Publications

The publication page is designed to update our visitors on selected publications from our cutaneous lymphoma group. This information can serve as a general reference guide on cutaneous lymphomas and to learn about our selected research activities.

These papers are available through online reference libraries or Stanford’s Lane Medical Library resources.

The Joanne and Peter Haas, Jr., Professor for Cutaneous Lymphoma Research and Professor, by courtesy, of Medicine (Oncology) at the Stanford University Medical Center

Publications

  • Volumetric modulated arc therapy and 3-dimensional printed bolus in the treatment of refractory primary cutaneous gamma delta lymphoma of the bilateral legs. Practical radiation oncology Obeid, J., Gutkin, P. M., Lewis, J., Skinner, L., Wang, E. B., Khodadoust, M. S., Kim, Y. H., Weng, W., Hoppe, R. T., Hiniker, S. M. 2019

    Abstract

    Patients with extensive dermal and subcutaneous disease present a technical challenge for treatment with radiation therapy (RT). Volumetric arc therapy (VMAT) can effectively treat disease on circumferential surfaces while minimizing dose to the core structures. However, treatment of extensive areas of the bilateral lower extremities with this technique has not been previously reported. Here we report the successful treatment of a patient with primary cutaneous gamma-delta T-cell lymphoma of the bilateral legs using VMAT and a custom 3-dimensional printed bolus. This approach is applicable for the treatment of cutaneous malignancies of the lower extremities.

    View details for PubMedID 30836188

  • Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. The Lancet. Oncology Kim, Y. H., Bagot, M., Pinter-Brown, L., Rook, A. H., Porcu, P., Horwitz, S. M., Whittaker, S., Tokura, Y., Vermeer, M., Zinzani, P. L., Sokol, L., Morris, S., Kim, E. J., Ortiz-Romero, P. L., Eradat, H., Scarisbrick, J., Tsianakas, A., Elmets, C., Dalle, S., Fisher, D. C., Halwani, A., Poligone, B., Greer, J., Fierro, M. T., Khot, A., Moskowitz, A. J., Musiek, A., Shustov, A., Pro, B., Geskin, L. J., Dwyer, K., Moriya, J., Leoni, M., Humphrey, J. S., Hudgens, S., Grebennik, D. O., Tobinai, K., Duvic, M., MAVORIC Investigators, Abhyankar, S., Akilov, O., Alpdogan, O., Beylot-Barry, M., Boh, E., Caballero, D., Cowan, R., Dreno, B., Dummer, R., Fenske, T., Foss, F., Fukuhara, N., Giri, P., Habe, K., Hamada, T., Hatake, K., Iida, S., Ishikawa, O., Iversen, L., Kiyohara, E., Koga, H., Korman, N., Kuss, B. J., Lamar, Z., Lansigan, F., Lechowicz, M. J., Lerner, A., Magnolo, N., Mark, L., Miyagaki, T., Munoz, J., Nicolay, J. P., Nishiwaki, K., Okamoto, H., Ohtsuka, M., Pacheco, T., Querfeld, C., Rapini, R. P., Sano, S., Tanaka, M., Tharp, M. D., Uehara, J., Wada, H., Wells, J., Wilcox, R. A., William, B., Yonekura, K. 2018

    Abstract

    BACKGROUND: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma.METHODS: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sezary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sezary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805.FINDINGS: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p<0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related.INTERPRETATION: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sezary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma.FUNDING: Kyowa Kirin.

    View details for PubMedID 30100375

  • TNFR2-targeted elimination of Tregs and tumor-residing T cells in advanced cutaneous T cell lymphoma Faustman, D. L., Torrey, H., Khodadoust, M., Defusco, A., Baum, D., Rahbar, Z., Kim, Y. H. AMER ASSOC CANCER RESEARCH. 2018
  • The Use of Central Pathology Review With Digital Slide Scanning in Advanced-stage Mycosis Fungoides and Sezary Syndrome A Multi-institutional and International Pathology Study AMERICAN JOURNAL OF SURGICAL PATHOLOGY Gru, A. A., Kim, J., Pulitzer, M., Guitart, J., Battistella, M., Wood, G. S., Cerroni, L., Kempf, W., Willemze, R., Pawade, J., Querfeld, C., Schaffer, A., Pincus, L., Tetzlaff, M., Duvic, M., Scarisbrick, J., Porcu, P., Mangold, A. R., DiCaudo, D. J., Shinohara, M., Hong, E. K., Horton, B., Kim, Y. H. 2018; 42 (6): 726–34

    Abstract

    This pathology PILOT study aims to define the role and feasibility of centralized pathology review in a cohort of 75 patients from different centers in the United States and Europe using digital slide scanning. The pathologic material from 75 patients who had been diagnosed with mycosis fungoides/Sézary syndrome and were clinically staged as IIb or above was retrieved from 11 participating centers. Each pathology reviewer was provided with the pathologic diagnosis (by the referring pathologist), and the following list of histopathologic criteria (presence or absence) from the initial report: epidermotropism, folliculotropism (FT), large cell transformation, syringotropism, and granulomas. Patients with advance stage were selected for this study as this is a population where there is significant variability in the diagnosis of pathologic prognostic and predictive biomarkers. The slides were digitally scanned with an Aperio scanner and consensus review of cases occurred when major or minor discrepancies between the referral diagnosis and central pathology review occurred. Among the 75 cases, 70 (93.3%) had a final consensus diagnosis between the 3 central review pathologists. The overall agreement between the consensus review and the referring pathologist was 60%. The overall agreement was also higher between the reviewers and consensus review, compared with the referring pathologist and consensus. 65.3% of cases had some type of discrepancy (major or minor) between the outside and consensus review. Major discrepancies were seen in 34 of 73 cases (46.6%; 73 cases indicated a yes or no response). Minor discrepancies were seen in 32 of 75 (42.7%) of cases. Most of the major discrepancies were accounted by a difference in interpretation in the presence or absence of large cell transformation or FT. Most minor discrepancies were explained by a different interpretation in the expression of CD30. We found digital slide scanning to be a beneficial, reliable, and practical for a methodical approach to perform central pathology review in the context of a large clinical prospective study.

