Nodal T-cell Research Articles

Cutaneous manifestations of peripheral T-cell lymphoma, not otherwise specified: a case series highlighting the diagnostic challenges for this heterogeneous group.

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a rare, heterogeneous group of nodal and extranodal mature T-cell lymphomas that do not correspond to any of the defined T-cell entities, according to the World Health Organization classification. Most cases present with late stage nodal disease; however extranodal involvement is common. Skin and subcutaneous involvement is reported in approximately 20% of cases. Little attention has been given to the highly variable skin manifestations in the literature. It is our experience that lesions can present in ways other than previously described nodular or tumourous lesions that often ulcerate. We present a case series from a large tertiary institution of seven cases of PTCL, NOS with skin involvement, highlighting the variable presentations and diagnostic challenges for this heterogeneous group.

Nodal Peripheral T-Cell Lymphoma – a Clinical and Epidemiological Analysis at Medicine School of Sao Paulo University

Background: Peripheral T-cell lymphoma (PTCL) are a biologically and clinically heterogeneous group of rare diseases arising from mature or activated post-thymic T lymphocytes. Correspond to 10% to 15% of lymphoid malignancies with marked geographical variation in incidence. According to the WHO classification they are divided into nodal, extranodal, primary cutaneous and leukemic or disseminated and encompass 18 distinct entities. The nodal group involves the peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic lymphoma (AITL), anaplastic large cell lymphoma ALK positive (ALCL-ALK+) and anaplastic large cell lymphoma ALK negative (ALCL-ALK-). The literature of PTCL is scarce, especially in our country where data of epidemiology, clinical features and outcomes are usually rarely available. So, to better understand PTCL we performed a retrospective study with patients treated in a reference service for cancer treatment in Brazil.Methods: Eight-seven nodal PTCL patients treated with anthracyclne-based regimen (CHOP or, CHOEP) from January 2000 to June 2014 were evaluated retrospectively at the Medicine School of Sao Paulo University, Brazil. All patients lower than 60 years were consolidated with autologous hematopoietic stem cell transplantation (ASCT) in first CR or PR except that with ALCL-ALK+ diagnosis. Refractory and relapsed patients were salvaged with 3-4 cycles of IVAC (Ifosphamide 1.5 g/m2 i.v D1-D5, etoposide 100mg/m2 i.v D1-D5, aracytin 2g/m2 i.v twice a day D1-D2) regimen and submitted to ASCT. It was performed a central histopathological review and clinical and epidemiological data were obtained from medical records. Patients were evaluated for overall response (OR) including complete response (CR) and partial response (PR), overall survival (OS) and progression free survival (PFS). Statistical analysis was performed using the STATA-3 program using and a p-value ≤ 0.05 was considered statistically significant.Results: Of the 87 patients, 34 (39.08%) cases were classified as ALCL-ALK-, 27 (31.03%) as PTCL-NOS, 16 (18.39%) as ALCL-ALK+, 6 (6.89%) as AITL and in 4 (4.1%) cases the diagnosis could not be performed and an expansion of the immunohistochemical is ongoing. Thirty-six (45.38%) cases were female and 51(54.62%) were male, 59(67.81%) patients were lower than 60 years. Seventy-six (87.35%) patients presented in advanced stage (III or IV) at diagnosis but 73(83.90%) patients presented an ECOG < 2 and 14(16.10%) ≥ 2. Eighteen (20.70%) patients were of low-risk, 26 (29.88%) of low-intermediate risk and 43(49.42%) of high-intermediate and high-risk of international prognostic index (IPI). The CR and PR was obtained for 44(50.57%) and 8(9.19%), respectively with 59.76% OR. Thirty (34.48%) patients were primary refractory and five remain under treatment. In a median of follow of 30 months, ALCL-ALK+ show higher OS (median 140.98 months) than ALCL-ALK- (44.20 months), PTCL-NOS (median 20.62 months) and AITL (median 7.24 months) (p=0.41) (Figure 1A). The median of PFS was 3.84 months for AITL, 23.44 months for ALCL-ALK+, 40.03 months for PTCL-NOS and was not yet reached for ALCL-ALK- (p=0.0006) (Figure 1B). [Display omitted] [Display omitted] Conclusion: In this study we showed that ALCL-ALK+ as well as found in the literature presented a better OS in comparison to others nodal T-cell lymphoma as AITL, PTCL-NOS and ALCL-ALK-. Surprisingly the PFS of ALCL-ALK+ was statistically significant lower than of ALCL-ALK-. We thought that this result may be explained because in our service until to perform this analysis we did not indicate ASCT in first CR for ALCL-ALK+, but for all ALCL-ALK-. This hypothesis may be reinforced as the most of our cases presented high-intermediate and high-risk of IPI and that could equalize the favorable effect of ALK expression. In addition, we changed our approach and we are also indicating ASCT in first line for patients with ALCL-ALK+ with intermediate-high and high-risk of IPI. DisclosuresNo relevant conflicts of interest to declare.

