ABSTRACT
In the last decade, there has been increased understanding of the pathologic features and biology of peripheral T cell lymphomas (PTCLs) through development of multi omics and molecular profiling techniques. In addition, international collaborations through multi center trials as well as prospective registry studies have improved our knowledge of host and tumor genomic factors and treatment factors affecting disease outcomes. In our review today, we aim to highlight the current epidemiology, latest advances in classification, disease biology and the evolving treatment landscape for nodal PTCLs.
ABSTRACT
Natural killer (NK)/T-cell lymphomas failing L-asparaginse regimens have no known salvage and are almost invariably fatal. Seven male patients with NK/T-cell lymphoma (median age, 49 years; range, 31-68 years) for whom a median of 2 (range, 1-5) regimens (including l-asparaginase regimens and allogeneic hematopoietic stem-cell transplantation [HSCT] in 2 cases) failed were treated with the anti-programmed death 1 (PD1) antibody pembrolizumab. All patients responded, according to various clinical, radiologic (positron emission tomography), morphologic, and molecular (circulating Epstein-Barr virus [EBV] DNA) criteria. Two patients achieved complete response (CR) in all parameters. Three patients achieved clinical and radiologic CRs, with two having molecular remission (undetectable EBV DNA) but minimal EBV-encoded RNA-positive cells in lesions comprising predominantly CD3+CD4+ and CD3+CD8+ T cells (which ultimately disappeared, suggesting they represented pseudoprogression) and one having detectable EBV DNA despite morphologic CR. Two patients achieved partial response (PR). After a median of 7 (range, 2-13) cycles of pembrolizumab and a follow-up of a median of 6 (range, 2-10) months, all five CR patients were still in remission. The only adverse event was grade 2 skin graft-versus-host disease in one patient with previous allogeneic HSCT. Expression of the PD1 ligand was strong in 4 patients (3 achieving CR) and weak in 1 (achieving PR). PD1 blockade with pembrolizumab was a potent strategy for NK/T-cell lymphomas failing l-asparaginase regimens.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , DNA, Viral/antagonists & inhibitors , Epstein-Barr Virus Infections/therapy , Hematopoietic Stem Cell Transplantation , Lymphoma, Extranodal NK-T-Cell/therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Adult , Aged , Antineoplastic Agents/therapeutic use , Asparaginase/therapeutic use , Epstein-Barr Virus Infections/diagnostic imaging , Epstein-Barr Virus Infections/genetics , Epstein-Barr Virus Infections/immunology , Gene Expression , Herpesvirus 4, Human/drug effects , Herpesvirus 4, Human/growth & development , Herpesvirus 4, Human/immunology , Humans , Lymphoma, Extranodal NK-T-Cell/diagnostic imaging , Lymphoma, Extranodal NK-T-Cell/genetics , Lymphoma, Extranodal NK-T-Cell/immunology , Male , Middle Aged , Positron-Emission Tomography , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , Retrospective Studies , Sustained Virologic Response , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/virology , Transplantation, Homologous , Treatment FailureABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for around 30-60% of all cases. The management of DLBCL in Asia has several unmet needs due to the diversity of the population, the heterogeneity of local clinical guidelines for DLBCL and the wide disparity in resources and healthcare systems across different regions. Rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) is widely recognized as the standard first-line treatment for DLBCL; however, alternative regimens are required to improve patient outcomes in challenging subtypes, such as patients with high International Prognostic Index scores, old/frail patients, and patients with double-hit and double-expressor DLBCL or concurrent central nervous system disease. This review article draws from the expertise of practicing hematologists/oncologists in the region, with the aim of integrating data from current scientific evidence to address the unmet needs and unique socioeconomic challenges faced by challenging high risk patient groups in the Asia-Pacific region.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Lymphoma, Large B-Cell, Diffuse , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Asia/epidemiology , Cyclophosphamide/therapeutic use , Vincristine/therapeutic useABSTRACT
Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Humans , Prognosis , Lymphoma, Large B-Cell, Diffuse/pathology , Gene Expression Profiling , Transcriptome , Germinal Center/pathology , Tumor Microenvironment/geneticsABSTRACT
Genomic profiling to identify myeloid-malignancy-related gene mutations is routinely performed for patients with suspected or definite myeloid malignancies. The most common specimen types in our experience are peripheral blood and bone marrow aspirates. Although primarily intended to identify somatic mutations, not infrequently, potentially clinically significant germline variants are also identified. Confirmation of the germline status of these variants is typically performed by hair follicle or skin fibroblast testing. If the germline variant is classified as a pathogenic or likely pathogenic variant and occurs in a gene known to be associated with a disease relevant to the patient's phenotype (for example, the identification of a DDX41 pathogenic variant in an individual with acute myeloid leukemia), the management algorithm is typically quite straightforward. Challenging situations may occur such as when the germline variant is classified as a pathogenic or likely pathogenic variant and occurs in a gene not known to be associated with the patient's phenotype/presenting complaint. We have encountered several such challenging cases in which potentially clinically significant germline variants were identified on the initial genomic profiling of peripheral blood or bone marrow aspirate. In this article, we present these cases and discuss the genetic counseling and management approaches.