    View details for PubMedID 29543675

  • Variability in the Expression of Immunohistochemical Markers: Implications for Biomarker Interpretation in Cutaneous T-Cell Lymphoma JOURNAL OF INVESTIGATIVE DERMATOLOGY Rahbar, Z., Li, S., Tavallaee, M., Novoa, R. A., Kim, J., Kim, Y. H. 2018; 138 (5): 1204–6

    View details for PubMedID 29247659

  • Transcript-indexed ATAC-seq for precision immune profiling. Nature medicine Satpathy, A. T., Saligrama, N., Buenrostro, J. D., Wei, Y., Wu, B., Rubin, A. J., Granja, J. M., Lareau, C. A., Li, R., Qi, Y., Parker, K. R., Mumbach, M. R., Serratelli, W. S., Gennert, D. G., Schep, A. N., Corces, M. R., Khodadoust, M. S., Kim, Y. H., Khavari, P. A., Greenleaf, W. J., Davis, M. M., Chang, H. Y. 2018

    Abstract

    T cells create vast amounts of diversity in the genes that encode their T cell receptors (TCRs), which enables individual clones to recognize specific peptide-major histocompatibility complex (MHC) ligands. Here we combined sequencing of the TCR-encoding genes with assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis at the single-cell level to provide information on the TCR specificity and epigenomic state of individual T cells. By using this approach, termed transcript-indexed ATAC-seq (T-ATAC-seq), we identified epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers and primary leukemic T cells from patient samples. In peripheral blood CD4+ T cells from healthy individuals, we identified cis and trans regulators of naive and memory T cell states and found substantial heterogeneity in surface-marker-defined T cell populations. In patients with a leukemic form of cutaneous T cell lymphoma, T-ATAC-seq enabled identification of leukemic and nonleukemic regulatory pathways in T cells from the same individual by allowing separation of the signals that arose from the malignant clone from the background T cell noise. Thus, T-ATAC-seq is a new tool that enables analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity and immunotherapy.

    View details for PubMedID 29686426

  • Novel treatment of cutaneous T cell lymphoma: Targeting TNFR2, an oncogene and marker of potent Tregs, with anti-TNFR2 antibodies Torrey, H., Defusco, A., Baum, D., Rahbar, Z., Khodadoust, M., Kim, Y. H., Faustman, D. BMC. 2017
  • Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial LANCET Prince, H., Kim, Y. H., Horwitz, S. M., Dummer, R., Scarisbrick, J., Quaglino, P., Zinzani, P., Wolter, P., Sanches, J. A., Ortiz-Romero, P. L., Akilov, O. E., Geskin, L., Trotman, J., Taylor, K., Dalle, S., Weichenthal, M., Walewski, J., Fisher, D., Dreno, B., Stadler, R., Feldman, T., Kuzel, T. M., Wang, Y., Palanca-Wessels, M., Zagadailov, E., Trepicchio, W. L., Zhang, W., Lin, H., Liu, Y., Huebner, D., Little, M., Whittaker, S., Duvic, M., ALCANZA Study Grp 2017; 390 (10094): 555–66

    Abstract

    Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas.In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499.Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p<0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group.Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene.Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.

    View details for PubMedID 28600132

  • Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas MODERN PATHOLOGY Guitart, J., Martinez-Escala, M., Subtil, A., Duvic, M., Pulitzer, M. P., Olsen, E. A., Kim, E., Rook, A. H., Samimi, S. S., Wood, G. S., Girardi, M., Junkins-Hopkins, J., Ivan, D. S., Selim, M., Sable, K. A., Virmani, P., Pincus, L. B., Tetzlaff, M. T., Kim, J., Kim, Y. H. 2017; 30 (5): 761–72

    Abstract

    Primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the latest 2016 World Health Organization Classification of Cutaneous lymphomas. We sought to better characterize and provide diagnostic and therapeutic guidance of this rare cutaneous lymphoma. Thirty-four patients with a median age of 77 years (range 19-89 years) presented primarily with extensive annular necrotic plaques or tumor lesions with frequent mucous membrane involvement. The 5-year survival was 32% with a median survival of 12 months. A subset of 17 patients had a prodrome of chronic patches prior to the development of aggressive ulcerative lesions. We identified cases with lack of CD8 or αβ T-cell receptor expression yet with similar clinical and pathological presentation. Allogeneic stem cell transplantation provided partial or complete remissions in 5/6 patients. We recommend the term primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma as this more broad designation better describes this clinical-pathologic presentation, which allows the inclusion of cases with CD8 negative and/or αβ/γδ T-cell receptor chain double-positive or double-negative expression. We have identified early skin signs of chronic patch/plaque lesions that are often misdiagnosed as eczema, psoriasis, or mycosis fungoides. Our experience confirms the poor prognosis of this entity and highlights the inefficacy of our standard therapies with the exception of allogeneic stem cell transplantation in selected cases.

    View details for PubMedID 28128277

    View details for PubMedCentralID PMC5413429

  • Chromatin Accessibility Landscape of Cutaneous T Cell Lymphoma and Dynamic Response to HDAC Inhibitors. Cancer cell Qu, K., Zaba, L. C., Satpathy, A. T., Giresi, P. G., Li, R., Jin, Y., Armstrong, R., Jin, C., Schmitt, N., Rahbar, Z., Ueno, H., Greenleaf, W. J., Kim, Y. H., Chang, H. Y. 2017

    Abstract

    Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by ATAC-seq. Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic, host, and normal CD4(+) T cells. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Clinical response to histone deacetylase inhibitors (HDACi) is strongly associated with a concurrent gain in chromatin accessibility. HDACi causes distinct chromatin responses in leukemic and host CD4(+) T cells, reprogramming host T cells toward normalcy. These results provide a foundational framework to study personal regulomes in human cancer and epigenetic therapy.