Impact of Partial Response Versus Complete Response before RIC/RTC Allogeneic Stem Cell Transplantation on Survival in a Cohort of 115 Chemosensitive Advanced NHL

Allogeneic Hematopoietic stem cell transplantation (Allo-HSCT) is a curative option for advanced Non Hodgkin Lymphoma (NHL). Reduced intensity conditioning or reduced toxicity conditioning (RIC/RTC) allows improving survival and decreasing non-relapse mortality. Nevertheless it is well known that status disease before transplant is highly related to survival. Indeed, patients in non-responsive disease (ie stable disease or progressive disease (SD/PD)) have very poor outcomes compared to patients achieving a response. We addressed the question whether in responsive patients the level of response (partial response (PD) vs. complete response (CR)) had a profound impact on outcome in the context of RIC/RTC transplantation.Inclusion criteria for this bi-centric retrospective study were 1) first Allo-HSCT 2) aggressive NHL including Diffuse Large B-cell Lymphoma (DLBCL), Mantle-cell Lymphoma (MCL) and nodal T-cell NHL 3) Matched related donor (MRD), 8/8 or 10/10 matched unrelated donor (MUD) and Haploidentical related donor (HRD) 4) conditioning including RIC or RTC. All patients in this cohort are considered as intermediate risk group in the DRI classification (Armand et al, Blood, 2012). Extranodal T-cell NHL, NK-cell NHL, Cord Blood Unit transplant, partially matched (HLA 7/8 or 9/10) unrelated donor, myeloablative conditioning and patients in SD/PD before transplantation were not included in this study. We used Cheson criteria (Cheson et al, JCO, 2007) to evaluate the disease status before Allo-HSCT and we focused on patients with PET positivity using Deauville criteria before transplantation.115 patients included between 06.1999 and 09.2013. Diagnoses were DLBCL, MCL and nodal T-cell NHL in 40%, 30% and 30% respectively. Median age was 54 years old. Median line of treatments before transplantation was 3 (1-5), 81% of patients received an autologous SCT (31% in a tandem auto/allo and 50% relapsed after auto SCT). Donor types were MRD, MUD and HRD in 57,4%, 25,1%, and 57,4% of patients respectively. Conditioning was for 86% of patients a RIC and for 14% a RTC generally including Thiothepa.Patients were in CR in 80 cases (69.6%) and in PR in 35 cases (31.4%) according to Cheson criteria. 5-years PFS and OS for patients in CR were 61.1% (49,1-76) and 64,3% (52,6-78,6) respectively, whereas 5-years PFS and OS for patients in PR were 38,7% (21,9-68,4) and 38,1% (21,5-67,6) respectively with a significant difference (p=0,04 and p=0,05 respectively). Among this cohort, 80 patients (33 DLBCL, 19 MCL and 28 nodal T-cell NHL) had a PET TDM before Allo-HSCT and 11 patients had a positive PET using Deauville criteria. PFS and OS for patients with PET negative were 65.5% and 65,8% respectively and PFS and OS for PET positive patients were 46,8% and 45,5% (p=0,32 and 0,33 respectively). In multivariate analysis including histology, type of donor, type of conditioning, age and status disease at transplantation, the only factor having a negative impact both on PFS and OS were disease status according to Cheson criteria: PR at transplantation is associated with a lower PFS an OS with a Hazard Ratio of 2 (p= 0,04).In conclusion: for aggressive NHL, PR before Allo-HSCT evaluated with Cheson Criteria increases by 2 fold the risk of death or relapse in comparison with CR, indicating that either better response should be searched or transplant procedure should be adjusted to this risk. DisclosuresBlaise:Sanofi: Honoraria, Research Funding.

Role of routine imaging in detecting recurrent lymphoma: A review of 258 patients with relapsed aggressive non‐Hodgkin and Hodgkin lymphoma

After first-line therapy, patients with Hodgkin lymphoma (HL) and aggressive non-HL are followed up closely for early signs of relapse. The current follow-up practice with frequent use of surveillance imaging is highly controversial and warrants a critical evaluation. Therefore, a retrospective multicenter study of relapsed HL and aggressive non-HL (nodal T-cell and diffuse large B-cell lymphomas) was conducted. All included patients had been diagnosed during the period 2002-2011 and relapsed after achieving complete remission on first-line therapy. Characteristics and outcome of imaging-detected relapses were compared with other relapses. A total of 258 patients with recurrent lymphoma were included in the study. Relapse investigations were initiated outside preplanned visits in 52% of the patients. Relapse detection could be attributed to patient-reported symptoms alone or in combination with abnormal blood tests or physical examination in 64% of the patients. Routine imaging prompted relapse investigations in 27% of the patients. The estimated number of routine scans per relapse was 91-255 depending on the lymphoma subtype. Patients with imaging-detected relapse had lower disease burden (P = 0.045) and reduced risk of death following relapse (hazard ratio = 0.62, P = 0.02 in multivariate analysis). Patient-reported symptoms are still the most common factor for detecting lymphoma relapse and the high number of scans per relapse calls for improved criteria for use of surveillance imaging. However, imaging-detected relapse was associated with lower disease burden and a possible survival advantage. The future role of routine surveillance imaging should be defined in a randomized trial.

