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.     

SOHO State of the Art Updates and Next Questions | New Pathways and New Targets in PTCL: Staying on Target

While the peripheral T-cell lymphomas (PTCL) remain a therapeutic challenge, and increasingly account for a disproportionate number of lymphoma-related deaths, improved understanding of disease pathogenesis and classification, and the development of novel therapeutic agents over the past decade, all provide reasons for a more optimistic outlook in the next. Despite their genetic and molecular heterogeneity, many PTCL are dependent upon signaling input provided by antigen, costimulatory, and cytokine receptors. While gain-of-function alterations effecting these pathways are recurrently observed in many PTCL, more often than not, signaling remains ligand–and tumor microenvironment (TME)–dependent. Consequently, the TME and its constituents are increasingly recognized as “on target”. Utilizing a “3 signal” model, we will review new–and old–therapeutic targets that are relevant for the more common nodal PTCL subtypes.     

Peripheral T-cell lymphoma: a clinicopathologic study of 42 cases

We analysed the clinical and pathologic features of 42 patients with immunologically confirmed peripheral T-cell lymphoma. The median age was 60 years and the male to female ratio was 1:1. A prior lymphoproliferative or autoimmune disorder was present in 14 per cent of the patients. Signs of advanced disease were usually present from the onset, such as B symptoms (55 per cent), generalized lymphadenopathy (57 per cent), stage III/IV disease (62 per cent), and elevated levels of serum lactate dehydrogenase (68 per cent). Primary extranodal disease (14 per cent), hepatomegaly (12 per cent), splenomegaly (12 per cent), lung/pleural involvement (12 per cent), skin involvement (21 per cent), and bone marrow involvement (28 per cent) were uncommon. Lymphocytopenia was present in 64 per cent of the patients, and none of nine patients tested were serologically positive for human T-cell leukemia/lymphoma virus (HTLV-I) infection. Among 38 patients receiving combination chemotherapy, 20 (53 per cent) achieved a complete remission. The actuarial median survival of all patients was 17 months. Age greater than 60 years and stage III/IV disease predicted a poor clinical outcome, whereas the large cell histological subtype predicted a favourable outcome. Prospective clinical studies using uniform treatments and a uniform histologic classification scheme are needed to confirm these findings.     

HTLV-I Induced Extranodal Lymphomas

HTLV-I induced not only nodal but also primary extranodal lymphomas. In this report we describe 12 patients with HTLV-I induced extranodal T-cell lymphoma collected from the literature and our institute experience. There were 5 males and 7 female patients of middle age positive for HTLV-1 antibody. The sites of primary tumor were gastrointestinal, Waldeyer's ring, skin, facial sinuses, and the pleura. All of these were histologically diffuse lymphomas and most of them were found to be a helper/inducer T-cell phenotype, showing integration of HTLV-I proviral DNA. Late leukemic changes and skin infiltration often occurred, but hypercalcemia was rare. Survival time varied from 4 to 35 months, and late organ infiltrations were common. These HTLV-I induced extranodal lymphomas were compared with HTLV-I unrelated extranodal lymphomas or HTLV-I induced nodal lymphomas (lymphoma type ATL). Between 1981 and 1990, we had 110 ATL patients and of these, 5 (4.6%) were HTLV-I induced primary extranodal lymphomas. The frequency of HTLV-I induced extranodal lymphoma might be much higher than expected because until now attention has not been paid to this entity. From the present review, it is suggested that HTLV-I could cause primary extranodal lymphoma which may have some different characteristics from other types of lymphoma. Therefore, patients with T-cell extranodal lymphomas should be investigated further for the presence of HTLV-I antibody and the tumor cells should be examined for the integration of HTLV-I proviral DNA using Southern blot analysis. However, this is sometimes difficult to detect with small specimens and in these cases the PCR method for detection of HTLV-I proviral DNA is worthwhile doing. It should be stressed that characterization of a monoclonal T-cell tumoral expansion with the integration of HTLV-I proviral DNA can be done by surface marker studies and gene analysis at the primary sites in patients with T-cell lymphoma and HTLV-I antibody. Further collection of cases with HTLV-I induced primary extranodal lymphoma is necessary in order to elucidate the clinical characteristics of this rare variant of ATL more precisely.     

