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Lymphoma refers to a group of heterogeneous malignancies originating from the reticuloendothelial and lymphatic systems. The clinical manifestations, treatment strategies, and disease outcomes of different types of lymphoma considerably vary. Recent developments in high-throughput sequencing technologies have enhanced understanding of the pathogenesis and molecular stratification of lymphoma. In the era of new drugs, precise stratification and targeted drug selection can not only improve the prognosis of patients with lymphoma but also reduce the toxic side effects of traditional chemotherapy, ultimately achieving the accurate diagnosis and individualized treatment of tumors. This article reviews the research progress of molecular diagnosis and individualized treatment of different lymphoma subtypes and lymphoma-related research in important meetings such as ASCO, EHA, and ICML in 2023.
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Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%-50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.
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PD-1 / PD-L1 (programmed cell death 1 / programmed cell death 1 ligand 1) and CTLA-4 (cytotoxic T lymphocyte antigen 4) are currently approved major immune checkpoints. Immune checkpoint inhibitors against them are novel monoclonal antibodies that perform well in a variety of malignancies such as melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma and Hodgkin's lympho-ma. However, with the increasing use of immune checkpoint inhibitors, immune-related adverse events can-not be ignored. The incidence of gastrointestinal toxicity is second only to skin toxicity. In this review, we focused on the mechanisms of these immune checkpoint inhibitors and the characteristics of gastrointestinal toxicity induced by them, and also discussed the clinical management strategies.
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PD-1/PD-L1 (programmed cell death 1/programmed cell death 1 ligand 1) and CTLA-4 (cytotoxic T lymphocyte antigen 4) are currently approved major immune checkpoints. Immune checkpoint inhibitors against them are novel monoclonal antibodies that perform well in a variety of malignancies such as melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma and Hodgkin′s lymphoma. However, with the increasing use of immune checkpoint inhibitors, immune-related adverse events cannot be ignored. The incidence of gastrointestinal toxicity is second only to skin toxicity. In this review, we focused on the mechanisms of these immune checkpoint inhibitors and the characteristics of gastrointestinal toxicity induced by them, and also discussed the clinical management strategies.
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The immune checkpoint inhibitors (ICI) represented by programmed death 1/programmed death ligand 1 (PD-1/PD-L1) antibody opened a new era of immunotherapy. However, PD-1/PD-L1 inhibitors have not been approved for indications in the field of malignant lymphoma except for classic Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma. Researchers have actively explored different lymphoma subtypes with single drugs or combined therapy, and achieved certain effect initially. The latest advances of ICI in cHL, B-cell non-Hodgkin lymphoma and T-cell lymphoma and the management of immune-related adverse events are briefly introduced in this paper.
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Objective@#To investigate the strong expression (S+) of P53 and BCL2 proteins in MYC/BCL2 double-expression DLBCL (DEL) and whether they can be used for the prognostic evaluation and stratified diagnosis of DELs.@*Methods@#Tissue microarray were made by filed FFPE blocks of 174 DLBCL cases. The translocation of MYC, BCL2 and BCL6 genes were detected by FISH, and the proteins were detected by IHC. Data of clinicopathologic features and follow up of patients were collected and OS (overall survival) and PFS (progression free survival) were analyzed by statistics.@*Results@#Eight double-hit lymphomas (DHLs) were identified in all cases, and 45 DELs were selected from 166 remaining cases, which have no significant difference in OS and PFS compared with non-DEL cases (P=0.668 and P=0.790) . Of 42 DEL-cases with follow up data, 24 cases with P53+ or/and BCL2 (S+) are significantly shorter OS and PFS than others (P=0.003 and P=0.000) , in which the cases with P53+/BCL2 (S+) co-expression were the worst prognosis, and P53/BCL2 co-weaker positive DEL cases even have superior OS and PFS than those non-DELs. Although statistics showed that the cases of P53+ or/and BCL2 (S+) have a lower OS and PFS in total cases (P=0.063 and P=0.024) , it is not the case when the DEL-cases take out from total cases, that is the cases with P53+ or/and BCL2 (S+) are as similar OS and PFS as others in non-DEL group (P=0.590 and P=0.550) .@*Conclusion@#The strong expression of P53 and BCL2 proteins can be used as indicators of stratified diagnosis and poor prognosis of DEL.
