John A. Zic

The treatment of cutaneous T‐cell lymphoma with photopheresis

ABSTRACT:  Photopheresis or extracorporeal photochemotherapy (ECP) is an immunomodulating procedure that has been available for the treatment of cutaneous T‐cell lymphoma (CTCL) since 1987. A concentrated white blood cell (WBC) sample spiked with 8‐methoxypsoralen (methoxsalen) is exposed to an ultraviolet A light source, then all blood components are returned to the patient. Treatment of mycosis fungoides (MF) and Sézary syndrome (SS) with ECP has been reported in over 400 patients. The combined overall response rate for all stages of CTCL is 55.7% (244 out of 438) with 17.6% (77 out of 438) achieving a complete response. Efficacy in treating certain clinical stages (IB, IIA, III and IVA) and skin stages (T2 and T4) of MF and SS is favorable, although randomized trials comparing ECP to other standard therapies are needed. The use of ECP to treat early stage patients remains controversial. Efforts to establish the effectiveness of combining ECP with other newer immunoadjuvant therapies and modifications of the procedure to enhance immunomodulation are exciting prospects for patients with CTCL.

Long-term follow-up of patients with cutaneous T-cell lymphoma treated with extracorporeal photochemotherapy

BACKGROUND Few studies have assessed the long-term outcome of patients with cutaneous T-cell lymphoma (CTCL) treated with extracorporeal photochemotherapy (ECP). OBJECTIVE Our objective was to assess the efficacy, safety, and survival of a cohort of patients with refractory T-cell lymphoma in various stages of cutaneous involvement who were treated with ECP. METHODS Twenty patients who had received at least 6 months of ECP between September 1988 and April 1991 were reevaluated and the data analyzed statistically to obtain outcome data through December 1995. RESULTS A complete response (disappearance of all lesions) was obtained in five patients (25%) and a partial response (disappearance of at least 50% of lesions) in five patients (25%). Of the 10 responders, seven (70%) were weaned from ECP. Two of seven patients had a relapse. Ten patients (50%) showed no response to ECP. No statistically significant differences between responders and nonresponders were found with respect to demographic, clinical, or laboratory variables. Seven patients died of causes directly related to CTCL and two patients died of unrelated causes. Median survival time for the entire cohort was 96 months (range, 16 to 152 months). An assessment of early response after 6 to 8 months of ECP had a sensitivity of 100% and a specificity of 90% for predicting long-term (> 4 years) outcome. Adverse effects were minimal. CONCLUSION ECP is a safe effective alternative therapy for CTCL that is refractory to other therapies; it can induce a long-term, disease-free remission in a minority of patients. Response in the first 6 to 8 months of treatment predicts long-term outcome.

Sézary syndrome: Immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC)

Sézary syndrome (SS) has a poor prognosis and few guidelines for optimizing therapy. The US Cutaneous Lymphoma Consortium, to improve clinical care of patients with SS and encourage controlled clinical trials of promising treatments, undertook a review of the published literature on therapeutic options for SS. An overview of the immunopathogenesis and standardized review of potential current treatment options for SS including metabolism, mechanism of action, overall efficacy in mycosis fungoides and SS, and common or concerning adverse effects is first discussed. The specific efficacy of each treatment for SS, both as monotherapy and combination therapy, is then reported using standardized criteria for both SS and response to therapy with the type of study defined by a modification of the US Preventive Services guidelines for evidence-based medicine. Finally, guidelines for the treatment of SS and suggestions for adjuvant treatment are noted.

Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides

The pathogenesis of mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is unknown. Although genetic alterations have been identified, none are considered consistently causative in MF. To identify potential drivers of MF, we performed whole-genome sequencing of MF tumors and matched normal skin. Targeted ultra-deep sequencing of MF samples and exome sequencing of CTCL cell lines were also performed. Multiple mutations were identified that affected the same pathways, including epigenetic, cell-fate regulation, and cytokine signaling, in MF tumors and CTCL cell lines. Specifically, interleukin-2 signaling pathway mutations, including activating Janus kinase 3 (JAK3) mutations, were detected. Treatment with a JAK3 inhibitor significantly reduced CTCL cell survival. Additionally, the mutation data identified 2 other potential contributing factors to MF, ultraviolet light, and a polymorphism in the tumor suppressor p53 (TP53). Therefore, genetic alterations in specific pathways in MF were identified that may be viable, effective new targets for treatment.

Extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma

BACKGROUND Many regimens are used for cutaneous T-cell lymphoma (CTCL), but with advanced disease response rates and patient survival are not adequate with any current therapy. Recently extracorporeal photochemotherapy (ECP) was proposed as an alternative therapy. OBJECTIVE Our purpose is to present the results of ECP in patients with CTCL refractory to other treatments. METHODS Patients with CTCL received ECP at 3- to 5-week intervals for at least 6 months. All patients except one were in stage T2 (patch/plaque) or higher. Eight patients had extracutaneous disease involving lymph nodes (six patients), bone marrow (five), or Sézary cells (six). The interval between initial symptoms and diagnosis was 5.9 +/- 1.9 years (mean +/- standard error of the mean) and the interval between diagnosis and ECP was 2.2 +/- 0.4 years. RESULTS A complete response (disappearance of all lesions) was obtained in five patients (25%) and a partial response (disappearance of at least 50% of lesions) in six patients (30%). Four patients (20%) showed stabilization of their disease and five progressed (25%). The only variable that predicted responders versus nonresponders was the number of ECP sessions (p < 0.05 by multivariate logistic regression). In contrast, no separate beneficial effect of adjunctive chemotherapy (p > 0.5) or electron beam therapy (p > 0.1) was found. CONCLUSION Long-term ECP may be an effective alternative treatment for CTCL refractory to other therapies and is likely to be even more useful when combined with other modalities.