    View details for PubMedID 28625481

  • Pembrolizumab for Treatment of Relapsed/Refractory Mycosis Fungoides and Sezary Syndrome: Clinical Efficacy in a Citn Multicenter Phase 2 Study Khodadoust, M., Rook, A. H., Porcu, P., Foss, F. M., Moskowitz, A. J., Shustov, A. R., Shanbhag, S., Sokol, L., Shine, R., Fling, S. P., Li, S., Rabhar, Z., Kim, J., Yang, Y., Yearley, J., Chartash, E., Townson, S. M., Subrahmanyam, P. B., Maecker, H., Alizadeh, A. A., Dai, J., Horwitz, S. M., Sharon, E., Kohrt, H., Cheever, M. A., Kim, Y. AMER SOC HEMATOLOGY. 2016
  • A Single-Arm PHASE 2A Study of NM-IL-12 (rHu-IL12) in Patients with Mycosis Fungoides-Type CTCL (MF) Undergoing Low-Dose TOTAL Skin Electron BEAM Therapy (LD-TSEBT) Kim, Y. H., Hoppe, R. T., Rook, A. H., Maity, A., Geskin, L. J., Horowitz, D. P., Finnegan, G., Khodadoust, M., Weng, W., Lares, A., Hong, E., Buchanan, M., Ma, V., Kha, H., Lawrence, C. E., Vainstein, V., Basile, L. A. AMER SOC HEMATOLOGY. 2016
  • Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician's Choice (Methotrexate or Bexarotene): The Phase 3 Alcanza Study Kim, Y. H., Whittaker, S., Horwitz, S. M., Duvic, M., Dummer, R., Scarisbrick, J. J., Quaglino, P., Zinzani, P., Wolter, P., Wang, Y., Palanca-Wessels, M., Zagadailov, E., Trepicchio, W. L., Liu, Y., Little, M., Prince, H. AMER SOC HEMATOLOGY. 2016
  • First-in-Human, Multicenter Phase I Study of IPH4102, First-in-Class Humanized Anti-KIR3DL2 Monoclonal Antibody, in Relapsed/Refractory Cutaneous T-Cell Lymphomas: Preliminary Safety, Exploratory and Clinical Activity Results Bagot, M., Porcu, P., Ram-Wolff, C., Khodadoust, M., Battistella, M., Marie-Cardine, A., Mathieu, S., Vermeer, M. H., Whittaker, S., Duvic, M., Bensussan, A., Paturel, C., Bonnafous, C., Thonnart, N., Widemann, A., Bonin, C., Sicard, H., Paiva, C., Pilz, K., Kim, Y. AMER SOC HEMATOLOGY. 2016
  • Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. Journal of clinical oncology Kim, Y. H., Tavallaee, M., Sundram, U., Salva, K. A., Wood, G. S., Li, S., Rozati, S., Nagpal, S., Krathen, M., Reddy, S., Hoppe, R. T., Nguyen-Lin, A., Weng, W., Armstrong, R., Pulitzer, M., Advani, R. H., Horwitz, S. M. 2015; 33 (32): 3750-3758

    Abstract

    In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored.In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety.Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event.Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.

    View details for DOI 10.1200/JCO.2014.60.3969

    View details for PubMedID 26195720

Henry S. Kaplan-Harry Lebeson Professor of Cancer Biology

Publications

  • STAGE I-IIIA NON-BULKY HODGKIN'S LYMPHOMA. IS FURTHER DISTINCTION BASED ON PROGNOSTIC FACTORS USEFUL? THE STANFORD EXPERIENCE INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Advani, R. H., Hoppe, R. T., Maeda, L. S., Baer, D. M., Mason, J., Rosenberg, S. A., Horning, S. J. 2011; 81 (5): 1374-1379

    Abstract

    In the United States, early-stage Hodgkin's lymphoma (HL) is defined as asymptomatic stage I/II non-bulky disease. European groups stratify patients to more intense treatment by considering additional unfavorable factors, such as age, number of nodal sites, sedimentation rate, extranodal disease, and elements of the international prognostic score for advanced HL. We sought to determine the prognostic significance of these factors in patients with early-stage disease treated at Stanford University Medical Center.This study was a retrospective analysis of 101 patients treated with abbreviated Stanford V chemotherapy (8 weeks) and 30-Gy (n=84 patients) or 20-Gy (n=17 patients) radiotherapy to involved sites. Outcomes were assessed after applying European risk factors.At a median follow-up of 8.5 years, freedom from progression (FFP) and overall survival (OS) rates were 94% and 97%, respectively. From 33% to 60% of our patients were unfavorable per European criteria (i.e., German Hodgkin Study Group [GHSG], n=55%; European Organization for Research and Treatment of Cancer, n=33%; and Groupe d'Etudes des Lymphomes de l'Adulte, n=61%). Differences in FFP rates between favorable and unfavorable patients were significant only for GHSG criteria (p=0.02) with there were no differences in OS rates for any criteria. Five of 6 patients who relapsed were successfully salvaged.The majority of our patients deemed unfavorable had an excellent outcome despite undergoing a significantly abbreviated regimen. Application of factors used by the GHSG defined a less favorable subset for FFP but with no impact on OS. As therapy for early-stage disease moves to further reductions in therapy, these factors take on added importance in the interpretation of current trial results and design of future studies.

    View details for DOI 10.1016/j.ijrobp.2010.07.041

    View details for PubMedID 20934280

  • REVISITING LOW-DOSE TOTAL SKIN ELECTRON BEAM THERAPY IN MYCOSIS FUNGOIDES INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Harrison, C., Young, J., Navi, D., Riaz, N., Lingala, B., Kim, Y., Hoppe, R. 2011; 81 (4): E651-E657

