. Ungewickell A, Bhuduri A, Rios E, Reuter J, Lee CS, Mah A, Zehnder A, Ohgami R, Kulkarni S, Armstrong R, Gratzinger D, Tavallaee M, Rook A, Snyder M, Kim Y, Khavari P.  Genomic analysis of mycosis fungoidse and Sézary syndrome identifies recurrent alterations in TNFR2.  Nature Genetics, accepted for publication June, 2015.

Novel therapeutics or treatment approaches in cutaneous lymphoma

I have led the clinical development of novel or new therapies and strategies to improve our management approach or options in CL. In partnership with Levy group at Stanford, I have contributed towards understanding immune activity of TLR9-agonists in cutaneous B and T cell lymphoma with use of novel in situ vaccination strategy. I have played critical roles in the design and conduct of clinical trials, which led to successful FDA approval of new agents, including romidepsin which as great activity in Sezary syndrome.  Our investigator initiated clinical trial with brentuximab vedotin in CTCL has allowed successful development of the current phase 3 trial and in rational development of combination trials.

    1. Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic, Scaribrick J, Reddy S, Robak T, Becker JC, samtsov A, McCullouch W, Kim YH.  Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.  J Clin Oncol  28:4485-91, 2010.
    2. Kim, YH, Gratzinger D, Harrison C, Brody JD, Czerwinski DK, Ai WZ, Morales A, Abdulla F, Xing L, Navi D, Tibshirani RJ, Advani RH, Lingala B, Shah S, Hoppe RT, and Levy R. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study.  Blood 119:355-63, 2012
    3. Duvic M, Pinter-Brown L, Foss FM, Jorgensen JL, Challagundla P, Dwyer KM, Zhang X, Kurman MR, Ballerini R, Liu L, Kim YH.  Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood 125:1883-9, 2015
    4. Kim YH, Tavallaee MT, Sundram U, Salva KA, Wood GS, Li S, Rozati S, Nagpal S, Krathen M, Reddy S, Hoppe RT, Nguyen-Lin A, Weng WK, Armstrong R, Pulitzer M, Advani RA, Horwitz SM.  Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable Cd30 expression level: a multi-institution collaborative project.  J Clin Oncol, Accepted for publication April, 2015

New tools for monitoring residual disease in MF and SS (CTCL)

In close collaboration with Stanford BMT/Weng group, we have been conducting NMA allogeneic hematopoietic stem cell transplantation (HSCT) in advanced MF and SS using a novel preparatory regimen of total skin electron beam therapy, total lymphoid irradiation and anti-thymocyte globulin.  As part of this transplant project, we have effectively applied targeted high-throughput sequencing (HTS) of TCR CDR3 to monitor molecular residual disease in patients treated with allogeneic HSCT or other therapies. Molecular cure or relapse assessed by HTS tool is likely to allow improved clinical management and outcome.

    1. Weng W-K, Armstrong R, Arai S, Desmarais C, Hoppe R, Kim YH: Minimal residual disease monitoring with high-throughput sequencing of T cell receptors in cutaneous T cell lymphoma. Sci Transl Med 5(214):214ra171, 2013

 

 

 

 

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