A new role for the SRC family kinase HCK as a driver of SYK activation in MYD88 mutated lymphomas.

The SRC family kinase (SFK) HCK is transcriptionally upregulated and activated by mutated MYD88 (MYD88Mut), a key adaptor for Toll-receptor signaling. HCK activates BTK, AKT, and ERK in MYD88Mut lymphomas. SYK, a B-cell receptor (BCR) component, is activated in MYD88Mut lymphoma cells. Although the SFK LYN serves as a trigger for SYK activation in MYD88Mut ABC DLBCL cells, LYN activity is muted in MYD88Mut Waldenstrom macroglobulinemia (WM) cells. We therefore investigated a role for HCK in mediating SYK activation. Overexpression of wild-type (WT) (HCKWT) or gatekeeper mutated (HCKThr333Met) HCK in MYD88Mut lymphoma cells triggered SYK activation. Conversely, HCK knockdown reduced p-SYK in MYD88Mut lymphoma cells. Coimmunoprecipitation experiments showed that HCK was complexed with p-SYK in MYD88Mut BCWM.1 and TMD8 cells, but not in MYD88 WT Ramos cells. Rescue experiments in MYD88Mut lymphoma cells expressing HCKThr333Met led to persistent HCK and SYK activation and resistance to the HCK inhibitor A419259. Treatment of primary MYD88Mut WM cells with A419259 reduced p-HCK and p-SYK expression. Taken together, our findings show that SYK is activated by HCK in MYD88Mut B-cell lymphomas cells, broaden the prosurvival signaling generated by aberrant HCK expression in response to MYD88Mut, and help define HCK as an important therapeutic target in MYD88Mut B-cell lymphomas.

Clinical pharmacology and PK/PD translation of the second-generation Bruton's tyrosine kinase inhibitor, zanubrutinib.

Introduction: Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell lymphomas. Zanubrutinib was designed to achieve improved therapeutic concentrations and minimize off-target activities putatively accounting, in part, for the adverse effects seen with other BTK inhibitors.Areas covered: This drug profile covers zanubrutinib clinical pharmacology and the translation of pharmacokinetics (PK) and pharmacodynamics (PD) to clinical efficacy and safety profiles, by highlighting key differences between zanubrutinib and other BTK inhibitors. We discuss PK, sustained BTK occupancy, and potential factors affecting PK of zanubrutinib, including food effects, hepatic impairment, and drug-drug interactions. These data, along with exposure-response analyses, were used to support the recommended dose of 320 mg, either once daily or as 160 mg twice daily. Translation of PK/PD attributes into clinical effects was demonstrated in a randomized, phase 3 head-to-head study comparing it with ibrutinib in patients with Waldenström macroglobulinemia.Expert opinion: Among the approved BTK inhibitors, zanubrutinib is less prone to PK modulation by intrinsic and extrinsic factors, leading to more consistent, sustained therapeutic exposures and improved dosing convenience. Zanubrutinib PK/PD has translated into durable responses and improved safety, representing an important new treatment option for patients who benefit from BTK therapy.

Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis.

DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression.

Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer.

Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies.

Decreases in different Dnmt3b activities drive distinct development of hematologic malignancies in mice.

