Autologous hematopoietic stem cell transplantation in chemotherapy-sensitive lymphoblastic lymphoma: treatment outcome and prognostic factor analysis

Objective： The study evaluated the effectiveness of autologous hematopoietic stem cell transplantation （AHSCT） in the treatment of lymphoblastic lymphoma （LL）. Methods： We relxospectively analyzed the data from 41 patients with chemotherapy-sensitive LL who underwent hematopoietic stem cell transplantation （HSCT） from December 1989 to December 2009 in a single institution. Results： HSCT was conducted as first-line consolidation therapy and salvage therapy in 36 and 5 patients, respectively. The median follow-up was 97.1 months （range, 24.6-173.1 months）. The 5-year overall survival （OS） and event-free survival （EFS） rate were 64% and 47% for the initially treated patients, respectively, and were both 20% for the relapsed ones. Bone marrow （BM） involvement and chemotherapy cycles prior to transplantation were identified as significant prognostic factors for EFS in multivariate analysis. Conclusions These results confirm that AHSCT is a reasonable option for chemotherapy-sensitive LL patients in first complete remission （CR1）.

PEG-asparaginase in BFM-90 regimen improves outcomes in adults with newly diagnosed lymphoblastic lymphoma

Objective： Although L-asparaginase（L-ASP） is a standard treatment for lymphoblastic lymphoma（LBL）,hypersensitivity reactions by some patients limit its application. Polyethylene glycol-conjugated asparaginase（PEGASP） has a lower immunogenicity and is a standard treatment in all pediatric acute lymphoblastic leukemia（ALL）.In this study, we investigated the efficacy and toxicity of PEG-ASP instead of L-ASP as used in the BFM-90regimen（PEG-ASP-BFM-90） for adult LBL.Methods： Between June 2012 and July 2015, we treated 30 adult patients with newly diagnosed LBL, using PEGASP-BFM-90 in a prospective, multicenter and single-arm clinical study at 5 participating institutions in China.Results： All the 30 patients, including 19 males and 11 females with a median age of 30（range： 18–62） years,completed 128 times of the PEG-ASP, with the median of 4（range： 2–6） times. Patients did not receive radiotherapy at this time. The overall response rate was 86.7%（26/30）, with 50.0%（15/30） complete response and36.7%（11/30） partial response. The 3-year overall survival was 46.0% [95% confidence interval（95% CI）,28.2%–64.8%], and the 3-year progression-free survival was 43.0%（95% CI, 25.7%–62.0%）. Major adverse events were myelosuppression, reduced fibrinogen, liver dysfunction and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded.Conclusions： Our clinical data and observed outcomes indicate that 1 dose of PEG-ASP can replace multiple doses of native L-ASP in BFM-90, with predominantly grade 3–4 neutropenia for adult LBL, and no therapyrelated deaths. The effect is similar to previous reports of PEG-ASP-containing regimens for adult ALL. Major advantages include less serious allergic reactions, 2–3 weeks of action duration, and convenience for patients and physicians.

Genomic landscape of T-cell lymphoblastic lymphoma

Objective: T-cell lymphoblastic lymphoma(T-LBL) is an aggressive neoplasm of precursor T cells, however,detailed genome-wide sequencing of large T-LBL cohorts has not been performed due to its rarity. The purpose of this study was to identify putative driver genes in T-LBL.Methods: To gain insight into the genetic mechanisms of T-LBL development, we performed whole-exome sequencing on 41 paired tumor-normal DNA samples from patients with T-LBL.Results: We identified 32 putative driver genes using whole-exome sequencing in 41 T-LBL cases, many of which have not previously been described in T-LBL, such as Janus kinase 3(JAK3), Janus kinase 1(JAK1), Runtrelated transcription factor 1(RUNX1) and Wilms’ tumor suppressor gene 1(WT1). When comparing the genetic alterations of T-LBL to T-cell acute lymphoblastic leukemia(T-ALL), we found that JAK-STAT and RAS pathway mutations were predominantly observed in T-LBL(58.5% and 34.1%, respectively), whereas Notch and cell cycle signaling pathways mutations were more prevalent in T-ALL. Notably, besides notch receptor 1(NOTCH1), mutational status of plant homeodomain(PHD)-like finger protein 6(PHF6) was identified as another independent factor for good prognosis. Of utmost interest is that co-existence of PHF6 and NOTCH1 mutation status might provide an alternative for early therapeutic stratification in T-LBL.Conclusions: Together, our findings will not only provide new insights into the molecular and genetic mechanisms of T-LBL, but also have tangible implications for clinical practice.

