Primary Mediastinal (thymic) Large B-cell Lymphoma Research Articles

Brentuximab Vedotin‐Nivolumab alone and then with Rituximab‐Cyclophosphamide‐Doxorubicin‐Prednisone as Frontline Therapy of Primary Mediastinal Large B‐cell Lymphoma

Introduction: Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma and affects primarily young adults. PMBCL shares several features with classic Hodgkin lymphoma, such as 9p24.1 amplification, increased programmed cell death protein 1 (PD-1) ligand, and CD30 expression. The trial CheckMate-436 treated relapsed/refractory (rr) PMBCL patients with nivolumab (antibody that binds to PD-1) and brentuximab vedotin ((BV) anti-CD30 antibody-drug conjugate), who showed an overall response rate (ORR) of 73% and complete response rate (CRR) of 43% (Zinzani et al. JCO 2019). Although most PMBL patients can be cured with frontline chemoimmunotherapy (CIT) with or without radiotherapy (XRT), the outcome of patients having rr-PMBCL is generally unfavorable. The discovery of new frontline regimens represents an unmet need for PMBL patients. We hypothesize that BV+Nivolumab will show ORR in frontline therapy at least as high as in the rr setting, may avoid chemoresistance, could deescalate the intensity of CIT, and alleviate the need for consolidative XRT. Methods: We are conducting a phase II, open-label, single-center clinical trial NCT04745949 combining BV-Nivolumab alone and then combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for patients with previously untreated PMBL. Patients 18 years or older with previously untreated PMBL, stage I to stage IV disease are eligible. However, patients previously treated with up to one cycle of standard-of-care therapy are eligible. Patients will receive BV 1.8 mg/Kg IV and Nivolumab 240 mg flat dose IV day 1 for cycles 1 and 2, in a 21-day cycle. During cycles 3 and 4, R-CHP will be added to BV-Nivolumab. Patients who have achieved complete response (CR) at PET/CT before cycle 5 will receive 2 more cycles of BV-Nivolumab+R-CHP (cycle 5 and 6) and BV-Nivolumab only for cycles 7 and 8 (A). In case of CR on PET/CT after cycle 8, therapy will be considered completed. Patients in PR on PET/CT before cycle 5 will receive 4 more cycles of BV-Nivolumab+R-CHP (cycles 5–8 (B)). The primary endpoint is CRR at the end of therapy (EOT). The maximum sample size for the PMBL cohort is 40 patients, with a target CRR at EOT of 70%. The null hypothesis is that the true CRR at EOT is 50%, and the alternative hypothesis is that the true CRR at EOT is 70%. The Simon's optimal two-stage design controls the one-sided type I error rate at 0.06 and yields the power of 0.8. The secondary endpoints will include the response rate of BV-Nivolumab+R-CHP at the end of the immune lead-in, landmark survival outcomes, safety, and patient-reported outcome. Exploratory analyses include assessing molecular response by sequencing cell-free DNA and multiplex immunofluorescence to analyze the tumor microenvironment. The research was funded by: Seagen, BMS (drug support only) Keywords: aggressive B-cell non-Hodgkin lymphoma, immunotherapy, ongoing trials Conflicts of interests pertinent to the abstract R. E. Steiner Research funding: Seagen, BMS, GSK, Rafael Pharmaceuticals P. Strati Consultant or advisory role Roche-Genentech, Kite-Gilead, Hutchinson MediPharma, Astrazeneca-Acerta, ADC Therapeutics, Sobi and TG Therapeutics Research funding: Astrazeneca-Acerta, ALX Oncology and ADC Therapeutics S. Ahmed Consultant or advisory role Tessa Therapeutic's advisory committee Research funding: Seattle Genetics, Merck, Xencor, and Tessa Therapeutics J. R. Westin Consultant or advisory role Research funding: Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Abbvie, SeaGen, MonteRosa, Regeneron Research funding: Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Kymera, Calithera

CRC-403: A Phase 1/2 Study of bbT369, a Dual CD79a and CD20 Targeting CAR T Cell Drug Product with a Gene Edit, in Relapsed and/or Refractory B Cell Non-Hodgkin's Lymphoma (NHL)

