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This study reported 2-year efficacy and safety of relma-cel in Chinese patients with relapsed/refractory (R/R) B-cell non-Hodgkin's lymphoma (B-NHL). In this phase 1 dose-escalating trial, patients received lymphodepleting chemotherapy for 3 days, followed by relma-cel as a single infusion in escalating dose levels (25 × 10

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BACKGROUND Academic studies have proved that anti-programmed death-1 (PD-1) monoclonal antibodies demonstrated remarkable activity in relapsed/refractory classical Hodgkin lymphoma (cHL). However, most patients ultimately experienced failure or resistance. It is urgent and necessary to develop a novel strategy for relapsed/refractory cHL. The aim of this case report is to evaluate the combination approach of low-dose decitabine plus a PD-1 inhibitor in relapsed/ refractory cHL patients with prior PD-1 inhibitor exposure. CASE SUMMARY The patient was a 27-year-old man who complained of enlarged right-sided cervical lymph nodes and progressive pain aggravation of the right shoulder over the past 3 mo before admission. Histological analysis of lymph node biopsy was suggestive of cHL. The patient experienced failure of eight lines of therapy, including multiple cycles of chemotherapy, PD-1 blockade, and anti-CD47 antibody therapy. Contrast-enhanced CT showed that the tumors of the chest and abdomen significantly shrunk or disappeared after three cycles of treatment with decitabine plus tislelizumab. The patient had been followed for 11.5 mo until March 2, 2021, and no progressive enlargement of the tumor was observed. CONCLUSION The strategy of combining low-dose decitabine with tislelizumab could reverse the resistance to PD-1 inhibitors in patients with heavily pretreated relapsed/ refractory cHL. The therapeutic effect of this strategy needs to be further assessed.

We aimed to assess the association between induction chemotherapy (CT) response and survivals and to explore an induction CT response-adapted treatment strategy for localized extranodal NK/T-cell lymphoma (NKTCL) receiving first-line sequential CT and radiation (RT).We retrospectively reviewed the data of patients with localized NKTCL receiving first-line CT+RT from 2010 to 2020 at two independent institutes (primary cohort,Patients with initial complete remission (CR) had higher final CR rate than the others (99.1% vs. 78.7%,Deep remission from induction CT was associated with favorable survivals in localized NKTCL receiving CT+RT, and an induction CT response-adapted individualized treatment strategy might be recommended in clinical practice.

Background The treatment outcomes and prognosis of lymphoma are affected by various factors such as hospital types. This study was to describe the temporal trend in the survival of lymphoma in an academic center in China. Methods A total of 3840 consecutive patients with lymphoma diagnosed between 1996 and 2015 were reviewed. Eighty patients were excluded, and finally, 3760 patients were analyzed in this study. The cohort was divided into four groups according to calendar periods at diagnosis: 1996‐2000, 2001‐2005, 2006‐2010, and 2010‐2015. The overall survival (OS) rates among the four groups were compared. Results The 5‐ and 10‐year OS for the whole cohort were 62% and 52%, respectively. The 5‐year OS of patient with classic Hodgkin lymphoma (cHL), mature B‐cell lymphoma (BCL), and peripheral T‐cell lymphoma (PTCL) were 79%, 63%, and 50%, respectively. Among mature BCL, the 5‐year OS was highest in follicular lymphoma (77.8%), followed by Burkitt lymphoma (76.5%), marginal zone lymphoma (74.1%), diffuse large B‐cell lymphoma (61.5%), small lymphocytic lymphoma/chronic lymphocytic leukemia (55.1%), and mantle cell lymphoma (44.3%). Among PTCL, the 5‐year OS was highest in ALK+anaplastic large cell lymphoma (79.0%), followed by ALK−anaplastic large cell lymphoma (63.1%), natural killer/T‐cell lymphoma (57.7%), angioimmunoblastic T‐cell lymphoma (34.9%, and peripheral T‐cell lymphoma not otherwise specified (27.6%). Significant improvement in the survival of lymphoma was observed, with the 5‐year OS increasing from 48% in 1996‐2000 to 65% in 2011‐2015 (P, Increase in overall survival of lymphoma from 1996 to 2015.