Phenotypic Characterization of Subsets of T Cell Lymphoma: Towards a Functional Classification of T Cell Lymphoma

T cell non-Hodgkin's lymphomas (T-NHL) have traditionally been classified according to a variety of criteria including histological and clinical features, sites of involvement and etiologic agents. Except in select T-NHL types (e.g. CD30-positive anaplastic large cell lymphoma (ALCL)), immunophenotypic criteria are not used for routine subclassification of T-NHL. In this article, we outline the current models for classification and diagnosis of T cell tumors. We also briefly review the current understanding of non-neoplastic T cell subsets with regards to expression of activation markers belonging to the tumor necrosis factor receptor (TNFR) gene family. We summarize the currently available information on expression of these subset markers in T cell tumors, focusing on TNFR family members CD30 and CD134/OX40. CD134/OX40 expression is characteristic of certain entities (angioimmunoblastic lymphoma, angiocentric T-NHL) and a subset of T-NHLs of unspecified type, whereas CD30 expression is characteristic of ALCL and a largely non-overlapping subset of T-NHLs of unspecified type. Immunophenotypie stratification of T-NHL, using TNFR family members and other T cell subset-specific gene products, may provide a functional model for T-NHL classification as is currently the case for B cell tumors.     

Treatment outcome of angiocentric T-cell and NK/T-cell lymphoma, nasal type: radiotherapy versus chemoradiotherapy

OBJECTIVE: The purpose of this study was to evaluate the treatment outcome of angiocentric T-cell and natural killer (NK)/T-cell lymphoma, nasal type. METHODS: Between February 1989 and March 2001, 53 patients with newly diagnosed angiocentric T-cell and NK/T-cell lymphoma, nasal type involving the head and neck, were treated with radiation therapy (RT). There were 37 males and 16 females. The median age of the patients was 45 years (range 19-73). Twenty of them were treated with chemoradiotherapy (CRT), while 33 with treated with RT alone. The median follow-up period was 74 months (range 6-173). RESULTS: The 5-year overall survival rate of all patients was 69%. CRT appeared to be inferior to RT alone in terms of 5-year overall survival, though the difference was not statistically significant (59 versus 76%, P = 0.27). CONCLUSIONS: There was no difference in survival between RT and CRT in angiocentric T-cell and NK/T-cell lymphoma, nasal type.     

Primary T-cell lymphoma of the thyroid: case report and review of the literature

Here we report a rare case of primary T-cell lymphoma of the thyroid gland. A 32-year-old Chinese man was admitted to our hospital because of marked goiter and subcutaneous nodules. Computed tomography (CT) scan of the neck disclosed diffuse enlargement of the thyroid gland. A diagnosis of peripheral T-cell lymphoma was made according to cytopathological findings of fine-needle aspiration (FNA) of the thyroid gland and skin biopsy. Immunohistochemistry stain showed that the tumor was positive for CD3 and negative for CD20. Clonal T-cell receptor (TCR-γ) gene rearrangements were demonstrated by polymerase chain reaction. After six cycles of combination chemotherapy (bleomycin, cyclophosphamide, doxorubicin, vincristine, and prednisone), the thyroid retracted to normal size gradually.     

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.     

Clinicopathological features and prognostic factors of Japanese patients with "peripheral T-cell lymphoma, unspecified" diagnosed according to the WHO classification

Clinicopathological features of 36 patients, male: 58.3%; median: 68 years, with “peripheral T-cell lymphoma, unspecified” diagnosed by the WHO criteria were reviewed. Majority (69.4%) had stage IV disease with frequent involvements into bone marrow, spleen, liver, and skin. According to the IPI, 72.2% were categorized as high or high-intermediate risk group. CR and PR were achieved in 12 and 10 out of 31 patients treated by CHOP-based chemotherapy, respectively. One- and two-year overall survivals were 60.6 and 25.0%, respectively. Performance status, serum LDH, and B symptom were significant prognostic factors. Survival of CD4−/CD8+ cases, corresponding to cytotoxic T-cell lymphoma, was significantly worse than that of CD4+/CD8−.     

Bexarotene in Patients With Peripheral T-cell Lymphomas: Results of a Retrospective Study

Background

Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas that portend poor prognosis with currently available therapies. Bexarotene, a retinoic acid derivative, has efficacy in cutaneous T-cell lymphomas, but its activity in PTCL is unknown.