    Abstract

    Total skin electron beam therapy (TSEBT) is a highly effective treatment for mycosis fungoides (MF). The standard course consists of 30 to 36 Gy delivered over an 8- to 10-week period. This regimen is time intensive and associated with significant treatment-related toxicities including erythema, desquamation, anhydrosis, alopecia, and xerosis. The aim of this study was to identify a lower dose alternative while retaining a favorable efficacy profile.One hundred two MF patients were identified who had been treated with an initial course of low-dose TSEBT (5-<30 Gy) between 1958 and 1995. Patients had a T stage classification of T2 (generalized patch/plaque, n = 51), T3 (tumor, n = 29), and T4 (erythrodermic, n = 22). Those with extracutaneous disease were excluded.Overall response (OR) rates (>50% improvement) were 90% among patients with T2 to T4 disease receiving 5 to <10 Gy (n = 19). In comparison, OR rates between the 10 to <20 Gy and 20 to <30 Gy subgroups were 98% and 97%, respectively. There was no significant difference in median progression free survival (PFS) in T2 and T3 patients when stratified by dose group, and PFS in each was comparable to that of the standard dose.OR rates associated with low-dose TSEBT in the ranges of 10 to <20 Gy and 20 to <30 Gy are comparable to that of the standard dose (≥ 30 Gy). Efficacy measures including OS, PFS, and RFS are also favorable. Given that the efficacy profile is similar between 10 and <20 Gy and 20 and <30 Gy, the utility of TSEBT within the lower dose range of 10 to <20 Gy merits further investigation, especially in the context of combined modality treatment.

    View details for DOI 10.1016/j.ijrobp.2011.01.023

    View details for Web of Science ID 000309412300060

    View details for PubMedID 21489711

  • In Situ Vaccination With a TLR9 Agonist Induces Systemic Lymphoma Regression: A Phase I/II Study JOURNAL OF CLINICAL ONCOLOGY Brody, J. D., Ai, W. Z., Czerwinski, D. K., Torchia, J. A., Levy, M., Advani, R. H., Kim, Y. H., Hoppe, R. T., Knox, S. J., Shin, L. K., Wapnir, I., Tibshirani, R. J., Levy, R. 2010; 28 (28): 4324-4332

    Abstract

    Combining tumor antigens with an immunostimulant can induce the immune system to specifically eliminate cancer cells. Generally, this combination is accomplished in an ex vivo, customized manner. In a preclinical lymphoma model, intratumoral injection of a Toll-like receptor 9 (TLR9) agonist induced systemic antitumor immunity and cured large, disseminated tumors.We treated 15 patients with low-grade B-cell lymphoma using low-dose radiotherapy to a single tumor site and-at that same site-injected the C-G enriched, synthetic oligodeoxynucleotide (also referred to as CpG) TLR9 agonist PF-3512676. Clinical responses were assessed at distant, untreated tumor sites. Immune responses were evaluated by measuring T-cell activation after in vitro restimulation with autologous tumor cells.This in situ vaccination maneuver was well-tolerated with only grade 1 to 2 local or systemic reactions and no treatment-limiting adverse events. One patient had a complete clinical response, three others had partial responses, and two patients had stable but continually regressing disease for periods significantly longer than that achieved with prior therapies. Vaccination induced tumor-reactive memory CD8 T cells. Some patients' tumors were able to induce a suppressive, regulatory phenotype in autologous T cells in vitro; these patients tended to have a shorter time to disease progression. One clinically responding patient received a second course of vaccination after relapse resulting in a second, more rapid clinical response.In situ tumor vaccination with a TLR9 agonist induces systemic antilymphoma clinical responses. This maneuver is clinically feasible and does not require the production of a customized vaccine product.

    View details for DOI 10.1200/JCO.2010.28.9793

    View details for Web of Science ID 000282272700032

    View details for PubMedID 20697067

    View details for PubMedCentralID PMC2954133

  • TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors BLOOD Kohrt, H. E., Turnbull, B. B., Heydari, K., Shizuru, J. A., Laport, G. G., Miklos, D. B., Johnston, L. J., Arai, S., Weng, W., Hoppe, R. T., Lavori, P. W., Blume, K. G., Negrin, R. S., Strober, S., Lowsky, R. 2009; 114 (5): 1099-1109

    Abstract

    A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)-matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.

    View details for DOI 10.1182/blood-2009-03-211441

    View details for PubMedID 19423725

  • Cutaneous Peripheral T-Cell Lymphoma Associated With a Proliferation of B Cells AMERICAN JOURNAL OF CLINICAL PATHOLOGY Mattoch, I. W., Fulton, R., Kim, Y., Hoppe, R., Warnke, R. A., Sundram, U. N. 2009; 131 (6): 810-819

    Abstract

    Although the new World Health Organization-European Organization for Research and Treatment of Cancer classification focuses on providing uniformity in the diagnosis of cutaneous lymphomas, cutaneous peripheral T-cell lymphoma (PTL) remains a poorly defined subgroup. As follow-up to a study of systemic PTL complicated by a proliferation of B cells, we studied 16 cases of cutaneous PTL that contained morphologically atypical T cells associated with a significant infiltrate of B cells (about 20%-50%). A clonal T-cell receptor gamma chain gene rearrangement was present in all cases. In contrast, a clonal immunoglobulin heavy chain gene rearrangement was present in only 1 case. Clinical staging in 14 cases identified systemic involvement in 2. At last follow-up, both patients with systemic involvement had died of disease, and the majority of patients with primary cutaneous disease were alive (11/12). The presence of numerous atypical B cells and T cells caused diagnostic confusion in these cases. Comprehensive pathologic studies, coupled with clinical staging, are necessary for the accurate diagnosis of this unusual manifestation of cutaneous PTL.

    View details for DOI 10.1309/AJCP5W0VOCSVOBRA

    View details for Web of Science ID 000266238600010

    View details for PubMedID 19461087

  • Prognostic Factors in Primary Cutaneous Anaplastic Large Cell Lymphoma Characterization of Clinical Subset With Worse Outcome 49th Annual Meeting of the American-Society-of-Hematology Woo, D. K., Jones, C. R., Vanoli-Storz, M. N., Kohler, S., Reddy, S., Advani, R., Hoppe, R. T., Kim, Y. H. AMER MEDICAL ASSOC. 2009: 667–74