Clinical, Pathological, and Prognostic Characteristics Of Mature Nodal Or Extranodal T-Cell and NK-Cell Non-Hodgkin´s Lymphoma (NHL) In a Single Mexican Institution

BackgroundMature nodal or extranodal T-cell and NK-cell NHL are a rare and heterogeneous group of NHL with aggressive behavior and poor clinical outcome. Their incidence varies according to geographical region and racial characteristics. Mexico is included in those countries known to have a high incidence of extranodal T/NK-cell lymphoma, type nasal (NKTCL). ObjectiveTo evaluate the outcome and prognosis of patients with mature nodal or extranodal T-cell or NK-cell NHL in a single institution in Mexico City. MethodsClinicopathological characteristic, treatment, outcome, and prognosis of patients admitted to our institution between August, 1991 and December 2009 were analyzed. Prognostic Index T-cell (PIT) was used in all subtypes of lymphomas except in NKTCL subtype. All tissue biopsies and immunophenotypic markers were reviewed by an expert hematopathologist and reclassified according to the WHO 2008 classification. Univariate analysis using log-rank test was used to determine the correlation between clinical features and overall survival (OS). Multivariate analysis using Cox proportional hazard models were performed. A p value < 0.05 was considered significant. ResultsA total of 67 patients were analyzed. Median age was 37 years. B symptoms were presented in 83.6%, 74.6% had at least one site with extranodal disease, 73.1% advanced clinic stage, 32.8% high risk by International Prognostic Index (IPI) and 47.5% high risk by PIT. According to WHO 2008 classification the most common subtype was peripheral T-cell lymphoma not otherwise (PTCL NOS) specified in 38 patients (56.7 %), angioimmunoblastic T-cell lymphoma (AITL) and NKTCL were the second most common subtypes with 8 cases in each group (11.9 %), anaplastic large cell lymphoma (ALCL) kinase-positive (ALK-positive) was identified in 3 patients (4.5 %), ALCL ALK-negative in 2 cases (3.0 %), lymphoblastic lymphoma and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) with 3 patients in each group (4.5 %), hepatosplenic T-cell lymphoma (HSTL) and aggressive NK-cell leukemia with one case in each group (1.5 %). CHOP-like therapy was used in 71.6 % of patients. Nine percent of patients did not receive treatment. The response was evaluated in 53 patients in whom overall response was 71.7 % with 44.8 % achieving complete remission (CR). Median OS was 2760 days (CI 95 % 1153.145-4366.855). Histopathology subtype did not predict OS. Both prognostic scores, IPI and PIT, were able to identify 4 groups of patients with different outcomes. The analysis failed to demonstrate any advantage of adding etoposide to the chemotherapy schedule. Multivariate analysis showed that, IPI, PIT, and CR were predictive for OS (Table 1). ConclusionPrevious publications in Mexican population, with larger number of patients included, were particularly focus on clinical characteristics and prognosis of NKTCL. Our series provides data of mature nodal or extranodal T-cell and NK-cell NHL in Mexico. The current study confirms the poor prognosis of aggressive forms of mature nodal or extranodal T-cell and NK-cell NHL regardless of the chemotherapy schedule employed. Disclosures:No relevant conflicts of interest to declare.

Peripheral T-cell and NK-cell lymphomas in the WHO classification: pearls and pitfalls

Peripheral T-cell and NK-cell lymphomas are functionally, pathologically, and clinically complex. Most nodal T-cell lymphomas belong to the adaptive immune system, whereas many extranodal T-cell and NK-cell lymphomas are derived from innate immune cells. The pathological manifestations often reflect the functional attributes of the neoplastic cells. Several forms of peripheral T-cell lymphoma are derived from T-follicular helper cells (TFH), and include angioimmunoblastic T-cell lymphoma, the follicular variant of peripheral T-cell lymphoma, not otherwise specified, and primary cutaneous small/medium CD4-positive T-cell lymphoma. TFH-derived neoplasms are often associated with atypical and clonal B-cell proliferations, which take a number of forms, sometimes mimicking classical Hodgkin's lymphoma, and sometimes showing marked plasmacytic differentiation. Most extranodal T-cell lymphomas are cytotoxic and often arise in mucosal-associated sites. They can be derived from either αβ or γδ cytotoxic T cells, and include subcutaneous panniculitis-like T-cell lymphoma, and enteropathy-associated T-cell lymphomas, both Type I and Type II. Type I enteropathy-associated lymphomas occur in association with celiac disease, whereas Type II lymphomas are more often sporadic. For some T-cell lymphomas, such as hepatosplenic T-cell lymphoma, immunophenotypic heterogeneity is seen within a single disease entity. New data are emerging on the molecular pathogenesis of T-cell and NK-cell lymphoma, but most tumor types remain poorly characterized.

Identification of Multiple Subclones in Peripheral T-Cell Lymphoma, Not Otherwise Specified with Genomic Aberrations