放射治疗上呼吸道T细胞淋巴瘤34例临床预后分析

目的：分析上呼吸道T细胞淋巴瘤放射治疗的远期疗效和影响其预后的相关因素。方法：对经病理证实的34例上呼吸道T细胞淋巴瘤病例，按病变累及部位，有无发热，不同照射剂量和服用CCNU合并化疗等因素将病例分组，经放射治疗后观察其生存期。结果：病变累及两个或以上解剖部位病例组的生存率低于累及一个部位的病例组；无发热症状的病例组3年和5年生存率高于有发热病例组，放射剂量以50－60Gy的病例组生存率较高，结论：放射治疗是上呼吸道T细胞淋巴瘤的首选治疗，发病越早，临床症状越轻，预后越好。     

中线外周T细胞淋巴瘤19例临床分析

目的：分析探讨中线外周T细胞淋巴瘤（midline peripheral T-cell lymphoma,MPTL)的临床特点，诊断，分型，治疗方法的选择和预后。方法：经免疫组化证实的MPTL患者19例。病变累及一个解剖部位的局限型9例。其中8例单纯放射治疗，1例放疗加化疗的综合治疗；病变累及两个及两个以上解剖部位的广泛型10例，其中9例综合治疗，1例单纯化疗化疗方案为CCNU（环己亚硝脲）和CHOP（环磷酰胺。阿霉素，长春新碱，强的松）各5例。结果：19例MPTL患者3年生存率68.4%(13/19)。5年生存率55.6%(5/9)。其中局限型3年生存率88.9%(8/9)。广泛型3年生存率50.0%(5/10)。综合治疗CCNU方案3年生存2/5，CHOP方案3年生存4/5。结论：MPTL是以鼻面中线部位进行性破坏性病变为特征的恶性淋巴瘤。临床表现和病理形态呈现多样化，无特异性。免疫组化染色检查有助本病的诊断。依据病变侵犯的范围可将MPTL分为单一解剖部位受累的局限型和两个及两个以上解剖部位受累的广泛型，前者预后较好。可单纯放射治疗；后者采用放疗加化疗或化疗加放疗的综合治疗可提高远期生存率。辅助化疗以CCNU或CHOP方案为佳。     

外周T细胞淋巴瘤(非特指型)的诊断与治疗进展

外周T细胞淋巴瘤，非特指型（peripheral T-cell lymphoma-unspecified，PTCL-U）是新近WHO淋巴肿瘤病理分类中一个较新的亚型它是起源于胸腺后T淋巴细胞的一类恶性肿瘤。病因不清，可能与Epstein-Barrvirus（EBV）和人类T细胞白血病／淋巴瘤病毒-Ⅰ（HTLV-Ⅰ）有关：其诊断需结合临床、细胞形态、免疫及遗传学特征，并排除其它特指型T细胞淋巴瘤．常规化疗疗效不佳，易复发，5年生存率22％～27％，应寻找更有效的治疗方法。     

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.     

Clinical features associated with transformation of cerebriform T-cell lymphoma to a large cell process

Some patients with cerebriform T-cell lymphoma (CTCL) undergo morphologic transformation to a large cell lymphoma. From a series of 113 patients with CTCL, 22 patients were identified with transformed CTCL. Stages of involvement at diagnosis were: I (seven), II (four), III (four), IV (seven). Nine patients had transformation at the initial diagnosis while the median time from diagnosis to transformation in the other 13 patients was 16 months (range: 3 months-6 years). Thirteen had transformation extracutaneously: lymph nodes (eight), central nervous system (two), and other extranodal sites (three). T cell markers were identified in all cases; of 15 cases with complete phenotypes, there were eight T-helper, three T-suppressor, and four aberrant T phenotypes. Serology for human T-leukemia virus-I (HTLV-I) was negative in eight patients tested. Median survival from diagnosis was 27 months compared to 53 months in 53 patients without transformation (p = 0.003). Despite combination chemotherapy in 12 patients following transformation, median survival after transformation was 12 months and only 7 months with extracutaneous disease. The likelihood of transformation could not be predicted by the initial histology, immunophenotype, or stage of disease.