BACKGROUND: Currently approved CD19 directed CAR T cell therapies have improved outcomes for non-Hodgkin lymphoma (NHL) patients, however only 30-40% of patients treated at 2nd relapse or later obtain long term remission after this treatment (Neelapu et al. 2017; Schuster et al. 2019). A next generation autologous CAR T cell, bbT369, has been devised specifically to address and overcome hypothesized mechanisms of CD19 CAR T cell treatment failure including loss/downregulation of target antigen, loss of co-stimulation pathways on tumor cells, exhaustion of CAR T cells, and CAR T cell dysfunction due to an immunosuppressive microenvironment (Shah and Fry 2019). bbT369 is a dual targeting (CD79a/CD20) CAR T cell that uses an OR gated design (encounter with either antigen activates the CAR T cell) to limit antigen escape. The construct contains split costimulatory domains (CD28 and 41BB) to enhance T cell activation and a gene edit knocking-out CBLB function intended to enhance potency and reduce T cell exhaustion. Studies have demonstrated CD79a and CD20 may be ideal targets in B cell lymphoma, with high tissue restricted expression. In Daudi cell and mouse models, bbT369 outperformed CD19 directed CAR T cells demonstrating increased IL-2 secretion and longer durations of tumor control (Certo et al, 2022). METHODS: CRC-403 (NCT05169489) is a non-randomized, open label, multi-site Phase 1/2 study enrolling relapsed and/or refractory B Cell Non-Hodgkin's Lymphoma (NHL), including diffuse large B cell lymphoma (DLBCL), high-grade B cell lymphoma (HGBCL), primary mediastinal (thymic) large B cell lymphoma (PMBCL), follicular lymphoma (FL) 3b, and DLBCL transformed from FL (tFL). Patients must have relapsed after ASCT or after at least 2 prior lines of therapy, including an anti-CD20 monoclonal antibody and an anthracycline containing chemotherapy regimen. Patients with tFL must be relapsed after receipt of ASCT or at least 2 prior therapies after documentation of transformation. In addition to patients naïve to CAR T cell therapy, patients with prior exposure to non-investigational CD19 CAR T cell therapy are eligible for enrollment if they did not experience disease progression within 6 weeks of initial CAR T cell infusion. Approximately 50 patients will be enrolled during the dose escalation phase to ensure a maximum of 36 subjects will be treated with bbT369. The primary endpoint of the phase 1 portion of this study is incidence of safety events, including adverse event, adverse events of special interest and dose limiting toxicities. Secondary endpoints include investigator assessed overall response rate including complete response rate, time to response, time to complete response and time to next therapy for B-NHL. Exploratory endpoints include OS, DOR, PFS, bbT369 expansion kinetics including expansion and persistence, immunophenotype in peripheral blood and tumor biopsy tissue with the objective of correlating findings with clinical response. The starting dose of bbT369 is 50x106 CAR+ T cells and a BOIN design is being used for dose escalation/de-escalation decisions during the study. Upon establishment of the RP2D, the phase 2 portion will begin enrollment.

CRC-403: A phase 1/2 study of bbT369, a dual targeting CAR T-cell drug product with a gene edit, in relapsed and/or refractory B-cell non-Hodgkin lymphoma (NHL).

TPS7580 Background: Although CD19 directed CAR T cell therapies have improved outcomes for non-Hodgkin's lymphoma (NHL) patients, only about 30-40% of 3L+ patients obtain long term remission after this treatment (Neelapu et al. 2017; Schuster et al. 2019). bbT369, a next generation, dual targeted (CD79a/CD20), gene edited (CBLB gene knock out) autologous CAR T cell therapy was devised to overcome hypothesized mechanisms of CD19 CAR T cell treatment failure including loss/downregulation of target antigen, loss of co-stimulation pathways on tumor cells, exhaustion of CAR T cells, and CAR T cell dysfunction due to an immunosuppressive microenvironment (Shah and Fry 2019). bbT369 uses an OR gated design to limit antigen escape and contains split costimulatory domains (CD28 and 41BB) to enhance T cell activation. Methods: CRC-403 (NCT05169489) is a non-randomized, open label, multi-site phase 1/2 study enrolling relapsed and/or refractory B cell non-Hodgkin’s lymphoma (NHL), including diffuse large B cell lymphoma (DLBCL), high-grade B cell lymphoma (HGBCL), primary mediastinal (thymic) large B cell lymphoma (PMBCL), follicular lymphoma (FL) 3b, and DLBCL transformed from FL (tFL). Patients must have relapsed after ASCT or at least 2 prior lines of therapy. Patients with tFL must be relapsed after receipt of ASCT or at least 2 prior therapies after documentation of transformation. Patients with previous exposure to non-investigational CD19 directed CAR T cell therapy who did not experience disease progression within 6 weeks of initial CAR T cell infusion are eligible for enrollment. Approximately 50 patients will be enrolled in the phase 1 portion. The primary endpoints of the phase 1 portion are determination of the MTD, determination of recommended phase 2 dose (RP2D) and safety. Secondary endpoints include overall response rate, complete response rate, time to response and time to next anti-lymphoma treatment. Exploratory endpoints include DOR, PFS, OS, CAR+ T cell expansion and correlations between clinical response and T cell phenotype or antigen expression on tumor cells. The starting dose of bbT369 will be 50x106 CAR+ T cells and a BOIN design will be used for dose escalation/de-escalation decisions during the study. Upon establishment of the RP2D, the phase 2 portion will begin enrollment. Clinical trial information: NCT05169489.