DNA methylation regulates gene transcription and is involved in various physiological processes in mammals, including development and hematopoiesis. It is catalyzed by DNA methyltransferases including Dnmt1, Dnmt3a, and Dnmt3b. For Dnmt3b, its effects on transcription can result from its own DNA methylase activity, the recruitment of other Dnmts to mediate methylation, or transcription repression in a methylation-independent manner. Low-frequency mutations in human DNMT3B are found in hematologic malignancies including cutaneous T-cell lymphomas, hairy cell leukemia, and diffuse large B-cell lymphomas. Moreover, Dnmt3b is a tumor suppressor in oncogene-driven lymphoid and myeloid malignancies in mice. However, it is poorly understood how the different Dnmt3b activities contribute to these outcomes. We modulated Dnmt3b activity in vivo by generating Dnmt3b+/- mice expressing one wild-type allele as well as Dnmt3b+/CI and Dnmt3bCI/CI mice where one or both alleles express catalytically inactive Dnmt3bCI. We show that 43% of Dnmt3b+/- mice developed T-cell lymphomas, chronic lymphocytic leukemia, and myeloproliferation over 18 months, thus resembling phenotypes previously observed in Dnmt3a+/- mice, possibly through regulation of shared target genes. Interestingly, Dnmt3b+/CI and Dnmt3bCI/CI mice survived postnatal development and were affected by B-cell rather than T-cell malignancies with decreased penetrance. Genome-wide hypomethylation, increased expression of oncogenes such as Jdp2, STAT1, and Trip13, and p53 downregulation were major events contributing to Dnmt3b+/- lymphoma development. We conclude that Dnmt3b catalytic activity is critical to prevent B-cell transformation in vivo, whereas accessory and methylation-independent repressive functions are important to prevent T-cell transformation.

BIRD-2, a BH4-domain-targeting peptide of Bcl-2, provokes Bax/Bak-independent cell death in B-cell cancers through mitochondrial Ca2+-dependent mPTP opening.

Anti-apoptotic Bcl-2 critically controls cell death by neutralizing pro-apoptotic Bcl-2-family members at the mitochondria. Bcl-2 proteins also act at the endoplasmic reticulum, the main intracellular Ca2+-storage organelle, where they inhibit IP3 receptors (IP3R) and prevent pro-apoptotic Ca2+-signaling events. IP3R channels are targeted by the BH4 domain of Bcl-2. Some cancer types rely on the IP3R-Bcl-2 interaction for survival. We previously developed a cell-permeable, BH4-domain-targeting peptide that can abrogate Bcl-2's inhibitory action on IP3Rs, named Bcl-2 IP3 receptor disrupter-2 (BIRD-2). This peptide kills several Bcl-2-dependent cancer cell types, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukaemia (CLL) cells, by eliciting intracellular Ca2+ signalling. However, the exact mechanisms by which these excessive Ca2+ signals triggered by BIRD-2 provoke cancer cell death remain elusive. Here, we demonstrate in DLBCL that although BIRD-2 activates caspase 3/7 and provokes cell death in a caspase-dependent manner, the cell death is independent of pro-apoptotic Bcl-2-family members, Bim, Bax and Bak. Instead, BIRD-2 provokes mitochondrial Ca2+ overload that is rapidly followed by opening of the mitochondrial permeability transition pore (mPTP). Inhibiting mitochondrial Ca2+ overload using Ru265, an inhibitor of the mitochondrial Ca2+ uniporter complex counteracts BIRD-2-induced cancer cell death. Finally, we validated our findings in primary CLL patient samples where BIRD-2 provoked mitochondrial Ca2+ overload and Ru265 counteracted BIRD-2-induced cell death. Overall, this work reveals the mechanisms by which BIRD-2 provokes cell death, which occurs via mitochondrial Ca2+ overload but acts independently of pro-apoptotic Bcl-2-family members.

Synthesis and biological activity of imidazole group-substituted arylaminopyrimidines (IAAPs) as potent BTK inhibitors against B-cell lymphoma and AML.

Bruton's tyrosine kinase (BTK) is a member of the Tec kinase family and plays a key role in the modulation of the B-cell receptor (BCR)-mediated signaling pathway. Inhibition of BTK has been proven to be an effective therapeutic approach for various hematological malignancies, such as chronic lymphocytic leukemia (CLL), mantle cell leukemia (MCL), diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML). Here, a new series of imidazole group-substituted arylaminopyrimidines (IAAPs) were designed and synthesized as potent inhibitors of the enzymatic activity of BTK with a half maximal inhibitory concentration (IC50) ranging from 13.10 to 42.40 nM. In particular, 11a and 11b exhibited stronger antiproliferative activity against AML and B lymphomas cell lines compared with BTK inhibitor ibrutinib and showed low cytotoxicity against normal peripheral blood mononuclear cells (PBMCs). In addition, analysis of the mechanism of action of these compounds revealed that 11a and 11b induced significant apoptosis in AML and B lymphoma cells by arresting the cell cycle at the G1/G0 or G2/M stage and blocked BTK autophosphorylation as well as the ensuing abrogation of pro-survival AKT and ERK signaling. Taken together, these results suggest that 11a and 11b might serve as valuable preclinical candidates for the treatment of AML and B-cell lymphoma.

