Prognostic impact of pretreatment cell-free DNA concentration in newly diagnosed peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) have a poor prognosis and, to date, there are no reliable predictive biomarkers of response. In this work we explored the prognostic impact of cell-free DNA (cfDNA) concentration in 75 newly diagnosed patients enrolled in a prospective multicenter study. Pre-treatment cfDNA was strongly associated with clinical risk factors and was identified as a superior predictor for shorter progression-free survival in multivariable analysis, outweighing canonical risk parameters. Furthermore, we identified a cfDNA value above which survival worsens. In conclusion, pre-treatment cfDNA concentration represents an easily usable predictive biomarker that is highly associated with survival of PTCL patients.

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

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

A novel lncRNA TCLlnc1 promotes peripheral T cell lymphoma progression through acting as a modular scaffold of HNRNPD and YBX1 complexes.

Long noncoding RNAs (lncRNAs) play an essential role in tumor progression. Few researches focused on the clinical and biological relevance of lncRNAs in peripheral T cell lymphoma (PTCL). In this research, a novel lncRNA (ENST00000503502) was identified overexpressed in the main subtypes of PTCL, and designated as T cell lymphoma-associated lncRNA1 (TCLlnc1). Serum TCLlnc1 was associated with extranodal involvement, high-risk International Prognostic Index, and poor prognosis of the patients. Both in vitro and in vivo, overexpression of TCLlnc1 promoted T-lymphoma cell proliferation and migration, both of which were counteracted by the knockdown of TCLlnc1 using small interfering RNAs. As the mechanism of action, TCLlnc1 directly interacted with transcription activator heterogeneous nuclear ribonucleoprotein D (HNRNPD) and Y-box binding protein-1 (YBX1) by acting as a modular scaffold. TCLlnc1/HNRNPD/YBX1 complex upregulated transcription of TGFB2 and TGFBR1 genes, activated the tumor growth factor-ß signaling pathway, resulting in lymphoma progression, and might be a potential target in PTCL.

Low serum cholesterol levels predict inferior prognosis and improve prognostic index scoring for peripheral T-cell lymphoma, unspecified.

Peripheral T-cell lymphomas, unspecified (PTCL-U) is a heterogeneous group of non-Hodgkin lymphomas, arising from the transformation of mature, post-thymic T-cells. Prognostic index for PTCL-U (PIT) is based on Europeans and may not be applicable for Chinese PTCL-U patients. Besides, low circulating cholesterol concentration is associated with elevated cancer incidence and mortality. The purpose of our study was to assess the prognostic value of serum lipid levels in PTCL-U and improve PIT. We screened the prognostic factors associated with progression-free survival (PFS) and overall survival (OS) by multivariate Cox regression analysis in ninety-one enrolled patients. The results showed that low-level high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were associated with unfavorable OS. Furthermore, we developed a new risk model, PITC, based on low-level HDL-C, LDL-C and PIT. In Chinese PTCL-U, PITC was superior to PIT in PFS and OS. In conclusion, serum cholesterol levels may be good candidates for predicting prognosis in PTCL-U.

The derived neutrophil-to-lymphocyte ratio is an independent prognostic factor in patients with angioimmunoblastic T-cell lymphoma.

To determine whether inflammatory markers, derived neutrophil-to-lymphocyte ratio (dNLR), haemoglobin/platelet ratio (HPR) or platelet/lymphocyte ratio (PLR) are predictive for prognosis in angioimmunoblastic T-cell lymphoma (AITL), we derived dNLR, HPR and PLR values for 110 AITL patients and appropriate cut-off point values to define overall survival (OS) and progression-free survival (PFS). dNLR ≥ 2·2, HPR ≥ 0·4 or PLR < 100 were significant factors for shorter OS and PFS. On univariate analysis, these three parameters were significantly associated with worse OS and PFS. On multivariate analysis, only dNLR remained a significant, independent prognostic factor for both OS and PFS.

Incidence and outcomes of rare T cell lymphomas from the T Cell Project: hepatosplenic, enteropathy associated and peripheral gamma delta T cell lymphomas.

