Aggressive Peripheral T-cell Lymphoma Research Articles

The aggressive peripheral T-cell lymphomas: 2015.

T-cell lymphomas make up approximately 10%-15% of lymphoid malignancies. The frequency of these lymphomas varies geographically, with the highest incidence in parts of Asia. The diagnosis of aggressive peripheral T-cell lymphoma (PTCL) is usually made using the World Health Organization classification. The ability of hematopathologists to reproducibly diagnosis aggressive PTCL is lower than that for aggressive B-cell lymphomas, with a range of 72%-97% for the aggressive PTCLs. Patients with aggressive PTCL are staged using the Ann Arbor Classification. Although somewhat controversial, positron emission tomography scans seem to be useful as they are in aggressive B-cell lymphomas. The most commonly used prognostic index is the International Prognostic Index. The specific subtype of aggressive PTCL is an important risk factor, with the best survival seen in anaplastic large-cell lymphoma-particularly young patients with the anaplastic lymphoma kinase positive subtype. Anaplastic large-cell lymphoma is the only subgroup to have a good response to a CHOP-like regimen. Angioimmunoblastic T-cell lymphoma has a prolonged disease-free survival in only ~20% of patients, but younger patients who have an autotransplant in remission seem to do better. PTCL-not otherwise specified is not one disease. Anthracycline-containing regimens have disappointing results, and a new approach is needed. Natural killer/T-cell lymphoma localized to the nose and nasal sinuses seems to be best treated with radiotherapy-containing regimens. Enteropathy-associated PTCL and hepatosplenic PTCL are rare disorders with a generally poor response to therapy, although selected patients with enteropathy-associated PTCL seem to benefit from intensive therapy.

Clinical analysis of 25 patients with aggressive peripheral T-cell lymphoma in advanced stage treated with autologous stem cell transplantation

目的探讨大剂量化疗联合自体造血干细胞移植（ASCT）治疗侵袭性外周T细胞淋巴瘤（PTCL）的疗效。方法回顾性分析1997年5月至2013年6月于完全缓解（CR）期接受ASCT治疗的25例侵袭性PTCL患者的临床资料。结果①25例患者中男16例，女9例，中位发病年龄30(12~54）岁。病理类型包括PTCL非特指型（PTCL-U) 16例、血管免疫母细胞淋巴瘤（AITL）4例、间变大细胞淋巴瘤（ALCL）3例和肝脾T细胞淋巴瘤（HSTL) 2例。临床分期Ⅲ期和Ⅳ期分别为8例和17例；其中合并骨髓侵犯者9例。移植前19例处于CR1期，另6例为CR2期。②2例HSTL均为骨髓侵犯、国际预后指数评分高危患者，联合化疗后获得CR1并行ASCT巩固治疗，但均于移植后12个月内早期复发、死亡。其余23例患者中位随访38(14~110）个月，3年无进展生存（PFS）率和总体生存（OS）率分别为（63.1±10.5）%和（71.8±9.9）%。CR1期（17例）移植者的生存有优于CR2期（6例）移植者的趋势[3年PFS率（74.9±11.0）％对（33.3±19.2）%，P=0.092; 3年OS率（80.2±10.4）％对（50.0±20.4）%，P=0.043]。无骨髓侵犯者的生存有优于骨髓侵犯者的趋势[3年PFS率（77.9±11.3）%对（40.0±17.4）%，P=0.142；OS率（84.4±10.2）％对（53.3±17.3）%，P=0.076]。结论ASCT改善化疗敏感侵袭性PTCL患者的生存。移植前非CR1状态和淋巴瘤骨髓侵犯可能是影响ASCT疗效的不良预后因素。HSTL患者预后差，ASCT后早期复发率高，需要进一步探索有效的治疗方案。

Mogamulizumab and the treatment of CCR4-positive T-cell lymphomas.