Classical Hodgkin lymphoma (cHL) has been identified with universal genetic alterations of chromosome 9p24.1, which contains PD-L1/PD-L2 genes. The amplification of 9p24.1 is associated with the increased expression of PD-L1 and PD-L2 on RS cells, which promotes their immune evasion, and subsequently makes cHL sensitive to PD-1 blockade. Several PD-1 inhibitors have shown significant efficacies with overall response rate (ORR) of 70%-90% in relapse/refractory (r/r) cHL and have acquired the approvals for this indication. Recently, more and more studies are conducted to investigate PD-1 blockade in earlier disease course and in combination with neo-agents or chemotherapy. Unlike cHL, non-Hodgkin lymphoma (NHL) consists of numerous subtypes harboring highly biological heterogeneity. Only a few subtypes have been shown to have genetic alteration of9p24.1 including primary mediastinal B cell lymphoma (PMBL), gray zone lymphoma (GZL) with features intermediate between diffuse large B cell lymphoma (DLBCL) and cHL, primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL). Epstein-Barr virus (EBV)-associated lymphomas have a virally mediated overexpression of PD-L1, also making them sensitive to PD-1 blockade. Therefore, PD-1 inhibitors are less effective in most r/r NHL than in r/r cHL. Further understanding of the biological features of NHL and immune checkpoint inhibitors (ICPi) combined therapy is the research focus in the future. In this review, we outlined the recent progress of ICPi in lymphoma originating from clinical studies.

CD19-targeted chimeric antigen receptor-T (CAR-T) cells with CD28 or 4-1BB (28z CAR-T and BBz CAR-T) have shown great promise to treat relapsed or refractory (r/r) B cell non-Hodgkin’s lymphoma (B-NHL). However, comparison of their clinical outcomes has never been reported. This study investigated their efficacy and adverse events in B-NHL therapy. Six patients with r/r B-NHL were initially enrolled and infused with 28z or BBz CAR-T cells at a dose of 0.75–5 × 105/kg. These CAR-T cells showed similar antitumor efficacies, with a complete response (CR) rate of 67% within 3 months. BBz CAR-T was well tolerated. However, severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in the 28z CAR-T cohort, resulting in the termination of further evaluation of 28z CAR-T. Three more patients were enrolled to investigate BBz CAR-T cells in-depth at an escalated dose (1 × 106/kg). All cases achieved CR within 3 months, and only grade 1/2 adverse events occurred. This study suggests that 4-1BB is more beneficial for the clinical performance of CAR-T cells than CD28 in CD19-targeted B-NHL therapy, at least under our manufacturing process., Graphical Abstract

BackgroundThe optimal first-line treatment for extra-nodal NK/T-cell lymphoma (ENKTL) has not been well-defined. This study aimed to evaluate the efficacy and safety of pegaspargase, cyclophosphamide, vincristine, etoposide and prednisone (COEPL) regimen combined with radiotherapy for patients with newly diagnosed ENKTL.MethodsOur study is a prospective, open-label clinical trial. Patients with newly diagnosed ENKTL and an ECOG performance status of 0 to 2 were eligible for enrollment. For patients with stage I/II nasal ENKTL, treatment included 2 cycles of induction COEPL regimen followed by concurrent chemoradiotherapy, then by 2 cycles of COEPL regimen as consolidation. For patients with stage III/IV or primary extra-nasal ENKTL, treatment included 6-8 cycles of COEPL regimen with or without radiotherapy to local sites, and autologous stem cell transplantation was given in selected patients.ResultsA total of 80 patients were enrolled. The median age was 41 years (range, 15-76 years). Sixteen patients (20%) had stage III/IV disease, and 10 (12.5%) had a PINK score≥2. Complete response and overall response rates were 75.9% and 87.3%, respectively. With a median follow-up of 41.4 months (range 2.7-76.2 months), the 3-year progression-free survival (PFS) and overall survival (OS) rates were 71.3% (95%CI 61.1-81.5%) and 73.3% (95%CI 63.1-83.5%), respectively. For patients with stage I/II nasal ENKTL (n=62), the 3-year PFS and OS were 78.1% and 81.2%, respectively. For patients with stage III/IV or primary extra-nasal ENKTL (n=18), 3-year PFS and OS were 48.1% and 45.7%, respectively. Major grade 3-4 adverse events were anemia (21.3%), leucopenia (22.5%), neutropenia (18.8%), and thrombocytopenia (7.6%). No treatment-related death was observed.ConclusionsPegaspargase-COEP chemotherapy in combination with radiotherapy is highly effective and safe for patients with newly diagnosed ENKTL.