UNEXPECTED CAUSE OF POSTPARTUM CARDIAC ARREST: PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA

TOPIC: Disorders of the Mediastinum TYPE: Medical Student/Resident Case Reports INTRODUCTION: Lymphoma is the fourth most common malignancies in pregnancy, and a high portion is primary mediastinal (thymic) large B-cell lymphoma (PMBCL). It presents many challenges to diagnose lymphoma during pregnancy while avoiding fetal harm. CASE PRESENTATION: 41-year-old G2P1 female without significant past medical history experienced shortness of breath starting in her second trimester. She only had a telehealth appointment amid the COVID19 pandemic. The patient was offered a chest X-ray (CXR) but declined due to her concern of radiation. She was empirically managed as asthma triggered by acid reflux. At 39W of gestation, she presented to the hospital for labor and delivery. She was hypoxic and required three liters of oxygen. The physical exam was unremarkable. Lab were pertinent for mild leukocytosis and anemia. The patient still declined CXR. She was taken for C-section after failing trial of vacuum. The newborn was healthy. After delivering, she developed profound hypoxia in the OR requiring intubation. Tracheal compression was noted during intubation. CXR after intubation showed mediastinal widening. Following intubation, patient developed tachycardia, hypotension and ultimately cardiac arrest requiring CPR. Extracorporeal membrane oxygenation was activated. CT angiogram of the chest showed a 15 cm x 12 cm x 13 cm mass in the superior mediastinum that encases the aorta and great branches and was associated with direct extension into the sternum and invasion of the pericardium. The tumor also encased the trachea and left main bronchus. During her hospitalization, no neurological recovery was observed. The family decided to transition to comfort. The patient unfortunately passed away. The autopsy revealed neoplastic medium to large-size lymphoid cells in mediastinal mass, positive for CD45, CD20, BCL2, PAX-5, MUM-1, and MYC rearrangement negative for other markers. The final diagnosis was PMBCL. DISCUSSION: PMBCL is an aggressive B cell lymphoma arises from the thymus. Airway obstruction and superior vena cava syndrome are common due to local invasion. Dyspnea, B symptoms (fever, night sweats, weight loss) are possible symptoms. Labs may reveal elevated lactate dehydrogenase. Imaging studies typically illustrate an anterior mediastinal mass originating in the thymus. Final diagnosis can be made with biopsy and immunohistochemistry or flow cytometry analysis. Early recognition is important since these patients are at risk of cardiac and respiratory arrest during general anesthesia due to the mass location in the mediastinum. Pregnant patients should be informed that there is no evidence of fetal adverse outcome with imaging studies that expose the fetus to less than 50 mGy (CXR fetal dose: 0.0005 to 0.01 mGY). CONCLUSIONS: PMBCL should be identify early in pregnancy due to increased risk of cardiac and respiratory arrest. CXR is safe and harmless to the fetus. REFERENCE #1: Brenner B, Avivi I, Lishner M. Haematological cancers in pregnancy. Lancet. 2012;379(9815):580-587. REFERENCE #2: Dunleavy K, McLintock C. How I treat lymphoma in pregnancy. Blood. 2020 Nov 5;136(19):2118-2124. doi: 10.1182/blood.2019000961. PMID: 32797210. REFERENCE #3: Brent RL. The effect of embryonic and fetal exposure to x-ray, microwaves, and ultrasound: counseling the pregnant and nonpregnant patient about these risks. Semin Oncol. 1989 Oct;16(5):347-68. PMID: 2678486. DISCLOSURES: No relevant relationships by John Chronakas, source=Web Response No relevant relationships by Patrice Gillotti, source=Web Response No relevant relationships by Tien-Chan Hsieh, source=Web Response No relevant relationships by Oluwaseyi Olayinka, source=Web Response No relevant relationships by Nusrat Pathan, source=Web Response No relevant relationships by Akash Shah, source=Web Response No relevant relationships by Amanda Tissot, source=Web Response

Cytogenetic and Molecular Genetic Abnormalities of CIITA Gene in Patients with Primary Mediastinal (Thymic) Large B-Cell Lymphoma

Background. Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is an aggressive malignant lymphoproliférative disease which accounts for 2-3 % of all non-Hodgkin's lymphomas. In 40 % of PMBCL cases rearrangements of the MHC class II activator, i.e. CIITA gene, are observed. CIITA abnormalities lead to decreasing protein expression and surface expression of MHC class II, which results in lack of adaptive cell immunity targeted at tumor cells. Aim. To assess the rate and spectrum of cytogenetic and molecular genetic abnormalities of CIITA gene in PMBCL patients. Materials & Methods. The study enrolled 37 patients with diagnosed PMBCL: 10 men and 27 women aged 21-61 years (median of 31 years). Sanger sequencing was performed in 36 patients. In 20 patients CIITA/16p13.13 FISH and in 15 patients standard cytogenetic analysis were carried out. Results. In 3 (8.3 %) out of 36 patients the sequencing method detected mutations impairing CIITA gene function, as well as microdeletion in exon 1, deletion and nucleotide substitution in a splice donor site. Multiple somatic variations in intron 1 were identified in 21 (58.3 %) patients: in 11 (52.4 %) cases there were deletions and single nucleotide variants (SNV); the other 10 (47.6 %) patients showed only SNVs. In 13 (61.9 %) out of 21 cases the abnormalities of promoter IV and/or alternative exon 1 were observed. In 5 (25 %) out of 20 patients the FISH assay identified CIITA gene translocation. Standard cytogenetic analysis detected complex karyotype in 7 (46.6 %) out of 15 patients. The comparison of data showed hypermutagenesis in 8 out of 10 patients with FISH-detected chromosome aberrations, and in 3 (37.5 %) of them complex karyotype aberrations were found as well. Conclusion. Molecular genetic methods identified different somatic variations in CIITA gene affecting its functionally important regions, which can be of special interest for further studying the biology of tumors, including PMBCL.

