CHOP or THP‐COP regimens in the treatment of newly diagnosed peripheral T‐cell lymphoma,not otherwise specified: a comparison of doxorubicin and pirarubicin

The CHOP regimen consisting of cyclophosphamide, doxorubicin (DOX), vincristine and prednisolone has been the most used regimen for peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS). Pirarubicin [tetrahydropyranyladriamycin (THP)], a derivative of DOX, is an anthracycline with reportedly less cardiotoxicity than DOX. Here, we confirmed the efficacy of THP‐COP using THP instead of DOX in the treatment of PTCL‐NOS. The study protocol employed a retrospective, consecutive entry design. We retrospectively analysed 56 patients with PTCL‐NOS who had received THP‐COP or CHOP. These regimens were performed every 21 days. Twenty‐nine patients received THP‐COP, and 27 received CHOP. There were no significant differences in known prognostic factors, including in the International Prognostic Index (IPI) and the prognostic index for T‐cell lymphoma (PIT), between the two groups. Complete remission rates in patients with THP‐COP and CHOP were 52% in both groups; the 3‐year overall survival (OS) rates were 67% and 52% (p = 0.074), and the 3‐year progression‐free survival (PFS) rates were 51% and 29% (p = 0.070), respectively. In patients with low IPI (low or low‐intermediate), THP‐COP had significantly better 3‐year OS (100% vs. 64%; p < 0.001) and 3‐year PFS (75% vs. 33%; p < 0.05) than CHOP. Similar differences between THP‐COP and CHOP were observed in patients with a low PIT (groups 1 or 2). Our study showed that THP‐COP produced results equivalent to CHOP regarding efficacy and safety in patients with PTCL‐NOS. In patients with low IPI or PIT, THP‐COP resulted in significantly better prognosis. Copyright © 2015 John Wiley & Sons, Ltd.     

Evaluation of clinical trial eligibility and prognostic indices in a population‐based cohort of systemic peripheral T‐cell lymphomas from the Danish Lymphoma Registry

Clinical trials (CTs) are needed to improve the outcome for peripheral T‐cell lymphomas (PTCL), and accrual into CTs is one of the main recommendations in international treatment guidelines. The use of risk‐adapted strategies has been suggested as a way to optimize treatment outcome in PTCL. The aim of the present study was to evaluate CT eligibility and selected prognostic indices in a population‐based PTCL cohort of 481 PTCL patients identified from the Danish Lymphoma Registry in the period 2000–2010. According to five predefined parameters (age, performance status, P‐creatinine, P‐ALAT and measurable tumour lesion), patients were subdivided into four groups: ‘younger fit’, ‘elderly fit’, ‘frail’ and ‘not CT eligible’. International prognostic index (IPI), prognostic index for T‐cell lymphoma (PIT) and anaplastic lymphoma kinase (ALK) protein expression were tested at subtype‐specific level. Overall, 41% of the patients were considered eligible for interventional CTs implicating curatively intended multiagent chemotherapy, including, if considered appropriate, consolidating stem cell transplantation (SCT), as part of the upfront management strategy. Moreover, 28% was elderly fit and eligible for interventional CT, including those with SCT as part of the trial design. Approximately 7% were defined as ‘too frail’ for aggressive treatment schedules, whereas 24% were deemed not to be eligible for any CT. Both overall and progression‐free survivals were effectively predicted by IPI and PIT (p < 0.001). ALK‐positive anaplastic large cell lymphoma patients were significantly younger (median age 40 vs. 62, p < 0.001) and had a better outcome than their ALK‐negative counterparts (p < 0.001). However, ALK expression lost its prognostic significance when adjusting for age. In a population‐based cohort of adult Caucasian PTCL patients, approximately half were eligible for multiagent chemotherapy with or without consolidating SCT. Both IPI and PIT are useful prognostic indices in all ‘primary nodal’ PTCL entities. The prognostic value of ALK protein expression in anaplastic large cell lymphoma is significantly downsized when adjusting for age. Copyright © 2014 John Wiley & Sons, Ltd.     

