Matthias Steinhoff

Cutaneous lymphomas in Germany: an analysis of the Central Cutaneous Lymphoma Registry of the German Society of Dermatology (DDG).

Background: Primary cutaneous lymphomas form a heterogenous group of lymphatic neoplasias.They manifest themselves on the skin and are the second most frequent group of non‐Hodgkin lymphoma (NHL) following gastrointestinal lymphomas.The number of epidemiologic studies is small due to limited availability and limited comparability on population‐based data.

Vorinostat combined with bexarotene for treatment of cutaneous T-cell lymphoma: in vitro and phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition

Abstract The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m2/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.

Evaluation of T-cell clonality in archival skin biopsy samples of cutaneous T-cell lymphomas using the biomed-2 PCR protocol.

Recently, several European centers of lymphoma diagnosis and research developed various polymerase chain reaction (PCR) methods for clonality analysis in suspect T-cell and B-cell proliferations (Biomed-2 Concerted Action). They have mainly been applied to frozen material of systemic B-cell and T-cell malignancies. Thus far, only limited data exist with regard to cutaneous T-cell lymphoma (CTCL) and paraffin-embedded material. Thus, we applied the Biomed-2 T-cell receptor (TCR) γ and TCRβ PCR as well as an in-house TCRγ PCR to a collection of 107 archival skin samples (84 CTCL, 3 systemic TCL and 20 controls). As a result, the Biomed-2 TCRγ PCR revealed 81% clonality, the in-house TCRγ method revealed 86% clonality, and the Biomed-2 TCRβ revealed 78% clonality in CTCL samples generating at least the 300u2009bp fragment in the Biomed-2 control PCR. We found clonal TCRβ rearrangements in 5 of 17 CTCL samples that were polyclonal in the Biomed-2 TCRγ PCR. By combining all Biomed-2 assays, one or more clonal rearrangements were detected in 87% of CTCL and in all 3 systemic TCLs. By combining all TCR PCR assays applied here, clonality was shown in 90% of the CTCL cases. In conclusion, we showed that the Biomed-2 TCR PCR worked well with DNA from paraffin-embedded tissue, revealing a high-clonality detection rate in CTCL, and thus should be highly recommended for routine molecular analysis. In addition, the performance of our in-house TCRγ assay verifies our previously published findings on clonally expanded T-cells in CTCL.

Complete clinical remission of tumor-stage mycosis fungoides after acute extensive skin necroses, granulomatous reaction, and fever under treatment with bexarotene, vorinostat, and high-dose fenofibrate

Mycosis fungoides and its variants are a distinct entity with a variable, but well-characterized clinical course. We report on a 51-year-old patient with tumor-stage mycosis fungoides who developed several unusual features such as extensive necrosis of lymphoma lesions, granulomatous reaction, and venular thromboses while under treatment with bexarotene, vorinostat, and high-dose fenofibrate. After surgical removal of skin necroses, the patient recovered and was in complete clinical remission. Possible causal factors such as blastic transformation; hematophagic syndrome; or bacterial, fungal, or viral infection could be excluded. We hypothesize that combination of the high-dose fenofibrate (400 mg) with the retinoid X receptor ligand bexarotene and vorinostat might have induced an increased rate of apoptosis in lymphoma cells in our patient resulting in an extensive release of lymphoma antigens. Augmented antigen release along with changes in local cytokine milieu might have induced macrophage activation and granuloma formation.

Dominance of Nonmalignant T-Cell Clones and Distortion of the TCR Repertoire in the Peripheral Blood of Patients with Cutaneous CD30+ Lymphoproliferative Disorders

The CD30-positive cutaneous lymphoproliferative disorders (CLPD) include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T-cell lymphoma (cALCL). Despite the malign-appearing histology, an excellent prognosis and spontaneous regression of single lesions characterize LyP. Even after years of clinical remission newly erupting lesions often harbor a T-cell clone identical to the initial one. This fact raises the question whether the clonal T-cell population persists in the peripheral blood. Therefore we investigated genomic DNA of 126 samples of lesional skin and peripheral blood from 31 patients with CLPD, obtained during both active disease and clinical remission. We performed molecular genetic analysis by combining T-cell receptor (TCR)-gamma PCR with the GeneScan technique and assessed the TCR repertoire in selected blood samples by beta-variable complementarity-determining region 3 (CDR3) spectratyping qualitatively and quantitatively. We were able to detect a clonal T-cell population in 36/43 (84%) skin samples and in 35/83 (42%) blood samples. Comparison of the compartments in each patient demonstrated different T-cell clones in skin and blood, suggesting a reactive nature of the clonal T cells in the blood. Moreover, CDR3 spectratyping revealed a restricted T-cell repertoire in the blood, suggesting T-cell stimulation by an unknown antigen.