Protein arginine methyltransferase 5 represses tumor suppressor miRNAs that down-regulate CYCLIN D1 and c-MYC expression in aggressive B-cell lymphoma.

Protein arginine methyltransferase-5 (PRMT5) is overexpressed in aggressive B-cell non-Hodgkin's lymphomas, including mantle cell lymphoma and diffuse large B-cell lymphoma, and supports constitutive expression of CYCLIN D1 and c-MYC. Here, we combined ChIP analysis with next-generation sequencing to identify microRNA (miRNA) genes that are targeted by PRMT5 in aggressive lymphoma cell lines. We identified enrichment of histone 3 dimethylation at Arg-8 (H3(Me2)R8) in the promoter regions of miR33b, miR96, and miR503. PRMT5 knockdown de-repressed transcription of all three miRNAs, accompanied by loss of recruitment of epigenetic repressor complexes containing PRMT5 and either histone deacetylase 2 (HDAC2) or HDAC3, enhanced binding of co-activator complexes containing p300 or CREB-binding protein (CBP), and increased acetylation of specific histones, including H2BK12, H3K9, H3K14, and H4K8 at the miRNA promoters. Re-expression of individual miRNAs in B-cell lymphoma cells down-regulated expression of PRMT5, CYCLIN D1, and c-MYC, which are all predicted targets of these miRNAs, and reduced lymphoma cell survival. Luciferase reporter assays with WT and mutant 3'UTRs of CYCLIN D1 and c-MYC mRNAs revealed that binding sites for miR33b, miR96, and miR503 are critical for translational regulation of the transcripts of these two genes. Our findings link altered PRMT5 expression to transcriptional silencing of tumor-suppressing miRNAs in lymphoma cells and reinforce PRMT5's relevance for promoting lymphoma cell growth and survival.

New responsibilities for aged kinases in B-lymphomas.

The knowledge accumulated over the last decade on B-cell-derived non-Hodgkin lymphoma (B-NHL) pathogenesis has led to the identification of several molecular abnormalities, opening new perspectives in the design of novel therapies. Indeed, drugs targeting specific biochemical pathways critical for B-NHL cell survival, proliferation, and fitness within the malignant microenvironment are now available to the clinician: the B-cell receptor signaling inhibitors of BTK, PI3Kδ, ζ, γ, and SYK or the pro-apoptotic BH3-mimetics are clear examples of it. Moreover, it is emerging that malignant B-cell growth is sustained not only by mutations in oncogenes/tumor suppressors but also by the "addiction" to nononcogene (ie, nonstructurally altered) molecules. In this regard, a consistent body of data has established that the Ser/Thr kinases CK1, CK2, and GSK3 are involved in malignant lymphocyte biology and act as pro-survival and signaling-boosting molecules, both in precursor and mature B-cell tumors. Currently, an experimental and clinical groundwork is available, upon which to design CK1-, CK2-, and GSK3-directed antilymphoma/leukemia therapies. In this review, we have examined the main features of CK1, CK2, and GSK3 kinases, summarized the data in B-NHL supporting them as suitable therapeutic targets, and proposed a perspective on potential future research development.

Therapeutic potential of PI3K signaling in distinct entities of B-cell lymphoma.

