Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients

Background: Gemcitabine is a novel nucleoside analogue which has shown promising results in most solid tumors; like the arabinosylcytosine analogue, gemcitabine may be an active drug in lymphoproliferative malignancies. We tested it in pretreated peripheral T-cell lymphoma patients with isolated skin involvement.Patients and methods: We performed a phase II study with the drug in 13 pretreated patients with peripheral T-cell lymphoma, five of whom had advanced-stage mycosis fungoides (MF), and eight peripheral T-cell lymphoma unspecified (PTCLU). Patients were treated on days 1, 8, and 15 of a 28-day schedule at the dosage of 1200 mg/m2 for a total of three courses.Results: Of the 13 patients, one achieved complete response (CR) and eight achieved partial responses (PR); the remaining four showed no benefit from the treatment. Among the responders, one CR and four PR were documented in the PTCLU patients and four PR in MF patients. Treatment was well tolerated; hematologic toxicity was mild and no nausea/vomiting or organ toxicity was recorded.Conclusions: In view of its significant activity and its modest toxicity profile, the role of gemcitabine deserves further evaluation in the management of pretreated patients with peripheral T-cell lymphoma.     

Increased angiogenesis in cutaneous T-cell lymphomas

Primary cutaneous T-cell lymphomas (CTCL) represent a heterogeneous group of neoplasms derived from skin-homing T cells. CTCL behave similarly to indolent B-cell lymphomas. There is increasing evidence that angiogenesis may be important in lymphoproliferative disorders. The aim of the study was to evaluate microvessel density (MVD) as a parameter of tumor angiogenesis measured by the expression of CD34 in the skin samples in CTCL patients. Formaldehyde-fixed, paraffin-embedded skin tumor biopsy specimens from 25 patients (16 men, 9 women) with CTCL (mycosis fungoides), and 8 skin samples from healthy volunteers were analysed. The preparations were stained with haematoxylin and eosin, and evaluated histopathologically. Staining for endothelial cells with monoclonal antibody against CD34 revealed a mean number of 134 dots per mm² for CTCL and 106 dots/mm² for controls; the difference was statistically significant (p=0.0388). Our study shows a higher number of microvessels in primary CTCL compared with normal skin. Microvascular endothelial cells have become an important target in cancer therapy. Increased MVD in the skin of CTCL patients indicate that angiogenesis may play a role in the growth of CTCL, and raises the possibility of using angiogenesis inhibitors in CTCL therapy.     

Therapy options in cutaneous T-cell lymphoma

The treatment of cutaneous T-cell lymphoma (CTCL) is continually evolving, as new and emerging drugs are added to the growing arsenal of CTCL therapy. The availability of newly approved investigational therapies, such as bexarotene, denileukin diftitox (DAB₃₈₉-IL2), monoclonal antibodies and novel chemotherapeutic agents, adds complexity to decisions on the management and treatment of CTCL patients. In formulating a treatment plan, therapeutic options are best approached through consideration of overall clinical staging (stage IA–IVB) and skin staging (T1–T4), which affect prognosis and the characteristics of each individual patient’s disease. This article will present and discuss the optimal therapeutic agents for all clinical stages of CTCL patients, based on currently available and investigational agents.     

Mycosis on mycosis fungoides: zoophilic dermatophytosis selectively superimposed on pre-existing cutaneous T-cell lymphoma (mycosis fungoides) plaques

We report a case of tinea corporis caused by a cattle-derived strain of Trichophyton mentagrophytes in a 44-year-old male affected by cutaneous T-cell lymphoma (CTCL, so-called mycosis fungoides). Fungal colonization of glabrous skin was strictly confined within pre-existing lymphomatous plaques. Either oral itraconazole or griseofulvin, or topical terbinafine were ineffective until the patient, who was treated with systemic retinoids and interferon-alpha for his CTCL, was shifted from leucocyte to lymphoblastoid interferon. The hypothesis that a local immunodisturbance could be responsible for the selective superimposition of tinea on CTCL lesions ('mycosis on mycosis'), and that such an immunodisturbance could be partially corrected by the interferon switch is discussed.     

Phase II study of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma

E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin-2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single-arm phase II study of E7777 in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T-cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression-free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment.     

