Treatment Of T-cell Lymphoblastic Lymphoma Research Articles

Pre-Clinical Evaluation of the Hypomethylating Agent Decitabine for the Treatment of T-Cell Lymphoblastic Lymphoma.

T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, often diagnosed at a young age. Patients are treated with intensive chemotherapy, potentially followed by a hematopoietic stem cell transplantation. Although prognosis of T-LBL has improved with intensified treatment protocols, they are associated with side effects and 10-20% of patients still die from relapsed or refractory disease. Given this, the search toward less toxic anti-lymphoma therapies is ongoing. Here, we targeted the recently described DNA hypermethylated profile in T-LBL with the DNA hypomethylating agent decitabine. We evaluated the anti-lymphoma properties and downstream effects of decitabine, using patient derived xenograft (PDX) models. Decitabine treatment resulted in prolonged lymphoma-free survival in all T-LBL PDX models, which was associated with downregulation of the oncogenic MYC pathway. However, some PDX models showed more benefit of decitabine treatment compared to others. In more sensitive models, differentially methylated CpG regions resulted in more differentially expressed genes in open chromatin regions. This resulted in stronger downregulation of cell cycle genes and upregulation of immune response activating transcripts. Finally, we suggest a gene signature for high decitabine sensitivity in T-LBL. Altogether, we here delivered pre-clinical proof of the potential use of decitabine as a new therapeutic agent in T-LBL.

PET/CT Evaluation of the Effect of Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of T-Cell Lymphoblastic Lymphoma.

The aim of this study was to investigate the clinical value of positron emission tomography/computerized tomography scanning (PET/CT) in the evaluation of the effect of allogeneic hematopoietic stem cell transplantation in the treatment of T lymphoblastic lymphoma. 12 relevant research articles were collected through layer-by-layer screening in large databases such as Pubmed, Baidu Scholar, and China How Net, and analyzed and summarized using indicators such as progression-free survival (PFS), overall survival (OS), hazard ratio (HR), maximum standardized uptake value (SUV max), total metabolic tumor volume (TMTV), total lesion glycolysis (TLG), elevated lactate dehydrogenase (LDH), and β2-microglobulin (β2-MG). The results showed that before treatment, 18F-FDG PET/CT baseline diagnosis could accurately stage the patients; during treatment, 18F-FDG PET/CT detection could provide effective treatment information; and after treatment, complications were found during 18F-FDG PET/CT detection. In summary, 18F-FDG PET/CT can monitor and evaluate treatment prognosis at baseline, middle, and late stages, and 18F-FDG PET/CT has become an indispensable and important examination technique in clinical work.

Outcome of Allogeneic Stem Cell Transplantation in T Cell Lymphoblastic Lymphoma

Background T cell lymphoblastic lymphoma (T-LBL) is an aggressive form of non-Hodgkin lymphoma occurring in predominantly adolescent and young adults.Although T-LBL is achemotherapy-sensitive disease, relapse is common with conventional chemotherapies. Allogeneic stem cell transplantation (allo-SCT) may be effective in patients with high-risk features or relapsed/refractory patients.Objective To investigate the effect of allo-SCT in the treatment of T-LBL.Methods T-LBL patients who received allo-SCT from August 2007 to March 2017 in our center were recruited in this retrospective study.Results (1) 37 T-LBL patients were enrolled in this study, including 25 males and 12 females with a median age of 21 years old (ranged from 8 to 47 years old). A total of 10 (27%) from HLA-matched siblings,24 (65%) patients received grafts from haploidentical family donors, 2 (5%) from matched unrelated donors,and 1(3%) from cord blood. (2) With a median follow up of 20 months (4 - 119 months), 3 year overall survival (OS) ,progression-free survival (PFS) and relapse were 71.7%, 69.5% and 23.6%,respectively. (3) 12/37 patients developed acute graft-versus-host diease (GVHD) ,including 6 (16%) with grade III-IV aGVHD. 8/37 patients developed chronic GVHD. The transplant-related mortality was 13.5%.(4) Allo-SCT in first complete remission (CR1) was associated with improved OS (3-year estimates: 79.1% vs 45.5%, P=0.001) and improved PFS (62.5% vs 39.1%, P=0.001). On multivariable analysis, allo-SCT in CR1 was the factor associated with the prolonged OS (hazard ratio [HR] = 0.095;95% confidence interval [CI] : 0.014-0.655; P=0.017) and PFS (HR=,0.085 95% CI=0.014-0.515; P=0.007).Conclusion Allo-SCT for T-LBL patients revealed a proming outcome. Disease status the only independent factor affecting the OS and PFS, and allo-SCT should be recommended in CR1. DisclosuresNo relevant conflicts of interest to declare.