Backgroud : CD19-directed chimeric antigen receptor T (CAR-T) cell therapy has shown great promise for cure of relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL). Previous studies reported that 4-1BB-based CD19 CAR-T was more beneficial for the clinical outcomes than CD28-based CAR-T, especially lower rates of severe adverse events. However, the median progression-free survival (mPFS) of 4-1BB-based product Kymriah was shorter than that of the CD28-based Yescarta (2.9 v.s. 5.9 months), suggesting that the long-term effectiveness of Kymriah was limited. Thus, a safe and durable 4-1BB-based CD19 CAR-T needs to be developed. Methods Here we presented a CD19 CAR-T (named IM19) with FMC63 scFv, 4-1BB and CD3ζ intracellular domain, which was manufactured into a memory T-enriched formulation and launched a clinical trial for treatemt of r/r B-NHL. The clinical outcomes of IM19 were evaluated in 22 r/r B-NHL patients in a Phase I/II trial with dose-escalation investigation (5×105, 1×106 and 3×106/kg). Results All patients received a single infusion of IM19 after 3-day conditional regimen. Cytokine release syndrome (CRS) occurred in 13 patients (59%), with 54.5% of grade 1–2 and 4.5% of grade 3, whereas Kymriah led to 22% of > grade 3 CRS. Only one patient showed > grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS). At 6 months, the overall response rate was 47.62%, and the complete response rate was 42.86%. The mPFS of IM19 achieved 9 months and the 1-year overall survival rate was 78%. Conclusions These results demonstrated the safety and durable efficacy of IM19 with FMC63 scFv, 4-1BB and CD3ζ intracellular domain, that is promising for further development and clinical investigation. Trial registration : The registration date of the clinical trial is May 17, 2018(17/05/2018) and the trial registration numbers is NCT03528421.

Background Extranodal natural killer (NK) cell/T-cell lymphoma (NKTCL), a rare type of non-Hodgkin's lymphoma, has strongly been associated with Epstein-Barr virus (EBV) infection. However, there are no EBV genomes isolated from NKTCL, and the roles the variations of EBV strains play in the pathogenesis of NKTCL are still unclear. Materials and Methods In this study, whole EBV genomes from eight primary NKTCL biopsy specimens were obtained using next-generation sequencing, designated NKTCL-EBV1 to NKTCL-EBV8. Results Compared with the six mostly referenced EBV strains, NKTCL-EBVs closely resemble the GD1 strain but still harbor 2,072 variations, including 1,938 substitutions, 58 insertions, and 76 deletions. The majority of nonsynonymous mutations were located in latent and tegument genes. Moreover, the results from phylogenetic analysis of whole NKTCL genomes and specific genes demonstrated that all the NKTCL-EBVs were related to Asian EBV strains. Based on the amino acid changes in certain residues of latent membrane protein 1 (LMP1) and EBV-determined nuclear antigen 1 (EBNA1), all the NKTCL-EBVs were sorted to China 1 and V-val subtype, respectively. Furthermore, changes in CD4+ and CD8+ T-cell epitopes of EBNA1 and LMP1 may affect the efficacy for a cytotoxic T lymphocyte (CTL)-based therapy. Conclusion This is the first large study to our knowledge to obtain EBV genomes isolated from NKTCL and show the diversity of EBV genomes in a whole genome level by phylogenetic analysis. Implications for Practice In this study, the full-length sequence of Epstein-Barr virus (EBV) isolated from eight patients with nasal natural killer/T-cell lymphoma (NKTCL) was determined and further compared with the sequences previously reported isolated from other malignancies. Phylogenetic analysis showed that NKTCL-EBV strains are close to other Asian subtypes instead of non-Asian ones, leading to the conclusion that EBV infections are more likely affected by different geographic regions rather than particular EBV-associated malignancies. Therefore, these data have implications for the development of effective prophylactic and therapeutic vaccine approaches targeting the personalized or geographic-specific EBV antigens in these aggressive diseases.