CCR10 is expressed in cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is characterized by recruitment of malignant T-cell clones into the skin. The mechanisms involved in tumor homing are still not fully elucidated, though chemokines and chemokine receptors have been suggested to play a role in the pathogenesis. Here, we demonstrate extensive expression of CCR10 in skin biopsies of patients with Sezary syndrome (SS, n = 3), mycosis fungoides (MF, n = 2) and unspecified CTCL (n = 3). In addition, we expand prior findings of CXCR3 expression in MF to other entities of CTCL. Expression of CCR5 was detected in 2 of the examined skin biopsies. The functionality of CCR10 and CXCR3 in SS was demonstrated using the SS T-cell line HUT78. Our data support a potential role of CXCR3 in CTCL and strongly suggest that CCR10 and its ligand CCL27 may contribute to the skin infiltration of malignant T-cells in this group of lymphoproliferative disorders.     

Pentostatin in T-cell malignancies--a phase II trial of the EORTC. Leukemia Cooperative Group.

Purpose: Within this phase II EORTC trial, we have investigated the safety and efficacy of pentostatin in lymphoid malignancies. We have previously reported the results in T- and B-cell prolymphocytic leukemia, B-cell chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia. This report focuses on the outcome in T-cell malignancies: T-CLL, Sézary syndrome (Sézary), mycosis fungoides (MF) and T-zone lymphoma (TZL).Patients and methods: Of the 92 patients with these diagnoses enrolled, 76 were evaluable for response and toxicity, i.e., 25 of 28 with T-CLL, 21 of 26 with Sézary, 22 of 26 with MF, and 8 of 12 with TZL. All patients had progressive and advanced disease. Pentostatin was administered at a dosage of 4 mg/m² every week for the first 3 weeks, then 4 mg/m² every 14 days for another 6 weeks, followed by maintenance therapy of 4 mg/m² monthly for a maximum of 6 months.Results: Response rates (complete and partial responses) in patients with Sézary (n = 22) or MF (n = 21) were 33% and 23%, respectively, and in patients with T-CLL (n = 21) or TZL (n = 8) 8% and 25%, respectively. Sixteen (21%) patients died during the first ten weeks of treatment: twelve of progressive disease, two of infectious complications with progressive disease, one of myocard infarction and one of renal failure related to administration of i.v. contrast. Major toxicity (grade 3–4) included infection in 11% of patients, nausea/vomiting in 4%, diarrhea in 3%. Hematologic toxicity was mild to non-existent.Conclusions: We conclude that pentostatin is active in Sézary and MF but showed marginal activity in T-CLL or TZL. Toxicities are mild to moderate at the dose schedule administered. Due to its relatively specific lympholytic effect and its favorable toxicity spectrum, pentostatin might be especially useful for the palliative treatment of T-cell malignancies.     

Romidepsin: a new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors

Romidepsin is a histone deacetylase inhibitor (HDI), approved by the US FDA for the treatment of cutaneous T-cell lymphoma (CTCL). Although various mechanisms have been proposed for the activity of HDIs, including induction of genes controlling cell cycle, acetylation of cytoplasmic proteins and direct induction of apoptosis, the mechanism underlying activity of romidepsin and other HDIs in CTCL is not known. Romidepsin induces long-lasting responses. The side-effect profile is similar to that of other HDIs, causing fatigue, nausea and thrombocytopenia. Management of the CTCL population requires vigilence to prevent infection with skin contaminants, and monitoring of potassium and magnesium, electrolytes found to be low in a large proportion of patients. Electrocardiographic (ECG) changes are common but are not associated with myocardial damage. When molecular end points were evaluated in 61 patients enrolled on a Phase II trial with romidepsin, response was associated with persistence of acetylated histone H3, suggesting that drug exposure is important in effective therapy with romidepsin. Future studies will endeavor to identify combination strategies to increase the efficacy both in resistant CTCL and in solid tumors and to identify biomarkers of response that will allow selection of patients most likely to benefit from the therapy.     