The T Cell Project was the largest prospective trial to explore the incidence, treatment patterns, and outcomes for T cell lymphomas. The rare subtypes of T cell lymphomas, including hepatosplenic T cell lymphoma (HSTCL), enteropathy associated T cell lymphoma (EATL), and peripheral gamma delta T cell lymphomas (PGDTCLs) are poorly represented in most studies and there is little data regarding treatment patterns. We report results from 115 patients with hepatosplenic (n = 31), enteropathy associated (n = 65), and PGDTCLs (n = 19). While anthracycline regimens were most commonly used as first line therapy, response rates ranged from 20%-40% and were suboptimal for all groups. Autologous stem cell transplantation was performed as a consolidation in first remission in a small number of patients (33% of HSTCL, 7% of EATL, and 12% of PGDTCL), and four patients with HSTCL underwent allogeneic stem cell transplantation in first remission. The progression free survival at 3 years ranged from 28%-40% for these rare subtypes, and the overall survival at 3 years was most favorable for PGDTCL (70%). These data highlight the need for novel treatment approaches for rare subtypes of T cell lymphomas and for their inclusion in clinical trials.

Absolute monocyte count is a predictor of overall survival and progression-free survival in nodal peripheral T cell lymphoma.

Nodal peripheral T cell lymphomas (nPTCL) present aggressive clinical course, and its heterogeneous nature and poor prognosis with current therapeutic strategies make it a target for the development of new prognostic markers. Thus, we investigated tumor-associated macrophages (TAM) according to the number of cells expressing CD68 in biopsies and the absolute monocyte count (AMC) in peripheral blood of 87 patients with nPTCL. The median overall survival (OS) was 3 years (95% CI 1.3-8.4 years) and estimate 5 years OS of 43.3% (95% CI 32.5-53.7%). The median progression-free survival (PFS) was 1.5 years (95% CI 0.8-2.6 years) with estimate 5 years PFS of 29.2% (95% CI 19.7-39.3%). The cutoff for AMC was 1.5 × 109/L and the median OS for patients with AMC ≥ 1.5 × 109/L was 0.83 years versus 3.7 years for those with AMC < 1.5 × 109/L (HR 2.32, 95% CI 1.03-5.22, p = 0.035). The median PFS for patients with AMC ≥ 1.5 × 109/L was 0.50 years versus 1.5 years for those with AMC < 1.5 × 109/L (HR 2.25, 95% CI 1.05-4.78, p = 0.031). CD68 was evaluated in 26/87 (29.8%) patients with a median expression of 34% and positivity cutoff of 43%. CD68 expression was not associated with OS or PFS either with AMC values. Our findings suggest that the AMC of ≥ 1.5 × 109/L at diagnosis in peripheral blood is associated with poor prognosis in nPTCL. Further investigations in a larger cohort are required to better validate our results.

High Level of Serum Soluble Interleukin-2 Receptor Is Associated With Poor Survival in Patients With First Relapsed or Refractory Peripheral T-Cell Lymphoma, Not Otherwise Specified: A Retrospective Study.

BACKGROUND: Patients with relapsed or refractory peripheral T-cell lymphoma, not otherwise specified (R/R-PTCL-NOS) usually have short survival with conventional salvage chemotherapies. Prediction of poor survival in patients who undergo conventional salvage chemotherapies might help identify candidates for novel therapies that have been recently available for R/R-PTCL-NOS. However, no prognostic marker other than the second-line International Prognostic Index (sIPI) has been reported. We aimed to investigate the prognostic value of serum soluble interleukin-2 receptor (sIL-2R) level in patients with R/R-PTCL-NOS. PATIENTS AND METHODS: We retrospectively analyzed 37 patients with R/R-PTCL-NOS who underwent salvage chemotherapy. Serum sIL-2R level was measured within a week before salvage chemotherapy initiation. We determined the cutoff level of serum sIL-2R as 4.03 times the upper limit of normal by using receiver operating characteristic curve analysis. RESULTS: The 3-year overall survival (3yOS) was 5.2% and 37.5% in high sIL-2R and low sIL-2R groups, respectively (P = .005). In multivariate analysis, high sIL-2R level was independently associated with lower 3yOS (hazard ratio, 2.30; 95% confidence interval, 1.04-5.11; P = .040). In subgroup analysis, high sIL-2R level did not affect 3yOS in patients with high-risk sIPI (NA [not available] vs. 7.1%; P = .354), but was significantly associated with poor 3yOS in patients with low-risk sIPI (NA vs. 60.0%; P = .037). CONCLUSION: Serum sIL-2R is a useful prognostic marker for patients with R/R-PTCL-NOS. In particular, high sIL-2R level can identify groups of patients with low-risk sIPI who have poor prognosis. Our results suggest that novel therapeutic approaches might be necessary for patients with high-risk sIPI and/or high sIL-2R level.