e19531 Background: Immune checkpoint inhibitors (ICIs) showed strong activity and tolerable toxicity in those patients with relapsed or refractory classical Hodgkin lymphoma. However, there was limited data on the long-term survival outcome of those patients after remission due to ICIs treatment. Methods: The data was collected from 4 pivotal phase 2 clinical trials: AK105-201 (penpulimab, NCT03722147), BGB-A317 (tislelizumab, NCT03209973), SHR-1210 (camrelizumab, NCT03155425), GLS-010 (zimberelimab, NCT03655483). The key inclusion criteria included age ≥18 years, relapsed or refractory classical Hodgkin lymphoma, lines of prior chemotherapy ≥ 2, treated with ICIs monotherapy, achieving complete remission (CR) or partial remission (PR). The progression-free survival (PFS) and overall survival (OS) were estimated from the time of registration. Results: Among 324 screened patients, 260 patients (140 with CR, 120 with PR) were enrolled. The median age was 32 years with a male/female ratio of 1.3:1. The median lines of prior chemotherapy was 3 (range, 2-11). Additionally, 184 patients had refractory disease, and 54 patients received autologous stem cell transplantation (n = 45) or brentuximab vedotin (n = 9). With a median follow-up period of 31.1 months, 116 (44.6%) patients underwent disease progression and 18 (6.9%) patients died. The 3-year PFS and OS rates of 55.1% and 89.7% for all patients, respectively. Compared with those with CR, patients with PR had inferior survival outcome (3-year PFS, 29.5% vs. 72.3%, P < 0.001; 3-year OS, 81.5% vs. 94.4%, P = 0.017). In terms of duration of treatment, the 3-year PFS and OS rates were 28.6% and 71.6%, and 74.5% and 98.5% for patients with duration of treatment < 24 and > 24 month, respectively ( P values were both < 0.001). Among patients with CR, longer duration of treatment (> 24 month) remained positive impact on the survival outcome (3-year PFS, 81.3% vs. 47.1%, P < 0.001; 3-year OS, 98.1% vs. 82.9%, P < 0.001). Conclusions: Deeper remission and longer duration and led to favorable survival outcome for patients with relapsed or refractory classical Hodgkin lymphoma who achieved remission during ICIs treatment.

Background The unprecedented efficacy of chimeric antigen receptor T (CAR-T) cell immunotherapy of CD19+ B-cell malignancies has opened a new and useful way for the treatment of malignant tumors. Nonetheless, there are still formidable challenges in the field of CAR-T cell therapy, such as the biodistribution of CAR-T cells in vivo. Methods NALM-6, a human B-cell acute lymphoblastic leukemia (B-ALL) cell line, was used as target cells. CAR-T cells were injected into a mice model with or without target cells. Then we measured the distribution of CAR-T cells in mice. In addition, an exploratory clinical trial was conducted in 13 r/r B-cell non-Hodgkin lymphoma (B-NHL) patients, who received CAR-T cell infusion. The dynamic changes in patient blood parameters over time after infusion were detected by qPCR and flow cytometry. Results CAR-T cells still proliferated over time after being infused into the mice without target cells within 2 weeks. However, CAR-T cells did not increase significantly in the presence of target cells within 2 weeks after infusion, but expanded at week 6. In the clinical trial, we found that CAR-T cells peaked at 7–21 days after infusion and lasted for 420 days in peripheral blood of patients. Simultaneously, mild side effects were observed, which could be effectively controlled within 2 months in these patients. Conclusions CAR-T cells can expand themselves with or without target cells in mice, and persist for a long time in NHL patients without serious side effects. Trial registration The registration date of the clinical trial is May 17, 2018 and the trial registration numbers is NCT03528421.