Primary Mediastinal B-Cell Lymphoma: The Dilemma of Radiotherapy

Introduction: According to the WHO classification, primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a distinct entity, which has a close relationship with nodular sclerosing classical Hodgkin's lymphoma (cHL) in terms of clinical and molecular characteristics and sharing an excellent prognosis. When PMBCL is treated with R-CHOP, the addition of radiotherapy (RT) turns more than 90% of positron emission tomography (PET) positive cases into complete remissions (CR) and increases 5-year overall survival (OS) to 93%. However, the fear of potential late toxicities due to RT, has led an increasing number of centers to favor more intensive regimens like DA-EPOCH-R without RT. This controversy is deepened by the recent comparison between the latter regime with R-CHOP, unfavorable to the DA-EPOCH-R for toxicity reasons. Objective: Evaluate the effectiveness and late toxicities of R-CHOP plus RT in our center and secondarily compare these results with the ones obtained in our cHL patients with bulky and early stage disease. Methods: Retrospective analysis of patients with PMBCL treated between Jan/2007 and Dec/2017 according to clinical characteristics, late toxicities, rate of CR, OS and disease-free survival (DFS) estimated by Kaplan-Meier method. Results: In 32 patients with a median age of 34 years (23-70), 56% were male, 91% had limited stage and 6% had an unfavorable IPI. The rate of CR was 91% (2 patients needed second line therapy to achieve CR) with 2 relapses (at 6 and 11 months, respectively) rescued with autologous transplantation. Three deaths were recorded due to disease progression. With a median follow-up of 86 months, OS and DFS at 10 years were 91% and 93%, respectively. As for late toxicities, besides 2 cases of severe pulmonary fibrosis, there were no other relevant late toxicities registered. These results overlap those obtained in our cHL patients with bulky and early stage disease treated with Stanford V plus RT with an OS and an event free survival of 93% and 84%, respectively. Conclusion: These results support PMBCL's excellent prognosis, parallel to that of cHL. Given the low probability of late toxicities with this regimen our data uphold against the therapeutic strategy of more intensive regimens, that have an increased management complexity and are clinically more toxic. Disclosures No relevant conflicts of interest to declare.

Primary Mediastinal (Thymic) Large B-cell Lymphoma: The Working Diagnosis vs WHO Classification Criteria

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is an uncommon but distinct entity in the WHO classification of hematologic malignancies. Accurately diagnosing PMBCL is challenging as it is a clinicopathological entity. There are no pathognomonic features. Many characteristics overlap with diffuse large B-cell lymphoma NOS, nodular sclerosis Hodgkin lymphoma, and so-called “grey-zone” lymphomas. Thus, it is likely that patients are occasionally misdiagnosed as having PMBCL. Accurate diagnosis is critical as it impacts systemic therapy selection and receipt of radiation therapy (RT). We sought to investigate the fidelity between a working diagnosis of PMBCL at our institution and the clinicopathological criteria established within the 2017 WHO classification. Patients treated for stage I-II PMBCL from 1998-2018 at our institution were retrospectively reviewed for clinical and pathological conformity with WHO criteria in collaboration with a hematopathologist who reviewed archival tissue. Patients were characterized as definitely having PMBCL if they had all of the following: an anterior mediastinal mass +/- regional lymph node involvement, no extranodal disease, B-cell antigen expression, and supportive feature(s)- female gender, young age, bulky primary tumor, CD30 weakly positive, compartmentalizing alveolar fibrosis, lack of surface immunoglobulin expression, and MUM1 or CD23 positivity. Patients without supportive features were characterized as equivocal. PMBCL was excluded if they had any of the following: no anterior mediastinal mass, distant lymph node involvement or extranodal disease, lack of B cell antigen expression, or EBV positivity. 63 patients were evaluated. 71% were female. Median age- 35 years (range, 20-73). Stage 1- 51%; stage II- 49%. Median mediastinal mass size- 10 cm (range, 3-20). 48% of patients received R-CHOP, 32% R-EPOCH, and 21% received other chemotherapy regimens; 79% received rituximab; 83% of patients received 6 chemotherapy cycles. 86% of patients had a post chemotherapy PET/gallium response assessment (78% CR; 22% PR). 64% of patients received RT with PR patients more likely to receive RT (83% vs 62%, p = 0.16). Median follow up was 6 years. Overall, 92% of patients met WHO criteria for PMBCL; 5% (n = 3) did not meet criteria, all due to a lack of an anterior mediastinal mass. 3% were equivocal- grey zone lymphoma (n = 1) and lack of supportive features (n = 1). 5-year PFS and OS was 67% (95% CI 54-77%) and 81% (95% CI 68-89%), respectively. Failure to receive rituximab was the only predictor associated with inferior PFS on univariate analysis, HR 2.79 (1.15, 6.78). Despite the complexity of the clinicopathological criteria of PMBCL, most (92%) patients who were treated for stage I-II PMBCL at our institution appear to have been accurately diagnosed. Treatment regimens varied significantly given changes in patterns of care over the time period. The importance of rituximab was confirmed.