Common clonal T‐cell origin in a patient with T‐prolymphocytic leukaemia and associated cutaneous T‐cell lymphomas

Summary. An unusual course was observed in a patient with indolent T‐prolymphocytic leukaemia (T‐PLL) who subsequently developed mycosis fungoides (Mf), lymphomatoid papulosis (LyP) and cutaneous CD30+ anaplastic large cell lymphoma (ALCL). Polymerase chain reaction analysis demonstrated identical monoclonal T‐cell receptor‐β and ‐γ gene rearrangements in all the different clinical entities. Furthermore, cytogenetic studies revealed the same aberrant clone with trisomy of chromosome 8 in T‐PLL and ALCL cells. This unique observation suggests that in T‐PLL, the leukaemic cells might undergo secondary transformation, subsequently resulting in different phenotypes of cutaneous T‐cell lymphoma.

Yttrium-90 ibritumomab tiuxetan radioimmunotherapy in primary cutaneous B-cell lymphomas: first results of a prospective, monocentre study

Radioimmunotherapy with Yttrium-90 (90Y) ibritumomab tiuxetan (IT) has been shown to be effective in systemic B-cell lymphomas. We conducted a pilot study to evaluate the outcome and assess complications of 90Y IT therapy in patients with primary cutaneous B-cell lymphomas (PCBCL). Ten patients, all but one, with relapsed PCBCL were included and treated with rituximab (250 mg m−2/body surface) on days 1 and 8 followed by a single dose of 90Y IT (11–15 MBq kg−1). The overall response rate was 100%. The complete response rate was 100%. The median time to relapse was 12 months. Ongoing remissions were achieved in four patients (median follow-up 19 months). Transient and reversible myelosuppression (grade 3–4) was the most frequent adverse event. Radioimmunotherapy with 90Y IT is an effective treatment in relapsed primary cutaneous follicle centre lymphomas and diffuse large B-cell lymphoma leg-type. Further investigations in controlled randomised clinical trials evaluating the role of 90Y IT versus rituximab in PCBCL are needed.

Prevalence of genetically defined tumor cells in CD7 as well as CD26 positive and negative circulating T-cell subsets in Sézary syndrome

For diagnosis and monitoring of Sézary syndrome flow cytometric quantification of CD7- and CD26- T-cells is widely used. Because antigen loss is a characteristic but not disease-specific finding we investigated the significance of this approach. Therefore we analyzed the prevalence of tumor cells in FACS-sorted CD7+/- as well as CD26+/- circulating T-cells applying a clone-specific qualitative and quantitative T-cell receptor PCR. Tumor cells varied considerably in the CD7+ and CD7- cell subset but were largely confined to the CD26- population. We conclude that quantification of CD26- T-cells reflects the tumor cell amount more accurate and should be preferred in the clinical setting.

Hepatosplenic T-cell lymphomas and therapy with TNF-α-blocking biologics: a risk for psoriasis patients?

Tumor necrosis factor (TNF)‐α antagonists have considerably improved the therapeutic approach to chronic inflammatory disorders including psoriasis vulgaris. Recently, some cases of highly aggressive hepatosplenic T‐cell lymphoma (HSTCL) have developed in patients with inflammatory bowel diseases (IBD) being treated with infliximab or adalimumab. Analysis of the published data suggests that the emergence of HSTCL is favored by the combination of purine analogues and infliximab or adalimumab in the therapy of a granulomatous inflammation involving Vδ1+γδ T cells. Because psoriasis vulgaris is different from IBD in regard to the type of inflammation, the concomitant therapies used and the tissue‐specific subsets of γδ T cells, the use of infliximab or adali‐mumab in psoriasis may not necessarily be associated with an increase in the risk of HSTCL.

Zanolimumab, a human monoclonal antibody targeting CD4 in the treatment of mycosis fungoides and Sézary syndrome

Background: The most common type of primary cutaneous T cell-lymphomas (CTCLs), which are characterised by a clonal proliferation of malignant skin-homing CD4+ lymphocytes, is mycosis fungoides (MF) and its rare leukaemic variant Sézary syndrome (SS). Objective: Zanolimumab is a high affinity human monoclonal IgG1k antibody, targeting the CD4-molecule. It exhibits cytotoxic and antiproliferative effects and has previously shown efficacy in CTCLs. Methods: Literature and reference research was done by using Pubmed and updates of ongoing studies were taken from American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH )annual meeting abstracts. Results: This article gives an overview about efficacy, tolerability and safety as well as chemistry, pharmacodynamics and pharmacokinetics of zanolimumab in the treatment of CTCLs.