Abstract 298Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a heterogeneous group of nodal and extra-nodal mature T-cell lymphomas that do not belong to any of the hitherto characterized T cell lymphoma subtypes. Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). PTCL, NOS with genomic aberrations has been shown to resemble lymphoma-type ATLL in terms of genomic aberration patterns, histopathology and prognosis (Clin Cancer Res., 15:30–38). We have recently shown that a majority of patients with acute-type ATLL have multiple subclones that were likely produced in lymph nodes (Blood, 117:5473–5478). In this study, high-resolution oligo-array comparative genomic hybridization (CGH) was employed to determine whether PTCL, NOS with genomic aberrations also possesses multiple subclones as found in ATLL. Thirteen cases of PTCL, NOS were available for 44K high-resolution array CGH analysis. These samples analyzed in this study were shown to be monoclonal by Southern blot analysis. We obtained average log2 ratios of regions where aberrations continued over 400 probes and showed a linear average ratio of >0.1 or <-0.1. The log2 ratio imbalance was defined when a patient had a different average log2 ratio for gain or loss regions. The results showed that 11 of the 13 cases (84.6%) had a log2 ratio imbalance, suggesting that multiple subclones exist in PTCL, NOS with genomic aberrations. As previously demonstrated, the average log2 ratio of aberrant regions reflected the ratio of tumors (Blood, 117:5473–5478). In one case, as represented in Figure 1, all tumor cells had regions of loss on chromosomes 3 and 13. Fifty-four percent of tumor cells had a region of loss on chromosome 16, and 83% of tumor cells had loss on chromosome 17. It is therefore speculated that clonal evolution took place as shown in Figure 2. In an effort to examine the association between multiple subclones and prognosis, we used our previous BAC array data for 24 cases and found that the presence of multiple subclones was associated with a poor prognosis (p=0.0279) (Figure 3). Our finding concerning the presence of multiple subclones in PTCL, NOS and ATLL should assist greatly in revealing the mechanism of lymphoma development, progression and drug-resistance associated with these diseases. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Combating Cancer Predisposition in Association With Idiopathic Immune Deficiency: A Recurrent Nodal and Cutaneous T-Cell Lymphoproliferative Disease in a Patient With Cartilage-Hair Hypoplasia

Address for correspondence: Mervi Taskinen, MD, Department of Pediatrics, Children’s Hospital, Helsinki University Central Hospital, PO Box 281 and 00029 HUS, Helsinki, Finland Clinical Pra ● Cartilage-hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia characterized by severe short-limbed short stature and hypoplastic hair. CHH is a primary immunodeficiency syndrome with impairment of cellular immunity in more than 85% of the patients. In addition, CHH is a cancer syndrome, with a 7-fold increase in incidence of cancer. The most frequent cancer diagnoses have been non-Hodgkin lymphoma of B-cell origin and basal cell carcinoma. ● We report on a male patient with CHH who developed 2 clinically distinct and altering CD30 T-cell lym-

Primary Cutaneous Follicular Helper T-cell Lymphoma

Peripheral nodal follicular T-cell lymphomas expressing follicular helper T-cell (T(FH)) markers have recently been identified. Such lymphomas are characterized by a nodal neoplastic T-cell proliferation accompanied by numerous reactive B cells and demonstrate some overlap with nodal angioimmunoblastic T-cell lymphoma (AITL). We identified 5 cases of cutaneous T-cell lymphoma with a peculiar pathologic aspect and expression of T(FH) markers. The mean age of the patients was 61 years (range, 33-78 years). Four patients had multiple papules, plaques, and nodules predominating on the trunk and the head. One had a nodular plaque on the face. Lesional T-cell clonality was found in all 5 patients, and blood T-cell clonality in 4 of the 5. Nodal involvement was never found. Patients had no systemic symptoms and no biological signs of AITL. In 3 cases, findings from skin biopsy specimens were initially misdiagnosed as primary cutaneous follicle B-cell lymphoma due to major B-cell infiltrate and CD10 positivity. Rituximab-containing therapies were ineffective in these cases, and biopsy specimens after treatment with rituximab showed medium- to large-sized atypical T-cell skin infiltrate expressing T(FH) markers (CD10, Bcl-6, PD-1, CXCL13, and ICOS). The final diagnosis proposed for all patients was cutaneous T(FH) lymphoma. The patient with localized disease was successfully treated with radiotherapy. Patients with diffuse disease showed marked resistance to treatments, with only 1 case of complete remission after allogeneic hematopoietic stem cell transplantation followed by bortezomib and donor-lymphocyte infusion. Bexarotene, methotrexate, thalidomide, interferon alfa, gemcitabine, liposomal doxorubicin, or multiagent chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) were either ineffective or induced transitory partial remission. We describe an original clinicopathologic series of primary cutaneous lymphomas with T(FH) phenotype, suggesting the existence of a new entity among cutaneous T-cell lymphomas. Relations of these lymphomas with the provisional entity of primary cutaneous small to medium CD4 pleomorphic T-cell lymphoma need to be further addressed.

Genetic alterations in systemic nodal and extranodal non-cutaneous lymphomas derived from mature T cells and natural killer cells

Mature (peripheral) T-cell and natural killer (NK)-cell lymphomas comprise a series of rather different neoplasms. Based on morphologic, immunophenotypic, genetic, and clinical data, the World Health Organization classification recognizes more than 20 entities or provisional entities. The variable clinical presentations, the objective recognition and pathological stratification, the difficulties regarding treatment, and the hardly predictable response to therapy indicate that the management of these entities requires novel tools. In contrast to B-cell lymphomas or precursor T-cell neoplasms, few recurrent translocations have been identified so far in T-cell non-Hodgkin's and NK-cell lymphomas. Additionally, some of the entities recognized by the World Health Organization classification are very rare and very scarce molecular data are available for T-cell lymphomas. Here, we have reviewed published reports focusing on the genetic lesions and gene expression profiling underlying systemic nodal and extranodal non-cutaneous mature T-cell and NK-cell lymphomas. We also provide a summary of new agents in clinical development and outline some future directions.