Current status and future directions of T-lymphoblastic lymphoma in children and adolescents.

The main challenges in the treatment of T-cell lymphoblastic lymphoma (T-LBL) in children and adolescents are twofold: to increase survival rates in concert with reduction of acute and long-term toxicities including the rate of secondary malignancies. The need for molecular and prognostic markers in T-LBL is crucial to allow for systematic treatment optimization and may serve as targets for new treatment approaches.

Highlights of This Issue

The majority of alveolar rhabdomyosarcomas (aRMS) are driven by the oncogenic fusion protein PAX3-FOXO1. Novel therapies are needed to target PAX3-FOXO1 or pathways supporting its tumorigenic properties. To this end, Kephart and colleagues conducted a screen for genes that collaborate with PAX3-FOXO1, and identified the secreted Wnt inhibitor SFRP3. Genetic suppression of SFRP3 in aRMS cell lines decreased proliferation and increased apoptosis and differentiation. In a murine xenograft model, suppression of SFRP3 inhibited aRMS tumor growth and sensitized tumors to vincristine, part of the chemotherapeutic backbone of RMS therapy, suggesting that targeting SFRP3 may be a promising therapeutic strategy.Hong and colleagues conducted a phase I clinical trial of lenvatinib—a multikinase inhibitor of VEGFR 1–3, FGFR 1–3, PDGFRα, RET and KIT—in patients with solid tumors. The maximum tolerated dose was 10 mg twice daily. Drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%). Twelve patients (15.6%) achieved partial response (PR, n = 9) or unconfirmed PR (n = 3); 19 (24.7%) achieved stable disease ≥23 weeks. The toxicity profile and antitumor activity of lenvatinib are encouraging.Little is known about miRNAs in the development and treatment of T-cell lymphoblastic lymphoma (T-LBL). Using microRNA microarrays, Qian and colleagues reported, for the first time, that the downregulation of miR-374b was frequently detected in primary T-LBL tissues, which was significantly associated with worse overall survival and increased risk of recurrence. Moreover, in vitro and in vivo studies showed that miR-374b suppressed cell tumorigenicity and promoted cellular apoptosis by inhibiting AKT signal pathway though directly repressing Wnt-16 and AKT1. Targeting miR-374b pathway may represent novel prognostic biomarkers and new therapeutic strategies to improve the therapy and survival of patients with T-LBL.Cancer-associated fibroblasts (CAFs) have been associated to recurrence and survival in colon cancer. After proteomic characterization, the authors identified LOXL2 as an upregulated protein in purified colon CAFs. High expression of LOXL2 showed a clear association, either disease-free or overall survival in colon cancer patients. In addition, it displayed a significant prognostic value in the stratification of high-risk stage II and III patients. Thus, LOXL2 shows promise as a relevant tool in clinical practice for risk classification, which could lead to a more aggressive therapy and better outcomes for stage II patients.

MicroRNA-374b Suppresses Proliferation and Promotes Apoptosis in T-cell Lymphoblastic Lymphoma by Repressing AKT1 and Wnt-16.

Deregulation of microRNA (miRNA) has been extensively investigated in both Hodgkin and non-Hodgkin lymphomas (NHL); however, little is known about the roles of miRNAs in T-cell lymphoblastic lymphoma (T-LBL). The aim of the present study was to investigate the potential roles of miR-374b in the development and treatment of T-LBL. MiRCURY LNA array was used to generate a miRNA-expressing profile. Real-time quantitative PCR and immunohistochemistry (IHC) were applied to detect the expression of miR-374b, AKT1, and Wnt16 in T-LBL samples. The dual-luciferase reporter assay was conducted to confirm target associations of miR-374b. The tumor-suppressive effect of miR-374b was determined by both in vitro and in vivo studies. The expression of 380 miRNAs was evaluated in five human T-LBL tissues and five infantile thymus samples by microRNA microarrays. Downregulation of miR-374b was frequently detected in primary T-LBL tissues, which was significantly associated with worse overall survival and increased risk of recurrence of the 58 patients enrolled in this study. miR-374b suppressed T-LBL cell proliferation in vitro and in vivo and sensitized cells to serum starvation- and chemotherapeutic agent-induced apoptosis. Furthermore, we characterized two AKT pathway-associated molecules, AKT1 and Wnt16, as direct targets of miR-374b. Consistently, in T-LBL patient tissues, AKT1 and Wnt16 expression was inversely correlated with miR-374b levels, and was an independent predictor of recurrence and survival. Our data highlight the molecular etiology and clinical significance of miR-374b in T-LBL. Targeting miR-374b may represent a new therapeutic strategy to improve therapy and survival for T-LBL patients.