Glyco-engineering has been developed to enhance the pharmacological properties of monoclonal antibodies (mAbs) resulting in superior immune effector function. Mogamulizumab is the first approved glyco-engineered therapeutic antibody and first approved mAb to target the CC chemokine receptor 4 (CCR4). CCR4 is principally expressed on Tregs and helper T cells (Th) where it functions to induce homing of these leukocytes to sites of inflammation. Tregs play an essential role in maintaining immune balance; however, in malignancy, Tregs impair host antitumor immunity and provide a favorable environment for tumors to grow. CCR4 is highly expressed by aggressive peripheral T-cell lymphomas (PTCLs), particularly adult T-cell leukemia/lymphoma (ATL) and cutaneous T-cell lymphomas (CTCLs). Mogamulizumab is a humanized anti-CCR4 mAb with a defucosylated Fc region that enhances antibody-dependent cellular cytotoxicity (ADCC). In addition, mogamulizumab depletes CCR4(+) Tregs, potentially evoking antitumor immune responses by autologous effector cells. This ability is highly pertinent as subsets of malignant T cells are believed to function as CD4(+) Tregs, overexpressing CCR4. Clinical trials with mogamulizumab have demonstrated clinical efficacy and tolerability for the treatment of relapsed/refractory aggressive T-cell lymphomas, previously associated with very poor outcomes.

Allogeneic and autologous stem cell transplantation for hepatosplenic T-cell lymphoma: a retrospective study of the EBMT Lymphoma Working Party.

The objective of this registry study was to analyse the outcome of patients who underwent allogeneic or autologous haematopoietic stem cell transplantation (HSCT) for hepatosplenic T-cell lymphoma (HSTL), a rare and extremely aggressive peripheral T-cell lymphoma subtype. Patients were eligible if they had histologically verified HSTL and underwent HSCT between 2003 and 2011. Seventy-six patients were identified in the European Society for Bone and Marrow Transplantation database. Additional baseline and follow-up information could be obtained from the referring centres for 36 patients. Eleven of these were excluded following histopathology review, leaving 25 patients in the final study cohort (alloHSCT 18, autoHSCT 7). With a median follow-up of 36 months, 2 patients relapsed after alloHSCT, resulting in a 3-year progression-free survival of 48%. After autoHSCT, 5 patients relapsed and subsequently died. This study indicates that graft-versus-lymphoma activity conferred by alloHSCT can result in long-term survival for a substantial proportion of patients with HSTL.

Should patients with aggressive peripheral T-cell lymphoma all be treated the same?

Should patients with aggressive peripheral T-cell lymphoma all be treated the same?

Aggressive Adult HTLV-Associated Peripheral T-Cell Lymphoma Diagnosed During Maxillary Implant Surgery

Aggressive Adult HTLV-Associated Peripheral T-Cell Lymphoma Diagnosed During Maxillary Implant Surgery

Activating Mutations In Fyn Kinase In Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non Hodgkin lymphomas with poor prognosis. Molecular and cytogenetic studies have shown a prominent role for kinase fusion oncogenes, mostly NPM-ALK, in ALK+ anaplastic large cell lymphomas (ALCLs) and ITK-SYK kinase in unspecified PTCLs. To gain further insight on the genetics and pathogenic mechanisms of aggressive PTCLs we performed an integrated mutation analysis using whole exome sequencing (n=12) and RNAseq (n=35) data. This analysis identified 288 candidate coding somatic mutations in 268 genes including known recurrent mutations in the TET2, DNMT3A and IDH2 epigenetic factor genes and pointed to the FYN kinase gene as a new recurrently mutated oncogene in T-cell transformation. The FYN tyrosine kinase is, with LCK, the predominant SRC family kinase found in T lymphocytes and plays an important role in T-cell activation upon T-cell receptor (TCR) stimulation. FYN mutations in PTCL included a FYN L174R mutation detected in one AITL patient sample, a FYN R176C allele recurrently found in two PTCL NOS cases and a FYN Y531H mutation present in a PTCL NOS sample. Notably, each of these alleles are predicted to specifically disrupt the inhibition of FYN kinase activity by the C terminal SRC kinase (CSK). Thus, structure analysis of FYN and FYN mutant proteins predicted that FYN L174R and, most prominently, FYN R176C and FYN Y531H can disrupt the inhibitory interaction of the FYN SH2 domain with the CSK-phosphorylated Y531. Consistently, pull down assays using GST-FYN-SH2 recombinant proteins and biotinylated C-terminal FYN peptides encompassing Y531 showed abrogation of the interaction between FYN-SH2 and P-Y531 in each of these mutants. In agreement with these results, expression of FYN L174R, FYN R176C and FYN Y531H resulted in increased levels of FYN activation. Moreover, CSK expression effectively inhibited wild type FYN, but failed to abrogate FYN L174R, FYN R176C or FYN Y531H activation. In contrast, pharmacologic kinase inhibition with dasatinib, a multikinase inhibitor which blocks ABL1 and SRC kinases, effectively abrogated the activity of FYN L174R, FYN R176C and FYN Y531H mutant proteins and suppressed the growth of cells transformed via expression of activated FYN mutant alleles. Overall these results support an oncogenic role for FYN activating mutations in the pathogenesis of PTCL and support a role for SRC kinase inhibitors for the treatment of this disease. Disclosures:No relevant conflicts of interest to declare.