Plasma soluble programmed death ligand 1 levels predict clinical response in peripheral T-cell lymphomas.

Immune checkpoints, including PD-1/PD-L1, play an important role in immunosuppression in various malignancies. Elevated levels of soluble programmed death ligand 1 (sPD-L1) are associated with worse prognosis in multiple myeloma and diffuse large B cell lymphoma. Herein, the purpose of this study is to investigate the relationships between plasma sPD-L1 levels and clinical response in peripheral T-cell lymphoma (PTCL) patients. A total of 37 PTCL patients and 20 healthy volunteers were enrolled. Peripheral blood from patients was collected prior to systemic therapy. Plasma levels of sPD-L1 and IFN-γ were measured by enzyme-linked immunosorbent assay (ELISA). PD-L1 expression in tissues was detected by immunohistochemistry (IHC). Clinical response for patients was evaluated. ONCOMINE database analyses showed that PD-L1 mRNA expression was significantly upregulated in PTCLs. The median sPD-L1 level was 0.729 ng/mL for 20 healthy volunteers and 1.696 ng/mL for 37 PTCL patients which was significantly higher than that in healthy volunteers (0.000). The sPD-L1 level was positively correlated with IFN-γ level (0.000, r = 0.849) and was also positively associated with clinical staging (0.045), LDH level (0.003), and ß2-MG level (0.045). Patients with high sPD-L1 level had lower overall response rate than those with low sPD-L1 level (88.9% vs 50.0%, 0.022) and tended to have poorer PFS and OS. PD-L1 expression in tissues matched very well with the sPD-L1 level in PTCL patients. In conclusion, PTCL patients had higher sPD-L1 level compared with healthy volunteers. High sPD-L1 level was correlated with worse clinical response, suggesting that sPD-L1 level was an underlying plasma biomarker to predict the prognosis for PTCL patients.

Prognostic Value of Platelet Count in Patients with Peripheral T Cell Lymphoma.

BACKGROUND: Peripheral T cell lymphoma (PTCL) is a heterogeneous entity with poor survival. We evaluated the neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and platelet count as new prognostic factors for PTCL. PATIENTS AND METHODS: We retrospectively analyzed 77 patients with PTCL initially treated with anthracycline-based chemotherapy. Survival curves were compared between groups with different initial NLR (iNLR), end-point NLR (eNLR), initial ALC, and platelet counts. Cox regression was used to analyze the risk factor for survival. RESULTS: Patients with a higher eNLR (≥3), lymphopenia (< 1,000/µL), and thrombocytopenia (< 150 K/µL) had an inferior progression-free survival (PFS) and overall survival (OS) compared to their counterparts, while a higher iNLR (≥3) was predictive of a shorter OS but not PFS. Among these, thrombocytopenia was an independent poor prognostic factor for both PFS and OS, with a hazard ratio of 2.42 (p = 0.012) for PFS and 4.21 (p = 0.006) for OS. The presence of thrombocytopenia further stratified patients with a worse prognosis within overlapping risk-groups by the prognostic index for PTCL. CONCLUSIONS: Our study showed that thrombocytopenia at diagnosis was an independent prognostic factor for survival in patients with PTCL.

Soluble programmed death-ligand 1 are highly expressed in peripheral T-cell lymphoma: a biomarker for prognosis.

PURPOSE: To investigate the role of soluble programmed cell death ligand 1 (sPD-L1) protein in plasma of patients with Peripheral T-cell lymphoma (PTCL). METHODS: In total, 80 patients with newly diagnosed PTCL and 75 healthy controls were enrolled. Levels of sPD-L1 were measured by ELISA at diagnosis and after 3-8 courses of chemotherapy. The expression of PD-L1 in tumor tissues from nine PTCL patients was also detected. RESULTS: sPD-L1 was higher in PTCL patients at diagnosis compared to healthy subjects (P < 0.0001). Patients in the intermediate/high-risk disease group had a higher level of sPD-L1 than patients in the low-risk group (P = 0.0003). Elevated sPD-L1 (≥176.30 pg/ml) was the only biomarker for PTCL that retain statistical significance in multivariate analysis. Patients in the low-risk group with sPD-L1 ≥ 176.30 pg/ml had an adverse prognosis. Histological analysis showed that the expression of PD-L1 in tissues was positively correlated with sPD-L1 levels in plasma (Spearman = 0.9177, P = 0.0013). CONCLUSIONS: sPD-L1 is a sensitive biomarker predicting clinical outcomes in PTCL.