Molecular Cloning of a Novel PPEF-1 Gene Variant from a T-Cell Lymphoblastic Lymphoma Cell Line

To determine if there is a gene variant of protein serine-threonine phosphatase with EF hand (PPEF-1) in T-cell lymphoblastic lymphoma SUP-T1 cell line, both in silico and in vitro approaches were conducted. In silico, a cDNA clone showing similar sequence to PPEF-1 was isolated from the SUP-T1 cDNA library and named PPEF-1V. The full-length of the PPEF-1V cDNA clone is a 2135bp containing a 1503bp open reading frame extending from 188bp to 1690bp, which corresponds to an encoded protein of 501 amino acid residues with a predicted molecular mass of 57.8 kDa. Alignment on both PPEF-1V and PPEF-1 sequences showed that PPEF-1V is a 350bp deletion in the nucleotide sequence of PPEF-1 from 128-477bp and a 152-amino-acid N-terminal deletion in the amino acid sequence of PPEF-1. In vitro, PPEF-1V transcript fragment was only highly expressed in T-cell lymphoblastic lymphoma cell line. In conclusion, the present patent showed that PPEF-1V could be a potential target for diagnosis or treatment of T-cell lymphoblastic lymphoma.

VPDL Chemotherapy for T-cell Lymphoblastic Lymphoma (T-LBL) in Adults: Comparison with Upfront Autologous Stem Cell Transplantation in a Single Center

Background: Treatment of T-cell lymphoblastic lymphoma (T-LBL) with CHOP or CHOP-like chemotherapy has resulted in poor long-term outcomes. High-dose chemotherapy followed by ASCT has been applied for this dreaded disease. However, the efficacy is still controversial. T-LBL is considered the nodal/extranodal presentation of acute lymphoblastic leukemia. Favorable results with VPDL chemotherapy have been reported in the setting of adult lymphoblastic leukemia. We, therefore, treated T-LBL patients with modified VPDL chemotherapy and compared the outcomes with those achieved using upfront ASCT. Methods: We retrospectively reviewed the outcomes of 24 T-LBL patients treated either with upfront ASCT (n=11) or VPDL chemotherapy without ASCT (n=13) between January 1996 and October 2005. Results: The median follow-up duration for surviving patients was 17 months (range, 5∼109 months). The two-year event-free survival (EFS) rates were 83.1% in the VPDL group and 27.3% in the upfront ASCT group (P=0.008). The two-year overall survival (OS) rates were 83.9% in the VPDL group and 27.3% in the upfront ASCT group (P=0.006). Conclusion: This study suggests that VPDL chemotherapy is very effective and may be superior to upfront ASCT in the treatment of T-LBL patients.

Primary therapy for adults with T-cell lymphoblastic lymphoma with hematopoietic stem-cell transplantation results in favorable outcomes

Controversy exists regarding the role of high-dose therapy followed by stem-cell transplant (SCT) in the treatment of T-cell lymphoblastic lymphoma (T-LBL). We conducted an intention-to-treat analysis of the strategy of SCT as definitive treatment of T-LBL. From July 1987 to March 2005, 34 adults with T-LBL were diagnosed and treated in British Columbia. Treatment, before planned SCT, consisted of a non-Hodgkin's lymphoma (NHL)/acute lymphoblastic leukemia hybrid chemotherapy protocol (28 patients) or a standard NHL chemotherapy regimen (six patients). Median follow-up of the 23 surviving patients is 51 months (range 13-142 months). Twenty-nine proceeded to SCT (four allogeneic, 25 autologous). For all 34 patients, 4-year overall survival (OS) and event-free survival (EFS) are 72% and 68%, respectively. For patients proceeding to SCT, the 4-year OS and EFS are 79% and 73%, respectively. All patients who received allografts are alive without disease at 38-141 months since diagnosis. For patients who received autografts, the 4-year EFS is 69%. Bone marrow involvement was a significant prognostic factor predicting for a worse survival (P = 0.02). A treatment strategy for adults with chemosensitive T-LBL that includes planned consolidation with SCT in first response produces favorable long-term outcome.