Recurrent Rhoa Mutations In Peripheral T-Cell Lymphoma

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous and poorly understood group of aggressive non Hodgkin lymphomas with poor prognosis. To gain further insight on the genetics and pathogenic mechanisms of aggressive PTCLs we performed whole exome sequencing of matched tumor and normal DNA samples from 12 PTCL patients including 6 PTCL not otherwise specified (PTCL-NOS) tumors, 3 angioimunoablastic (AITL) T-cell lymphomas, 2 nasal type NK-/T-cell lymphomas and one enteropathy-associated T-cell lymphoma (EATL). This analysis identified 288 candidate coding somatic mutations in 268 genes and a mean mutation load of 24 non synonymous mutations per sample (range 4 – 57). Among these we noted the presence of a recurrent heterozygous mutation in the RHOA small GTPase gene (RHOA G17V) present in two independent AITL samples and one PTCL NOS biopsy. Analysis of a broad and diverse panel of 126 PTCL samples identified the presence of the RHOA G17V allele in 32 samples with a high prevalence in AITL (24/36, 67%, P < 0.001) and PTCL NOS cases (8/44, 18%, P < 0.002). The RHOA protein belongs to the Rho family of small GTPases, a group of Ras-like proteins responsible for linking a variety of cell-surface receptors to different intracellular signaling proteins. As is the case for RAS and most other small GTPases, RHOA activation is mediated by guanine exchange factors (GEFs), which catalyze the switch of RHOA from an inactive GDP-bound to an active GTP-bound state. Thus, and to test the functional significance of the RHOA G17V mutation we analyzed the capacity of this mutant to load GTP. This analysis revealed that RHOA G17V fails to incorporate GTP in response to an activated GEF in vitro. Moreover, and consistent with its inability to bind GTP, RHOA G17V failed to interact with rhotekin, a RHOA effector protein that selectively interacts with the GTP-bound active form of RHOA. However and most notably, the lack of RHOA G17V activation is not the result of a defect in RHOA-GEF interaction as RHOA G17V pull down assays demonstrated effective binding of this mutant protein to activated GEF proteins in T-cells. Based on these results we proposed an inhibitory role for RHOA G17V via sequestration of active GEF proteins. Consistently, while forced activation of RHOA signaling by GFP-RHOA overexpression induced loss of adhesion and round cell morphology in HEK293T cells, transfection of GFP-RHOA-G17V induced increased elongation and cellular protrusions as result of RHOA inactivation. In addition, immunoflourescence analysis of actin stress fiber formation by RHOA demonstrated effective abrogation of RHOA mediated cytoskeleton remodeling in cells expressing RHOA G17V. Overall these results show novel insight on the genetic basis of PTCLs and demonstrate a prominent role for RHOA G17V in the pathogenesis of AITL via disruption of RHOA signaling. Disclosures:No relevant conflicts of interest to declare.