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Chimeric antigen receptor T-cell (CAR-T) is one of the effective methods for treatment of lymphoma. The way to improve the efficacy and control the reverse reactions still needs to be explored further. Several clinical trials have indicated CAR-T could have favorable effects on the B-cell lymphoma patients with controllable reverse reactions. However, antigen loss is a major factor for the acquired resistance to CD19 CAR-T therapy. Other clinical researches, including CD22 for treatment of B-cell lymphoma and CD30 for Hodgkin lymphoma, have increased the efficacy of CAR-T. Moreover, lots of trials have suggested that the patients who received cyclophosphamide or bendamustine plus fludarabine lymphodepletion can get a high effective rate.
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Cancer immunotherapy uses the host′s immune system to mobilize immune cells to rec-ognize and eventually eliminate cancer cells .At present, studies in terms of cancer immunotherapy mainly focus on programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) antibody, cytotoxic T-lymphocyte-associated protein 4 ( CTLA-4 ) antibody, chimeric antigen receptor T-cell immunotherapy (CAR-T), T cell receptor Immunotherapy (TCR-T), etc.Despite the fact that cancer immunotherapies elicit unprecedented durable responses in clinical therapy , they appear to be ineffective to some patients .In addition, some responders relapse and show resistance to immunotherapies even if their symptoms are re -lieved for a time .Resistance to cancer immunotherapy can be categorized into primary , adaptive and ac-quired, which can occur in every stage during the process of anti-tumor response.In this review, we discuss the known mechanisms of resistance and provide a rationale for the use of combination therapy to overcome resistance.
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Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (DLBCL) is a rare and distinct variant of DLBCL. It is classified as a unique subtype of DLBCL in the 2008 WHO classification of lymphomas. No standard and effective therapeutic regi-men is available for ALK+DLBCL because it shows a more aggressive clinical course and frequent relapse. Therefore, a standardized and individualized treatment is needed to benefit more patients diagnosed with ALK+DLBCL through a multiple disciplinary team. This arti-cle presents a case of an ALK+DLBCL patient who relapsed after transplantation and was successfully treated with the ALK kinase inhibi-tor Crizotinib.
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Objective To retrospectively analyze the treatment outcomes and prognostic factors for primary bone lymphomas ( PBL) . Methods Forty patients with PBL who were admitted to our center from 1964 to 2014 were enrolled as subjects. In those patients, 10 were treated with chemotherapy alone, 10 with radiochemotherapy, 10 with postoperative chemotherapy, 9 with postoperative radiochemotherapy, and 1 with surgery alone. The median radiation dose was 36 Gy. The Kaplan?Meier method was used to calculate survival rates . The log?rank test was used for survival difference analysis and univariate prognostic analysis . Results The follow?up rate was 100%. The 3?year sample size was 36. In all patients, the 1?and 3?year overall survival rates were 60% and 42%, respectively, while the 1?and 3?year disease?free survival rates were 45%and 34%, respectively. The univariate analysis showed that no pathological fracture at diagnosis, normal lactate dehydrogenase level, an International Prognostic Index score of ≤1, early clinical stage ( stageⅠE ) , complete response after initial treatment, no less than 6 cycles of chemotherapy, a radiation dose of≥40 Gy, no progression outside radiation field after radiotherapy, and grade<3 bone marrow suppression during the treatment were prognostic factors for survival ( P=0. 027, 0. 037, 0. 000, 0. 016, 0. 000, 0. 000, 0. 022, 0. 014, and 0. 030). Conclusions The incidence of PBL is low. Comprehensive treatment can achieve satisfactory outcomes. As a PBL staging system, Ann Arbor has limitations. The staging of PBL should be based on local bone destruction and metastasis.