Reappraisal of nodal Epstein‐Barr Virus‐negative cytotoxic T‐cell lymphoma: Identification of indolent CD5+ diseases

Nodal cytotoxic molecule (CM)‐positive peripheral T‐cell lymphoma (CTL) has recently been recognized as a clinicopathologically distinct disease. To further characterize this disease, here we compared 58 patients with Epstein‐Barr virus (EBV)‐negative CTL to 48 patients with EBV‐positive CTL. The two groups did not differ in histopathology, T‐cell receptor (TCR) expression or rearrangement incidences, or survival curves. However, patients with EBV‐negative CTL less frequently showed hepatic involvement (P = .007), B symptoms (P = .020), hemophagocytosis (P = .024), and detectable CD4 (P = .002) and CD5 (P = .009). Univariate and multivariate analyses identified three factors that independently predicted favorable survival, onset age <60 years (P = .002), CD5 expression (P = .002), and mixed morphology (P = .013), TCRαβ was not an independent predictor (P = .30), but was strongly linked with long survivorship among patients younger than 60 years old. A prognostic model incorporating these factors worked well for prognostic delineation, independently of the International Prognostic Index (P = .007 vs P = .082) and Prognostic Index for PTCL (P = .020 vs P = .15). Moreover, this constellation of findings indicated two nodal indolent diseases: CD5⁺TCRαβ (n = 13), and CD5⁺ NK‐cell type lacking TCR expression or clonal TCRγ rearrangement (n = 4). The survival curves for these two groups were significantly superior to others (n = 29, P < .001). These diseases appear to be unique in their indolent clinical behavior, and should be managed differently from other diseases.     

Serum concentrations of l‐kynurenine predict clinical outcomes of patients with peripheral T‐cell lymphoma,not otherwise specified

Indoleamine 2,3‐dioxygenase exerts intense immunomodulatory effects due to enzymatic activities that catalyze the breakdown of the essential amino acid l ‐tryptophan. The activity of indoleamine 2,3‐dioxygenase can be estimated by measuring serum l ‐kynurenine concentrations. Here, we aimed to determine the role of l ‐kynurenine as a prognostic factor for peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) in a retrospective analysis of data derived from 31 consecutive patients between June 2000 and March 2013 who were histologically diagnosed with PTCL‐NOS according to the World Health Organization classification and treated with 6?8 cycles of cyclophosphamide, doxorubicin or pirarubicin, vincristine, and prednisolone. l ‐kynurenine concentrations in serum samples collected at admission were measured using high‐performance liquid chromatography. The median serum concentration of l ‐kynurenine was 3.28 (range 0.92–8.16) μM. The l ‐kynurenine cutoff was set at 3.07 μM using receiver operating characteristics curves. The complete remission rates of patients with l ‐kynurenine <3.07 and ≥3.07 μM were 69% and 51%, respectively. The 5‐year overall survival (OS) rates for patients with l ‐kynurenine <3.07 and ≥3.07 μM were 80.2% and 23.4%, respectively (p < 0.001). More advanced age, poor performance status, elevated lactate dehydrogenase, an unfavorable International Prognostic Index, and a poor prognostic index for T‐cell lymphoma were significantly worse factors for OS. Multivariate analyses revealed only l ‐kynurenine as an independent prognostic factor for OS. In conclusion, serum concentrations of l ‐kynurenine might comprise a novel prognostic factor with which to determine the outcomes of treatment for PTCL‐NOS. Copyright © 2016 John Wiley & Sons, Ltd.     

Interim report of a phase 2 clinical trial of lenalidomide for T‐cell non‐Hodgkin lymphoma

BACKGROUND:

Novel therapies are needed to improve outcomes in T‐cell lymphomas. The authors report the interim results of a prospective multicenter trial evaluating lenalidomide in T‐cell lymphomas.

METHODS:

Patients with recurrent and refractory T‐cell lymphomas other than mycosis fungoides and untreated patients ineligible for combination chemotherapy were prescribed oral lenalidomide (25 mg daily) on Days 1 to 21 of each 28‐day cycle until disease progression, death, or unacceptable toxicity. The primary endpoint was overall response rate. Secondary endpoints were progression‐free survival (PFS), overall survival (OS), and safety. The 2‐stage design allows for up to 40 patients.

RESULTS:

At the time of this interim analysis, 24 patients were enrolled in this study, and 23 were evaluable for response. The median age was 65 years. The overall response rate was 7 (30%) of 23; all were partial responses. Two patients had stable disease for ≥5 cycles. Responses were seen in anaplastic, angioimmunoblastic, and peripheral T‐cell unspecified histologies. Median PFS was 96 days (range, 8‐696+ days). Median OS was 241 days (range, 8‐696+ days). The most common grade 4 adverse event was thrombocytopenia (33%). The most common grade 3 adverse events were neutropenia (21%), febrile neutropenia (17%), and pain not otherwise specified (17%). Rash correlated with response to therapy (P = .003).