    Abstract

    To identify prognostic factors in primary cutaneous anaplastic large cell lymphoma (pcALCL), focusing on extensive limb disease (ELD), defined as initial presentation or progression to multiple skin tumors in 1 limb or contiguous body regions, and to study gene expression profiles of patients with pcALCL.Retrospective cohort study.The Stanford Comprehensive Cancer Center and dermatology ambulatory clinics.A total of 48 patients with pcALCL evaluated from 1990 through 2005.Hazard ratios (HRs) for prognostic factors for overall survival (OS) and disease-specific survival (DSS) and risk factors for progression to extracutaneous disease were identified using Cox regression. Gene expression profiles of 9 typical pcALCL and 3 ELD samples were investigated using complementary DNA microarrays.Univariate analysis demonstrated age, ELD, and progression to extracutaneous disease as significant prognostic factors for OS, whereas ELD and progression to extracutaneous disease were significant for DSS. In multivariate analysis, age (HR, 1.83; 95% confidence interval [CI], 1.02-3.26) and progression to extracutaneous disease (HR, 6.42; 95% CI, 1.39-29.68) remained significant for OS, whereas ELD (HR, 29.31; 95% CI, 1.72-500.82) and progression to extracutaneous disease (HR, 13.12; 95% CI, 1.03-167.96) remained independent prognostic factors for DSS. Presentation with T3 disease was a risk factor for progression to extracutaneous disease (HR, 10.20; 95% CI, 1.84-56.72). Microarray data revealed that patients with ELD and typical pcALCL formed distinct clusters.Patients with ELD have a more aggressive course associated with a differential gene expression profile. More aggressive treatments may be indicated for patients with ELD and those whose disease progresses to extracutaneous disease because they have poorer outcomes.

    View details for PubMedID 19528422

  • Low Stage Follicular Lymphoma: Biologic and Clinical Characterization According to Nodal or Extranodal Primary Origin AMERICAN JOURNAL OF SURGICAL PATHOLOGY Weinberg, O. K., Ma, L., Seo, K., Beck, A. H., Pai, R. K., Morales, A., Kim, Y., Sundram, U., Tan, D., Horning, S. J., Hoppe, R. T., Natkunam, Y., Arber, D. A. 2009; 33 (4): 591-598

    Abstract

    Studies suggest that primary extranodal follicular lymphoma (FL) is not infrequent but it remains poorly characterized with variable histologic, molecular, and clinical outcome findings. We compared 27 extranodal FL to 44 nodal FL using morphologic, immunohistochemical, and molecular genetic techniques and evaluated the clinical outcome of these 2 similarly staged groups. Eight cases of primary cutaneous follicle center lymphoma were also studied. In comparison to nodal FL, a greater number of extranodal FL contained a diffuse growth pattern (P=0.004) and lacked CD10 expression (P=0.014). Fifty-four percent of extranodal and 42% of nodal FL cases showed evidence of t(14;18), with minor breakpoints (icr, 3'BCL2, 5'mcr) more commonly found in extranodal cases (P=0.003). Outcome data showed no significant differences in overall survival (P=0.565) and progression-free survival (P=0.627) among extranodal, nodal, and primary cutaneous follicle center lymphoma cases. Analysis of all cases by t(14;18) status indicate that the translocation-negative group is characterized by a diffuse growth pattern (P=0.043) and lower BCL2 expression (P=0.018). The t(14;18)-positive group showed significantly better overall survival (P=0.019) and disease-specific survival (P=0.006) in comparison with the t(14;18)-negative group. In low stage FL, the status of t(14;18) seems to be more predictive of outcome than origin from an extranodal versus nodal site.

    View details for Web of Science ID 000264818800014

    View details for PubMedID 19065102

  • Dynamic CD8 T-Cell Responses to Tumor-Associated Epstein-Barr Virus Antigens in Patients With Epstein-Barr Virus-Negative Hodgkin's Disease ONCOLOGY RESEARCH Kohrt, H., Johannsen, A., Hoppe, R., Horning, S. J., Rosenberg, S. A., Advani, R., Lee, P. P. 2009; 18 (5-6): 287-292

    Abstract

    In almost half of patients diagnosed with Hodgkin's disease (HD), the malignant Reed-Sternberg (RS) cells express Epstein-Barr virus (EBV) antigens. Multiple translational efforts are actively investigating antitumor immune strategies by stimulating cytotoxic T lymphocytes (CTL) against tumor-associated EBV antigens. It has previously been believed that this therapeutic strategy and presence of EBV-specific CTLs are limited to EBV-positive HD. In an effort to explore the EBV-specific immune response, here we characterize EBV-specific CTL responses to lytic and latent EBV antigens in 12 consecutive EBV carriers with EBV-negative HD. Compared to healthy donors, we detected weak, baseline EBV-specific responses to both lytic and latent antigens by IFN-gamma ELISPOT in patients with EBV-negative HD at diagnosis. Chemoradiotherapy was associated temporally with a decrease EBV-specific responses. At final follow-up (24 months), recovery of EBV-specific CTL responses was observed with robustness of lytic-specific response equivalent to healthy controls. We confirm evidence of EBV-specific CTLs in patients with EBV-negative HD and provide the first report of dynamic variance in this population during treatment. Our observation challenges prior belief that patients with HD remain immunodeficient following therapy and argues that the clinical significance of the EBV-specific immune response in EBV-negative HD should be further investigated.

    View details for DOI 10.3727/096504009X12596189659169

    View details for PubMedID 20225766

Assistant Professor of Medicine (Oncology) and of Dermatology at the Stanford University Medical Center

Publications

  • Pembrolizumab in mycosis fungoides and Sezary syndrome: Updated results of the CITN multicenter Phase 2 study Khodadoust, M. S., Rook, A. H., Porcu, P., Foss, F., Moskowitz, A., Shustov, A. R., Shanbhag, S., Sokol, L., Fling, S. P., Li, S., Fong, S., Kim, J., Yang, Y., Yearley, J., Subrahmanyam, P., Maecker, H., Horwitz, S. M., Sharon, E., Cheever, M. A., Kim, Y. H. ELSEVIER SCI LTD. 2018: S37
  • B cell lymphomas present immunoglobulin neoantigens. Blood Khodadoust, M. S., Olsson, N., Chen, B., Sworder, B., Shree, T., Liu, C. L., Zhang, L., Czerwinski, D. K., Davis, M. M., Levy, R., Elias, J. E., Alizadeh, A. A. 2018

    View details for PubMedID 30545830

  • Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens NATURE Khodadoust, M. S., Olsson, N., Wagar, L. E., Haabeth, O. A., Chen, B., Swaminathan, K., Rawson, K., Liu, C. L., Steiner, D., Lund, P., Rao, S., Zhang, L., Marceau, C., Stehr, H., Newman, A. M., Czerwinski, D. K., Carlton, V. E., Moorhead, M., Faham, M., Kohrt, H. E., Carette, J., Green, M. R., Davis, M. M., Levy, R., Elias, J. E., Alizadeh, A. A. 2017; 543 (7647): 723-?