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Objective To study the clinical features, effects of therapeutic regimen and prognosis of patents with mantle cell lymphoma (MCL). Methods Clinical data of 27 MCL patients admitted in Tianjin Medical University Cancer Institute&Hospital from January 2008 to December 2014 were retrospectively analyzed. Cox regression analysis was used to analyze influencing factors of prognosis of MCL. Results The median age was 68 years old for 27 patients, and the male-to-female ratio was 4.4∶1. Ann Arbor staging showed that 25 cases were stageⅢ-Ⅳ(92.6%), 8 cases were heptosplenomegaly (29.6%), 7 cases showed extranodal involvement (25.9%). ECOG scoring showed that 4 cases with scores of 2-4 (14.8%), 8 cases were 0-3 (29.6%), 14 cases were 4-5 (51.9%) and 5 cases were 6-11 (18.5%). The Ki-67 index≤30%was found in 9 cases (33.3%), and>30%was found in 18 cases (67.7%). Patients with B symptom was found in 10 (37.0%). The elevated lactate dehydrogenase (LDH) was found in 17 cases (63.0%). The increased Beta 2- microglobulin was found in 8 cases (29.6%). Seven patients were found with bone marrow involvement. The total effective rate (ORR) was 81.8%in group with R-CHOP method, and the ORR was 68.8%in group with CHOP method. Multivariate analysis showed that age, LDH and Ki-67 were independent factors influencing the prognosis of MCL (P60 years, elevated LDH and Ki-67 index>30%are with poor prognosis.
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The human immune system has the regulatory functions of eradicating pathogens and limiting excessive inflammation, which protect the surrounding tissue from being damaged. The immune bal-ance of self-limiting is mainly controlled by complex interactions between antigen-presenting cells ( APCs ) and T cells. However, the immune balance is destroyed in cancer, which results in immune evasion and tumor metastasis or promotes the development of drug resistance. Immune checkpoints play critical roles in the immune system. Therefore, blocking tumor immune evasion by targeting the immune checkpoints has be-come a research focus in the treatment of relapsed or refractory malignant tumors. Currently, in the studies of malignant lymphomas, some phaseⅠ/Ⅱclinical studies of immune checkpoint inhibitors have achieved sur-prising results. This review will discuss the regulation and immunotherapy of immune checkpoints in malig-nant lymphomas.
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Objective:To compare the therapeutic efficacy and safety of Hyper-CVAD/MA regimen and CHOP/CHOP-like regimen in the treatment of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Methods:The 78 primary PTCL-NOS patients who were initially diagnosed and treated in Tianjin Medical University Cancer Institute and Hospital and Tianjin Union Medical Center from June 2004 to June 2012 were retrospectively analyzed. The patients were then divided into two groups:Hyper-CVAD/MA group (n=21) and CHOP/CHOP-like group (n=57). Curative efficacies and toxicities were analyzed by Chi-square test, and survival was estimated by Ka-plan-Meier method. Results: In the Hyper-CVAD/MA group, complete response (CR) was 42.9%, overall response rate (ORR) was 85.7%, median progression-free survival (PFS) was 20 months, and the three-year overall survival (OS) was 56.9%. In the CHOP/CHOP-like group, the CR, ORR, and three-year OS were 28.1%, 59.6%, and 49.6%, respectively, and the median PFS was 13 months. Compara-tive analysis showed that the ORR and three-year OS were statistically significant (P0.05). The incidence rates ofⅢ/Ⅳneutrocytopenia and thrombocytopenia in Hyper-CVAD/MA group (66.7%and 61.9%, respectively) were significantly higher than those of the CHOP/CHOP-like group (22.8%and 14.0%, respec-tively) (P<0.05). Conclusion:Hyper-CVAD/MA regimen can achieve satisfactory efficacy in parents with PTCL-NOS, and toxicity can be controlled with granulocyte colony stimulating factor (G-CSF).
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The BCL6 (B-Cell Lymphoma 6) gene is a proto-oncogene that is often expressed in diffuse large B-cell lymphomas (DLBCLs). BCL6 loss of function can kill DLBCL cells, demonstrating that BCL6 is necessary for the survival of DLBCL cells and could be a therapeutic target. In this study, we found that BCL6 protein levels were consistently upregulated in DLBCL tissues, whereas its mRNA levels varied randomly in tissues, suggesting that a post-transcriptional mechanism was involved in BCL6 regulation. We used bioinformatics analysis to search for miRNAs, which potentially target BCL6, and identified specific targeting sites for miR-10a in the 3'-untranslated region (3'-UTR) of BCL6. We further identified an inverse correlation between miR-10a levels and BCL6 protein levels, but not mRNA levels, in DLBCL tumor tissue samples. By overexpressing or knocking down miR-10a in DLBCL cells, we experimentally validated that miR-10a directly recognizes the 3'-UTR of the BCL6 transcript and regulated BCL6 expression. Furthermore, we demonstrated that negatively regulating BCL6 by miR-10a suppressed the proliferation and promoted apoptosis of DLBCL cells.