Relapsed/refractory primary mediastinal large B-cell lymphoma: a structured review of epidemiology, treatment guidelines and real-world treatment practices

ABSTRACTBackground: Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is an uncommon subtype of diffuse large B-cell lymphoma. Approximately 10–30% of patients experience refractory or relapsed PMBCL (rrPMBCL) after first-line therapy. Data and treatment guidelines for rrPMBCL are scarce, and management is based on clinical experience.Methods: Two structured literature reviews were undertaken to determine the incidence, prevalence, and mortality rates associated with rrPMBCL, and to identify clinical practice guidelines and real-world patterns of care.Results: Epidemiology studies included reported lymphomas (n = 1), non-Hodgkin lymphoma (n = 1), lymphoid neoplasm (n = 1), PMBCL (n = 6), and rrPMBCL (n = 1). Of 12 published treatment guidelines, only four provided recommendations for rrPMBCL. Sixteen studies provided data on real-world treatment patterns, but most were single-center studies with small patient numbers. Chemotherapy/immunochemotherapy, followed by high-dose treatment (HDT) and stem cell transplantation, was a mainstay of salvage therapy in most studies; real-world care generally followed treatment guidelines.Conclusions: Salvage chemotherapy (often with rituximab and radiotherapy), followed by HDT and stem cell transplantation, appears to be the standard real-world treatment for rrPMBCL. However, large prospective and retrospective studies are warranted to improve our knowledge of real-world treatment patterns.

Rearrangements of Immunoglobulin Genes in Tumor Cells of Patients with Primary Mediastinal (Thymic) Large B-Cell Lymphoma

Background. Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a malignant tumor with large atypical lymphoid cells expressing post-germinal differentiation markers. Rearrangements of immunoglobulin genes in PMBCL are revealed in 30-65 % of cases. Immunoglobulin molecules, however, are expressed neither on the surface, nor in cytoplasm of tumor cells. Aim. To assess cell clonality rate on the basis of rearrangements of immunoglobulin heavy/light chain genes; to determine rearrangement stability at the time of relapse development; to study the range of rearrangements and clonal relationship with primary tumor in metachronous development of mediastinal gray zone lymphoma. Materials & Methods. The assessment of rearrangements of immunoglobulin heavy/light chain genes was based on molecular analysis of 29 primary tumor biopsies and 4 tissue samples with histologically and immunohistochemically verified relapses or metachronous lymphoma development. Results. In 16 (55.2 %) out of 29 cases a rearrangement of immunoglobulin heavy chain genes was reported, in 7 (24.1 %) cases a rearrangement of light chain genes was identified, in 6 (20.7 %) cases no rearrangements of immunoglobulin heavy/light chain genes were found. On the basis of immunoglobulin gene analysis in 2 patients with early relapse a tumor clone was detected that was identical with the one identified at the onset of the disease. In 2 patients with complete remission a metachronous development of mediastinal gray zone lymphoma was reported, whereas molecular genetic analysis revealed a change/disappearance of initial clonal rearrangements of immunoglobulin genes. Conclusion. Total detection rate of B-cell clonality in PMB-CL was 79.3 %. Molecular genetic analysis confirmed that initial clonal rearrangements of immunoglobulin genes were preserved in early relapses, and invalidated tumor clonal relationship in a metachronous development of mediastinal gray zone lymphoma.

Primary Mediastinal (Thymic) Large B-Cell Lymphoma: Experience in Treating 131 Patients at a National Medical Research Center in Russia

Background. Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is one of the primary extranodal tumors and originates from B-cells of thymic medulla. This disease is characterized by specific immunomorphologic and genetic features which distinguish it from other malignant lymphoproliferative disorders with similar parameters. Standard PMBCL treatment consists of immunochemotherapy and subsequent radiotherapy of residual mediastinal tumor. The advantages of one immunochemotherapy regimens over the other in controlled studies have not been shown. Aim. To study current approaches to chemoradiation in PMBCL patients with an attempt to individualize them focusing on various prognostic factors. Materials & Methods. The data of 131 patients with newly diagnosed PMBCL were analyzed, all of them were treated at NN Blokhin National Medical Cancer Research Center in the period from 2000 to 2017. More than a half were women (58 %), median age was 30 years (range 16-70). At different historical periods PMBCL treatment was performed using different immunochemotherapy regimens: MACOP-B±R in 55 (42 %) patients, R-CHOP in 40 (30.5 %) patients, and R-DA-EPOCH in 36 (27.5 %) patients. Radiotherapy was used to treat 99 out of 131 patients. Results. In general, the treatment of all PMBCL patients (n = 131) appeared to be highly effective. The remission rate was 87 %, 3-year progression-free survival (PFS) and overall survival (OS) was 78 % and 88 %, respectively. With median follow-up of 37 months relapses and progression of the disease were detected in 17 (13 %) out of 131 patients within a period of 13 months after initiation of antitumor treatment. There was not a single case of late relapse. The treatment of relapsed patients was not effective: 12-month OS was not higher than 37 %. Intensive immunochemotherapy regimens ACOP±R, R-DA-EPOCH) do not differ in their effectiveness, but they have significant advantages over the standard R-CHOP regimen. The results of positron emission tomography (PET) considered to be an important prognostic factor in PMBCL treatment: 3-year PFS in the PET-negative group was 92 % vs. 26 % in the PET-positive group. Conclusion. The optimal algorithm of PMBCL treatment was elaborated with consideration of clinical factors, immunochemotherapy programs, degrees of tumor regression, its metabolic activity, and radiotherapy method and irradiation area.