Introduction: Aberrant phosphatidylinositide 3-kinase (PI3K) signaling drives survival and proliferation of malignant B-cells of different lymphoma entities. Thus, inhibition of PI3K isoforms represents a novel and promising therapeutic approach for the treatment of patients with B-cell lymphomas.Areas covered: Here the authors provide an overview about the PI3K signaling pathway as well as available preclinical and clinical results of different PI3K inhibitors in both indolent and aggressive lymphoma entities.Expert opinion: PI3K inhibitors have shown to be efficacious in different entities of B-cell lymphoma, at this stage particularly in relapsed/refractory settings. However, responses of PI3K inhibitors widely vary among different lymphomas. Additionally, especially infectious and immune-mediated toxicities limit their use at this stage. Thus, the decision to use PI3K inhibitors needs to be balanced between the potential efficacy and associated toxicities as well as the availability of other therapeutic options. Future research might eventually lead to the stratification of patients according to the specific oncogenic addictions of the underlying lymphoma. Additionally, PI3K inhibitors will need to be combined with other therapeutic agents for more specific and effective treatment regimens.

The role of aurora A and polo-like kinases in high-risk lymphomas.

High-risk lymphomas (HRLs) are associated with dismal outcomes and remain a therapeutic challenge. Recurrent genetic and molecular alterations, including c-myc expression and aurora A kinase (AAK) and polo-like kinase-1 (PLK1) activation, promote cell proliferation and contribute to the highly aggressive natural history associated with these lymphoproliferative disorders. In addition to its canonical targets regulating mitosis, the AAK/PLK1 axis directly regulates noncanonical targets, including c-myc. Recent studies demonstrate that HRLs, including T-cell lymphomas and many highly aggressive B-cell lymphomas, are dependent upon the AAK/PLK1 axis. Therefore, the AAK/PLK1 axis has emerged as an attractive therapeutic target in these lymphomas. In addition to reviewing these recent findings, we summarize the rationale for targeting AAK/PLK1 in high-risk and c-myc-driven lymphoproliferative disorders.

Inhibiting Bruton's Tyrosine Kinase in CLL and Other B-Cell Malignancies.

Inhibitors of Bruton's tyrosine kinase (BTK), a major kinase in the B-cell receptor (BCR) signaling pathway, mediating B-cell proliferation and apoptosis, have substantially altered the management, clinical course, and outcome of patients with B-cell malignancies. This is especially true for patients with previously limited treatment options due to disease characteristics or coexisting diseases. Ibrutinib was the first orally available, nonselective and irreversible inhibitor of BTK approved for the treatment of patients with various B-cell malignancies. Newer and more selective BTK inhibitors are currently in clinical development, including acalabrutinib, which is currently US FDA approved for previously treated mantle cell lymphoma. Significant efforts are underway to investigate the optimal combinations, timing, and sequencing of BTK inhibitors with other regimens and targeted agents, and to capitalize on the immunomodulatory modes of action of BTK inhibitors to correct tumor-induced immune defects and to achieve long-lasting tumor control. This review describes the major milestones in the clinical development of BTK inhibitors in chronic lymphocytic leukemia and other B-cell malignancies, highlights the most recent long-term follow-up results, and evaluates the role of BTK inhibitors and their combination with other agents in B-cell malignancies and other indications.

Development of BTK inhibitors for the treatment of B-cell malignancies.

BTK is a key component of B-cell receptor signaling and functions as an important regulator of cell proliferation and survival in B-cell malignancies. The first-in-class BTK inhibitor ibrutinib is a small molecule drug that binds covalently to BTK and has been proved to be an effective treatment for various B-cell malignancies. However, it has off-target activities on non-BTK kinases that are related to side effects or might be translated into clinical limitations, with resistance to ibrutinib also reported. Much progress has been made in the development of more selective and second-generation BTK inhibitors. A recent shift in the mechanisms of action of BTK inhibitors is noteworthy, and novel inhibitors acting through noncovalent BTK inhibition are now being developed. This review describes key characteristics of ibrutinib, including current issues of its clinical use, and summarizes preclinical properties and clinical developments of second-generation BTK inhibitors for the treatment of B-cell malignancies. A review of novel noncovalent BTK inhibitors are also included.

Targeting Bruton's Tyrosine Kinase Across B-Cell Malignancies.

