Juliet Fraser Gibson

CD4 + primary cutaneous small/medium-sized pleomorphic T-cell lymphoma: a retrospective case series and review of literature.

Abstract CD4 + primary cutaneous small/medium-sized pleomorphic T-cell lymphoma (CD4 + PCSM-TCL) is a rare T-cell lymphoma associated with a favorable prognosis. A retrospective study of 23 patients with CD4 + PCSM-TCL as defined by World Health Organization–European Organisation for Research and Treatment of Cancer (WHO-EORTC) and WHO classifications was conducted. Median age was 63 years. The head and neck were the most commonly affected locations, followed by the trunk. Two patients had evidence of systemic involvement at relapse. All tumors were CD3 + and CD4+. CD5 and CD7 loss occurred in 52% and 84%, respectively. The median follow-up was 33.6 months. Eleven patients had excisional biopsy only, six had localized radiotherapy and two received excision and localized radiation. Cytotoxic chemotherapy and localized radiation were used in one patient with aggressive and invasive features. All patients had a complete remission but one developed systemic involvement. Our case series demonstrates that CD4 + PCSM-TCL is an indolent T-cell lymphoma that can be treated with local modalities and raises the question of its current classification as a lymphoma.

Hematopoietic stem cell transplantation for primary cutaneous γδ T-cell lymphoma and refractory subcutaneous panniculitis-like T-cell lymphoma

BACKGROUND The panniculitic T-cell lymphomas (TCLs) comprise 2 distinct entities, αβ subcutaneous panniculitis-like TCL (SPTCL) and the γδ cutaneous TCLs with pannicular involvement primary cutaneous γδ (PCGD)-TCL. Although outcomes for most patients with SPTCL are favorable, those with PCGD-TCLs generally have an inferior outcome, and treatment strategies have not been well defined. Allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to be a potentially curative strategy in aggressive TCLs and in refractory and advanced-stage mycosis fungoides. OBJECTIVE We sought to analyze the outcomes of HSCT for panniculitic cutaneous TCL. RESULTS Fourteen patients (4 SPTCL, 10 PCGD-TCL) presented with primarily pannicular T-cell infiltrates. Seven patients underwent allogeneic HSCT from matched-related donors and matched-unrelated donors of which 4 (57%) are alive (1 SPTCL, 3 PCGD-TCL) at 7.8, 6.9, 6.2, and 0.25 years. Two patients underwent autologous HSCT (1 SPTCL, 1 PCGD-TCL) and both are alive at a median follow-up of 1.91 years. LIMITATIONS This study is limited by its retrospective nature and small sample size because of the rarity of SPTCL and PCGD-TCL. CONCLUSION Aggressive therapy followed by allogeneic HSCT is a promising treatment modality for patients with PCGD-TCL.

Langerhans Cells Facilitate UVB-Induced Epidermal Carcinogenesis

Ultraviolet B (UVB) light is considered the major environmental inducer of human keratinocyte DNA mutations, including within the tumor-suppressor gene p53, and chronic exposure is associated with cutaneous squamous cell carcinoma (SCC) formation. Langerhans cells (LC) comprise a dendritic network within the suprabasilar epidermis, yet the role of LC in UVB-induced carcinogenesis is largely unknown. Herein, we show that LC-intact epidermis develops UVB-induced tumors more readily than LC-deficient epidermis. While levels of epidermal cyclopyrimidine dimers (CPD) following acute UVB exposure are equivalent in the presence or absence of LC, chronic UVB-induced p53 mutant clonal islands expand more readily in association with LC which remain largely intact and are preferentially found in proximity to the expanding mutant keratinocyte populations. The observed LC facilitation of mutant p53 clonal expansion is completely αβ and γδ T-cell independent, and is associated with increased intraepidermal expression of interleukin (IL)-22 and the presence of group 3 innate lymphoid cells (ILC3). These data demonstrate that LC play a key role in UVB-induced cutaneous carcinogenesis, and suggest that LC locally stimulate keratinocyte proliferation and innate immune cells that provoke tumor outgrowth.