The aggressive peripheral T‐cell lymphomas: 2013

T-cell lymphomas make up approximately 10-15% of lymphoid malignancies. The frequency of these lymphomas varies geographically, with the highest incidence in parts of Asia. The diagnosis of aggressive peripheral T-cell lymphoma (PTCL) is usually made using the WHO classification. The ability of hematopathologists to reproducibly diagnosis aggressive PTCL is lower than for aggressive B-cell lymphomas, with a range of 72-97% for the aggressive PTCLs. Patients with aggressive PTCL are staged using the Ann Arbor Classification. Although somewhat controversial, PET scans appear to be useful as they are in aggressive B-cell lymphomas. The most commonly used prognostic index is the International Prognostic Index. The specific subtype of aggressive PTCL is an important risk factor, with the best survival seen in anaplastic large cell lymphoma-particularly young patients with the anaplastic lymphoma kinase positive subtype. Anaplastic large cell lymphoma is the only subgroup to have a good response to a CHOP-like regimen. Angioimmunoblastic T-cell lymphoma has a prolonged disease-free survival in only ~20% of patients, but younger patients who have an autotransplant in remission seem to do better. PTCL-NOS (not otherwise specified) is not one disease. Anthracycline containing regimens have disappointing results and a new approach is needed. NK/T-cell lymphoma localized to the nose and nasal sinuses seems to be best treated with radiotherapy containing regimens. Enteropathy associated PTCL and hepatosplenic PTCL are rare disorders with a generally poor response to therapy, although selected patients with enteropathy associated PTCL seem to benefit from intensive therapy.

Dexabeam versus ICE salvage regimen prior to autologous transplantation for relapsed or refractory aggressive peripheral T-cell lymphoma: A retrospective evaluation of parallel patient cohorts of one center.

8548 Background: High-dose chemotherapy (HDT) followed by autologous stem-cell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T-cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. Methods: We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline based first-line chemotherapy who received either DexaBEAM (n=16) or ICE (n=15) regimen as first salvage chemotherapy followed by HDT and ASCT between 1996 and 2009. The median patient age was 46 years (range, 18-66) in the DexaBEAM group and 40 years (range, 17-59) in the ICE group. Patients were included independent of WHO stage and IPI score. Results: The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69%) as compared to the ICE group (20%; P=0.01), with higher complete response (CR; 38% vs. 7%) as well as partial response (PR; 31% vs. 13%) rate. Changing regimen due to failure of the first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58% (33% CR, 25% PR) with DexaBEAM as second salvage therapy, whereas in 3 patients receiving ICE after DexaBEAM failure only 1 patient achieved an OR (1 PR). Median progression-free survival (PFS) was significantly higher in the DexaBEAM group (6.4 vs. 2 months; P=0.01). Median overall survival (OS) was not different between the two groups (22.8 vs. 29.8 months; P=0.72), most likely due to the good response rate of patients to DexaBEAM as 2nd salvage regimen after failure of ICE chemotherapy. Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. Conclusions: In this retrospective comparison DexaBEAM salvage chemotherapy was superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher but manageable treatment-related toxicity.

DexaBEAM versus ICE salvage regimen prior to autologous transplantation for relapsed or refractory aggressive peripheral T cell lymphoma: a retrospective evaluation of parallel patient cohorts of one center

High-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline-based first-line chemotherapy who received either DexaBEAM (dexamethasone, carmustine, etoposide, cytarabine, and melphalan; n = 16) or ICE (ifosfamide, carboplatin, and etoposide; n = 15) regimen as first salvage chemotherapy followed by HDT/ASCT. The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69%; 95% confidence interval 46.0-91.5%) as compared to the ICE group (20%; 95% confidence interval -0.2-40.2%; P = 0.01), with higher complete response (CR; 38%; 95% confidence interval 13.8-61.2%; vs. 7%; 95% confidence interval -6.0-19.6%) as well as partial response (PR; 31 vs. 13%) rate. Changing regimen due to failure of first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58% (33% CR, 25% PR) with DexaBEAM as second salvage therapy, whereas in three patients receiving ICE after DexaBEAM failure, only one achieved an OR (1 PR). Median progression-free survival was significantly higher in the DexaBEAM group (6.4 vs. 2months; P = 0.01). Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. For all patients proceeding to HDT/ASCT, a 3-year overall survival was 50%. Together, considering the limitations of the retrospective design of the evaluation and the small sample size, our data suggest that DexaBEAM salvage chemotherapy is superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher but manageable treatment-related toxicity.

Should Patients With Aggressive Peripheral T-Cell Lymphoma All Be Treated the Same?