The spectrum of lymphoblastic, nodal and extranodal T-cell lymphomas: characteristic features and diagnostic dilemmas

T-cell lymphomas represent a heterogeneous group of neoplasms that encompass considerable clinical, morphologic, and immunophenotypic variation. The diagnosis of T-cell lymphoma is challenging because of its relative rarity, the lack of an immunophenotypic marker of clonality, and significant morphologic overlap with infectious/inflammatory processes and neoplasms, including Hodgkin and other non-Hodgkin lymphomas, and even mesenchymal or epithelial lesions. In the current World Health Organization classification of hematopoietic tumors, all except 1 subtype (ie, T-lymphoblastic lymphoma) are recognized as mature neoplasms derived from postthymic T cells. In addition to T-lymphoblastic lymphoma, this review will focus on nodal and extranodal T-cell lymphomas and exclude T-cell lymphomas presenting primarily in the skin. Extranodal natural-killer-cell/T-cell lymphoma, nasal type, will also be discussed because the derivation of this lymphoma from natural killer and natural killer-like T cells shows morphologic and immunophenotypic features that overlap with other T-cell lymphomas. In this review, we discuss the salient clinicopathologic, immunophenotypic, and genetic features, as well as our approaches to the diagnosis of lymphoblastic, nodal, and extranodal T-cell lymphomas.

Guidelines for the management of mature T‐cell and NK‐cell neoplasms (excluding cutaneous T‐cell lymphoma)

The peripheral T-cell neoplasms are a biologically and clinically heterogeneous group of rare disorders that result from clonal proliferation of mature post-thymic lymphocytes. Natural killer (NK) cell neoplasms are included in this group. The World Health Organization classification of haemopoietic malignancies has divided this group of disorders into those with predominantly leukaemic (disseminated), nodal, extra-nodal or cutaneous presentation. They usually affect adults and are more commonly reported in males than in females. The median age at diagnosis is 61 years with a range of 17-90 years. Although some subtypes may follow a relatively benign protracted course most have an aggressive clinical behaviour and poor prognosis. Excluding anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), which has a good outcome, 5-year survival for other nodal and extranodal T-cell lymphomas is about 30%. Most patients present with unfavourable international prognostic index scores (>3) and poor performance status. The rarity of these diseases and the lack of randomized trials mean that there is no consensus about optimal therapy for T- and NK-cell neoplasms and recommendations in this guideline are therefore based on small case series, phase II trials and expert opinion.

Regulatory T-Cell Depletion in Angioimmunoblastic T-Cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is the most frequent nodal T-cell lymphoma and is characterized by a polymorphic lymph node infiltrate, various dysimmune disorders, and a poor prognosis. Regulatory T-cells (Treg) play an emerging role in the prognosis of non-Hodgkin B-cell lymphoma and mediate significant autoreactive T-cell suppression. In this report, we demonstrate that numbers of Treg are significantly decreased in AITL lymph nodes [n = 30, 91 (40-195) per high power fields] compared with follicular lymphoma [n = 19, 179 (86-355)] and reactive lymph nodes [n = 8, 186 (140-265)]. Moreover, the few Treg in lymph nodes of AITL are resting Treg (rTreg) and have a naive CD45RA+, PD1-, and ICOS- phenotype [n = 5, 57% of Treg are CD45RA+ (16-96)], in contrast to the Treg in follicular lymphomas [n = 5, 7.4% (1-13)] or reactive lymph nodes [n = 7, 18.6% (6-48)]. Interestingly, Treg depletion was not observed in AITL peripheral blood at diagnosis. Altogether, these data suggest that Treg depletion could contribute to the nodal neoplastic T(FH) expansion and dysimmune symptoms in AITL.

Expression of Master Regulators of Helper T-Cell Differentiation in Peripheral T-Cell Lymphoma, Not Otherwise Specified by Immunohistochemical Analysis.