Primary Mediastinal (Thymic) Large B-Cell Lymphoma: Diagnostics of Extramediastinal Lesions and Treatment Opportunities

Background. Current diagnostic methods and the introduction of molecular investigations into clinical practice allow to improve the understanding of classical primary mediastinal (thymic) large B-cell lymphoma (PMBCL). Aim. To investigate clinical characteristics of PMBCL patients with extramediastinal lesions. Materials & Methods. The study was performed from 2007 to 2017 in the National Medical Hematology Research Center and included 157 PMBCL patients. The data of 16 (10.2 %; 4 men and 12 women) patients with extramediastinal lesions were analyzed; the median age was 27 years (range 23-69). Results. The extramediastinal lesions were found in pancreas (6; 37.5 %), kidneys (5; 31.2 %), ovaries (3; 18.7 %), liver (3; 18.7 %), bone marrow (3; 18.7 %), and breasts (2; 12 %); the lesions in stomach, bones, soft tissues, spleen, adrenals, and small pelvis were observed each in a single case. In 15 of 16 cases extramediastinal lesions were accompanied by involvement of superior mediastinum, and only 1 patient had an isolated lesion in thoracic soft tissues without mediastinal involvement. The samples of 8 out of 16 patients were analyzed using PCR. In all samples overexpression of 2 or more genes (JAK2, TRAF1, MAL, PDL1, PDL2) was determined which allowed to confirm, and in some cases to revise the diagnosis of PMBCL. Overall 5-year survival (93 %) of patients with classical PMBCL with thoracic involvement was similar to the cohort with extramediastinal lesions. All unfavourable events (progression/ relapse) were identified at an early stage, i.e. within a year after the completion of therapy. Conclusion. PMBCL patients can have not only superior mediastinum involvement, but extramediastinal lesions as well, including bone marrow. The spreading of the disease beyond superior mediastinum should be differentiated from diffuse large B-cell lymphoma using standard evaluation methods, and molecular analysis in some cases.

R-CHOP versus dose-adjusted R-EPOCH in frontline management of primary mediastinal B-cell lymphoma: a multi-centre analysis.

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is an uncommon subtype of non-Hodgkin lymphoma (NHL) that presents with a mediastinal mass and has unique clinicopathological features. Historically, patients with PMBCL were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy±involved field radiation. Since a phase II trial, published in April 2013, demonstrated excellent results using dose-adjusted (DA) R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), this treatment has gained popularity. We performed a retrospective, multicentre analysis of patients aged ≥18years with PMBCL since January 2011. Patients were stratified by frontline regimen, R-CHOP versus DA-R-EPOCH. 132 patients were identified from 11 contributing centres (56 R-CHOP and 76 DA-R-EPOCH). The primary outcome was overall survival. Secondary outcomes included progression-free survival, complete response (CR) rate, and rates of treatment-related complications. Demographic characteristics were similar in both groups. DA-R-EPOCH use increased after April 2013 (79% vs. 45%, P<0·001), and there was less radiation use after DA-R-EPOCH (13% vs. 59%, P<0·001). While CR rates were higher with DA-R-EPOCH (84% vs. 70%, P=0·046), these patients were more likely to experience treatment-related toxicities. At 2years, 89% of R-CHOP patients and 91% of DA-R-EPOCH patients were alive. To our knowledge, this represents the largest series comparing outcomes of R-CHOP to DA-R-EPOCH for PMBCL.

Primary Mediastinal (Thymic) Large B-Cell Lymphoma

Primary mediastinal (thymic) large B-cell lymphoma (PMB-CL) is one of the primary extranodal tumors and originates from thymic medulla B cells. The disease is more common in young women and declares itself by mainly locally advanced growth within the anterior upper mediastinum with frequent involvement of chest organs. PMBCL has specific morphological, immunological, and genetic characteristics that permit to differentiate it from other similar diseases: diffuse large В-cell lymphoma, nodular sclerosis Hodgkin’s lymphoma, and mediastinal gray zone lymphoma. Immunochemotherapy with subsequent irradiation of the residual mediastinal tumor is the standard treatment of PMBCL. No benefits of one drug therapy over another have been demonstrated to date in controlled studies. Application of new imaging techniques (PET/CT) may result in withdrawal of the radiotherapy in some PMBCL patients without impairment of delayed survival rates.