Subject(s)
Humans , 3' Untranslated Regions , Apoptosis , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Lymphoma, Large B-Cell, Diffuse , Genetics , Metabolism , Therapeutics , MicroRNAs , Genetics , Metabolism , Proto-Oncogene Proteins c-bcl-6 , GeneticsABSTRACT
Lung cancer, with growing morbidity and mortality worldwide, is one of the most malignant tumors, representing a significant threat to human health and life.The application of next-generation genomic technologies has offered a more comprehensive look at the mutational landscape across the different subtypes of nonsmall cell lung cancer (NSCLC).A number of recurrent mutations such as TP53, KRAS, and epidermal growth factor receptor (EGFR) have been identified in NSCLC.While targeted therapeutic successes have been demonstrated in the therapeutic targeting of EGFR and ALK, the majority of NSCLC tumors do not harbor these genomic events.This review looks at the current treatment paradigms for lung adenocarcinomas (LAC) and squamous cell carcinomas, examining genomic aberrations that dictate therapy selection, as well as novel therapeutic strategies for tumors harboring mutations in KRAS and TP53 which, to date, have been considered undruggable.A more thorough understanding of the molecular alterations that govern NSCLC tumorigenesis, aided by next-generation sequencing, will lead to targeted therapeutic options expected to dramatically reduce the high mortality observed in lung cancer.
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Objective:To evaluate the efficacy and toxicity of single-agent bendamustine in patients with indolent B-cell non-Hodgkin's lymphoma (NHL) refractory to rituximab. Methods:Between April 2010 and April 2013, 100 patients with rituximab-refrac-tory indolent B-cell NHL from 8 institutions were enrolled. Bendamustine was administered at 120 mg/m2 on days 1 and 2 every 21 days for 6-8 cycles. The primary endpoint was the overall response rate (ORR). The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results:One hundred patients with a median age of 56 (rang-ing from 28 to 74) years were recruited in this clinical study. The total number of chemotherapy was 447 cycles, and the median number was 4 cycles. Ninety-three patients could be evaluated for efficacy. Fifteen patients (16.1%) had complete remission (CR), 52 (55.9%) had partial remission (PR), 22 (23.7%) had stable disease (SD), and 4 (4.3%) had progression disease (PD). The ORR and DCR were 72%and 95.7%, respectively. After a median follow-up of 26.6 months (ranging from 2 to 48.4 months), 59 patients (63.4%) had PD.The median PFS was 8.53 (95%CI:6.518-10.542) months, and PFS rate for 1 year was (40.6±5.3)%. Forty-eight patients (48%) had 3/4 grade adverse events, including leucopenia (26%), neutropenia (24%), and anemia (11%). Conclusion:Single-agent bendamustine produced a high rate of objective responses in patients with rituximab-refractory indolent B-cell NHL and could be one of the new op-tions for second-line treatment of these patients. The most common adverse event is hematologic toxicity.
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Objective To compare the efficacy and adverse reaction of teniposide (VM-26) plus carboplatin (TC regimen) and etoposide (VP-16) plus carboplatin (EC regimen) in treatment of newly diagnosed small cell lung cancer (SCLC), and the possible role of VM-26 on prevention of brain metastasis of SCLC. Methods A total of 102 previously untreated SCLC patients without brain metastasis were divided into VP-16 group received EC regimen (n=64) and VM-26 group received TC regimen(n=38). The carboplatin dosages in two groups were calculated by blood concentration-area under the curve(AUC)=5, and intravenous infusion of 1 h for the first day. In VM-26 group, VM-26 70 mg/m2+normal saline 500 mL was intravenously infused of 2 h for 1-3 days. VP-16 100 mg/m2+normal saline 500 mL was given to VP-16 group, 1 h for 1-3 days. Twenty-one day was for 1 treatment cycle. The curative effect, prognosis and adverse reaction were compared between two groups. Results The overall response rates (ORR) and disease control rates (DCR) were 78.9%(30/38) and 97.4%(37/38) in VM-26 group, respectively, and 76.6%(49/64) and 95.3%(61/64) in VP-16 group, respectively, with no significant differences between the two groups (χ2=0.078 and 0.283, P0.05). The brain metastasis rate was significantly higher in VP-16 group [43.8%(28/64)] than that of VP-26 group [21.1%(8/38),χ2=5.379,P=0.02). The adverse reactions were mainly grade 1/2 bone marrow suppression in two groups. Conclusion TC is a highly active regimen for treatment of SCLC. There is no difference in the ef?fectiveness and adverse reactions versus EC. Application of VM-26 can reduce the incidence of brain metastasis in SCLC patients.