Abstract 5004 BackgroundPeripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) comprises nodal and extranodal mature T-cell lymphomas, which do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.During T-cell maturation, naïve T-cells include two distinct cell types, CD4-positive helper T-cells (Th) and CD8-positive cytotoxic T-cells. Following antigen stimulation, naïve Th cells differentiate into several subtypes of effector Th cells, including helper T-cells type1 (Th1), helper T-cells type 2 (Th2), follicular helper T-cells (TFH), regulatory T-cells (Treg), IL-17 producing T-cells (Th17), central memory T-cells (TCM), and effector memory T-cells (TEM).Previously, these subtypes of effector Th cells have been classified according to their pattern of cytokine secretion and expression of surface antigens, including chemokine receptors. More recent immunological researches have identified several transcription factors responsible for T-cell differentiation. The master regulators associated with Th, Th1, Th2, Th17, and Treg differentiation are reported to be Th-POK, T-Bet, GATA3, RORγt, and FOXP3, respectively.The origin of the neoplastic cells of PTCL-NOS is thought to be effector Th cells because the tumor cells usually express specific surface antigens such as pan-T-cell markers (CD2 and CD3), an effector T-cell marker (CD45RO), and a Th marker (CD4). However, the normal cellular derivation of PTCL-NOS remains unclear because the immunophenotypic profiles of PTCL-NOS are heterogeneous and not entirely disease specific.To presume the normal counterparts of PTCL-NOS, we used immunohistochemical analysis to examine the expression of the master regulators of T-cell differentiation and surface antigens, including chemokine receptors associated with the subtypes of Th cells. Patients and MethodsThe study population included ten Japanese patients who were diagnosed histopathologically with PTCL-NOS at the hospital of Kyoto Prefectural University of Medicine from 1993 to 2008. There were six male and four female patients who ranged in age from 26 to 78 years (mean 56 years) at diagnosis.Immunohistochemical staining was applied to 4-μm-thick paraffin-embedded sections of diagnostic lymph node, skin or liver tumor biopsy specimens. Sections were stained using a standard indirect avidin-biotin horseradish peroxidase method and diaminobenzidine (DAB) color development. Cases were considered positive if 25% or more of the tumor cells were stained with an antibody. For negative and positive staining controls, we used paraffin-embedded tissue sections of tonsillitis, nonspecific lymphadenitis, AILT, follicular lymphoma and diffuse large B-cell lymphoma. ResultsFirst, we examined the expression of the master regulator of helper T-cells (Th-POK) and the marker of effector T-cells (CD45RO), and all cases were positive for both.Next, we examined the expression of the master regulators of differentiation to subpopulations within Th cells (Th1, Th2, Treg and Th17). Three cases each were positive for T-Bet, and GATA3, but none of the cases showed FOXP3 or RORγt.Among the four cases not expressing these master regulators, two cases were positive for the surface antigens of central memory (TCM) (CCR7 and CD62L), and one case was positive for follicular helper T-cell (TFH) phenotype (BCL6, CXCL13 and PD-1). The remaining case was negative for all markers of effector Th subtypes. ConclusionsAll ten PTCL-NOS cases exhibited CD45RO and Th-POK, which characterized effector helper T-cells. Furthermore, the lymphoma cells of nine of the ten cases exhibited the expression of master regulators or surface antigens which characterized Th1, Th2, TCM and TFH. DisclosuresNo relevant conflicts of interest to declare.

Phase I Results of Combination Gemcitabine and Bortezomib (Velcade®) for Relapsed/Refractory Nodal T-Cell Non-Hodgkin Lymphoma (T-NHL) and Aggressive B-Cell NHL (B-NHL).

NF-κB is deregulated in several lymphoma subtypes, including aggressive B-NHL and T-NHL. The proteasome inhibitor, bortezomib, has the capacity to reverse some of the downstream consequences of NF-κB, but has only modest single-agent activity in aggressive NHL. Gemcitabine has a favorable toxicity profile and non-cross resistant mechanism of action with agents typically used in the first-line setting. Tumor cell lines and murine xenograft models demonstrate synergy between these two agents. Based on this data and the continued unmet clinical need for patients with relapsed/refractory aggressive NHL either ineligible for or relapsed after stem cell transplant (SCT), we conducted a phase I trial of the combination to determine a dosing regimen for phase II investigation. The phase I design was a 3+3 dose escalation of bortezomib (1.3 mg/m2 and 1.6 mg/m2, day (D) 1 and D8) with static gemcitabine dosing (800 mg/m2 D1 and D8) given on 21-day cycles. Following completion of bortezomib escalation, the phase II portion of the study was initiated. We report here the phase I study including toxicity and preliminary outcomes. 18 patients have enrolled, of whom 15 are evaluable for safety and preliminary efficacy. There were 8 women and 7 men, median age was 56 years (range 37–85 years), median prior therapies were 3 (range 2–5), and 67% had failed prior SCT. Histologies included diffuse large B-NHL (n=5) and T-NHL (1 hepatosplenic, 1 anaplastic, 2 angioimmunoblastic, 6 peripheral NOS). 11 pts accrued to the phase I portion. No dose limiting toxicity (DLT) was seen at bortezomib 1.3 mg/m2 (n=3 patients); 8 phase were tested at the next phase I dose level of bortezomib 1.6 mg/m2 since 2 patients experienced non-hematologic DLT (grade 3 hypertension and grade 3 liver function tests). The study continued to the phase II portion using bortezomib 1.6 mg/m2, in which 4 patients accrued. On planned analysis of the first 15 patients enrolled, it was noted that despite not meeting criteria for DLT, 10/15 patients experienced grade 3/4 neutropenia and/or thrombocytopenia resulting in repeated treatment delay(s). The median number of cycles delivered for all patients was 1 (range 1–3), while the median normalized dose-intensity was only 61%. Thus the trial was amended to institute a modified treatment schedule to administer gemcitabine and bortezomib on D1 and D15 on a 28-day schedule. Pre-planned analysis of the first 15 pts showed clinical activity/response allowing continuation of accrual onto the phase II portion (two partial remissions in T-NHL). In summary, our phase I study defined the safety/toxicity panel of combined bortezomib and gemcitabine dosing for patients with relapsed aggressive NHL. A planned analysis of the first 15 patients showed preliminary activity in heavily pre-treated patients allowing continuation to the 2nd stage, although repeated hematologic toxicities were seen leading to low dose intensity. Of note, data presented at ASCO 2008 (Luu et al. abstract #2563) studied the combination of bortezomib (D1, D4, D8, and D11) and gemcitabine (1,250 mg/m2 D1 and D8) in relapsed/ refractory advanced-stage solid tumors. The maximum tolerated dose of bortezomib there was 1.0 mg/m2 with gemcitabine. Furthermore, significant hematotoxicity was seen in that trial (grade 3/4 toxicity: 62% thrombocytopenia, 34% neutropenia, 17% anemia; with median of 2 cycles delivered). Accrual here continues to the phase II trial using a modified treatment schedule (gemcitabine 800 mg/m2 and bortezomib 1.6 mg/m2 both D1 and D15 on a 28-day schedule) in order allow more consistent delivery of the intended therapy.