CONCLUSIONS:

In patients with recurrent and refractory T‐cell lymphomas, oral lenalidomide monotherapy has clinical activity, and toxicity is consistent with the known safety profile of lenalidomide. Further study of lenalidomide in these diseases is warranted. Cancer 2010. © 2010 American Cancer Society.     

Comparison of peripheral T-cell lymphomas and diffuse large B-cell lymphoma

BACKGROUND: Peripheral T-cell lymphomas (PTCLs) are a biologically heterogeneous subgroup of lymphomas with poor prognosis. In this study, the authors analyzed the clinical behaviors of PTCLs and diffuse large B-cell lymphoma (DLBCL). METHODS: The authors compared the characteristics and outcomes of 59 patients with PTCLs, including 33 angioimmunoblastic T-cell lymphomas and 26 unspecified peripheral T-cell lymphomas, with the characteristics and outcomes of 193 patients with DLBCLs who were treated in the era before rituximab. RESULTS: Based on the clinical characteristics, elevated lactate dehydrogenase (LDH), poor PS, advanced stage, higher International Prognostic Index score, and B symptoms were more common in patients with PTCLs, and bulky mass was more common in patients with DLBCL. The rates of complete response (CR) or an unconfirmed CR (CRu) were higher in patients with DLBCL (72%) than in patients with PTCLs (56%; P = .03). The 5-year overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) rates were 31%, 26%, and 47%, respectively, in patients with PTCLs and 59%, 55%, and 73%, respectively, in patients with DLBCL (P = .001, P < .001, and P = .003, respectively). Although multivariate analysis identified several risk factors that were significant in PTCLs, but not in DLBCLs, for the CR/CRu, OS, PFS, and DFS rates, the immunophenotype was not identified as a risk factor. CONCLUSIONS: The poor response and survival of patients who had PTCLs, compared with patients who had DLBCL, was caused by numerous initial risk factors. T-cell phenotype itself did not appear to have a significant impact on either response or survival.     

Clinico-pathologic features and outcome of Japanese patients with peripheral T-cell lymphomas

We studied the clinico-pathologic features and treatment outcome of patients with peripheral T-cell lymphoma (PTCL). This study included 215 patients with T/natural killer (NK)-cell lymphoma, including 59 with PTCL-unspecified (PTCL-U), 42 with angioimmunoblastic T-cell lymphoma (AILT) and 20 with anaplastic large-cell lymphoma (ALCL). Most of the analyses were performed on patients with AILD, ALCL and PTCL-U. The patients with AILT and PTCL-U tended to be older than those with ALCL. Stage III/IV disease was seen in 90.5% of the AILT cases, 55% of the ALCL cases and 67.8% of the PTCL-U cases. In addition, 61.9% of the AILT cases had an international prognostic index (IPI) of H-I or H risk. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 72.2 and 76.1% among the ALCL cases, 40.7 and 42.2% among the PTCL-U cases and 31.2 and 49.3% among the AILT cases, respectively. Among the patients with PTCL-U, the 5-year PFS and OS rates in group low (L), low-intermediate (L-I), high-intermediate (H-I) or high (H) risk group of IPI were: 47.6 and 56.1%, 55.6 and 53.8%, 42.4 and 40.1% and 9.1 and 9.1%, respectively. The 5-year PFS and OS rates in group 1, 2, 3 or 4 by prognostic index of PTCL-U (PIT) were: 88.9 and 85.7%, 57.1 and 54.9%, 33.5 and 28.8% or 13.3 and 13.3%, respectively. The 5-year PFS and OS rates among patients who received CHOP therapy, CyclOBEAP [cyclophosphamide (CPA), vincristine (VCR), bleomycine, etoposide, doxorubicin (DXR), prednisone (PDN)] therapy or autologous stem cell transplantation were: 22 and 25.7%, 59 and 61.7% or 33.3 and 60%, respectively. Multivariate analysis revealed that the PIT score was associated with OS and PFS. These results indicate that the presence of bone marrow (BM) involvement is an independent prognostic factor which may predict both OS and PFS. PTCL-U is a heterogeneous disease with regard to histological type and pathological state. Because PTCL-U is generally not responsive to CHOP therapy, new treatment strategies need to be developed.     