    Abstract

    Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. However, the personalized identification and validation of neoantigens remains a major challenge. Here we discover neoantigens in human mantle-cell lymphomas by using an integrated genomic and proteomic strategy that interrogates tumour antigen peptides presented by major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically characterize MHC ligands from 17 patients. Remarkably, all discovered neoantigenic peptides were exclusively derived from the lymphoma immunoglobulin heavy- or light-chain variable regions. Although we identified MHC presentation of private polymorphic germline alleles, no mutated peptides were recovered from non-immunoglobulin somatically mutated genes. Somatic mutations within the immunoglobulin variable region were almost exclusively presented by MHC class II. We isolated circulating CD4(+) T cells specific for immunoglobulin-derived neoantigens and found these cells could mediate killing of autologous lymphoma cells. These results demonstrate that an integrative approach combining MHC isolation, peptide identification, and exome sequencing is an effective platform to uncover tumour neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.

    View details for DOI 10.1038/nature21433

    View details for PubMedID 28329770

  • Volumetric Modulated Arc Therapy and 3-Dimensional Printed Bolus in the Treatment of Refractory Primary Cutaneous Gamma Delta Lymphoma of the Bilateral Legs PRACTICAL RADIATION ONCOLOGY Obeid, J., Gutkin, P. M., Lewis, J., Skinner, L., Wang, E. B., Khodadoust, M. S., Kim, Y. H., Weng, W., Hoppe, R. T., Hiniker, S. M. 2019; 9 (4): 220–25
  • IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial. The Lancet. Oncology Bagot, M., Porcu, P., Marie-Cardine, A., Battistella, M., William, B. M., Vermeer, M., Whittaker, S., Rotolo, F., Ram-Wolff, C., Khodadoust, M. S., Bensussan, A., Paturel, C., Bonnafous, C., Sicard, H., Azim, H. A., Kim, Y. H. 2019

    Abstract

    BACKGROUND: IPH4102 is a first-in-class monoclonal antibody targeting KIR3DL2, a cell surface protein that is expressed in cutaneous T-cell lymphoma, and predominantly in its leukaemic form, Sezary syndrome. We aimed to assess the safety and activity of IPH4102 in cutaneous T-cell lymphoma.METHODS: We did an international, first-in-human, open-label, phase 1 clinical trial with dose-escalation and cohort-expansion parts in five academic hospitals in the USA, France, the UK, and the Netherlands. Eligible patients had histologically confirmed relapsed or refractory primary cutaneous T-cell lymphoma, an Eastern Cooperative Oncology group performance score of 2 or less, were aged 18 years or older, and had received at least two previous systemic therapies. Ten dose levels of IPH4102, administered as an intravenous infusion, ranging from 0·0001 mg/kg to 10 mg/kg, were assessed using an accelerated 3 + 3 design. The primary endpoint was the occurrence of dose-limiting toxicities during the first 2 weeks of treatment, defined as toxicity grade 3 or worse lasting for 8 or more days, except for lymphopenia. Global overall response by cutaneous T-cell lymphoma subtype was a secondary endpoint. Safety and activity analyses were done in the per-protocol population. The study is ongoing and recruitment is complete. This trial is registered with ClinicalTrials.gov, number NCT02593045.FINDINGS: Between Nov 4, 2015, and Nov 20, 2017, 44 patients were enrolled. 35 (80%) patients had Sezary syndrome, eight (18%) had mycosis fungoides, and one (2%) had primary cutaneous T-cell lymphoma, not otherwise specified. In the dose-escalation part, no dose limiting toxicity was reported and the trial's safety committee recommended a flat dose of 750 mg for the cohort-expansion, corresponding to the maximum administered dose. The most common adverse events were peripheral oedema (12 [27%] of 44 patients) and fatigue (nine [20%]), all of which were grade 1-2. Lymphopenia was the most common grade 3 or worse adverse event (three [7%]). One patient developed possibly treatment-related fulminant hepatitis 6 weeks after IPH4102 discontinuation and subsequently died. However, the patient had evidence of human herpes virus-6B infection. Median follow-up was 14·1 months (IQR 11·3-20·5). A confirmed global overall response was achieved in 16 (36·4% [95% CI 23·8-51·1]) of 44 patients, and of those, 15 responses were observed in 35 patients with Sezary syndrome (43% [28·0-59·1]).INTERPRETATION: IPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sezary syndrome. If confirmed in future trials, IPH4102 could become a novel treatment option for these patients. A multi-cohort, phase 2 trial (TELLOMAK) is underway to confirm the activity in patients with Sezary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2.FUNDING: Innate Pharma.

    View details for DOI 10.1016/S1470-2045(19)30320-1

    View details for PubMedID 31253572

  • Low-dose Total Skin Electron Beam Therapy for Refractory Cutaneous CD30 Positive Lymphoproliferative Disorders. The Journal of dermatological treatment Panjwani, N., Yoo, C. H., Wang, E., Khodadoust, M. S., Kim, Y. H., Hoppe, R. T., Hiniker, S. M. 2019: 1–5

    Abstract

    We describe a case of a 48-year-old woman with a refractory cutaneous CD30 positive lymphoproliferative disorder treated successfully with total skin electron beam radiotherapy (TSEBT).