Array CGH Analysis of Nodal T-Cell Lymphomas: Identification of Genomic Alterations Specific to Angioimmunoblastic and Unspecified Subtypes, and Correlation with Transcriptomic Data.

Genetic alterations underlying angioimmunoblastic and unspecified peripheral T-cell lymphomas (AITL and PTCL-u) are largely unknown. Seventeen AITL and 16 PTCL-u previously characterized by gene expression profiling, were analyzed by CGH on DNA microarrays comprising 4434 BAC clones with a resolution of about 600 KB. In the PTCL-u group, the mean number of chromosomal aberrations per case was 302 (range, 55 to 892). Gains (n=237, 41 to 587) were more frequent than losses (n=65, 8 to 305). AITL samples had, on average, a lesser number of genomic alterations than PTCL-u cases (n=243, range, 55 to 485), comprising more gains (n=201, 42 to 541) than losses (n=42, 9 to 262). Overall, the most frequent recurrent gains, present in 50% of all samples, were observed at 1p36.1; 1p36.3 ; 1q32 ; 2q37 ; 4p16 ; 5p15.3 ; 6q12 ; 7p22 ; 7p12 ; 7p11.2 ; 7q35-36 ; 8q24.3 ; 9q34 ; 11p15 ; 11q13 ; 16p13.3 ; 16q24 ; 17q12,q21,q25 ; 19p13.3 ; 19q13.2-q13.3 ; 20q11.2-q13.3 ; 22q11.1-q11.2 ; Xp11 ; Xp21-22 ; Xq27-28. The comparison of the genomic profiles of AITL and PTCL-u identified 73 genomic alterations (at clones or zones of clones) significantly associated with either group of tumors (Fisher test, p < 0,05). Six genomic gains mapping at 5p15 and 22q11 were associated with the AITL subtype. Thirty-four gains (mapping at 6p25, 7p1, 7q3, 8q24, 11p14, 14q32, 17q, 22q) and 33 losses (mapping at 6q, 10p and 13q), were overrepresented in PTCL-u. The coordinate analysis of the transcriptomic and CGH array data identified 10 regions with genomic imbalances containing genes differentially expressed in AITL versus PTCL-u. Seven regions amplified in PTCL-u contained genes overexpressed in PTCL-u, mostly related to metabolic pathways. Conversely, loss of genomic material at 13q12 correlated with decreased expression in PTCL-u of a few genes of the AITL signature. In AITL tumors, gain at 22q11 correlated with increased transcription of the LIF gene, previosuly characterized as part of the tumor cell signature in AITL. CD30+ PTCL-u samples had on average a higher number of genomic aberrations than CD30-negative cases (n=408 versus 238). Thirty-three genomic gains and 22 losses were exclusively seen in CD30+ tumors, and regions with chromosomal imbalances at 1q, 6q, 10p contained genes differentially expressed in CD30+ and CD30− tumors. For example, reduced transcription of FYN in CD30+ PTCL-u correlated with deletion of the corresponding chromosomal region. In conclusion,1.all 33 nodal PTCL analyzed harbor genomic imbalances (gains>losses), of which many are common to both AITL and PTCL-u subgroups;2.the pattern of genomic aberrations differs between the two subgroups, with certain aberrations being overrepresented in PTCL-u, and only a few specific for AITL;3.coordinate appraisal of transcriptomic and genomic data highlights correlations between genomic imbalances and gene expression signatures in subgroups of tumors.

Zanolimumab (HuMax-CD4™), a Fully Human Monoclonal Antibody: Efficacy and Safety in Patients with Relapsed or Treatment-Refractory Non-Cutaneous CD4+ T-Cell Lymphoma.

Combination chemotherapy has been the basis of treatment for peripheral T-cell lymphoma (PTCL) for many years, but relapses are frequent, often rapid and usually associated with a poor outcome. New treatment strategies are therefore required. Zanolimumab is a fully human monoclonal cytotoxic IgG1κ antibody, targeting the CD4 molecule on T-cells. The present open-labeled exploratory clinical trial investigated the efficacy and safety of Zanolimumab in 21 patients with biopsy-proven, treatment-refractory or relapsed CD4+ PTCL of non-cutaneous type. Zanolimumab was administered by i.v. infusion at a dose of 980 mg once weekly for 12 weeks. Patients (11 male, 10 female, median age 69 years) were enrolled with the following diagnoses: enteropathy-associated T-cell lymphoma (n=1), anaplastic large T-cell lymphoma (ALTL, n=4, 3 ALKneg subtype, 1 unknown), angioimmunoblastic T-cell lymphoma (n=9) and PTCL-unspecified (n=7). Patients had received a median of 1 previous treatment (range, 1–5) and 3 had undergone high dose chemotherapy with autologous stem cell rescue. The primary endpoint was objective tumor response. Responses were based on CT scan and clinical examination and classified according to the Cheson criteria. Objective tumor response was obtained in 5 out of 21 patients (23.8%; 95% CI: [8.2; 47.2]). Three patients (1 Anaplastic Large T-cell lymphoma and 2 angioimmunoblastic T-cell lymphoma) obtained a partial response of 43 and 51 days duration, respectively, one had not relapsed after 182 days, no further data available. Two patients (PTCL-unspecified and angioimmunoblastic T-cell lymphoma) obtained a complete response (unconfirmed) of 46 days duration and in the latter no relapse after 252 days was observed. 27 serious AEs were reported of which 6 were assessed as related to Zanolimumab treatment. Four infusion related AEs, one transient thrombocytopenia, one febrile neutropenia in a patient that was neutropenic at trial entry. All patients with serious AEs had complete recovery. Two non-serious grade 3 infusion related AEs were reported and one joint pain. In conclusion, zanolimumab was found to be active and well tolerated in heavily pretreated patients with aggressive PTCL. Zanolimumab in combination with CHOP is now being investigated in the setting of previously untreated patients with nodal T-cell lymphoma.