Phase I/II study of pralatrexate in Japanese patients with relapsed or refractory peripheral T‐cell lymphoma

Pralatrexate is a novel antifolate approved in the USA for the treatment of relapsed or refractory peripheral T‐cell lymphoma. To assess its safety, efficacy, and pharmacokinetics in Japanese patients with this disease, we undertook a phase I/II study. Pralatrexate was given i.v. weekly for 6 weeks of a 7‐week cycle. All patients received concurrent vitamin B₁₂ and folic acid. In phase I, three patients received pralatrexate 30 mg/m² and none experienced a dose‐limiting toxicity. In phase II, we treated 22 additional patients with that dose. The median number of treatment cycles was 1 (range, 1–9). Nine of 20 evaluable patients (45%) achieved an objective response by central review, including two complete responses. All responses occurred within the first treatment cycle. At the time of data cut‐off, median progression‐free survival was 150 days. Median overall survival was not reached. In the total population, the most commonly reported adverse events included mucositis (88%), thrombocytopenia (68%), liver function test abnormality (64%), anemia (60%), and lymphopenia (56%). Grade 3/4 adverse events included lymphopenia (52%), thrombocytopenia (40%), leukopenia (28%), neutropenia (24%), anemia (20%), and mucositis (20%). The pharmacokinetic profile showed no drug accumulation with repeat dosing. These results indicate that pralatrexate is generally well tolerated and effective in Japanese patients with relapsed or refractory peripheral T‐cell lymphoma. This trial was registered with ClinicalTrials.gov (NCT02013362).     

Clinical development of anti‐CD19 chimeric antigen receptor T‐cell therapy for B‐cell non‐Hodgkin lymphoma

B‐cell non‐Hodgkin lymphoma (B‐NHL) is the most frequent hematological malignancy. Although refined chemotherapy regimens and several new therapeutics including rituximab, a chimeric anti‐CD20 monoclonal antibody, have improved its prognosis in recent decades, there are still a substantial number of patients with chemorefractory B‐NHL. Anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy is expected to be an effective adoptive cell treatment and has the potential to overcome the chemorefractoriness of B‐cell leukemia and lymphoma. Recently, several clinical trials have shown remarkable efficacy of anti‐CD19 CAR T‐cell therapy, not only in B‐acute lymphoblastic leukemia but also in B‐NHL. Nonetheless, there are several challenges to overcome before introduction into clinical practice, such as: (i) further refinement of the manufacturing process, (ii) further improvement of efficacy, (iii) finding the optimal infusion cell dose, (iv) optimization of lymphocyte‐depleting chemotherapy, (v) identification of the best CAR structure, and (vi) optimization of toxicity management including cytokine release syndrome, neurologic toxicity, and on‐target off‐tumor toxicity. Several ways to solve these problems are currently under study. In this review, we describe the updated clinical data regarding anti‐CD19 CAR T‐cell therapy, with a focus on B‐NHL, and discuss the clinical implications and perspectives of CAR T‐cell therapy.     

Cytomorphologic examination of anaplastic large cell lymphoma by fine‐needle aspiration cytology

BACKGROUND.

The cytomorphology of anaplastic large cell lymphoma (ALCL) is distinctive yet variable. To the authors' knowledge, to date only small case series have described the cytologic findings noted in patients with ALCL. The current series is the largest case series presented to date to retrospectively review the cytomorpholgic findings noted in patients with ALCL, with specific attention paid to those with anaplastic lymphoma kinase (ALK)‐negative ALCL.

METHODS.

Over a 13‐year period, the available Diff‐Quik cytology smears and surgical excision specimens taken from patients with ALCL were evaluated. Different clinical and morphologic parameters were evaluated, including ALK status.

RESULTS.

A total of 37 cases were retrieved and evaluated, 19 of which had both cytology and surgical pathology specimens available for review. ALK‐negative ALCL cytology smears were found to have a high number of anaplastic cells compared with ALK‐positive cases. The hallmark cells in the ALK‐negative cases were not classic.

CONCLUSIONS.

ALCL can be diagnosed accurately by fine‐needle aspiration cytology (FNAC) alone when aided by immunocytochemistry in ALK‐positive cases. Ancillary studies should be anticipated such that material for cell block preparation and molecular studies is taken at the time of FNAC. The results of the current study demonstrate the varied FNAC morphology of ALCL. The presence of severe pleomorphism and anaplasia was found to correlate with ALK‐negative status. Cancer (Cancer Cytopathol( 2007. © 2007 American Cancer Society.     