ABSTRACT
Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6- unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance. SIGNIFICANCE: Using single-cell-resolved multiplexed imaging, we show that selected subpopulations of cells expressing specific combinations of oncogenes influence clinical outcomes in lymphoma. We describe a probabilistic metric for the estimation of cellular oncogenic coexpression from IHC or bulk transcriptomes, with possible implications for prognostication and therapeutic target discovery in cancer. This article is highlighted in the In This Issue feature, p. 1027.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Phosphatidylinositol 3-Kinases , Humans , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-bcl-6/genetics , Prognosis , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Oncogenes , Lymphoma, Large B-Cell, Diffuse/pathologyABSTRACT
We describe the allele and haplotype frequencies seen in a volunteer unrelated bone marrow donor registry, a public cord blood bank, and donor/recipient samples processed by the Health Sciences Authority (HSA) in Singapore. Historical human leukocyte antigen (HLA) typing reports were anonymized and combined. They were checked for HLA typing nomenclature discrepancies or ambiguities using the HLA-net UNIFORMATE tool, and for analysis, the validated data were subsequently separated into Chinese, Malay, Indian, and "Others," according to the race classification system used in Singapore. Individual ethnic allele and haplotype frequencies were calculated with the HLA-net GENE[RATE] pipeline using basic statistics. The Basic Statistics Tool of HLA-net was used to estimate haplotype frequency using an expectation maximization algorithm, given a set of multi-allelic data pairs for a given HLA locus. The outputs downloaded from the site comprised plain text files with haplotype frequency estimates, results of a global linkage disequilibrium test, and standardized residuals (stdres) corresponding to deviations from expected frequencies. HLA typing results from 59,186 individuals met the inclusion criteria, yielding 118,372 analyzable alleles. In our study population, the haplotype A*33:03-B*58:01-C*03:02-DRB1*03:01ï½DQB1*02:01:01G with a frequency of 4.91% was the most common. This haplotype was also the most common among Singaporean Chinese donors. Consistent with the predominant Chinese population, haplotypes with a frequency greater than 1% were also the most frequently observed haplotypes in the Singaporean population. In the Malay donor population, the most common haplotype was A*33:03ï½B*44:03ï½C*07:01:01Gï½ DRB1*07:01-DQB1*02:01:01G, with a frequency of 3.41%, whereas within the Indian donor population, the most common haplotype was A*01:01-B*57:01-C*06:02ï½DRB1*07:01-DQB1*03:03, with a frequency of 3.42%. Haplotype diversity and composition statistics within donor pools provide HLA background data required for the targeted recruitment of donors to support the hematopoietic stem cell donor requirements of the country. These data may be used in the future to devise donor recruitment strategies for optimizing the donor pool through targeted publicity and accruals.
ABSTRACT
Although combination therapy is the standard of care for relapsed/refractory non-Hodgkin's lymphoma (RR-NHL), combination treatment chosen for an individual patient is empirical, and response rates remain poor in individuals with chemotherapy-resistant disease. Here, we evaluate an experimental-analytic method, quadratic phenotypic optimization platform (QPOP), for prediction of patient-specific drug combination efficacy from a limited quantity of biopsied tumor samples. In this prospective study, we enrolled 71 patients with RR-NHL (39 B cell NHL and 32 NK/T cell NHL) with a median of two prior lines of treatment, at two academic hospitals in Singapore from November 2017 to August 2021. Fresh biopsies underwent ex vivo testing using a panel of 12 drugs with known efficacy against NHL to identify effective single and combination treatments. Individualized QPOP reports were generated for 67 of 75 patient samples, with a median turnaround time of 6 days from sample collection to report generation. Doublet drug combinations containing copanlisib or romidepsin were most effective against B cell NHL and NK/T cell NHL samples, respectively. Off-label QPOP-guided therapy offered at physician discretion in the absence of standard options (n = 17) resulted in five complete responses. Among patients with more than two prior lines of therapy, the rates of progressive disease were lower with QPOP-guided treatments than with conventional chemotherapy. Overall, this study shows that the identification of patient-specific drug combinations through ex vivo analysis was achievable for RR-NHL in a clinically applicable time frame. These data provide the basis for a prospective clinical trial evaluating ex vivo-guided combination therapy in RR-NHL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Lymphoma, Non-Hodgkin , Humans , Prospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Drug CombinationsSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Epstein-Barr Virus Infections/drug therapy , Lymphoma, Extranodal NK-T-Cell/drug therapy , Lymphoma, Primary Cutaneous Anaplastic Large Cell/drug therapy , Salvage Therapy , Skin Neoplasms/drug therapy , Tumor Virus Infections/drug therapy , Adolescent , Allografts , Bendamustine Hydrochloride/administration & dosage , Brentuximab Vedotin , Combined Modality Therapy , Drug Resistance, Neoplasm , Female , Hematopoietic Stem Cell Transplantation , Herpesvirus 4, Human/isolation & purification , Humans , Immunoconjugates/administration & dosage , Immunophenotyping , Ki-1 Antigen/analysis , Ki-1 Antigen/immunology , Lymphoma, Extranodal NK-T-Cell/therapy , Lymphoma, Extranodal NK-T-Cell/virology , Lymphoma, Primary Cutaneous Anaplastic Large Cell/therapy , Lymphoma, Primary Cutaneous Anaplastic Large Cell/virology , RNA, Viral/analysis , Remission Induction , Skin Neoplasms/therapy , Skin Neoplasms/virologyABSTRACT
CNS prophylaxis is commonly used in Diffuse Large B-Cell Lymphoma (DLBCL) patients with risk features for CNS relapse. This systematic review and meta-analysis compares CNS relapse rates with and without CNS prophylaxis, for patients at intermediate to high CNS relapse risk. Studies reporting CNS relapse risk category and CNS outcomes with and without CNS prophylaxis for antiCD20-CHOP treated DLBCL patients were included. 10 studies with 3770 patients at intermediate to high CNS relapse risk were analyzed. No significant difference in the pooled Absolute Risk Difference (ARD 0.01, 95 % CI -0.01 to 0.02, P = 0.61) or Risk (RR 1.22, 95 % CI 0.81-1.83, P = 0.34) was noted in patients with and without CNS prophylaxis. There were also no differences within pre-specified subgroups of IV Methotrexate or IT chemotherapy. However, the quality of evidence supporting these observations was low. A meta-analysis of individual patient data will help evaluate the benefit of CNS prophylaxis strategies.