The peripheral T-cell lymphomas represent about 15% to 20% of non-Hodgkin lymphomas and are marked by clinical and pathologic heterogeneity. The most common T-cell entities include peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma anaplastic lymphoma kinase-negative, which account for approximately 60% of T-cell lymphoma cases. Because of the rarity of T-cell lymphomas and lack of randomized prospective studies, treatment for these diseases is not well defined. Current treatment strategies draw from data from phase II studies, retrospective analyses, and personal experience. For fit patients who can tolerate treatment with curative intent, we treat peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma anaplastic lymphoma kinase-negative similarly with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based induction therapy followed by consolidation with autologous stem cell transplant. Given the marked differences in histology, biology, and clinical presentation for these diseases, it is likely that they should be approached differently. Furthermore, prognostic factors and degree of chemosensitivity as measured by FDG-PET (fluorodeoxyglucose positron emission tomography) should likely be used to guide patients along different treatment pathways. We have a long way to go toward perfecting the treatment for T-cell lymphoma. We believe that a uniform treatment approach for patients with aggressive T-cell lymphoma is not appropriate; however, we do not yet have enough data to support an individualized approach to treatment. Clinical and biologic prognostic factors, degree of chemosensitivity as measured by FDG-PET, and histology should all likely have a role in directing patients along different treatment pathways, but prospective studies are needed to confirm this.

Enforced expression of Lin28b leads to impaired T-cell development, release of inflammatory cytokines, and peripheral T-cell lymphoma

AbstractLIN28A and LIN28B, the mammalian homologs of lin-28, are implicated in malignant transformation in part because of their ability to promote degradation of the let-7 family of miRs. In the present study, we show that overexpression of Lin28b in vivo leads to an aggressive peripheral T-cell lymphoma (PTCL) characterized by widespread infiltration of parenchymal organs with malignant CD4+ cells. Similar to patients with PTCL, Lin28b-transgenic mice show signs of inflammation such as eosinophilia, increased C-reactive protein, release of inflammatory cytokines, and pleural effusion. The PTCLs that develop in Lin28b mice are derived from activated T cells and show decreased let-7 expression, increased Il6 expression, activation of NF-κB, and infiltration of B cells, all resulting in an inflammatory microenvironment. In addition, LIN28B is overexpressed 7.5-fold in PTCL patient samples compared with activated CD4+ cells. The results of the present study demonstrate for the first time that Lin28b can transform primary cells in vivo, identify a previously unsuspected link between Lin28b and PTCL, and provide a unique animal model for the study of PTCL biology and therapy.

The aggressive peripheral T‐cell lymphomas: 2012 update on diagnosis, risk stratification, and management

T-cell lymphomas make up approximately 10-15% of lymphoid malignancies. The frequency of these lymphomas varies geographically, with the highest incidence in parts of Asia. The diagnosis of aggressive peripheral T-cell lymphoma (PTCL) is usually made using the WHO classification. The ability of hematopathologists to reproducibly diagnose aggressive PTCL is lower than for aggressive B-cell lymphomas, with a range of 72-97% for the aggressive PTCLs. Patients with aggressive PTCL are staged using the Ann Arbor Classification. Although somewhat controversial, positron emission tomography (PET) scans appear to be useful as they are in aggressive B-cell lymphomas. The most commonly used prognostic index is the International Prognostic Index. The specific subtype of aggressive PTCL is an important risk factor, with the best survival seen in anaplastic large-cell lymphoma-particularly young patients with the anaplastic lymphoma kinase positive subtype. Anaplastic large-cell lymphoma is the only subgroup to have a good response to a cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like regimen. Angioimmunoblastic T-cell lymphoma has a prolonged disease-free survival in only ∼20% of patients, but younger patients who have an autotransplant in remission seem to do better. PTCL-not otherwise specified (NOS) is not one disease. Anthracycline containing regimens have disappointing results and a new approach is needed. NK/T-cell lymphoma localized to the nose and nasal sinuses seems to be best treated with radiotherapy containing regimens. Enteropathy associated PTCL and hepatosplenic PTCL are rare disorders with a generally poor response to therapy, although selected patients with enteropathy associated PTCL seem to benefit from intensive therapy.

Aggressive peripheral CD70-positive t-cell lymphoma associated with severe chronic active EBV infection

Severe chronic active Epstein-Barr virus infection (CAEBV) in T or NK cells is a rare complication of latent EBV infection. CAEBV associated T-cell lymphoproliferative disease (LPD) consists of polyclonal lesions as well as aggressive lymphomas. Here, we report such a patient. In addition, we show that this primary CAEBV associated T-cell lymphoma expresses CD70 and is sensitive to killing by CD70-specific T cells, identifying CD70 as a potential immunotherapeutic target for CAEBV-associated T-cell lymphoma.