A Human CD4 Monoclonal Antibody for the Treatment of T-Cell Lymphoma Combines Inhibition of T-Cell Signaling by a Dual Mechanism with Potent Fc-Dependent Effector Activity

Zanolimumab is a human IgG1 antibody against CD4, which is in clinical development for the treatment of cutaneous and nodal T-cell lymphomas. Here, we report on its mechanisms of action. Zanolimumab was found to inhibit CD4+ T cells by combining signaling inhibition with the induction of Fc-dependent effector mechanisms. First, T-cell receptor (TCR) signal transduction is inhibited by zanolimumab through a fast, dual mechanism, which is activated within minutes. Ligation of CD4 by zanolimumab effectively inhibits early TCR signaling events but, interestingly, activates signaling through the CD4-associated tyrosine kinase p56lck. An uncoupling of p56lck from the TCR by anti-CD4 allows the kinase to transmit direct inhibitory signals via the inhibitory adaptor molecules Dok-1 and SHIP-1. Second, CD4+ T cells are killed by induction of antibody-dependent cell-mediated cytotoxicity, to which CD45RO+ cells are more sensitive than CD45RA+ cells. Finally, zanolimumab induces down-modulation of CD4 from cell surfaces via a slow Fc-dependent mechanism. In conclusion, zanolimumab rapidly inhibits T-cell signaling via a dual mechanism of action combined with potent Fc-dependent lysis of CD4+ T cells and may act long-term by down-regulating CD4.

Morphologic and Immunophenotypic Variants of Nodal T-Cell Lymphomas and T-Cell Lymphoma Mimics

Given their relative rarity, one of the primary diagnostic difficulties in nodal T-cell lymphomas is recognizing their range of histologic patterns. This is complicated by the fact that most mature T-cell lymphomas retain some functional characteristics of nonneoplastic T cells, ie, the capacity to secrete cytokines and costimulate immune cell growth, and, thus, are associated with obscuring nonneoplastic immune cells. Sessions 2 and 3 of the Society for Hematopathology/European Association for Haematopathology Workshop focused on these issues and conditions that may simulate T-cell lymphomas. We summarize salient features of presented cases, including the varied patterns seen in angioimmunoblastic T-cell lymphoma (AITL) and other more poorly characterized morphologic and functional nodal T-cell lymphoma subsets. Many cases illustrated the difficulties distinguishing AITL from peripheral T-cell lymphoma, unspecified, when the neoplasms manifest only some AITL features. The usefulness of separately classifying T-cell lymphomas that demonstrate follicular, perifollicular, or T-zone patterns of infiltration; significance of immunophenotypically distinct subsets that express cytotoxic markers or have features of central memory T cells; diagnostic difficulties posed by B-cell proliferations that accompany T-cell lymphomas; and T-cell lymphoma mimics related to genetic disorders, immune dysregulation, and drug reactions are also discussed.

Morphologic and Immunophenotypic Variants of Nodal T-Cell Lymphomas and T-Cell Lymphoma Mimics

Given their relative rarity, one of the primary diagnostic difficulties in nodal T-cell lymphomas is recognizing their range of histologic patterns. This is complicated by the fact that most mature T-cell lymphomas retain some functional characteristics of nonneoplastic T cells, ie, the capacity to secrete cytokines and costimulate immune cell growth, and, thus, are associated with obscuring nonneoplastic immune cells. Sessions 2 and 3 of the Society for Hematopathology/European Association for Haematopathology Workshop focused on these issues and conditions that may simulate T-cell lymphomas. We summarize salient features of presented cases, including the varied patterns seen in angioimmunoblastic T-cell lymphoma (AITL) and other more poorly characterized morphologic and functional nodal T-cell lymphoma subsets. Many cases illustrated the difficulties distinguishing AITL from peripheral T-cell lymphoma, unspecified, when the neoplasms manifest only some AITL features. The usefulness of separately classifying T-cell lymphomas that demonstrate follicular, perifollicular, or T-zone patterns of infiltration; significance of immunophenotypically distinct subsets that express cytotoxic markers or have features of central memory T cells; diagnostic difficulties posed by B-cell proliferations that accompany T-cell lymphomas; and T-cell lymphoma mimics related to genetic disorders, immune dysregulation, and drug reactions are also discussed.