Background GLS-010 (zimberelimab) is a novel, fully human, anti-programmed death-1 monoclonal antibody that shows promising efficacy and safety in advanced solid tumors. This trial aimed to evaluate the efficacy and safety of GLS-010 (zimberelimab) in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r-cHL). Methods This phase II, single-arm, open-label, multicenter clinical trial was conducted at 24 centers in China and enrolled patients with r/r-cHL after two or more lines of therapy. The patients were administered intravenous GLS-010 (zimberelimab) (240 mg, once every 2 weeks) until progression, death, unacceptable toxicity, or consent withdrawal. The primary end-point was the objective response rate assessed by an independent radiology review committee (IRC). This study was registered (NCT03655483). Results Eighty-five patients were enrolled between August 2018 and August 2019. The median follow-up was 15.8 months. Seventy-seven patients (90.6%; 95% confidence interval [CI] 82.3–95.9) had an IRC-assessed objective response. The complete response rate was 32.9% (n = 28). The 12-month progression-free survival and overall survival rates were 78% (95% CI 67.5–85.6) and 99% (95% CI 91.9–99.8), respectively. Treatment-related adverse events (TRAEs) were observed in 92.9% of participants. Grade III or IV TRAEs occurred in 24 (28.2%) of the 85 participants. The most common grade III or IV TRAEs were abnormal hepatic function (5.9%), hyperuricemia (4.7%), decreased neutrophil count (3.5%), and increased weight (3.5%). Only one grade V AE, gastrointestinal infection, occurred. Conclusions GLS-010 (zimberelimab) appears to be effective and safe for the treatment of Chinese patients with r/r-cHL. Long-term follow-up is required to confirm these clinical benefits.

Additional file 1: Table 1. Distribution of CAR-T cells in NCG mice. Table 2. Tissue distribution parameters in NCG mice. Table 3. Distribution of CAR-T cells in tumor-bearing NCG mice. Table 4. Changes of CAR-T cells in the blood of patients over time. Table 5. CAR-T peak in the blood of patients during the therapy. Table 6. Sequences of primers and probes for CAR-T detection

Targeting T cell receptor β-chain constant region 1 (TRBC1) CAR-T could specifically kill TRBC1+ T-cell malignancies. However, over-expressed CARs on anti-TRBC1 CAR transduced TRBC1+ T cells (CAR-C1) bound to autologous TRBC1, masking TRBC1 from identification by other anti-TRBC1 CAR-T, and moreover only the remaining unoccupied CARs recognized TRBC1+ cells, considerably reducing therapeutic potency of CAR-C1. In addition, co-culture of anti-TRBC1 CAR-T and TRBC1+ cells could promote exhaustion and terminal differentiation of CAR-T. These findings provide a rationale for pre-depleting TRBC1+ T cells before anti-TRBC1 CAR-T manufacturing. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-020-01282-7.

Backgroud: The unprecedented efficacy of chimeric antigen receptor (CAR) T-cell immunotherapy of CD19+ B-cell malignancies has opened a new and useful way for the treatment of malignant tumor. Nonetheless, there are still formidable challenges in the field of CAR-T cell therapy, such as the biodistribution of CAR-T cells in vivo.Methods: We demonstrated the distribution of CAR-T cells in the absence of target cells or with target cells in the mice and the dynamic changes in the patient blood over time after infusion were deteced by qPCR and FACS. Results: CAR-T cells still proliferated in the mice without target cells and peaked at 2 weeks. However, CAR-T cells did not increase significantly in the presence of target cells within 2 weeks after infusion, but expanded at 6 weeks. In the clinical trial, we found that CAR-T cells peaked at 7-21days after infusion and can last for as long as 510 days in the peripheral blood of patients. Simultaneously, mild side-effects were noted which can be effectively controlled within two months in these patients.Conclusions: CAR-T cells can expand themselves with or without target cells in mice. CAR-T cells can persistence for a long time in patients.

Patients with advanced-stage natural killer/T-cell lymphoma (NKTCL) usually have a poor prognosis. However, there is limited data of comprehensive analysis on this particular patient population due to the rarity of the disease. The present study aimed to investigate the treatment models, survival outcomes, and prognosis of advanced-stage NKTCL. Data from 336 patients with advanced-stage NKTCL diagnosed between 2006 and 2015 in the China Lymphoma Collaborative Group database were retrospectively analyzed. The median age was 42 years and the male/female ratio was 2.4:1. About 97% of patients had stage IV disease and 77% had >1 extranodal involvement site. All patients received chemotherapy, with the most common option being asparaginase (Asp)-containing regimens (n=146; 43.5%). Among 286 patients with available response data, the overall response rate (ORR) was 57.3% with a complete remission (CR) rate of 35.7%. Asp-containing regimens led to better ORRs (86/132, 65.2% vs. 54/113, 47.8%, P = 0.006) and CR rates (60/132, 45.5% vs. 27/113, 23.9%, P < 0.001) than non-Asp-containing regimens. The expected 5-year progression-free survival (PFS) and overall survival (OS) rates were 22.6 and 32.0%, respectively, for the whole cohort. Compared to non-Asp-containing chemotherapy, Asp-containing chemotherapy improved 5-year PFS (34.2 vs. 17.1%, P < 0.001) and OS (45.3 vs. 27.8%, P < 0.001). A trend toward improvement in OS was observed when gemcitabine was added to Asp-containing chemotherapies. Moreover, those undergoing autologous hematopoietic stem cell transplantation had prolonged survival time. In conclusion, Asp-containing chemotherapy could improve the prognosis of advanced-stage NKTCL, and refinement of treatment models is warranted in the future.