我国皮肤T细胞淋巴瘤发病情况分析

目的:通过回顾性数据分析,探讨皮肤T细胞淋巴瘤在中国的发病情况。方法:通过检索公开发表的有关淋巴瘤和皮肤T细胞淋巴瘤的发病情况研究文献,应用聚类分析法对符合纳入标准的文献进行纳入并统计其中皮肤T细胞淋巴瘤的发病率。经过汇总整理与《中国淋巴瘤亚型分布国内多中心性病例10 002例分析》进行对比。结果:本研究共纳入17篇文献,涉及13个省市自治区,共计16 885例患者。分析结果显示,中国皮肤T细胞淋巴瘤从1993年到2017年发病率约为0.69/105,与《中国淋巴瘤亚型分布国内多中心性病例10 002例分析》中的结果一致,与国外文献报道中美国皮肤T细胞淋巴瘤发病率0.64/105也基本一致。结论:皮肤T细胞淋巴瘤在中国和有关国家都是发病率很低的一种恶性肿瘤,属于WHO定义的罕见病。     

皮肤T细胞淋巴瘤的免疫治疗

阐述免疫治疗包括细胞因子[白介素—2(IL—2)、白介素-12(IL—12)]、免疫核素(^131I—T101)、免疫毒素IL—2—融合毒素(DAB389-IL2)]、单克隆抗体抗CD5(T101)和某些新的局部免疫调节剂(如CTLA4—1g、LFA-tip、BCX—34)、维甲酸类药物如targretin、panretin与光效应药物如hypercin或δ—ALA试治皮肤T细胞淋巴瘤。     

Results of a phase II trial of oral bexarotene (Targretin) combined with interferon alfa-2b (Intron-A) for patients with cutaneous T-cell lymphoma

BACKGROUND: Bexarotene is one of the most active single agents for the treatment of recurring or refractory cutaneous T-cell lymphoma (CTCL). Interferon alfa has also been used for many years as an effective treatment for this disease. The results in recent case reports of the combination of bexarotene and interferon alfa have been promising. Based on more extensive results reported with the combination of other retinoids with interferon alfa, the present study attempted to determine the response rate, response duration, and safety of bexarotene (Targretin capsules, Ligand Pharmaceuticals, San Diego, Calif) alone and then with the addition of interferon alfa-2b (Intron-A, Schering-Plough, Kenilworth, NJ). METHODS: Patients with biopsy-proven CTCL, TNM stages IB, IIA, IIB-IV, were treated with oral bexarotene 300 mg/m2/day for at least 8 weeks. If a complete response was not seen after 8 weeks, interferon alfa-2b 3 million units (MU) subcutaneously was added, and increased to 5 MU if tolerated, 3 times a week. RESULTS: A total of 22 patients were enrolled at 5 sites, and 18 patients were assessable for response. Overall response rate for combined bexarotene and interferon alfa was 39% (95% confidence interval [CI]: 17%-64%), including 1 patient with a clinical complete response, 6 patients with partial response, 3 patients with stable disease, and 8 patients with progressive disease. Three partial responses were first noted during the bexarotene-alone phase. Adverse events were generally manageable, and only 1 patient was withdrawn from study for hypertriglyceridemia. CONCLUSIONS: The addition of interferon alfa-2b did not increase the response rate that would have been expected with bexarotene alone.     

Pulmonary manifestations in patients with cutaneous T-cell lymphomas

BACKGROUND: Lungs are among the most common organs of extranodal involvement by cutaneous T-cell lymphomas (CTCLs), yet the magnitude of lung involvement is not clear, and only a few case reports have addressed this issue to date. The objective of this study was to present the authors' observations on how to recognize lung involvement by CTCL and evaluate the clinical and radiologic differences between involvement of the lungs by CTCL and by pneumonia. METHODS: A retrospective analysis was conducted of all 710 patients with confirmed CTCL who presented to The University of Texas M. D. Anderson Cancer Center between January 1996 and January 2005. Demographics, tumor characteristics, respiratory symptoms, thoracic imaging, microbiology, and laboratory studies were reviewed. RESULTS: During the 9-year period that was studied, 122 patients presented with pulmonary radiologic abnormalities, including 67 patients who also had respiratory symptoms. Pneumonia (n = 27 patients) or lung involvement (n = 6 patients) in patients with CTCL were associated with high mortality rates (hazard ratio, 1.82; 95% confidence interval, 1.08-3.07%; P = .026). The pathogens that were isolated from lower respiratory cultures were Staphylococcus aureus (n = 4 patients), Aspergillus fumigatus (n = 2 patients), Mycobacterium avium-intracellulare (n = 2 patients), Pseudomonas aeruginosa (n = 1 patient), respiratory syncytial virus (n = 1 patient), and Candida parapsilosis (n = 1 patient). Most of the radiologic findings in patients with pneumonia were opacities. Six patients had involvement of lung by CTCL, and most common radiologic pulmonary findings were either a solitary nodule or multiple progressing pulmonary nodules. CONCLUSIONS: Pneumonia and lung involvement by CTCL are relatively rare but portend poor survival. Thus, patients with CTCL should be evaluated thoroughly with thoracic imaging when they experience respiratory symptoms.     

