Camrelizumab plus gemcitabine and oxaliplatin for relapsed or refractory classical Hodgkin lymphoma: a phase II trial.

BACKGROUND: Classical Hodgkin lymphoma (cHL) is a highly curable disease, while novel therapy is needed for refractory or relapsed (R/R) patients. This phase II trial aimed to evaluate the role of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in R/R cHL patients. METHODS: Transplant-eligible patients with R/R cHL were enrolled and received two 14-day cycles of camrelizumab 200 mg intravenously (IV) and two 28-day cycles of camrelizumab 200 mg IV, gemcitabine 1000 mg/m2 IV, and oxaliplatin 100 mg/m2 IV on days 1 and 15. Patients with partial response (PR) or stable disease received an additional cycle of combination therapy. Those who achieved complete response (CR) or PR proceeded to autologous stem cell transplantation (ASCT). The primary endpoint was the CR rate at the end of protocol therapy before ASCT. RESULTS: Forty-two patients were enrolled. At the end of protocol therapy, the objective response rate and CR rate were 94.9% (37/39) and 69.2% (27/39) in the evaluable set, and 88.1% (37/42) and 64.3% (27/42) in the full analysis set, respectively. Twenty-nine patients (69.0%) proceeded to ASCT, and 4 of 5 patients with PR achieved CR after ASCT. After a median follow-up of 20.7 months, the 12-month progression-free survival rate was 96.6% and the 12-month overall survival rate was 100%. Grade 3 or higher treatment emergent adverse events occurred in 28.6% of patients (12/42), mainly hematological toxicity. CONCLUSIONS: Camrelizumab combined with GEMOX constitutes an effective salvage therapy for R/R cHL, proving to be relatively well-tolerated and facilitating ASCT in most patients, thus promoting sustained remission. TRIAL REGISTRATION: ClinicalTrials.gov NCT04239170. Registered on January 1, 2020.

Immunotyping of peripheral blood lymphocytes by flow cytometry reveals Th cell as a potential prognostic biomarker for extranodal NK/T-cell lymphoma.

This study aimed to explore the distribution, characteristics and prognostic value of baseline peripheral blood lymphocyte subsets in patients with extranodal NK/T-cell lymphoma (NKTCL). We conducted this cross-sectional study of 205 newly-diagnosed NKTCL patients receiving first-line chemotherapy and radiation at our institute between 2010 and 2020. Baseline peripheral blood lymphocytes were detected using flow cytometry, and the clinical value was analyzed. Compared with healthy controls, patients with NKTCL presented with a distinct peripheral immunity with higher levels of cytotoxic CD8+ T cells (33.230 ± 12.090% vs. 27.060 ± 4.010%, p < 0.001) and NKT cells (7.697 ± 7.219% vs. 3.550 ± 2.088%, p < 0.001) but lower proportions of suppressive regulatory T cells (Treg, 2.999 ± 1.949% vs. 3.420 ± 1.051%, p = 0.003) and CD4+ helper T cells (Th, 33.084 ± 11.361% vs. 37.650 ± 3.153%, p < 0.001). Peripheral lymphocytes were differentially distributed according to age, stage, and primary site in patients with NKTCL. The proportion of Th cells/lymphocytes was associated with tumor burden reflected by stage (p = 0.037), serum lactate dehydrogenase (p = 0.0420), primary tumor invasion (p = 0.025), and prognostic index for NK/T-cell lymphoma (PINK) score (p = 0.041). Furthermore, elevated proportions of T cells (58.9% vs. 76.4%, p = 0.005), Th cells (56.3% vs. 68.8%, p = 0.047), or Treg cells (49.5% vs. 68.9%, p = 0.040) were associated with inferior 5-year progression-free survivals (PFS) via univariable survival analysis. Multivariate cox regression revealed elevated Th cells as an independent predictor for unfavorable PFS (HR = 2.333, 95% CI, 1.030-5.288, p = 0.042) in NKTCL. These results suggested the proportion of Th cells positively correlated with tumor burden and was a potential non-invasive biomarker for inferior survival for patients with NKTCL.

Up-front autologous hematopoietic stem cell transplantation after first complete remission improved prognosis of advanced extra-nodal NKT cell lymphoma: A multicenter real-world study in China.