Prognostic factors in patients with HIV‐associated peripheral T‐cell lymphoma: A multicenter study

HIV infection has been associated with an increased risk of developing several types of malignancies, including aggressive peripheral T-cell lymphomas (PTCL). However, this is a rare occurrence with no more than a hundred cases reported in the literature. The purpose of this multicenter study is to describe the characteristics and to identify prognostic factors in patients with HIV-associated PTCL. Data from HIV-positive patients with a pathological diagnosis of non-primary cutaneous, non-leukemic PTCL were gathered retrospectively and are reported using descriptive statistics. Univariate and multivariate survival analyses were also performed. Fifty one patients were included in our analysis. Median age was 38 years with a 5:1 male-to-female ratio. Patients presented with a median CD4(+) count of 173 cells mm⁻³, and a median HIV viral load of 334,787 copies ml⁻¹. The median time from HIV diagnosis to PTCL diagnosis was 4.5 years. About 75% of patients presented with advanced clinical stage and 66% with B symptoms. The most common subtypes were PTCLU (61%) and anaplastic large cell lymphoma (ALCL, 22%). None of the ALCL patients tested expressed ALK. The median overall survival (OS) for the group was 12 months. In the multivariate survival analysis, the use of HAART and patients' performance status were independently associated with OS. HIV-associated PTCL presents predominantly in young men with low CD4(+) counts and high HIV viral loads. Both HIV-related and lymphoma-related factors were associated with OS.

A Decade of Progress in Lymphoma: Advances and Continuing Challenges

Our ability to manage patients with non-Hodgkin lymphoma and Hodgkin lymphoma has improved dramatically in the past decade. The survival of patients with the two most frequent lymphomas (ie, diffuse large B-cell lymphoma and follicular lymphoma), have improved significantly with the incorporation of rituximab as a standard treatment regimen. New insights into the biology of lymphomas provided by studying patterns of gene expression have improved our ability to classify these diseases. Identifying the treatments most effective with different patterns of gene expression offers the opportunity to further improve treatment outcomes. We now cure most patients with Hodgkin lymphoma, but the past decade has seen advances in our ability to identify patients who are most likely to be cured with less toxic treatment approaches. Unfortunately, our ability to improve the treatment of patients with peripheral T-cell lymphoma has not kept pace with the management of those suffering from B-cell lymphomas. However, better classification systems, improved understanding of the biology of these disorders, and clinical trials aimed specifically at identifying optimal regimens for patients with aggressive peripheral T-cell lymphomas offer hope to improve treatment results over the next decade.

Pralatrexate Is An Effective Treatment for Heavily Pretreated Patients with Relapsed/Refractory Transformed Mycosis Fungoides (tMF)