Utility of baseline 18FDG-PET/CT functional parameters in defining prognosis of primary mediastinal (thymic) large B-cell lymphoma

AbstractThe International Extranodal Lymphoma Study Group (IELSG) 26 study was designed to evaluate the role of 18F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) in the management of primary mediastinal (thymic) large B-cell lymphoma (PMBCL). We examined the prognostic impact of functional PET parameters at diagnosis. Metabolic activity defined by the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) was measured on baseline 18FDG PET/CT following a standard protocol in a prospectively enrolled cohort of 103 PMBCL patients. All received combination chemoimmunotherapy with doxorubicin- and rituximab-based regimens; 93 had consolidation radiotherapy. Cutoff values were determined using the receiver-operating characteristic curve. At a median follow-up of 36 months, progression-free survival (PFS) and overall survival (OS) were 87% and 94%, respectively. In univariate analysis, elevated MTV and TLG were significantly associated with worse PFS and OS. Only TLG retained statistical significance for both OS (P = .001) and PFS (P < .001) in multivariate analysis. At 5 years, OS was 100% for patients with low TLG vs 80% for those with high TLG (P = .0001), whereas PFS was 99% vs 64%, respectively (P < .0001). TLG on baseline PET appeared to be a powerful predictor of PMBCL outcomes and warrants further validation as a biomarker. The IELSG 26 study was registered at www.clinicaltrials.gov as #NCT00944567.

Large B-cell lymphomas in adolescents and young adults in comparison to adult patients: a matched-control analysis in 55 patients

The aim of our study was to assess whether large B-cell lymphoma (LBCL) in adolescents and young adults (AYA) should be considered as a clinocopathological entity, and to evaluate the prognostic value of age. Fifty-five patients aged > 15–30 years were fully matched to 365 adult patients aged 31–65 years. We found a high incidence of primary mediastinal thymic LBCL subtype (33% vs. 5%), while histological transformation was rare (2% vs. 14%). LBCL in AYA presented with a bulky mediastinal mass (51% vs. 21%), and the lactate dehydrogenase (LDH) value was significantly higher (73% vs. 54%). The complete response rate to chemotherapy was similar in the two groups. Five-year overall survival (OS) and event-free survival (EFS) of AYA were 73% and 68%, respectively. The matched-control analysis showed no difference for either OS or EFS. LBCL in AYA presents with some critical features which differ from those of older adults. However, the outcome is equivalent to that observed in older patients.

Clinicopathological analysis of mediastinal large B-cell lymphoma and classical Hodgkin lymphoma of the mediastinum

Primary mediastinal (thymic) large B-cell lymphoma (PMLBCL) and nodular sclerosing classical Hodgkin lymphoma (NSCHL) are the major histological types of lymphoma affecting the mediastinum. We reviewed 27 patients with PMLBCL and 14 patients with NSCHL. A poor performance status, high serum lactate dehydrogenase level and strong positivity for PAX5 were all significantly more common in patients with PMLBCL than in those with NSCHL. Severe fibrosis was frequent in NSCHL, but not in PMLBCL. PDL1 was expressed by 11/25 PMLBCLs (44.0%) vs. 1/9 NSCHLs (11.1%). Expression of BCL6 was significantly more frequent in PDL1-positive PMLBCL than in PDL1-negative PMLBCL, but there were no clinical differences between these two groups. Two patients with PMLBCL with a poor prognosis had CD20(−), CD79a(+), CD15(−), and CD30(−), possibly representing a subtype of mediastinal gray zone lymphoma.

Clinicopathologic study of 40 cases of mediastinal tumours of haematopoietic and lymphoid tissues

To study clinical and histopathological features, and diagnosis of mediastinal tumours of haematopoietic and lymphoid tissues (MTHL). Forty cases of MTHL were analyzed for clinicopathology by microscopy and immunohistochemical staining and in situ hybridization, according to the updated 2008 WHO classification of tumours of haematopoietic and lymphoid tissues. In 40 cases of MTHL, there were 20 males and 20 females. The ratio of male/female was 1:1. The mean age was 31.8 years and median age was 29 years (range, 12 - 70 years).Superior vena cava syndrome was observed in 28 cases. The specimens of 4 cases were obtained by lumpectomy, whereas 36 cases by biopsy (25 cases by thoracoscopy, 1 by core needle aspiration). Twenty cases lay in anterior mediastinum, and 2 in posterior, 1 in superior, 8 in anterior and superior, 2 in posterior and superior, 2 in anterior and middle, 1 in middle and anterior mediastinum.Frozen section were performed in 28 cases, and 17 cases were diagnosed as tumours of haematopoietic and lymphoid tissues (consistency ratio was 60.7%). Twelve cases were classical Hodgkin lymphomas (cHL) (8 were nodular sclerosis subtype, and 3 were mixed cellarity, 1 was lymphocyte-rich subtype), and 10 were primary mediastinal (thymic) large B cell lymphoma (PMBCL), 10 were precursor lymphocyte neoplasm [8 were T lymphoblastic leukemia/lymphomas (T-LBL), 2 were B-LBL], 1 was MALT lymphoma, 1 was composite lymphoma (PMBCL and cHL), 2 were myeloid sarcomas, 4 were gray zone lymphomas (GZL) (3 had morphology reminiscent of cHL, and 1 of DLBCL, all cases were positive for CD20, PAX5, CD30 and CD15).EBER were detected in 11 cases by in situ hybridization, 2 of which were positive (18.2%), and the 2 positive cases were cHL. MTHLs occur predominantly in adolescents and young adults, mainly present as superior vena cava syndrome and anterior mediasinal masses. cHL, PMBCL, T-LBL were the most common MTHLs.GZLs mainly occur in young adults, those whose morphology reminiscent of cHL, immunohistochemistry reminiscent of PMBCL, and vice versa. Thoracoscopy, frozen section and a suitable panel of antibodies were practical approaches to MTHL.