Comprehensive cytogenetic study of primary cutaneous gamma-delta T-cell lymphoma by means of spectral karyotyping and genome-wide single nucleotide polymorphism array

Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL), which originates from activated mature gamma-delta T cells with a cytotoxic phenotype is a rare T-cell lymphoproliferative disease. The prognosis of PCGD-TCL has been rather unfavorable due to poor response to conventional chemotherapy, and its molecular features and pathophysiology underlying disease development remain unknown. We report here a case with primarily treatment-resistant PCGD-TCL featuring highly complex cytogenetic and genetic aberrations detected by spectral karyotyping and genome-wide single nucleotide polymorphism (SNP) array. Chromosomal aberrations included several chromosomal translocations involving breakpoints at 9p21, 14q11.2, 14q32.1, or 16q23.1, suggesting the involvement of WWOX, TCL gene cluster, and BCL11B, which are crucial for tumorigenesis in T-cell lymphomas. SNP analysis also identified genome copy number gains and losses in various regions, which can potently deregulate expression of various pro- and anti-oncogenic genes involved in RAS-related protein pathways, PI3K/AKT/MTOR-related pathways, MYC-related signaling, or TP53-related signaling. Thus, this case report may shed some light on the complex molecular abnormalities involved in the development of PCGD-TCL and on information that can aid the search for druggable target molecules in this disease.     

皮下脂膜炎样T细胞淋巴瘤六例临床及病理特点分析

目的 皮下脂膜炎样T细胞淋巴瘤(subcutaneous pannieulitis-like T cell lymphoma,SPTCL)是一类非常罕见的皮肤T细胞恶性淋巴瘤,相关报道较少且易误诊.本研究旨在分析SPTCL患者的临床及病理特征.方法 回顾性分析2010-01-01-2015-12-31天津医科大学肿瘤医院收治的6例SPTCL患者的临床治疗、预后及病理特征.结果 6例SPTCL患者中,男3例,女3例.6例患者的年龄2～53岁,平均诊断年龄为29岁,其中4例的患者＜30岁.起病部位主要为四肢,5例患者表现为皮下的硬结肿物,1例患者表现为皮肤溃疡和渗出.皮肤损害出现的中位时间为13个月(1～60个月).6例患者中无伴发嗜血细胞综合症(hemophagocytic syndrome,HPS)者.6例患者镜下共同特征是小或中等大小的不典型肿瘤细胞围绕脂肪细胞生长.免疫组化特征为CD3+(100％)、CD4+ (100％)、CD8+(100％)、CD20-(100％)、CD56-(83％)、TCRβF-1+ (100％)、TIA-1+ (100％)、GrB+ (100％)、穿孔素阳性(100％).6例SPTCL患者均接受了以CHOP或CHOP样方案为主的多药联合化疗,化疗后3例患者获得CR,2例患者PR,1例患者SD.CR的3例患者中有2例患者出现复发,其中1例患者经自体造血干细胞移植后获得CR,1例在间断化疗状态下维持SD.获得PR的1例患者经自体造血干细胞移植后获得CR.中位随访时间为47个月(7～73个月),1例失访,3例患者无病生存,2例患者带瘤生存.结论 本研究SPTCL患者呈惰性进展且预后较好,常用的化疗方案为CHOP或CHOP样方案,早期复发或化疗效果欠佳的患者采取自体造血干细胞移植可能获益.     

Treatment of a patient with a nodal peripheral T-cell lymphoma (Angioimmunoblastic T-cell lymphoma) with a human monoclonal antibody against the CD4 antigen (HuMax-CD4)

A patient with a CD4+ refractory peripheral T-cell lymphoma (PTL), subtype angioimmunoblastic T-cell lymphoma (AILD), was treated with a human monoclonal anti-CD4 antibody (HuMax-CD4) iv once weekly for 10 wk. Early during treatment all palpable enlarged lymph nodes disappeared. A decline of normal CD4+ T-cells in the blood mirrored the treatment effect. Shortly after stopping treatment the patient relapsed with new enlarged lymph nodes. This time no antitumor effect was seen when HuMax-CD4 treatment was reinstituted. No severe side effects were observed during the antibody treatment. This case report is the first describing that HuMax-CD4 has antilymphoma activity in PTL and is an interesting drug to study further in patients with CD4+ PTL.