A case of AITL complicated by EBV-positive B cell and monoclonal plasma cell proliferation and effectively treated with lenalidomide.

Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma with an aggressive clinical course and poor prognosis after conventional chemotherapy, for which there is no current standard of care. We describe here an 87-year-old woman with AITL, whose clinical diagnosis was complicated by the presence of B immunoblasts positive for Epstein-Barr virus in the lymph nodes and monoclonal plasma cells in the bone marrow at initial presentation. Rebiopsy of the lymph node led to the correct diagnosis of AITL with concurrent smoldering plasma cell myeloma. She was treated with several courses of conventional chemotherapy, resulting in progressive disease, and then switched to the immunomodulatory drug lenalidomide, which used in Japan for the treatment of multiple myeloma. Lenalidomide was effective in controlling both AITL and plasma cell myeloma.

Multicenter phase 1/2 study of forodesine in patients with relapsed peripheral T cell lymphoma.

Peripheral T cell lymphomas are an aggressive group of non-Hodgkin lymphomas with poor outcomes for most subtypes and no accepted standard of care for relapsed patients. This study evaluated the efficacy and safety of forodesine, a novel purine nucleoside phosphorylase inhibitor, in patients with relapsed peripheral T cell lymphomas. Patients with histologically confirmed disease, progression after ≥ 1 prior treatment, and an objective response to last treatment received oral forodesine 300 mg twice-daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Forty-eight patients (median age, 69.5 years; median of 2 prior treatments) received forodesine. In phase 1 (n = 3 evaluable), no dose-limiting toxicity was observed during the first 28 days of forodesine treatment. In phase 2 (n = 41 evaluable), the ORR for the primary and final analyses was 22% (90% CI 12-35%) and 25% (90% CI 14-38%), respectively, including four complete responses (10%). Median PFS and OS were 1.9 and 15.6 months, respectively. The most common grade 3/4 adverse events were lymphopenia (96%), leukopenia (42%), and neutropenia (35%). Dose reduction and discontinuation due to adverse events were uncommon. Secondary B cell lymphoma developed in five patients, of whom four were positive for Epstein-Barr virus. In conclusion, forodesine has single-agent activity within the range of approved therapies in relapsed peripheral T cell lymphomas, with a manageable safety profile, and may represent a viable treatment option for this difficult-to-treat population.

Profiles of serum cytokines and their clinical implications in patients with peripheral T-cell lymphoma.

To better predict the outcomes of patients with peripheral T-cell lymphoma (PTCL), we measured the levels of various cytokines in serum samples from patients with PTCL and analyzed their clinical outcomes. We measured 34 cytokines in samples from 121 PTCL patients (55 PTCL-not otherwise specified (NOS), 44 angioimmunoblastic T-cell lymphoma (AITL), and 22 ALK- anaplastic large cell lymphoma) at diagnosis. Their impact on clinical outcomes, including overall survival and complete response rate, were analyzed with other clinical variables. The median age of patients was 58 years (range, 20-85 years) and 81 patients (66.9%) were male. The median overall survival among all patients was 56.1 months (95% CI 21.4-90.8) and median progression-free survival was 19.3 months (95% CI 12.3-26.3). Patients with AITL were more likely to express higher levels of serum cytokines, and 7 cytokines showed mean levels that were significantly higher than those in other subtypes. In this subgroup, IL-10 higher than 3.8 pg/mL was associated with adverse outcomes. In patients with ALK- anaplastic large cell lymphoma, 9 cytokines showed a prognostic impact, with higher levels of interferon γ, interleukin (IL)-8, IL-10, IL-17, IL-23, IP-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1ß, and RANTES negatively affecting clinical outcomes. In PTCL-NOS, patients with elevated levels of interferon γ, IL-7, and IL-23 showed poor outcomes. The current analysis demonstrated different cytokine profiles according to histologic subtype, which revealed the heterogeneity of PTCL. In addition, cytokine levels can be used as prognostic markers and may be useful for therapeutic applications in PTCL patients.

Rapidly progressive renal failure due to tubulointerstitial infiltration of peripheral T-cell lymphoma, not otherwise specified accompanied by uveitis: a case report.