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Histone deacetylase inhibitors (HDACI) can improve the acetylation status of histone N-terminal, which will exert the effect on treatment. The N-terminal of histone modifications belongs to the category of epigenetics. Epigenetics mainly refers to the study of the heritable variation without change in DNA sequence. HDACI had been paid much attention as a new non-cytotoxic an-ti-cancer targeted drug. Thus, the application of this drug in clinical research is widespread. After the U.S. Food and Drug Administra-tion approved two HDACIs for the treatment of cutaneous T-cell lymphoma, the clinical applications of HDACI in other subtypes of T-cell lymphoma have obtained increasing attention. Studies on the mechanism of HDACI provide the theoretical basis for the applica-tion of HDACIs in other subtypes of T-cell lymphoma. In this article, we reviewed the mechanism and clinical trials of HDACIs on the treatment of T-cell lymphoma.
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Objective:To observe the clinical efficacy and toxicities of bendamustine hydrochloride in patients with rituximab-re-fractory indolent B-cell non-Hodgkin's lymphoma (NHL). Methods:A total of 25 patients with rituximab-refractory NHL received bendamustine hydrochloride 120 mg/m2 intravenously on days 1 and 2 of the 21-day cycle. The short-term response, progression free survival, and toxicities were evaluated. Results:The total number of chemotherapy of the 25 patients was 122 cycles, and the median number was 5 cycles. All patients could be evaluated for efficacy. Among the patients, 6 had complete remission, 13 had partial remis-sion, 3 had stable disease, and 3 had progression disease. The overall response rate and clinical benefit rate were 76%and 88%, respec-tively. Until the deadline, 13 patients had progression disease. The median duration of response was 8 months, and the median progres-sion-free survival (PFS) was 9.3 months. Subgroup analysis showed that PFS is significantly related to bone marrow involvement and serum LDH level (P<0.05). The main adverse effects were myelosuppression, gastrointestinal reactions, and infection. Rash was found in 2 patients, and 1 case of gastric cancer was discovered after 5 cycles of treatment. Conclusion:Bendamustine hydrochloride was ef-fective and tolerable in patients with rituximab-refractory indolent B-cell NHL.
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Objective:To evaluate the efficacy and safety of pegaspargase plus GEMOX (pegaspargase, gemcitabine, oxaliplatin) regimen in the initial treatment of nasal NK/T-cell lymphoma. Methods: Twelve preliminarily diagnosed nasal NK/T-cell lymphoma patients in Tianjin Medical University Cancer Institute and Hospital from June 2011 to March 2012 were analyzed. All patients took the pegaspargase plus GEMOX regimen (gemcitabine 800-1 000 mg/m2 on days 1 and 8, oxaliplatin 130 mg/m2 on day 1, and pegaspargase 2 500 IU/m2 on day 2), every three weeks for one cycle. The efficacy and toxicity of the regimen were evaluated in the follow-up treat-ment. Results:After two cycle treatments, 1 patient dropped out of treatment because of acute pancreatitis;the remaining 11 patients had response, in which 1 achieved complete response , 7 had partial response, 2 had stable disease, and 1 had progressive disease. The objective response rate was 72.7%, and the disease control rate was 90.9%. The 2-year overall survival rate was 90.9%. With median 6-cycle P-GEMOX regimen treatment, 81.8% of 11 patients presented side effects, primarily myelosuppression and hepatic dysfunc-tion. Conclusion:Pegaspargase plus GEMOX regimen showed high efficacy on the initial treatment of nasal NK/T-cell lymphoma pa-tients, but the incidence of adverse effect was still high.