Hyper-CVAD/MA 和CHOP方案治疗外周T 细胞淋巴瘤非特指型的78例临床分析

目的:比较Hyper-CVAD/MA与CHOP 方案一线治疗外周T 细胞淋巴瘤- 非特指型（peripheral T-cell lymphoma,not otherwise specified,PTCL-NOS）的临床疗效和不良反应。方法:回顾性分析天津医科大学肿瘤医院和天津市人民医院肿瘤中心2004年6 月至2012年6 月收治的78例初诊PTCL-NOS 患者,根据一线治疗分成Hyper-CVAD/MA方案组（21例）和CHOP/CHOP样方案组（57例）,采用χ2检验分析近期疗效及不良反应,应用Kaplan-Meier 法进行生存分析。结果:Hyper-CVAD/MA组中完全缓解（complete response,CR）为42.9% ,总有效率（overall response rate,ORR ）为85.7% ,中位无进展生存期（progression-free survival,PFS）为20个月,3 年总生存期（overall survival,OS）为56.9% ;CHOP/CHOP样组中CR为28.1% ,ORR 为59.6% ,中位PFS 为13个月,3 年OS为49.6% 。Hyper-CVAD/MA组总有效率和中位PFS 显著高于后者（P < 0.05）。 而两组患者复发率（57.1% vs . 77.2%）和3 年OS差异无统计学意义（P > 0.05）。 不良反应方面,两组Ⅲ/ Ⅳ级粒细胞减少发生率分别为66.7% 和22.8% ,Ⅲ/ Ⅳ级血小板减少发生率分别为61.9% 和14.0% ,Hyper-CVAD/MA组骨髓抑制显著高于后者（P < 0.05）。 结论:Hyper-CVAD/MA方案治疗PTCL-NOS 疗效较好,不良反应较高但可控,建议在粒细胞集落刺激因子支持下进行。      

BCL2 mutation spectrum in B‐cell non‐Hodgkin lymphomas and patterns associated with evolution of follicular lymphoma

BCL2 is a target of somatic hypermutation in t(14;18) positive and also in a small fraction of t(14;18) negative diffuse large B‐cell lymphoma (DLBCL), suggesting an aberrant role of somatic hypermutation (ASHM). To elucidate the prevalence of BCL2 mutations in lymphomas other than DLBCL, we Sanger‐sequenced the hypermutable region of the BCL2 gene in a panel of 69 mature B‐cell lymphomas, including Richter's syndrome DLBCL, marginal‐zone lymphomas, post‐transplant lymphoproliferative disorders, HIV‐associated and common‐variable immunodeficiency‐associated DLBCL, all known to harbour ASHM‐dependent mutations in other genes, as well as 16 t(14,18) negative and 21 t(14;18) positive follicular lymphomas (FLs). We also investigated the pattern of BCL2 mutations in longitudinal samples from 10 FL patients relapsing to FL or transforming to DLBCL (tFL). By direct sequencing, we found clonally represented BCL2 mutations in 2/16 (13%) of t(14;18) negative FLs, 2/16 (13%) HIV‐DLBCLs, 1/9 (11%) of Richter's syndrome DLBCL, 1/17 (6%) of post‐transplant lymphoproliferative disorders and 1/2 (50%) common‐variable immunodeficiency‐associated DLBCL. The proportion of mutated cases was significantly lower than in FLs carrying the t(14;18) translocation (15/21, 71%). However, the absence of t(14;18) by FISH or PCR and the molecular features of the mutations strongly suggest that BCL2 represents an additional target of ASHM in these entities. Analysis of the BCL2 mutation pattern in clonally related FL/FL and FL/tFL samples revealed two distinct scenarios of genomic evolution: (i) direct evolution from the antecedent FL clone, with few novel clonal mutations acquired by the tFL major clone, and (ii) evolution from a common mutated long‐lived progenitor cell, which subsequently acquired distinct mutations in the FL and in the relapsed or transformed counterpart. Copyright © 2014 John Wiley & Sons, Ltd.     