Subject(s)
Central Nervous System Neoplasms , Lymphoma, Large B-Cell, Diffuse , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/prevention & control , Cyclophosphamide , Doxorubicin , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Neoplasm Recurrence, Local , Prednisone/therapeutic use , Rituximab/therapeutic use , Vincristine/therapeutic useABSTRACT
Plasmablastic lymphoma is a rare variant of a diffuse, large B-cell lymphoma, which typically presents in the oral cavity in immunocompromised patients. In HIV positive patients, this tumor has a tendency to manifest in extramedullary sites. In this report, we document a rare instance in which this neoplasm besides affecting the bone marrow also involved the lung. In addition, the lymphoma in our case disclosed CD10 positivity on immunohistochemistry and t(8;14)(q24;q34) translocation on cytogenetic analysis, mimicking a Burkitt/atypical Burkitt lymphoma. The problems in diagnosis are discussed.
Subject(s)
Bone Marrow Neoplasms/pathology , Chromosomes, Human, Pair 14 , Chromosomes, Human, Pair 8 , Lung Neoplasms/pathology , Lymphoma, Large B-Cell, Diffuse/pathology , Neprilysin/metabolism , Translocation, Genetic/genetics , Bone Marrow Neoplasms/diagnosis , Bone Marrow Neoplasms/metabolism , Burkitt Lymphoma/diagnosis , Burkitt Lymphoma/metabolism , Burkitt Lymphoma/pathology , Diagnosis, Differential , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/metabolism , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/metabolism , Male , Middle AgedABSTRACT
A male lifelong nonsmoker aged 58 years with no prior asbestos exposure complained of gradual worsening breathlessness over 3 months. This was associated with abdominal and leg swelling and a 2-kg weight loss. He had no fever, night sweats, hemoptysis, joint pain, rash, abdominal pain, chest pain, or orthopnea. The patient had no recent travel or contact with pulmonary TB. He had stage I left-side testicular seminoma treated with left-sided radical orchidectomy 10 years previous and recently received a diagnosis of Child's B alcoholic liver cirrhosis. His hepatitis B and C screen result was normal.
Subject(s)
Ascites/diagnosis , Ascites/etiology , Herpesvirus 8, Human , Lymphoma, Primary Effusion/complications , Lymphoma, Primary Effusion/diagnosis , Pleural Effusion/diagnosis , Pleural Effusion/etiology , Antineoplastic Agents/therapeutic use , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Drug Therapy, Combination , Fatal Outcome , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Lymphoma, Primary Effusion/virology , Male , Middle Aged , Polyethylene Glycols/therapeutic use , Positron-Emission Tomography , Recombinant Proteins/therapeutic use , Tomography, X-Ray Computed , Vincristine/therapeutic useSubject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Killer Cells, Natural/drug effects , Lymphoma, T-Cell/drug therapy , Lymphoma, T-Cell/genetics , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Adult , Aged , Female , Humans , Male , Middle Aged , Whole Genome Sequencing/methodsABSTRACT
Delayed recovery of platelet count post allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been associated with worse transplant outcomes. Thrombopoietic agents have been successfully used in immune mediated thrombocytopenia or thrombocytopenia from bone marrow failure syndromes; however, the experience regarding their use after allo-HSCT is limited. Here we report on the safety and efficacy of romiplostim used in 3 consecutive patients with thrombocytopenia post allogeneic transplantation. Two patients had prolonged platelet recovery due to poor graft function while one had secondary failure of platelet recovery, likely immune mediated, post transplantation. Successful use of such agents post-transplant may improve platelet recovery, decrease rates of complications and potentially improve outcomes.