Adolescents and young adults versus adults’ patients with large B-cell lymphoma: A matched-control analysis on 55 patients.

e18526 Background: Among non-Hodgkin’s lymphomas, large B-cell lymphoma (LBCL) accounts for 60% in adolescents and young adults (AYA). There are no so many reports in the literature on LBCL in AYA patients. Moreover, there are no data available to suggest whether AYA patients with LBCL would benefit more from pediatric-chemotherapy regimen or from adult rituximab-chemotherapy treatment. In order to clarify this point, we conducted a matched-control analysis comparing AYA patients and adult’s patients with LBCL. Methods: We performed a clinical and pathological review of LBCL cases referred to our institution over a 15-year period from 1996 to 2010. Fifty-five AYA (16-30 years) were fully matched to 165 adult’s patients aged between 31 years and 65 years (ratio 1/3) for each of the following factors: international prognostic index (IPI), chemotherapy regimen, and rituximab delivery. Results: When compared to LBCL adults’ patients, pathological features in AYA showed a high incidence of primary mediastinal thymic LBCL subtype (33% vs. 5%, P= 0, 0001), while histological transformation was rare (2% vs. 14%, P= 0, 01). LBCL in AYA also presented with a bulky mediastinal mass (51% vs. 21%, P= 0, 0001), gastrointestinal tract involvement was less frequent (2% vs. 13%, P=0, 03), and LDH value was significantly higher (73% vs. 54%, P= 0, 01). The complete response rate to chemotherapy combination regimen was at 82% in AYA, with no difference with that observed in adult patients (82%, P=0, 8). With a median follow-up of 80 months, the 5-year overall survival (OS) and event-free survival (EFS) of AYA patients were at 73% ± 12% and 68% ± 12%, respectively. The matched-control analysis showed no difference either for OS (P = 0.8) or EFS (P = 0.9). Conclusions: LBCL in AYA should be considered as a true clinical and pathological entity. However, age does not confer a prognostic value different from that observed in LBCL in patients older than 30 years.

Mediastinal lymphomas: Primary Mediastinal (Thymic) Large B-cell Lymphoma versus classical Hodgkin lymphoma, histopathologic dilemma solved?

Primary Mediastinal (Thymic) Large B-cell Lymphoma (PMLBL) frequently demonstrates clinical, morphologic and/or immunohistochemical (IHC) features that overlap with mediastinal-classical Hodgkin lymphoma (cHL). Our study compared the immunohistochemical profile of PMLBL versus mediastinal cHL in a cohort of 18 patients, 11 of whom were diagnosed as having PMLBL, and 7 were diagnosed as having mediastinal cHL. Biopsy slides and blocks of all patients were retrieved, and further immunohistochemical workup was done on all the cases. This included staining with a panel of antibodies, including LCA, CD 20, CD 3, CD 30, CD 15, and IRF4/MUM1. All PMLBL cases (100%) showed positivity both for LCA and Pan B (CD 20), and negativity for Pan T (CD 3). All mediastinal cHL cases (100%) showed negativity both for LCA and Pan T (CD 3). Both entities showed variable positivity for IRF4/MUM1, i.e., 73% in PMLBL versus 100% in cHL. CD 30 was expressed in 36% cases of PMLBL versus 100% cases of cHL. CD 15 was expressed in a single case of PMLBL versus 86% cases of cHL. We conclude that ‘Leucocyte Cell Antigen’ (LCA) is the only marker that was consistently positive in PMLBL and negative in cHL. Other IHC markers, though still helpful, may be expressed in either entity.

Molecular profiling provides evidence of primary mediastinal large B-cell lymphoma as a distinct entity related to classic Hodgkin lymphoma: implications for mediastinal gray zone lymphomas as an intermediate form of B-cell lymphoma.

Expanding on prior studies that have used molecular profiling to elucidate the heterogeneity of diffuse large B-cell lymphomas (DLBCLs), two recent studies (Rosenwald et al and Savage et al) have characterized a third molecularly distinct subtype of DLBCL, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL). Both groups found distinct gene expression patterns that were able to reliably diagnose PMLBCL and distinguish it from other DLBCLs. Notably, the signature gene expression profile of PMLBCL was more closely related to classic Hodgkin lymphoma (CHL) than other DLBCL subtypes. These studies provide further evidence that PMLBCL and nodular sclerosis CHL may represent related tumors on either ends of a continuum, whose interface includes an intermediate form of disease, mediastinal gray zone (MGZL) lymphoma. MGZLs are tumors that have a transitional morphology and phenotype, combining features of both PMLBCL and nodular sclerosis CHL, and provide a diagnostic challenge to pathologists. These studies provide insights into the biology of PMLBCL and CHL and demonstrate the utility of genomic technologies in defining and diagnosing hematopoietic tumors. The ability to map specific pathologic signal transduction pathways regulating hematopoietic differentiation, proliferation, and apoptosis through genomic or proteomic technologies promises to provide the basis for the development of individualized molecularly targeted therapies for specific tumors.