BRD2 induces drug resistance through activation of the RasGRP1/Ras/ERK signaling pathway in adult T-cell lymphoblastic lymphoma

Background:Adult patients with T-cell lymphoblastic lymphoma(T-LBL)are treated with high-intensity chemotherapy regimens,but the response rate is still unsatisfactory because of frequent drug resistance.We aimed to investigate the potential mechanisms of drug resistance in adults with T-LBL.Methods:Gene expression microarray was used to identify differential mRNA expression profiles between chemotherapy-resistant and chemotherapy-sensitive adult T-LBL tissues.Real-time PCR and immunohistochemistry were performed to detect the expression of bromodomain-containing protein 2(BRD2)and c-Myc in fresh-frozen T-LBL tissues from 85 adult patients.The Ras pull-down assay was performed to monitor Ras activation.Chromatin immunoprecipitation assays were used to analyze the binding of E2F transcription factor 1(E2F1)/BRD2 to the RAS guanyl releasing protein 1(RasGRP1)promoter region.The drug resistance effect and mechanism of BRD2 were determined by both in vivo and in vitro studies.Results:A total of 86 chemotherapy resistance-related genes in adult T-LBL were identified by gene expression microarray.Among them,BRD2 was upregulated in chemotherapy-resistant adult T-LBL tissues and associated with worse progressionfree survival and overall survival of 85 adult T-LBL patients.Furthermore,BRD2 suppressed doxorubicin(Dox)-induced cell apoptosis both in vitro and in vivo.The activation of RasGRP1/Ras/ERK signaling might contribute to the Dox resistance effect of BRD2.Besides,OTX015,a bromodomain and extra-terminal(BET)inhibitor,reversed the Dox resistance effect of BRD2.Patient-derived tumor xenograft demonstrated that the sequential use of OTX015 after Dox showed superior therapeutic effects.Conclusions:Our data showed that BRD2 promotes drug resistance in adult T-LBL through the RasGRP1/Ras/ERK signaling pathway.Targeting BRD2 may be a novel strategy to improve the therapeutic efficacy and prolong survival of adults with TLBL.

Comprehensive view on genetic features, therapeutic modalities and prognostic models in adult T-cell lymphoblastic lymphoma

Adult T-cell lymphoblastic lymphoma(T-LBL)is a rare and aggressive subtype of non-Hodgkin’s lymphoma that differs from pediatric T-LBL and has a worse prognosis.Due to its rarity,little is known about the genetic and molecular characteristics,optimal treatment modalities,and prognostic factors of adult T-LBL.Therefore,we summarized the existing studies to comprehensively discuss the above issues in this review.Genetic mutations of NOTCH1/FBXW7,PTEN,RAS,and KMT2D,together with abnormal activation of signaling pathways,such as the JAK-STAT signaling pathway were described.We also discussed the therapeutic modalities.Once diagnosed,adult T-LBL patients should receive intensive or pediatric acute lymphoblastic leukemia regimen and central nervous system prophylaxis as soon as possible,and cranial radiation-free protocols are appropriate.Mediastinal radiotherapy improves clinical outcomes,but adverse events are of concern.Hematopoietic stem cell transplantation may be considered for adult T-LBL patients with high-risk factors or those with relapsed/refractory disease.Besides,several novel prognostic models have been constructed,such as the 5-miRNAs-based classifier,11-gene-based classifier,and 4-CpG-based classifier,which have presented significant prognostic value in adult T-LBL.

Primary lymphoblastic B-cell lymphoma of the stomach:A case report

Primary stomach lymphoblastic B-cell lymphoma (B-LBL) is a rare tumor. We describe a primary stomach B-LBL in a 38 years old female who presented with nonspecific complaints of fatigue and vomiting for 2 mo. Gastrofiberscopy revealed a large gastric ulcer, which was successfully resected. Pathology showed a lymphoblastic cell lymphoma arising from the stomach, and there was no evidence of disease at any extrastomach site. Immunohistochemical staining and gene rearrangement studies supported that the stomach tumor was a clonal B-cell lymphoma. Therefore, the diagnosis of B-LBL was made based on the stomach specimen.

Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma

T-cell lymphoblastic lymphoma(T-LBL)is a highly aggressive non-Hodgkin lymphoma with a poor prognosis.P21-activated kinase(PAK)is a component of the gene expression-based classifier that can predict the prognosis of T-LBL.However,the role of PAK in T-LBL progression and survival remains poorly understood.Herein,we found that the expression of PAK1 was significantly higher in T-LBL cell lines(Jurkat,SUP-T1,and CCRF-CEM)compared to the human T-lymphoid cell line.Moreover,PAK2 mRNA level of 32 relapsed T-LBL patients was significantly higher than that of 37 cases without relapse(P=.012).T-LBL patients with high PAK1 and PAK2 expression had significantly shorter median RFS than those with low PAK1 and PAK2 expression(PAK1,P=.028;PAK2,P=.027;PAK1/2,P=.032).PAK inhibitors,PF3758309(PF)and FRAX597,could suppress the proliferation of T-LBL cells by blocking the G1/S cell cycle phase transition.Besides,PF could enhance the chemosensitivity to doxorubicin in vitro and in vivo.Mechanistically,through western blotting and RNA sequencing,we identified that PF could inhibit the phosphorylation of PAK1/2 and downregulate the expression of cyclin D1,NF-κB and cell adhesion signaling pathways in T-LBL cell lines.These findings suggest that PAK might be associated with T-LBL recurrence and further found that PAK inhibitors could suppress proliferation and enhance chemosensitivity of T-LBL cells treated with doxorubicin.Collectively,our present study underscores the potential therapeutic effect of inhibiting PAK in T-LBL therapy.

Cryptic NUP214-ABL1 fusion with complex karyotype, episomes and intra-tumor genetic heterogeneity in a T-cell lymphoblastic lymphoma

T-lymphoblastic lymphoma(T-LBL)is a rare and aggressive form of non-Hodgkin’s lymphoma and little is known about their molecular background.However,complex karyotypes were already related to this group of malignancy and associated with poor outcome.Here,we describe a 17-year-old female being diagnosed with T-LBL and a normal karyotype after standard G-banding with trypsin-Giemsa(GTG)-banding.However,further analyses including high-resolution molecular approaches,array-comparative genomic hybridization(aCGH),multiplex ligation-dependent probe amplification,fluorescence in situ hybridization and multicolor chromosome banding revealed a cryptic complex karyotype,NUP214-ABL1 gene fusion,episomes and intra-tumor genetic heterogeneity.In addition,homozygous loss of CDKN2A,as well as amplification of oncogene TLX1(HOX11)were detected.Actually,NUP214-ABL1 fusion gene replicated autonomously in this case as episomes.Overall,highly amplification of NUP214-ABL1 fusion gene defines possibly a new subgroup of T-LBL patients which accordingly could benefit from treatment with tyrosine kinase inhibitors.As episomes are missed in standard karyotyping aCGH should be performed routinely in T-LBL to possibly detect more of such cases.

A rare case of giant solitary spinal B cell lymphoblastic lymphoma

Background:Common B cell lymphoma locations are lymph nodes,skin,bone,mediastinum and it accounts for 2 ％ of NHL.Giant solitary spinal B-LBL has not yet been described.Case presentation:A 15-years old boy was admitted for a painful swelling of the thoracolumbar spine and paraplegia.MRI showed a voluminous mass of the thoracolumbar spine.Initial treatment consisted of surgical decompression and stabilization,followed by chemotherapy and radiotherapy.Histological examination showed a B-LBL.The quality of life improved significantly.Conclusion:To the best of our knowledge,this is the first case of giant solitary spinal B-LBL ever reported.Indication to choose a treatment method over another should weigh on individual priorities.Surgery should be considered as initial treatment option in this atypical lesion.

Peripheral Central Venous Catheter Induced Supraventricular Tachycardia in a Patient of Acute Lymphoblastic Leukemia

Central venous catheters (CVCs) are used in intensive care units (and, increasingly, in other locations) to administer intravenous fluids and blood products, drugs, parenteral nutrition, and to monitor haemodynamic status. The risk of complication during the insertion or exchange of central venous catheters has been well documented. The majority of complications involve mechanical problems, although rarely it may induce arrhythmias as well [1]. Herein we present a case of peripheral central venous catheter induced supraventricular tachycardia in a young patient of acute lymphoblastic leukemia.