Bruton's tyrosine kinase (BTK) is crucial in B-cell development and survival. The role of BTK as a downstream kinase in the B-cell receptor (BCR) signaling pathway is well described. As a key player in the pathogenesis of B-cell malignancies, targeting of dysregulated BCR signaling has been explored by development of inhibitors of downstream mediators. Discovery of the biological function of BTK and the development of covalent inhibitors for clinical use, ibrutinib as the lead agent and acalabrutinib as the second clinically approved BTK inhibitor, have revolutionized the treatment options for B-cell malignancies. Currently, ibrutinib is approved for mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma and chronic graft versus host disease, while acalabrutinib is approved for mantle cell lymphoma. Potential expansion of indications in other diseases is under investigation in several clinical trials, while combination of BTK inhibitors with either chemoimmunotherapy or other targeted agents is being systematically explored in B-cell malignancies.

Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy.

Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 patients with MPN, including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4 (5.8%) of 69 patients receiving JAK1/2 inhibition compared with 2 (0.36%) of 557 with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 patients with MPN. Considering primary myelofibrosis only (N = 216), 3 lymphomas were observed in 31 inhibitor-treated patients (9.7%) vs 1 (0.54%) of 185 control patients. Lymphomas were of aggressive B-cell type, extranodal, or leukemic with high MYC expression in the absence of JAK2 V617F or other MPN-associated mutations. Median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months. Clonal immunoglobulin gene rearrangements were already detected in the bone marrow during myelofibrosis in 16.3% of patients. Lymphomas occurring during JAK1/2 inhibitor treatment were preceded by a preexisting B-cell clone in all 3 patients tested. Sequencing verified clonal identity in 2 patients. The effects of JAK1/2 inhibition were mirrored in Stat1-/- mice: 16 of 24 mice developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B cells. Transplantations of bone marrow from diseased mice unmasked the outgrowth of a malignant B-cell clone evolving into aggressive B-cell leukemia-lymphoma. We conclude that JAK/STAT1 pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. Detection of a preexisting B-cell clone may identify individuals at risk.

Targeting Bruton's tyrosine kinase for the treatment of B cell associated malignancies and autoimmune diseases: Preclinical and clinical developments of small molecule inhibitors.

B cell receptor (BCR) signaling plays a key role in B cell development and function. Aberrant BCR signaling has been confirmed as a central driver for the pathogenesis of various B cell malignancies. Bruton's tyrosine kinase (BTK) is a vital component of BCR signaling and exhibits overexpression in various B cell leukemias and lymphomas. Inhibiting BTK has been proved as an efficient way for B cell malignancy intervention. Remarkable achievements have been made in the pursuit of selective BTK inhibitors, represented by the success of the irreversible BTK inhibitors, ibrutinib and acalabrutinib. Constantly emerging agents exhibiting superior efficacy and safety in preclinical and clinical studies provide promising therapeutics for the treatment of B cell malignancies.

Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study.