OBJECTIVES: The advanced extra-nodal NK/T-cell lymphoma (ENKTL) is highly aggressive and lacks effective treatment with a poor prognosis. This study aimed to investigate the effectiveness and safety of autologous hematopoietic stem cell transplantation (ASCT) in CR1. METHODS: Forty of 121 patients with advanced ENKTL from four Chinese hospitals between January 2006 to December 2021 who achieved first complete remission (CR1) and received at least 4 cycles chemotherapy, were enrolled for analysis. Twenty patients received ASCT as up-front consolidation therapy (Group A), and 20 patients only received chemotherapy (Group B). Clinical features, treatment and follow-up information were collected. RESULTS: With a median follow-up of 27 months (range, 4-188 months), the 2-year overall survival (OS) in Group A, 61% (95% CI 37%-85%), was better than that in Group B, 26% (95% CI 2%-50%), p = .018. The 2-year progression-free survival (PFS) was 56% (95% CI 32%-80%) in Group A, 26% (95% CI 2%-50%) in Group B, p = .026. III-IV grade hematological toxicity was the most common adverse event. No treatment-related deaths were observed in both groups. CONCLUSION: Up-front ASCT could improve survival of advanced ENKTL patients in first complete remission, but need be confirmed by a prospective clinical trial.

A durable 4-1BB-based CD19 CAR-T cell for treatment of relapsed or refractory non-Hodgkin lymphoma.

Objective: Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor (CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells, especially the lower incidence rate of severe adverse events. However, the median progression-free survival (mPFS) of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta (2.9 monthsvs. 5.9 months), suggesting that Kymriah was limited in the long-term efficacy. Thus, a safe and durable 4-1BB-based CD19 CAR-T needs to be developed. Methods: We designed a CD19-targeted CAR-T (named as IM19) which consisted of an FMC63 scFv, 4-1BB and CD3ζ intracellular domain and was manufactured into a memory T-enriched formulation. A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory (r/r) B cell non-Hodgkin lymphoma (B-NHL). Dose-escalation investigation (at a dose of 5×105/kg, 1×106/kg and 3×106/kg) was performed in 22 r/r B-NHL patients. All patients received a single infusion of IM19 after 3-day conditional regimen. Results: At month 3, the overall response rate (ORR) was 59.1%, the complete response rate (CRR) was 50.0%. The mPFS was 6 months and the 1-year overall survival rate was 77.8%. Cytokine release syndrome (CRS) occurred in 13 patients (59.1%), with 54.5% of grade 1-2 CRS. Only one patient (4.5%) experienced grade 3 CRS and grade 3 neurotoxicity. Conclusions: These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T, IM19, which is promising for further development and clinical investigation.

Distribution of chimeric antigen receptor-modified T cells against CD19 in B-cell malignancies.

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 .

Pre-depletion of TRBC1+ T cells promotes the therapeutic efficacy of anti-TRBC1 CAR-T for T-cell malignancies.

Targeting T cell receptor ß-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.

Immune checkpoint inhibitors in malignant lymphoma: Advances and perspectives.

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.

Genome-Wide Analysis of Epstein-Barr Virus Isolated from Extranodal NK/T-Cell Lymphoma, Nasal Type.

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.

ITK inhibition induced in vitro and in vivo anti-tumor activity through downregulating TCR signaling pathway in malignant T cell lymphoma.

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.

Prognostic value of 18F-fluorodeoxyglucose positron emission tomography using Deauville criteria in diffuse large B cell lymphoma treated with autologous hematopoietic stem cell transplantation.

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<0.001] and overall survival (OS) (HR=4.792, P=0.008; HR=26.138, P<0.001). Patients receiving upfront auto-HSCT after first-line treatment had better outcomes than relapsed/refractory DLBCL patients (3-year PFS, P<0.001; 3-year OS, P<0.001). In the relapsed/refractory patients, pre- and post-HSCT PET findings were also associated with 3-year PFS (P=0.003vs. P<0.001) and OS (P=0.027vs. P<0.001). A significant correlation was observed between clinical response to chemotherapy before auto-HSCT and outcomes of patients in the entire cohort (3-year PFS, P<0.001; 3-year OS, P<0.001) and in the subgroup of 21 patients with positive pre-HSCT PET (3-year PFS, P=0.084; 3-year OS, P=0.240). A significant association between survival and post-HSCT PET findings was observed in multivariate analysis (HR=5.168, P<0.001). CONCLUSIONS: PET results before and after HSCT are useful prognostic factors for DLBCL patients receiving HSCT. Patients who responded to chemotherapy, even those with positive pre-HSCT PET, are appropriate candidates for auto-HSCT.

PEG-L-CHOP treatment is safe and effective in adult extranodal NK/T-cell lymphoma with a low rate of clinical hypersensitivity.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Outcome and Prospective Factor Analysis of High-dose Therapy Combined with Autologous Peripheral Blood Stem Cell Transplantation in Patients with Peripheral T-cell Lymphomas.