    View details for DOI 10.1080/09546634.2019.1628913

    View details for PubMedID 31179774

  • Volumetric modulated arc therapy and 3-dimensional printed bolus in the treatment of refractory primary cutaneous gamma delta lymphoma of the bilateral legs. Practical radiation oncology Obeid, J., Gutkin, P. M., Lewis, J., Skinner, L., Wang, E. B., Khodadoust, M. S., Kim, Y. H., Weng, W., Hoppe, R. T., Hiniker, S. M. 2019

    Abstract

    Patients with extensive dermal and subcutaneous disease present a technical challenge for treatment with radiation therapy (RT). Volumetric arc therapy (VMAT) can effectively treat disease on circumferential surfaces while minimizing dose to the core structures. However, treatment of extensive areas of the bilateral lower extremities with this technique has not been previously reported. Here we report the successful treatment of a patient with primary cutaneous gamma-delta T-cell lymphoma of the bilateral legs using VMAT and a custom 3-dimensional printed bolus. This approach is applicable for the treatment of cutaneous malignancies of the lower extremities.

    View details for PubMedID 30836188

  • Reply to J. Wang et al. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. F., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C. L., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Newman, A. M., Duhrsen, U., Huttmann, A., Meignan, M., Casasnovas, O., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2019: JCO1801907

    View details for PubMedID 30753108

Associate Professor of Medicine (Blood and Marrow Transplantation) and, by courtesy, of Dermatology at the Stanford University Medical Center

Publications

  • Volumetric Modulated Arc Therapy and 3-Dimensional Printed Bolus in the Treatment of Refractory Primary Cutaneous Gamma Delta Lymphoma of the Bilateral Legs PRACTICAL RADIATION ONCOLOGY Obeid, J., Gutkin, P. M., Lewis, J., Skinner, L., Wang, E. B., Khodadoust, M. S., Kim, Y. H., Weng, W., Hoppe, R. T., Hiniker, S. M. 2019; 9 (4): 220–25
  • Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients JCI INSIGHT Meyer, E. H., Laport, G., Xie, B. J., MacDonald, K., Heydari, K., Sahaf, B., Tang, S., Baker, J., Armstrong, R., Tate, K., Tadisco, C., Arai, S., Johnston, L., Lowsky, R., Muffly, L., Rezvani, A. R., Shizuru, J., Weng, W., Sheehan, K., Miklos, D., Negrin, R. S. 2019; 4 (10)
  • Infusion of donor-derived CD8(+) memory T cells for relapse following allogeneic hematopoietic cell transplantation BLOOD ADVANCES Muffly, L., Sheehan, K., Armstrong, R., Jensen, K., Tate, K., Rezvani, A. R., Miklos, D., Arai, S., Shizuru, J., Johnston, L., Meyer, E., Weng, W., Laport, G. G., Negrin, R. S., Strober, S., Lowsky, R. 2018; 2 (6): 681–90

    Abstract

    Murine models showed that CD8+CD44hi memory T (TM) cells could eradicate malignant cells without inducing graft-versus-host disease (GVHD). We evaluated the feasibility and safety of infusing freshly isolated and purified donor-derived phenotypic CD8+ TM cells into adults with disease relapse after allogeneic hematopoietic cell transplantation (HCT). Phenotypic CD8 TM cells were isolated after unmobilized donor apheresis using a tandem immunomagnetic selection strategy of CD45RA depletion followed by CD8+ enrichment. Fifteen patients received CD8+ TM cells at escalating doses (1 × 106, 5 × 106, or 10 × 106 cells per kg). Thirteen received cytoreduction before CD8+ TM cell infusion, and 9 had active disease at the time of infusion. Mean yield and purity of the CD8+ TM infusion were 38.1% and 92.8%, respectively; >90% had CD8+ T effector memory phenotype, cytokine expression, and secretion profile. No adverse infusional events or dose-limiting toxicities occurred; GVHD developed in 1 patient (grade 2 liver). Ten patients (67%) maintained or achieved response (7 complete response, 1 partial response, 2 stable disease) for at least 3 months after infusion; 4 of the responders had active disease at the time of infusion. With a median follow-up from infusion of 328 days (range, 118-1328 days), median event-free survival and overall survival were 4.9 months (95% confidence interval [CI], 1-19.3 months) and 19.6 months (95% CI, 5.6 months to not reached), respectively. Collection and enrichment of phenotypic CD8+ TM cells is feasible, well tolerated, and associated with a low incidence of GVHD when administered as a manipulated infusion of donor lymphocytes in patients who have relapsed after HCT. This trial was registered at www.clinicaltrials.gov as #NCT01523223.

    View details for PubMedID 29572391

  • Potential Association of Anti-CCR4 Antibody Mogamulizumab and Graft-vs-Host Disease in Patients With Mycosis Fungoides and Sézary Syndrome. JAMA dermatology Dai, J., Almazan, T. H., Hong, E. K., Khodadoust, M. S., Arai, S., Weng, W. K., Kim, Y. H. 2018

    View details for PubMedID 29800117

  • Validation of the Hematopoietic Cell Transplantation-Specific Comorbidity Index in Nonmyeloablative Allogeneic Stem Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Veeraputhiran, M., Yang, L., Sundaram, V., Arai, S., Lowsky, R., Miklos, D., Meyer, E., Muffly, L., Negrin, R., Rezvani, A., Shizuru, J., Weng, W., Johnston, L. 2017; 23 (10): 1744–48