AbstractAbstract 1762 Background:Cutaneous T-cell lymphoma, which includes mycosis fungoides (MF) and the Sézary Syndrome, is an indolent T-cell lymphoma. Large-cell transformation (tMF) is a well-defined histopathological disease that is distinguished from primarily cutaneous MF by the presence of large cells that exceed 25% of total lymphoid infiltrate (Barberio et al. Br J Dermatol 2007; 157:284-9) and occurs in 11% to 23% of cases. tMF represents a significantly poorer prognostic subset of MF patients with median overall survival of 12 to 22 months from the time of diagnosis of large-cell transformation (Arulogun et al. Blood 2008; 112:3082-7). There is no standard therapy for tMF and most patients are treated with multiagent systemic chemotherapy regimens. Because of its poor outcome similar to that of aggressive peripheral T-cell lymphomas (PTCLs), tMF patients were included in PROPEL, the pivotal study that led to the accelerated approval of pralatrexate (FOLOTYN®) in the United States for the treatment of relapsed or refractory PTCL. Methods:Of 109 evaluable patients in the PROPEL trial, 12 patients had histologically confirmed tMF. All patients received pralatrexate at a dose of 30 mg/m2 weekly for 6 weeks in a 7 week cycle. Results:Of the 12 patients with tMF, the median age was 56.5 years. The median number of prior therapies was 6.5 (range 1 to 12), and 5 patients (42%) received ≥5 prior systemic regimens. The majority of patients had received prior multiagent chemotherapy, including cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or CHOP-based therapy in 67% of patients and other multiagent regimens in 17% of patients. Only 1 of 12 patients had a response to their most recent prior chemotherapy regimen. The objective response rate (ORR) to pralatrexate in this group of refractory tMF using International Workshop Criteria based on investigator assessment, was 58%. Consistent with the overall study population, the ORR by independent central review was 25%. The difference in ORR between independent central review and investigator assessment for tMF is mainly due to challenges with photodocumentation of response assessment of cutaneous lesions. The 12 patients with tMF received a median of 10 doses of pralatrexate and remained on treatment for a median of 89 days. The median response duration was 4.4 months and median PFS was 5.3 months, per investigator assessment. The median survival in this group of patients was 13 months. Mucosal inflammation was reported in 7 patients (58%) including 1 patient with grade 3. Grade 4 adverse events (AEs) were fatigue (1 patient) and thrombocytopenia (1 patient). Overall, patients with tMF were able to tolerate full-dose pralatrexate treatment, with no patients discontinuing due to an AE. Conclusions:Pralatrexate demonstrated significant activity in the 12 refractory tMF patients enrolled in the PROPEL trial with an investigator assessed response rate of 58%. Pralatrexate should be considered as a treatment option for patients with tMF. Disclosures:Foss:Allos Therapeutics, Inc.: Consultancy, Speaker. Horwitz:Allos Therapeutics, Inc.: Consultancy, Research Funding. Pinter-Brown:Allos Therapeutics, Inc.: Consultancy. Goy:Allos Therapeutics, Inc.: Consultancy, Honoraria. Pro:Allos Therapeutics, Inc.: Research Funding. Savage:Allos Therapeutics, Inc.: Consultancy, Honoraria. Shustov:Allos Therapeutics, Inc.: Honoraria, Research Funding. Zain:Allos Therapeutics, Inc. : Speakers Bureau. Koutsoukos:Allos Therapeutics, Inc.: Employment. Fruchtman:Allos Therapeutics, Inc.: Employment. O'Connor:Allos Therapeutics, Inc.: Research Funding.

Rituximab in combination with CHOP regimen in angioimmunoblastic T-cell lymphoma: Results of the phase II RAIL trial—A prospective study of the Groupe d'Etude des Lymphomes de l'Adulte (GELA).

8049 Background: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma with poor prognosis. The use of rituximab was based on the hallmark features of lymphoid B cel...

Exceptionally low metabolic activity in aggressive peripheral T-cell lymphoma

To investigate metabolic behavior of aggressive peripheral T-cell (PTC) lymphoma compared with other aggressive T-cell (OTC) nonHodgkin's lymphomas (NHLs) and the various grades (1, 2, 3) of follicular B-cell (FC) NHL as a reference cell type for indolent to aggressive behavior. Pretreatment 2-deoxy-2-[¹⁸F] fluoro-d-glucose positron emission tomography-computed tomography scans of 33 patients with pathologic diagnosis of aggressive T-cell NHL and FC (FC1 = 6, FC2 = 8, FC3 = 9, PTC = 6, OTC = 4) were analyzed. The maximal standardized uptake value (SUV) was measured over biopsy region (BxSUV) and the highest tumor activity of the body (BmSUV). There were significant differences in both BxSUV (P = 0.036) and BmSUV (P = 0.026) among these five groups with significantly lower metabolic activity in PTC compared with other aggressive NHL (FC3, OTC). BmSUV in PTC was significantly lower than that in OTC (8.2 ± 2.5 vs. 22.3 ± 7.0, P = 0.029) and was similar to that of FC1 (9.4 ± 1.9) and FC2 (9.7 ± 1.4) but lower than that of FC3 (14.6 ± 2.7). Similar findings were noted in BxSUV between PTC and OTC (6.7 ± 2.5 vs. 20.4 ± 7.2, P = 0.035). Although 2-deoxy-2-[¹⁸F]fluoro-d-glucose positron emission tomography has been found to reflect metabolic activity for the aggressiveness of B-cell NHL, PTC has an exceptionally low metabolic activity, similar to that of low-grade B-cell FC1 and FC2.