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.

Minimal change disease associated with anti-PD1 immunotherapy: a case report.

BACKGROUND: Oncologic immunotherapy is a form of therapy intended to reactivate the immune response to tumor cells using agents that modulate immune checkpoints, such as programmed cell death protein 1 and its ligand (PD-1/PD-L), and cytotoxic T-lymphocyte-associated antigen 4. Along with activation of the immune system to tumors, immune-mediated kidney side effects have been reported, most of which are cases of interstitial nephritis. Glomerular disease, however, appears rare. CASE PRESENTATION: Herein, we describe a patient with nephrotic syndrome related to treatment with an anti-PD1 antibody for Hodgkin lymphoma. Following the third dose of anti-PD1 antibody, the patient developed massive proteinuria and nephrotic syndrome. Kidney biopsy showed diffuse podocyte foot process effacement upon electron microscopy, which was consistent with minimal change disease. Corticosteroid treatment yielded full and rapid remission of nephrotic syndrome in 1 month. CONCLUSION: The present case suggests an association between anti-PD1 therapeutic immune activation and the development of nephrotic syndrome. Given the increasing prevalence of oncologic immunotherapy, patients should be routinely monitored for kidney side effects associated with these agents.

Prognostic value of pre- and post-transplantation 18F-fluorodeoxyglucose positron emission tomography results in non-Hodgkin lymphoma patients receiving autologous stem cell transplantation.

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.

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 (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.

Clinical features and survival of extranodal natural killer/T cell lymphoma with and without hemophagocytic syndrome.

Extranodal natural killer (NK)/T cell lymphoma-associated hemophagocytic syndrome (HPS) (NK/T-LAHS) is a heterogeneous and life-threatening disease, which warrants investigation of its risk factors and clinical features. We retrospectively analyzed the clinical records of 202 patients with extranodal NK/T cell lymphoma and compared the characteristics and survival of extranodal NK/T cell lymphoma patients with and without HPS. The cumulative incidence of NK/T-LAHS was 11.4 % (23/202). In a multivariate logistic regression model, younger age (p = 0.012), bone marrow involvement (p = 0.012), and reduced serum albumin (p < 0.001) were independent risk factors for developing HPS in patients with extranodal NK/T cell lymphoma. The survival of extranodal NK/T cell lymphoma patients was aggravated when complicated with HPS, with an overall 2-year survival of 72.1 and 30.4 %, respectively (p < 0.001). Six patients with HPS onset at lymphoma diagnosis tended to have a poor performance status (p = 0.040), while the rate of elevated bilirubin was significantly higher in 17 patients with HPS onset at lymphoma relapse (p = 0.045). After HPS onset, treatment response was poor (response rate, 17.4 %) and survival was dismal with a median of 26 days. Univariate analysis showed that patients with lactate dehydrogenase >1000 U/L (p = 0.048) and disseminated intravascular coagulation (p = 0.004) had shorter survival time. Extranodal NK/T cell lymphoma was frequently complicated with HPS, and survival was discouraging in this circumstance. Intensive chemotherapy regimens including L-asparaginase or pegaspargase and allogeneic stem cell transplantation should be investigated.

Safety and efficacy of bevacizumab combined with R-CHOP regimen in seven Chinese patients with untreated diffuse large B-cell lymphoma.

BACKGROUND: Rituximab plus CHOP (R-CHOP) significantly improved the outcome of diffuse large B cell lymphoma (DLBCL), a common sub-type of non-Hodgkin lymphoma. But 40% - 50% of DLBCL patients cannot be cured by this regimen. Some clinical trials showed that bevacizumab might be useful in the treatment of DLBCL. This study evaluated the safety and efficacy of bevacizumab combined with the R-CHOP (A-R-CHOP) regimen in Chinese patients with previously untreated DLBCL. METHODS: Patients with previously untreated DLBCL received A-R-CHOP regimen therapy. All patients with complete response (CR)/ unconfirmed complete response(CRu) after 8 cycles of A-R-CHOP received the bevacizumab maintenance therapy once every 3 weeks. The remained bulky disease was treated with radiotherapy. RESULTS: Seven Chinese patients were treated. All of them had bulky diseases. One patient had progressive disease after 4 cycles of A-R-CHOP therapy. The rest six patients completed 8 cycles of A-R-CHOP treatment. All of these six patients reached CR/CRu (5 CR, 1 CRu). Bevacizumab maintenance therapy was given to 4 CR patients. All 7 patients experienced Grade 3/4 hematologic adverse events; additionally, one had Grade 3 gastrointestinal toxicity and one had Grade 1 epistaxis. During bevacizumab maintenance therapy, one patient had Grade 1 gingival bleeding, another experienced Grade 1 proteinuria and then Grade 3 congestive heart failure 4 months after completion of maintenance therapy. At the end of July 2013, the patient who had progressive disease after 4 cycles of A-R-CHOP died of progressive disease, the other six remained CR response. CONCLUSIONS: The A-R-CHOP regimen is effective for untreated DLBCL, but may cause bevacizumab-specific toxicities, which should be monitored.