Additional file 1.

Background: Few studies have focused on risk stratification and adapted therapy for advanced-stage natural killer/T-cell lymphoma (NKTCL). Methods: This retrospective study evaluated 406 patients with advanced-stage NKTCL who were treated at 20 Chinese institutions. A model for predicting overall survival (OS) was developed using multivariate analysis of data from a South China cohort (n=198), and validation was performed using a North China cohort (n=208). The prognostic model was also used to evaluate the survival benefits of different chemotherapy regimens. Findings: The median age was 42 years and the male/female ratio was 2.5:1. All patients received chemotherapy, with the most common option being asparaginase (Asp)-containing regimens (n = 149; 36.7%). The expected 3-year OS rate was 37.3%. The prognostic model (advanced-stage NKTCL prognostic index, ASPRIN) was based on Eastern Cooperative Oncology Group performance status >1, elevated lactate dehydrogenase and solid organ involvement. The expected 3-year OS rates in the primary cohort were 54.8% for low-risk cases (no risk factors), 34.4% for intermediate-risk cases (1 risk factor), and 13.8% for high-risk cases (2–3 risk factors). Similar results were observed in the validation cohort. After matching according to ASPRIN scores, Asp-containing chemotherapy provided an approximately 12% increase in the expected 3-year OS rate, relative to non-Asp-containing chemotherapy. However, the inclusion of additional cytotoxic agents did not enhance the survival benefit provided by Asp-containing chemotherapy. Interpretation: The ASPRIN model was effective for stratifying the prognosis of advanced-stage NKTCL, which may help improve our understanding of the existing chemotherapy regimens. More effective risk-adapted therapeutic strategies are also needed. Funding Statement: This study was supported by the Capital’s Funds for Health Improvement and Research (grant no. 2018- 1-2151). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study’s retrospective protocol was approved by the participating centers’ institutional review boards and complied with the Declaration of Helsinki. The requirement for informed consent was waived based on the use of a deidentified data set.

The combination of chemotherapy and L-asparaginase (L-ASP) treatment significantly increased survival rate in an adult patient with extranodal natural killer (NK)/T-cell lymphoma (NKTCL). However, hypersensitivity reactions of L-ASP in some patients limited its application. Polyethylene glycol-conjugated asparaginase (PEG-ASP) has a lower immunogenicity and longer circulating half-life than unconjugated L-ASP, and has been reported to be effective and well-tolerated in children with acute lymphoblastic leukemia. Cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine), and prednisolone (CHOP) is the most common chemotherapy for non-Hodgkin lymphoma. In this report, we sought to study the efficacy and safety of PEG-L- CHOP in NKTCL in adult Chinese patients. Our study is a prospective, multi-center, open-label clinical trial. Patients with newly diagnosed adult NKTCL and an ECOG performance status of 0 to 2 were eligible for enrollment. Treatment included six cycles of PEG-L-CHOP regimen. Radiotherapy was scheduled after 2–4 cycles of PEG-L-CHOP regimen, depending on the stage and primary anatomic site. We enrolled a total of 33 eligible patients. All 33 patients completed 170 cycles of chemotherapy combined with radical radiotherapy. The overall response rate was 96.9% (32/33) with 75.8% (25/33) achieving complete responses and 21.2% (7/33) achieving partial responses. The overall survival (OS) at 1, 2, 3-year were 100, 90.61 and 80.54%, respectively. The major adverse effects were bone marrow suppression, reduction of fibrinogen level, liver dysfunction, and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded. PEG-L-CHOP chemotherapy in combination radiotherapy is safe and durably effective treatment for adult extranodal NK/T-cell lymphoma with fewer allergic reactions. This study was approved by the Peking University Beijing Cancer Hospital Ethics Review Committee (reference number: 2011101104). The clinical trial registration number ChiCTR1800016940 was registered on July 07, 2018 at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx ). The clinical trial was registered retrospectively.