BACKGROUND: Rapid decline in renal dysfunction due to primary renal lymphoma, or secondary renal lymphoma by infiltration from a primary origin, is extremely rare. There are notably few reports indicating infiltration of T-cell lymphoma into the kidney. CASE PRESENTATION: A 61-year-old woman with a sudden body rash and liver dysfunction was brought to our hospital presenting with a dull headache and blurred vision. Laboratory tests revealed rapidly progressive renal failure. Histological examination of the kidney and skin indicated infiltration of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Infiltration of PTCL-NOS to the liver and spleen, and presence of Uveitis masquerade syndrome were suspected. Imaging showed that the lesion was limited to extralymphatic organs. Renal function was improved with administration of steroids, including pulse steroid therapy, before administering cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) therapy. CONCLUSIONS: This is the first reported case of rapidly progressive renal failure caused by perivascular tubulointerstitial nephritis with the direct invasion of PTCL-NOS. In our case, a single steroid dose showed dramatic results with respect to renal symptoms.

Vitamin D deficiency is associated with inferior survival of patients with extranodal natural killer/T-cell lymphoma.

Vitamin D deficiency is a common health issue; however, the effect of vitamin D deficiency on the survival of T-cell lymphoma is still not clear. We evaluated the impact of serum vitamin D level of patients with peripheral T-cell lymphoma (PTCL) and extranodal natural killer/T-cell lymphoma (ENKTL) on survival outcome. Pretreatment levels of 25-hydroxyvitamin D [25(OH)D] and inflammatory cytokines were measured in serum samples that were archived at diagnosis, and we evaluated their association with survival in newly diagnosed patients with PTCL (n = 137) and ENKTL (n = 114) at a university-based hospital in Korea. An independent cohort from Rui Jin Hospital (Shanghai, China) was used for validation. The median 25(OH)D serum level was 12.0 ng/mL (1.3-60.0 ng/mL), and 40% had less than 10 ng/mL, which was defined as vitamin D deficiency. Median serum 25(OH)D levels were similar between PTCL (11.5 ng/mL) and ENKTL (12.9 ng/mL); however, vitamin D deficiency was associated with inferior survival in ENKTL but not with PTCL. The independent validation cohort (n = 115) also showed a significant association of vitamin D deficiency with poor survival in ENKTL. The 25(OH)D level had an inverse relation with inflammatory cytokines; this association had a negative effect only on survival of ENKTL, and not on PTCL. In conclusion, vitamin D deficiency was associated with inferior survival outcome of patients with ENKTL.

A lower ALC/AMC ratio is associated with poor prognosis of peripheral T-cell lymphoma-not otherwise specified.

Peripheral T-cell lymphomas-not otherwise specified (PTCL-NOS) generally have poor patient outcomes, with a 5-year survival rate of ∼32%. The most common prognostic system for patients with PTCL-NOS, the PTCL-U score, is often inadequate because it does not take into consideration the role of host immunity or the microenvironment induced by the tumor. In this paper we aimed to determine the correlation between the Absolute Lymphocyte Count/Absolute Monocyte Count (ALC/AMC) ratio and the prognosis of PTCL-NOS. Retrospective data from 58 patients diagnosed with PTCL-NOS were analyzed. We found that PTCL-NOS patients with lower ALC/AMC ratios (ALC/AMC < 2) had shorter overall survival (OS) and progression-free survival (PFS) periods (OS: P < 0.001; PFS: P = 0.001) compared with other patients (ALC/AMC ≥ 2). When we combined ALC/AMC ratio and PTCL-U scores, patients could be clearly divided into 3 groups with significantly different prognoses. This study suggests that the ALC/AMC ratio may be a simple, effective, and independent prognostic factor for OS and PFS, and may be helpful to identify high-risk PTCL-NOS patients. Since the ALC/AMC ratio is related to host immunity and tumor microenvironment and reflects immune status and individual differences, combining ALC/AMC with PTCL-U may be a better prognostic guide for PTCL-NOS patients.

Can folate replacement induce lymphoma progression?

A 43-year-old Japanese man with a low haemoglobin level of 1.3 g/dL and multiorgan dysfunction syndrome (MODS) was admitted to our hospital. He was diagnosed with folate deficiency, which was initially attributed to his malnutrition. He was transfused with several units of packed red blood cells and treated with folate, thiamine and vitamin B12 supplements; he showed a prompt haematological response and recovery from MODS. However, 3 weeks after the initial recovery, he had a relapse of pancytopenia and developed high-grade fever along with rapidly enlarging, generalised lymphadenopathy. Bone marrow biopsy revealed hemophagocytosis, and lymph node biopsy revealed peripheral T-cell lymphoma, not otherwise specified. Folate supplementation may have promoted lymphoma progression.