A phase 2 study of methotrexate,etoposide, dexamethasone,and pegaspargase chemotherapy for newly diagnosed,relapsed, or refractory extranodal natural killer/T‐cell lymphoma,nasal type: a multicenter trial in Northwest China

The nasal type of extranodal natural killer/T‐cell lymphoma is a rare aggressive lymphoma with poor prognosis. To discover a successful treatment, we investigated the efficacy and safety of chemotherapy with methotrexate, etoposide, dexamethasone, and polyethylene glycol‐asparaginase (MESA). Three cycles of MESA were administered to 46 patients with new or relapsed/refractory natural killer/T‐cell lymphoma. Complete response after 3 treatment cycles was 43.5%, the overall response rate was 87%, and 2‐year overall survival was 83.4%. Complete response was significantly better for newly diagnosed patients than for patients with relapsed/refractory disease. Patients with newly diagnosed disease had a significantly better overall response rate after 1, but not after 2 or 3 treatment cycles. Overall survival and progression‐free survival did not differ over 2 years. Grade 1/2 toxicities were frequent, but MESA was associated with fewer grade 3/4 events or treatment‐related deaths. These results will require confirmation in larger prospective trials.     

Presence of autoimmune disease affects not only risk but also survival in patients with B‐cell non‐Hodgkin lymphoma

Although autoimmune diseases (AIDs) are known to predispose to non‐Hodgkin lymphoma (NHL), their association with NHL prognosis has rarely been investigated. We examined associations between autoimmunity and B‐cell NHL onset by comparing AID history (determined by self‐report and medication review and supplemented by chart review where possible) among 435 adult B‐NHL patients in Hadassah‐Hebrew University Medical Center, diagnosed 2009‐2014, and 414 age‐and‐sex frequency‐matched controls. We examined AIDs as a whole, B‐ and T‐cell–mediated AIDs, and autoimmune thyroid diseases. Among cases, we used Kaplan‐Meier and Cox regression models to assess the association of AID with overall survival and relapse‐free survival, adjusting for prognostically important patient and disease characteristics such as Ki67% staining, International Prognostic Index, rituximab treatment, and histological subgroup. Autoimmune diseases were associated with B‐NHL (odds ratio [OR] = 1.95; 95% confidence interval (CI), 1.31‐2.92), especially AIDs mediated by B‐cell activation (OR = 5.20; CI, 1.90‐14.3), which were particularly associated with marginal zone lymphoma (OR = 19.3; CI, 4.59‐80.9). We found that time to relapse for all B‐NHL patients with AIDs was significantly shorter (mean of 49.21 mo [±3.22]) than among patients without AID (mean of 59.74 mo [±1.62]), adjusted hazard ratio [HR_adj] = 1.69 (CI, 1.03‐2.79). Specifically, in patients with diffuse large B‐cell lymphoma, of whom 91.8% had received rituximab, a history of B‐cell–mediated AIDs was associated with shorter relapse‐free survival and overall survival, HR_adj = 8.34 (CI, 3.01‐23.1) and HR_adj = 3.83 (CI, 1.20‐12.3), respectively. Beyond confirming the well‐known association between AIDs and B‐NHL, we found that AID is an adverse prognostic factor in B‐cell lymphoma, associated with a shortened time to relapse, suggesting that there are specific therapeutic challenges in the subgroup of patients suffering from both these diseases. Further work is required to address mechanisms of resistance to standard treatment in the setting of AID‐associated B‐NHL. In the era of immunotherapy, these findings have particular relevance.     

Frequency and clinical correlates of elevated plasma Epstein‐Barr virus DNA at diagnosis in peripheral T‐cell lymphomas

Epstein‐Barr virus (EBV)‐encoded RNAs (EBER) in tumor tissue and cell‐free plasma EBV‐DNA (pEBVd) are detected in EBV‐associated lymphomas. Studies have suggested that EBER+ peripheral T‐cell lymphomas (PTCL) have worse prognosis but the role of EBV in these neoplasms remains unclear. pEBVd is quantitative and more easily amenable to standardization than EBER, but frequency of pEBVd detection, clinical impact and agreement with EBER status in PTCL are unknown. We retrospectively assessed frequency of detectable pre‐treatment pEBVd, presence of EBER in tumor tissue, and outcomes in 61 of 135 EBV‐assessable PTCL patients. Fifteen of 61 patients (24.5%, 95% CI: 14–37%) were pre‐treatment pEBVd+, with no significant differences in baseline characteristics or treatment between pEBVd+ and pEBVd? patients. EBER‐ISH was performed on 10 pEBVd+ and 35 pEBVd? tumors. All 10 pEBVd+ patients were EBER+, but 9 pEBVd? patients were also EBER+. With median follow up of 24 months (range 1–96), overall survival (OS) was shorter in pEBVd+ compared to pEBVd? patients (13 vs . 72 months; p = 0.04). In our retrospective study, pre‐treatment pEBVd was elevated in 25% of PTCL patients, was highly specific for EBER+ tumors, and was associated with shorter survival. pEBVd should be further explored as a prognostic variable and tumor biomarker in PTCL.     