Cutaneous T-cell lymphoma (CTCL): Current practices in blood assessment and the utility of T-cell receptor (TCR)-Vβ chain restriction

BACKGROUND Accurate quantification of malignant cells in the peripheral blood of patients with cutaneous T-cell lymphoma is important for early detection, prognosis, and monitoring disease burden. OBJECTIVE We sought to determine the spectrum of current clinical practices; critically evaluate elements of current International Society for Cutaneous Lymphomas (ISCL) B1 and B2 staging criteria; and assess the potential role of T-cell receptor-Vβ analysis by flow cytometry. METHODS We assessed current clinical practices by survey, and performed a retrospective analysis of 161 patients evaluated at Yale (2011-2014) to compare the sensitivity, specificity, positive predictive value, and negative predictive value of parameters for ISCL B2 staging. RESULTS There was heterogeneity in clinical practices among institutions. ISCL B1 criteria did not capture 5 Yale cohort cases with immunophenotypic abnormalities that later progressed. T-cell receptor-Vβ testing was more specific than polymerase chain reaction and aided diagnosis in detecting clonality, but was of limited benefit in quantification of tumor burden. LIMITATIONS Because of limited follow-up involving a single center, further investigation will be necessary to conclude whether our proposed diagnostic algorithm is of general clinical benefit. CONCLUSION We propose further study of modified B1 criteria: CD4/CD8 ratio 5 or greater, %CD4(+) CD26(-) 20% or greater, or %CD4(+) CD7(-) 20% or greater, with evidence of clonality. T-cell receptor-Vβ testing should be considered in future diagnostic and staging algorithms.

Pilot study of sorafenib in relapsed or refractory peripheral and cutaneous T‐cell lymphoma

We carried out a pilot study of sorafenib in T-cell lymphoma (TCL) patients refractory to at least one prior systemic therapy. Sorafenib is a multikinase inhibitor that has in vitro effects on multiple intracellular pathways, including tumour proliferation and tumour angiogenesis, and is approved for renal cell and hepatocellular carcinoma (Escudier et al, 2007; Llovet et al, 2008). Sorafenib acts on the Ras/Raf/MEK/ERK MAPK signalling cascade and shows broad activity on vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor (PDGFR) (Wilhelm et al, 2004). Several investigators have described abnormal activation of tyrosine kinase signalling pathways in TCL and the potential therapeutic benefit of targeting these pathways. We hypothesized that sorafenib may have significant clinical activity in lymphoma patients by blocking signalling through PDGFR as well as VEGFR. This study involved 12 patients. An overall response rate (ORR) of 25% was to be considered clinically meaningful. Patients were treated for up to eight 28-d cycles or until unacceptable toxicity or progression. They were enrolled at Yale Cancer Center between 2010 and 2013 and treated according to an Institutional Review Board-approved protocol and good clinical practices. All were 18 years or older with measurable disease in either the skin or lymph nodes and had relapsed or refractory peripheral TCL (PTCL) or cutaneous T-cell lymphoma (CTCL) with an Eastern Cooperative Oncology Group performance status of 0–2. Response in CTCL patients was assessed using the modified skin-weighted assessment tool (mSWAT) (Olsen et al, 2007) and in PTCL patients by the International Workshop Criteria for lymphoma response (Cheson et al, 2007). Clinical endpoints included ORR, event-free survival (EFS) and duration of response or stable disease (SD). Twelve patients with a median age of 69 (range 38–85) years were treated (PTCL = 3, CTCL = 9) (Table I). Nine (75%) were female. Of the PTCL patients, one had PTCLnot otherwise specified (stage IV) and two had angioimmunoblastic TCL (stage IV); two had undergone prior autologous stem cell transplantation (ASCT). The median number of prior therapies for the PTCL patients was two (range 1–3) and included CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), denileukin diftitox, BEAM (carmustine, etoposide, cytarabine, melphalan) followed by ASCT, and romidepsin followed by ASCT. Of the nine CTCL patients, one was early stage (IB) and eight were advanced stage (IIB = 3, III = 2, IV = 3). Three patients had blood involvement detected by flow cytometry. This group had a median of eight prior therapies (range 3–11). Treatments included skin-based therapy (5), phototherapy (5), extracorporeal photopheresis (4), radiation therapy (7), chemotherapy (9) and immunotherapy (5). Five of 12 patients (42%) had a response (Fig 1). Four had a complete response (CR) with durations of 1 6, 1 2, 1, and 1 6 months; one had a partial response (PR) of 2 8 months. Four had SD for 4 2, 2 8, 2 1 and 6 6 months. Of the PTCL patients, three (100%) achieved CR and one underwent an allogeneic stem cell transplant (alloSCT). Of the CTCL patients, one had a CR (11%), one had a PR (11%), four had SD (44%) with one blood response but not in skin, and three had progressive disease (PD) (33%). Of the responders and SD patients (n = 9), two eventually discontinued the drug due to PD, one stopped the drug prior to alloSCT, and the remaining six discontinued the drug due to adverse effects (AEs). The median time to next therapy was 1 6 months. The median EFS of the entire cohort was 3 5 months (range 1 6–26 9); 2 8 months (range 1 9–6 9) for CTCL and 3 7 months (range 3 3–26 9) for PTCL. At a median follow-up of 11 2 months, 10 patients are alive (83%); two died after this trial, one from PD and one from sepsis. Overall, disease stabilization or reduction was noted in 75% of patients (CR, PR, SD). Eight patients (66%) required dose reductions due to AEs. The most common AE was skin toxicity, occurring in all but one of the CTCL patients. Skin toxicity usually occurred acutely and was mitigated by dose reductions, with 400 mg daily the most tolerable dose. Seven patients experienced rash; two had Grade 3–4 rashes, and four had rash with desquamation, including one Grade three desquamation. Other grade 3–4 toxicities included hypertension (1), fatigue (2), duodenal ulcer (1), systemic infection (1) and pain (3),