Background: For peripheral T-cell lymphomas (PTCLs) patients, high-dose therapy combined with autologous peripheral blood stem cell transplantation (HDT/ASCT) has been an alternative treatment option, due to the lack of efficacy from conventional chemotherapy. While not all PTCLs could have benefit in survival from HDT/ASCT. The aim of this study was to evaluate the value of high-dose therapy combined with autologous peripheral blood stem cell transplantation (HDT/ASCT) in Chinese patients with Peripheral T-cell Lymphomas (PTCLs), in order to determine the cohort most suitable to receive HDT/ASCT. Methods: A total of 79 patients with PTCLs who received HDT/ASCT in Peking University Cancer Hospital & Institute from January 2001 to august 2016 were retrospectively analyzed. Results: At a median follow-up time of 23.6 months, the 2-year progression-free survival (PFS) and 2-year overall survival (OS) of the entire cohort were 75.2% and 83.6% respectively. Patients with first complete remission (CR1) (2-year PFS 85.8%, 2-year OS 94.2%) were superior to others in survival. Patients with second complete remission (CR2) had no advantage in survival compared with those with first partial remission (PR1) (2-year PFS: 43.8% vs. 76.2%, p=0.128; 2-year OS: 72.9% vs. 77.1%, p=0.842). In multivariate analysis, response before HDT/ASCT (p=0.001) and LDH before HDT/ASCT (p=0.047) were highly predictive for PFS, while no factors could independently predict OS. Subgroup analysis revealed that HDT/ASCT could improve the survival of patients with angioimmunoblastic T-cell lymphoma (AITL), especially in patients with chemosensitivity. Patients with natural killer / T-cell lymphoma (NKTCL) who received HDT/ASCT with CR1 also had benefit in survival from HDT/ASCT, while nearly 90% of non-CR1 patients appeared bone marrow involvement after HDT/ASCT. Conclusion: Patients who achieved complete remission after first-line therapy, especially with AITL and NKTCL, should strongly be recommended to receive HDT/ASCT. The future prospective trial is warranted.

Background: Diagnosis of central nervous system (CNS) lymphoma remains a challenge. This study aimed to identify cerebrospinal fluid (CSF) proteins that distinguish patients with and without CNS lymphoma. Methods: We used one-dimensional SDS-polyacrylamide gel electrophoresis coupled with liquid chromatography- electrospray ionization-quadrupole-time of flight-mass spectrometry (LC-ESI-Q-TOF MS) to identify CSF proteins in CNS diffuse large B cell lymphoma (DLBCL) patients and controls. Results: Approximately 166 CSF proteins were identified, 12 for the first time in the CSF of lymphoma patients. Three proteins with significantly increased expression in CNS lymphoma patients compared with controls - haemopexin, apolipoprotein A1, and transferrin were verified by immunohistochemistry, and found to be strongly expressed in CNS DLBCL and nodal DLBCL. These proteins were found to be localized in the cytoplasm of a human DLBCL cell line by indirect immunofluorescence. ELISA confirmed expression at higher concentrations in the CSF of CNS lymphoma patients. CSF haemopexin, apolipoprotein A1, and transferrin concentrations were detected in CNS lymphoma patients and had diagnostic sensitivities of 80%, 83%, and 70%, and specificities of 75%, 89%, and 90%, respectively. Conclusion: Our study suggests that CSF proteins may be potential diagnostic biomarker for CNS lymphoma, especially for patients in which imaging and cytology do not provide a clear diagnosis.