Guidelines on the use of extracorporeal photopheresis

After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T‐cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi‐disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease.

A Phase II Study of SGN-30 in Cutaneous Anaplastic Large Cell Lymphoma and Related Lymphoproliferative Disorders

Purpose: An open-label, multicenter, phase II study was conducted to define the safety and antitumor activity of the monoclonal antibody SGN-30 in patients with CD30+ primary cutaneous anaplastic large cell lymphoma (pc-ALCL), lymphomatoid papulosis (LyP), or transformed mycosis fungoides (T-MF). Experimental Design: In the initial course (six doses), patients received i.v. SGN-30 every 3 weeks; eligible patients could receive two additional courses. The initial dose level of 4 mg/kg was increased to 12 mg/kg by protocol amendment. Results: The overall objective response rate [complete response (CR) + partial response (PR)] was 70% (16 of 23 patients): 10 patients achieved a CR and another 6 patients achieved a PR. Overall, clinical benefit of SGN-30, as assessed by achieving a response to therapy or stable disease (CR + PR + stable disease), was shown by 87% of patients during the study, including all patients with pc-ALCL or LyP and two thirds of patients with T-MF or with multiple clinical diagnoses. Nine of the 10 patients who achieved a CR and 5 of the 6 patients who achieved a PR were in remission at their follow-up evaluation (median duration, 84 days). Fifteen of 23 patients (65%) experienced at least one adverse event during the study, most of which were mild or moderate. Conclusions: SGN-30 was clinically active in 16 of 23 patients with heavily pretreated pc-ALCL, LyP, and T-MF and was well tolerated in this study. (Clin Cancer Res 2009;15(19):6217–24)

miR-223 regulates cell growth and targets proto-oncogenes in mycosis fungoides/cutaneous T-cell lymphoma.

The pathogenesis of the cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF) is unclear. MicroRNA (miRNA) are small non-coding RNA that target mRNA leading to reduced mRNA translation. Recently, specific miRNA were shown to be altered in CTCL. We identified significantly reduced expression of miR-223 in early stage MF skin, and the levels of miR-223 diminished further in advanced stage disease. CTCL peripheral blood mononuclear cells and cell lines also had reduced miR-223 as compared to controls. Elevated expression of miR-223 in these cell lines reduced cell growth and clonogenic potential, whereas inhibition of miR-223 increased cell numbers. Investigations into putative miR-223 targets with oncogenic function, including E2F1 and MEF2C, and the predicted miR-223 target, TOX, revealed all three are targeted by miR-223 in CTCL. E2F1, MEF2C, and TOX proteins were decreased with miR-223 overexpression, while miR-223 inhibition led to increased protein levels in CTCL. In addition, we showed the 3′-UTR of TOX mRNA was a genuine target of miR-223. Therefore, reduced levels of miR-223 in MF/CTCL lead to increased expression of E2F1, MEF2C, and TOX, which likely contribute to the development and/or progression of CTCL. Thus, miR-223 and its targets may be useful for the development of new therapeutics for MF/CTCL.

Large B-cell lymphoma of the leg: clinical and pathologic characteristics in a north american series

BACKGROUND Large B-cell lymphoma (LBCL) of the leg is an uncommon subset of primary cutaneous B-cell lymphoma that has been described in a series of European patients. OBJECTIVE Our purpose was to evaluate the clinical manifestation, diagnostic histopathology, immunophenotype, clinical course, and response to treatment of LBCL of the leg. METHODS We conducted a retrospective case series of 3 patients with primary LBCL of the leg. RESULTS The 3 elderly patients presented with progressive erythematous nodules on bilateral or unilateral lower extremities. All 3 patients had pre-existing peripheral edema or peripheral vascular disease. Histopathologic examination of the nodules showed dense lymphocytic infiltrates composed predominantly of large dysplastic lymphocytes that marked as B cells (CD20(+)). In 2 cases, the neoplastic cells were BCL-2 positive. All patients responded to initial therapy with localized electron beam radiation and chemotherapy but had disease progression. One patient had a complete and durable second response to anti-CD20 monoclonal antibody (rituximab). CONCLUSIONS The patients described have similar clinical and histopathologic features to those previously described. There may be an association between LBCL and pre-existing lower-extremity vascular disease. Treatment of LBCL is difficult, but 1 patient responded well to systemic anti-CD20 monoclonal antibody.

Intravascular large cell lymphoma: A patient with asymptomatic purpuric patches and a chronic clinical course

Intravascular large cell lymphoma (malignant angioendotheliomatosis) is a rare, multifocal, intravascular neoplasm of lymphoid cells that preferentially involves the vasculature of the skin and central nervous system. We describe a 54-year-old man with asymptomatic purpuric patches on the lower extremities for 10 years duration and a more recent lesion on the right arm. A biopsy specimen showed intravascular collections of tumor cells with irregular nuclear contours and prominent nucleoli. These cells were leukocyte common antigen (CD45), CD20, and CDW75 positive, but CD3, CD43, CD45RO, and cytokeratin negative. Polymerase chain reaction analysis of the skin for immunoglobulin heavy chain gene rearrangement detected a clonal population of B cells, supporting the diagnosis of a B-cell lymphoma. Peripheral blood showed no abnormal circulating cells. This case of malignant angioendotheliomatosis is unusual for its prolonged clinical course and presence of purpuric patches.