    Abstract

    The Hematopoietic Cell Transplantation (HCT)-Specific Comorbidity Index (HCT-CI) has been extensively studied in myeloablative and reduced-intensity conditioning regimens, with less data available regarding the validity of HCT-CI in nonmyeloablative (NMA) allogeneic transplantation. We conducted a retrospective analysis to evaluate the association between HCT-CI and nonrelapse mortality (NRM) and all-cause mortality (ACM) in patients receiving the total lymphoid irradiation and antithymocyte globulin (TLI/ATG) NMA transplantation preparative regimen. We abstracted demographic and clinical data from consecutive patients, who received allogeneic HCT with the TLI/ATG regimen between January 2008 and September 2014, from the Stanford blood and marrow transplantation database. We conducted univariable and multivariable Cox proportional hazards regression models to evaluate the association between HCT-CI and NRM and ACM. In all, 287 patients were included for analysis. The median age of the patients was 61 (range, 22 to 77) years. The median overall survival was 844 (range, 374 to 1484) days. Most patients had Karnofsky performance score of 90 or above (85%). Fifty-two (18%) patients relapsed within 3 months and 108 (38%) patients relapsed within 1 year, with a median time to relapse of 163 (range, 83 to 366) days. Among the comorbidities in the HCT-CI identified at the time of HCT, reduced pulmonary function was the most common (n = 89), followed by prior history of malignancy (n = 39), psychiatric condition (n = 38), and diabetes (n = 31). Patients with higher HCT-CI scores had higher mortality risks for ACM (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.14 for HCT-CI score 1 or 2 and HR, 1.85; 95% CI, 1.11 to 3.08 for HCT-CI score ≥ 3, compared with 0, respectively). Among individual HCT-CI variables, diabetes (HR, 2.31; 95% CI, 1.79 to 2.89; P = .003) and prior solid tumors (HR, 1.75; 95% CI, 1.02 to 3.00; P = .043) were associated with a higher risk of ACM. Higher HCT-CI scores were significantly associated with higher risk of death. HCT-CI is a valid tool for predicting ACM in NMA TLI/ATG allogeneic HCT.

    View details for PubMedID 28668491

  • Effect of voriconazole on risk of nonmelanoma skin cancer after hematopoietic cell transplantation JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Kuklinski, L. F., Li, S., Karagas, M. R., Weng, W., Kwong, B. Y. 2017; 77 (4): 706–12

    Abstract

    Voriconazole has previously been associated with increased risk for cutaneous squamous cell carcinoma (SCC) in solid organ transplant recipients. Less is known about the risk in patients after hematopoietic cell transplantation (HCT).We evaluated the effect of voriconazole on the risk for nonmelanoma skin cancer (NMSC), including SCC and basal cell carcionoma, among those who have undergone allogeneic and autologous HCT.In all, 1220 individuals who had undergone allogeneic HCT and 1418 who had undergone autologous HCT were included in a retrospective cohort study. Multivariate analysis included voriconazole exposure and other known risk factors for NMSC.In multivariate analysis, voriconazole use increased the risk for NMSC (hazard ratio, 1.82; 95% confidence interval, 1.13-2.91) among those who had undergone allogeneic HCT, particularly for SCC (hazard ratio, 2.25; 95% confidence interval, 1.30-3.89). Voriconazole use did not appear to confer increased risk for NMSC among those who had undergone autologous HCT.This is a retrospective study.Voriconazole use represents an independent factor that may contribute to increased risk specifically for SCC in the allogeneic HCT population.

    View details for PubMedID 28780363

  • Gain of CD26 expression on the malignant T-cells in relapsed erythrodermic leukemic mycosis fungoides. Journal of cutaneous pathology Cedeno-Laurent, F., Wysocka, M., Obstfeld, A. E., Novoa, R. A., Vittorio, C. C., Kim, E. J., Weng, W., Rook, A. H. 2017

    Abstract

    Loss of CD26 surface expression on the circulating malignant T-cell is the most widely accepted diagnostic marker in patients with leukemic cutaneous T-cell lymphoma (CTCL). CTCL cases with reemergence of CD7 and/or CD26 surface expression are unusual and of uncertain prognosis. We report the case of an erythrodermic leukemic mycosis fungoides patient who had achieved temporary remission after a several months on multimodality immunotherapy and extracorporeal photopheresis, but who relapsed with aggressive disease phenotypically characterized by CD4+ T-cells with high CD26 expression. Polymerase chain reaction (PCR) studies and high throughput sequencing analyses from peripheral blood mononuclear cells at presentation and relapse consistently showed an identical clonal T-cell receptor (TCR) suggesting evolution of her original malignant clone which lacked CD26 expression. Interestingly, quantitative expression of the sialomucin, CD164, mirrored her clinical picture, thus favoring its reliability as a novel biomarker in CTCL.

    View details for DOI 10.1111/cup.12899

    View details for PubMedID 28083948

  • HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity. Blood advances Spinner, M. A., Fernández-Viña, M., Creary, L. E., Quinn, O., Elder, L., Arai, S., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Shizuru, J. A., Weng, W. K., Laport, G. G., Strober, S., Lowsky, R., Rezvani, A. R. 2017; 1 (17): 1347–57

    Abstract

    Many patients lack a fully HLA-matched donor for hematopoietic cell transplantation (HCT), and HLA mismatch is typically associated with inferior outcomes. Total lymphoid irradiation and antithymocyte globulin (TLI-ATG) is a nonmyeloablative conditioning regimen that is protective against graft-versus-host disease (GVHD), and we hypothesized that the protective effect would extend beyond HLA-matched donors. We report outcomes for all consecutively transplanted patients at Stanford University from December 2001 through May 2015 who received TLI-ATG conditioning and HCTs from 8 to 9 out of 10 HLA-mismatched unrelated donors (MMUDs, N = 72) compared with 10 out of 10 HLA-matched unrelated donors (MUDs, N = 193). The median age of the patients was 60 years with a median follow-up of 2 years, and there was a similar distribution of lymphoid and myeloid malignancies in both cohorts. There were no significant differences between MMUD and MUD cohorts in overall survival (46% vs 46% at 5 years, P = .86), disease-free survival (38% vs 28% at 5 years, P = .25), nonrelapse mortality (17% vs 12% at 2 years, P = .34), acute GVHD grades III-IV (6% vs 3% at day +100, P = .61), or chronic GVHD (39% vs 35% at 5 years, P = .49). There was a trend toward less relapse in the MMUD cohort (45% vs 60% at 5 years, hazard ratio: 0.71, P = .094), which was significant for patients with lymphoid malignancies (29% vs 57% at 5 years, hazard ratio: 0.55, P = .044). Achieving full donor chimerism was strongly associated with lower relapse rates. TLI-ATG conditioning may overcome the traditionally poorer outcome associated with HLA-mismatched donors and may be particularly well suited for patients with lymphoid malignancies who lack HLA-matched donors.

    View details for PubMedID 29296777