Objective High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) is the standard of care in the upfront or relapsed/refractory setting in some patients with non-Hodgkin lymphoma (NHL). However, a proportion of patients do not respond to ASCT. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been widely used for staging, response evaluation, and prognosis prediction. Here, we investigated the prognostic role of PET/CT in NHL patients before and after ASCT. Methods A retrospective study was conducted at Peking University Cancer Hospital. All NHL patients who underwent ASCT between March 2010 and July 2016 were identified. Patients who had PET/CT scan before and after ASCT were included. Deauville criteria (5-point scale) were used to interpret PET scans. Univariate and multivariate survival analyses were performed using Cox regression. The predictive value of PET scanning was estimated by comparing the area under the receiver operating characteristic (ROC) curve. Results In total, 79 patients were enrolled in this study. In univariate analysis, pre- and post-ASCT PET result was identified as prognostic factors for 3-year progression-free survival (PFS) and overall survival (OS). Patients with negative pre-ASCT PET result demonstrated significantly better PFS (84.2% vs. 54.2%) and OS (89.2% vs. 63.6%) than patients with positive pre-ASCT PET result. PFS (91.6% vs. 25.3%) and OS (96.5% vs. 36.8%) were also significantly different between patients with negative and positive post-ASCT PET result. Multivariate analysis also showed a significant association between survival and post-ASCT PET result. ROC analysis revealed that the predictive value of post-ASCT PET result was superior to that of pre-ASCT PET result alone. Combined pre- and post-ASCT PET result is better for predicting outcomes in patients with NHL receiving transplantation. Deauville criteria score >3 was identified as the best cutoff value for post-ASCT PET. Conclusions Post-ASCT PET result was more important than pre-ASCT PET result in predicting outcomes for NHL patients who underwent ASCT. The prognostic significance can be improved when combining pre-ASCT PET result with post-ASCT PET result. Deauville criteria can be used for interpreting PET scans in this scenario.

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 (PEG-ASP) 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-90 regimen (PEG-ASP-BFM-90) for adult LBL. Methods Between June 2012 and July 2015, we treated 30 adult patients with newly diagnosed LBL, using PEG-ASP-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 and 36.7% (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 therapy-related 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.

Objective High-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) plays an important role in improving outcomes of diffuse large B cell lymphoma (DLBCL) patients. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) has been widely accepted in response assessment and prediction of prognosis in DLBCL. Here, we report the value of 18F-FDG PET/CT pre- and post-HSCT in predicting outcomes of patients with DLBCL. Methods DLBCL patients who had PET/CT scan before and after HSCT were included. PET results were interpreted based upon Deauville criteria. The prognostic value of 18F-FDG PET/CT in auto-HSCT was evaluated. Results Eighty-four patients were enrolled. In univariate analysis, pre- and post-HSCT PET findings were correlated with 3-year progression-free survival (PFS) [hazard ratio (HR)=4.391, P=0.001; HR=7.607, P

Background Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma and associated with poor outcomes. The activation status of T cell receptor (TCR) signaling has recently become a focus of attention in terms of the therapeutic targets. However, the molecular pathogenesis mechanisms and novel therapeutic targets are largely unknown. Methods Antibodies specific to phosphorylated ZAP70, ITK and PLCγ1 were used to identify the activation status of intracellular proteins involved in TCR signaling in AITL patients. Malignant T cell lymphoma cells were transduced with a lentiviral construct containing ITK shRNA for cellular and functional assays. The antitumor effects of the selective ITK inhibitor BMS-509744 were determined in vitro and in vivo. Results Immunohistochemistry staining showed that more than half of the AITL patients (n = 38) exhibited continuously activated intracellular TCR signaling pathway. Patients positive for phosphorylated ITK showed a lower rate of complete response (20% vs. 75%, P = 0.004) and a shorter progression-free survival (5.17 months vs. 25.1 months, P = 0.022) than patients negative for phosphorylated ITK. Genetic and pharmacological cellular ITK inhibition significantly compromised the proliferation, invasion and migration of malignant T cells. The selective ITK inhibitor BMS-509744 also induced the pro-apoptotic effects and G2/M phase cell cycle arrest in vitro and in vivo. Finally, inhibition of ITK synergistically enhanced the antitumor effect of vincristine and doxorubicin on malignant T cell lymphoma cell lines. Conclusions Our findings suggest that ITK may be a novel candidate therapeutic target for the treatment of patients with ITK-expressing malignant T-cell lymphomas. Electronic supplementary material The online version of this article (10.1186/s12935-019-0754-9) contains supplementary material, which is available to authorized users.