Bendamustine is effective therapy in patients with rituximab‐refractory,indolent B‐cell non‐Hodgkin lymphoma

BACKGROUND:

Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single‐agent bendamustine in patients with rituximab‐refractory, indolent B‐cell lymphoma.

METHODS:

Eligible patients (N = 100, ages 31‐84 years) received bendamustine at a dose of 120 mg/m² by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0‐6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression‐free survival (PFS).

RESULTS:

An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).

CONCLUSIONS:

Single‐agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab‐refractory indolent B‐cell lymphoma. Cancer 2010. © 2010 American Cancer Society.     

A salvage chemotherapy of R‐P‐IMVP16/CBDCA consisting of rituximab,methylprednisolone, ifosfamide,methotrexate, etoposide,and carboplatin for patients with diffuse large B cell lymphoma who had previously received R‐CHOP therapy as first‐line chemotherapy

We have reported the efficacy of the salvage chemotherapy P‐IMVP16/CBDCA for patients with diffuse large B cell lymphoma (DLBCL) who had previously received CHOP before the availability of rituximab (R). Here, we confirmed the efficacy of R combined with P‐IMVP16/CBDCA as a salvage chemotherapy for patients with DLBCL, who had previously received R‐CHOP. We retrospectively analysed 59 patients with relapse or refractory DLBCL (38 male patients and 21 female patients) presenting between June 2004 and June 2013. The patients received R 375 mg/m² on day 1, methylprednisolone 1000 mg/body for 3 days (from day 3 to day 5), ifosfamide 1000 mg/m² for 5 days (from day 3 to day 7), methotrexate 30 mg/m² on day 5 and day 12, etoposide 80 mg/m² for 3 days (from day 3 to day 5), and carboplatin 300 mg/m² on day 3 every 21 days. Patients aged 70 years or older were given 75% of the standard dose. The overall response rate (complete response + partial response) was 64.4%. The 2‐year overall survival rate was 55.3%. The 2‐year progression free survival rate was 34.7%. The 2‐year overall survival rate was 61.5% for the relapse patients, and 15.6% for the refractory patients (p < 0.0001). One patient died because of sepsis related to the treatment regimen. Non‐hematological adverse effects were mild and tolerable. The R‐P‐IMVP‐16/CBDCA regimen displayed a significant activity in relapsed DLBCL, with acceptable toxicity, and should be considered a candidate for salvage chemotherapy. Copyright © 2016 John Wiley & Sons, Ltd.     

Expression of activating natural killer‐cell receptors is a hallmark of the innate‐like T‐cell neoplasm in peripheral T‐cell lymphomas

Peripheral T‐ or natural killer (NK)‐cell lymphomas are rare and difficult‐to‐recognize diseases. It remains arduous to distinguish between NK cell‐ and cytotoxic T‐lymphocyte‐derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK‐cell receptors and examined the expression using immunohistochemistry in 22 cases with T‐ and NK‐cell neoplasms comprising angioimmunoblastic T‐cell lymphoma, anaplastic lymphoma kinase (ALK)‐positive and ‐negative anaplastic large‐cell lymphomas, extranodal NK/T‐cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T‐cell lymphoma, aggressive NK‐cell leukemia, and other peripheral T‐cell lymphomas. Inhibitory receptor leukocyte immunoglobulin‐like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK‐cell receptors were expressed predominantly in TIA‐1‐positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK‐cell neoplasms and cytotoxic T‐lymphocyte‐derived lymphomas including monomorphic epitheliotropic intestinal T‐cell lymphoma. One Epstein‐Barr virus‐harboring cytotoxic T‐lymphocyte‐derived lymphoma mimicking extranodal NK/T‐cell lymphoma, nasal type lacked these NK‐cell receptors, indicating different cell origin from NK and innate‐like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log‐rank test, P = .024). We propose that the presence of activating NK‐cell receptors may provide new insights into understanding peripheral T‐cell lymphomas and characterizing them as innate‐like T‐cell neoplasm.