A fatal case of primary cutaneous gamma-delta T-cell lymphoma complicated by HLH and cardiac amyloidosis.

Gamma–delta T‐cell lymphomas (GD‐TCL) are rare and rapidly fatal neoplasms that are often associated with Hemophagocytic Lymphohistiocytosis (HLH), a syndrome of fevers, cytopenias, and multiorgan failure that often leads to a rapid death. We report the first case demonstrating an association between GD‐TCL, HLH, and cardiac amyloidosis, presenting a novel mechanism for rapid deterioration in these patients.

Transplantation in the Treatment of Primary Cutaneous Aggressive Epidermotropic Cytotoxic CD8 Positive T-Cell Lymphoma

Background Primary cutaneous aggressive epidermotropic cytotoxic CD8 positive T‐cell lymphoma (CD8+ PCAETL) is a rare subtype of peripheral T‐cell lymphoma with poor outcomes and without a standardized treatment strategy. Allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested as a potential curative therapy. Patients and Methods We conducted a retrospective case series. We identified 8 patients with the diagnosis of CD8+ PCAETL, 4 of whom also underwent allogeneic HSCT. Results Eight patients were treated at our center with combination chemotherapy and several novel agents, including histone deacetylase inhibitors, brentuximab, and pralatrexate. Patients underwent a median of 8.5 treatments before HSCT. Six of the 8 patients examined, including all 4 who received an HSCT, were alive at their last follow‐up. Conclusion Allogeneic HSCT is a promising treatment modality for CD8+ PCAETL. Because of the aggressive nature of this disease and lack of sustained remission with currently available therapies, HSCT should be considered early in the course of treatment. Two novel agents, brentuximab and pralatrexate, showed significant activity against CD8+ PCAETL, and may be incorporated earlier in the treatment course. Micro‐Abstract Several studies have suggested that hematopoietic stem cell transplantation (HSCT) might provide a cure for primary cutaneous aggressive epidermotropic cytotoxic CD8‐positive T‐cell lymphoma (CD8+ PCAETL). We summarize published literature on this disease and present outcomes of 8 patients with CD8+ PCAETL treated at our institution. In our experience, allogeneic HSCT and the novel agents brentuximab and pralatrexate show substantial activity against this disease.