[Clinical features and prognosis of mucosa-associated lymphoid tissue lymphoma].

OBJECTIVE: To explore the clinical features and treatments of mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS: The clinical data of 80 MALT lymphoma patients treated from September 2000 to November 2012 were retrospectively analyzed. RESULTS: Among them, 32 (40.0%) had gastric MALT lymphoma and 48(60.0%) non-gastric MALT lymphoma. Gastric lymphoma associated anemia accounted for 50.0% (16/32) (25.0% (12/48) in non-gastric group, P = 0.022). In non-gastric group, stage III-IV diseases accounted for 35.4% (17/48) (12.5% (4/32) in gastric group, P = 0.022). During a median follow-up of 30 months, the 5-year overall survival (OS) rate was 90.0% and 5-year progression-free survival (PFS) rate 67.0%. For the non-gastric group, surgery plus chemotherapy group was superior in PFS to surgery alone group (the 3-year PFS rate 83.0% and 33.0%; median PFS 43.4 months and 20.3 months) (P = 0.040). Five-year OS in patients on first-line rituximab and chemotherapy without rituximab were 100.0% and 86.0% respectively (P = 0.106). Short-term response (OR = 0.258, P = 0.020) and low albumin (OR = 3.967, P = 0.009) were independent factor for PFS. CONCLUSIONS: Non-gastric MALT lymphoma is easily disseminated. Systemic treatment may be considered for advanced non-gastric MALT lymphoma. Surgery often leaves residual lesions for gastric MALT lymphoma.

[Clinical value of flow cytometry in assessing bone marrow involvement of non-Hodgkin's lymphoma].

OBJECTIVE: To evaluate the value of flow cytometry (FCM) in the diagnosis of bone marrow involvement in patients with non-Hodgkin's lymphoma (NHL). METHODS: The cytomorphology, biopsy and FCM tests were performed concurrently on bone marrow samples from 206 patients who were consecutively diagnosed as NHL from March 2013 to August 2013 at Peking University Cancer Hospital. The results were analyzed and compared. RESULTS: Totally bone marrow involvement occurred in 25.7% (53/206) patients. The detection positivity of bone marrow involvement by cytomorphology, biopsy and flow cytometry were 6/14, 6/14 and 9/14 respectively in 14 T-cell lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia (T-LBL/ALL) patients; 9.2% (14/152) , 19.1% (29/152) and 23.7% (36/152) respectively in 152 mature B-cell NHL patients; 0 (0/40) , 15.0% (6/40) and 2.5% (1/40) in 40 cases of mature T/NK-cell NHL. The overall rate of concordance of biopsy and flow cytometry was 88.3%. CONCLUSIONS: FCM has a high sensitivity in detecting bone marrow involvement in NHL patients, especially those with T-LBL/ALL and B-cell NHL. And a combination of morphology, biopsy and FCM may improve the sensitivity and accuracy in the detection of bone marrow involvement in NHL patients.

A Multifunctional Nanocatalytic Metal-Organic Framework as a Ferroptosis Amplifier for Mild Hyperthermia Photothermal Therapy.

Hyperthermia therapy is considered an effective anticancer strategy. However, high temperature can trigger an excessive inflammatory response, leading to tumor self-protection, immunosuppression, metastasis, and recurrence. To address this issue, we reported a multifunctional photothermal nanoplatform to achieve mild hyperthermia photothermal therapy (mild PTT) based on cisplatin (DDP) and a ferrocene metal-organic framework (MOF-Fc) nanocomposite, which can specifically enhance ferroptosis-triggered oxidative stress levels and synchronously amplify mild hyperthermia PTT-mediated anticancer responses. Both in vitro and in vivo antineoplastic results verify the superiority of mild PTT with DDP/MOF-Fc@HA. The combination of DDP and MOF-Fc exhibits Fenton catalytic activity and glutathione depletion capacity, magnifying mild hyperthermia effects via the radical oxygen species (ROS)-adenosine triphosphate (ATP)-HSP silencing pathway, with important implications for clinical hyperthermia therapy.