BACKGROUND: Activating enhancer of zeste homolog 2 (EZH2) mutations or aberrations of the switch/sucrose non-fermentable (SWI/SNF) complex (eg, mutations or deletions of the subunits INI1 or SMARCA4) can lead to aberrant histone methylation, oncogenic transformation, and a proliferative dependency on EZH2 activity. In this first-in-human study, we aimed to investigate the safety, clinical activity, pharmacokinetics, and pharmacodynamics of tazemetostat, a first-in-class selective inhibitor of EZH2. METHODS: We did an open-label, multicentre, dose-escalation, phase 1 study using a 3 + 3 design with planned cohort expansion at the two highest doses below the maximally tolerated dose. The study was done at two centres in France: Institut Gustave Roussy (Villejuif, Val de Marne) and Institut Bergonié (Bordeaux, Gironde). Eligible patients had relapsed or refractory B-cell non-Hodgkin lymphoma or an advanced solid tumour and were older than 18 years, with Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Tazemetostat was administered orally from 100 mg twice daily to 1600 mg twice daily in 28-day cycles. The primary endpoint was to establish the maximum tolerated dose or recommended phase 2 dose of tazemetostat, as determined by dose-limiting toxicities, laboratory values, and other safety or pharmacokinetic measures in cycle one according to local investigator assessment. Safety was assessed in patients who received at least one dose of tazemetostat; antitumour activity was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01897571. The phase 1 part of the study is complete, and phase 2 is ongoing. FINDINGS: Between June 13, 2013, and Sept 21, 2016, 64 patients (21 with B-cell non-Hodgkin lymphoma, and 43 with advanced solid tumours) received doses of tazemetostat. The most common treatment-related adverse events, regardless of attribution, were asthenia (21 [33%] of 64 treatment-related events), anaemia (nine [14%]), anorexia (four [6%]), muscle spasms (nine [14%]), nausea (13 [20%]), and vomiting (six [9%]), usually grade 1 or 2 in severity. A single dose-limiting toxicity of grade 4 thrombocytopenia was identified at the highest dose of 1600 mg twice daily. No treatment-related deaths occurred; seven (11%) patients had non-treatment-related deaths (one at 200 mg twice daily, four at 400 mg twice daily, and two at 1600 mg twice daily). The recommended phase 2 dose was determined to be 800 mg twice daily. Durable objective responses, including complete responses, were observed in eight (38%) of 21 patients with B-cell non-Hodgkin lymphoma and two (5%) of 43 patients with solid tumours. INTERPRETATION: Tazemetostat showed a favourable safety profile and antitumour activity in patients with refractory B-cell non-Hodgkin lymphoma and advanced solid tumours, including epithelioid sarcoma. Further clinical investigation of tazemetostat monotherapy is ongoing in phase 2 studies in adults and a phase 1 study for children, which are currently enrolling patients who have B-cell non-Hodgkin lymphoma and INI1-negative or SMARCA4-negative tumours. FUNDING: Epizyme and Eisai.

Lactate dehydrogenase levels and 18F-FDG PET/CT metrics differentiate between mediastinal Hodgkin's lymphoma and primary mediastinal B-cell lymphoma.

PURPOSE: This study aims to investigate whether clinical, laboratory, and fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT findings can discriminate between mediastinal Hodgkin's lymphoma and primary mediastinal B-cell lymphoma (PMBCL). PATIENTS AND METHODS: This retrospective study included 56 patients (42 with mediastinal Hodgkin's lymphoma and 14 with PBMCL). Differences in clinical, laboratory, and F-FDG PET/CT metrics were assessed between Hodgkin's lymphoma and PMBCL. RESULTS: Lactate dehydrogenase (LDH) and F-FDG PET/CT-based maximum tumor diameter, lesion-to-liver ratio maximum standardized uptake value (SUVmax), and lesion-to-liver ratio peak standardized uptake value (SUVpeak) were all significantly higher (P<0.001) in PMBCL than in Hodgkin's lymphoma, and PMBCL also significantly more frequently (P=0.001) exhibited necrosis on F-FDG PET/CT than Hodgkin's lymphoma. LDH, maximum tumor diameter, lesion-to-liver ratio SUVmax, and lesion-to-liver ratio SUVpeak yielded areas under the receiver operating characteristic curve of 0.968 [95% confidence interval (CI): 0.923-1.000], 0.866 (95% CI: 0.765-0.968), 0.875 (95% CI: 0.776-0.975), and 0.874 (95% CI: 0.771-0.976), respectively. LDH (with cutoff of 236 U/l) achieved sensitivity and specificity of 81.6 and 100%, respectively; maximum tumor diameter (with cutoff of 9.98 cm) achieved sensitivity and specificity of 87.2 and 78.3%, respectively; lesion-to-liver ratio SUVmax (with cutoff of 7.12) achieved sensitivity and specificity of 94.9 and 64.3%, respectively; lesion-to-liver ratio SUVpeak (with cutoff of 11.45) achieved sensitivity and specificity of 97.4 and 64.3%, respectively; and the presence of necrosis achieved sensitivity and specificity of 78.6 and 74.4%, respectively, in discriminating PMBCL from Hodgkin's lymphoma. CONCLUSION: LDH levels and several F-FDG PET/CT findings (tumor size, presence of necrosis, and degree of F-FDG uptake) are helpful in discriminating mediastinal Hodgkin's lymphoma from PMBCL.