Primary Mediastinal Large B-cell Lymphoma Patients Research Articles

Evaluating Outcome Prediction via Baseline, End-of-Treatment, and Delta Radiomics on PET-CT Images of Primary Mediastinal Large B-Cell Lymphoma.

Accurate outcome prediction is important for making informed clinical decisions in cancer treatment. In this study, we assessed the feasibility of using changes in radiomic features over time (Delta radiomics: absolute and relative) following chemotherapy, to predict relapse/progression and time to progression (TTP) of primary mediastinal large B-cell lymphoma (PMBCL) patients. Given the lack of standard staging PET scans until 2011, only 31 out of 103 PMBCL patients in our retrospective study had both pre-treatment and end-of-treatment (EoT) scans. Consequently, our radiomics analysis focused on these 31 patients who underwent [18F]FDG PET-CT scans before and after R-CHOP chemotherapy. Expert manual lesion segmentation was conducted on their scans for delta radiomics analysis, along with an additional 19 EoT scans, totaling 50 segmented scans for single time point analysis. Radiomics features (on PET and CT), along with maximum and mean standardized uptake values (SUVmax and SUVmean), total metabolic tumor volume (TMTV), tumor dissemination (Dmax), total lesion glycolysis (TLG), and the area under the curve of cumulative standardized uptake value-volume histogram (AUC-CSH) were calculated. We additionally applied longitudinal analysis using radial mean intensity (RIM) changes. For prediction of relapse/progression, we utilized the individual coefficient approximation for risk estimation (ICARE) and machine learning (ML) techniques (K-Nearest Neighbor (KNN), Linear Discriminant Analysis (LDA), and Random Forest (RF)) including sequential feature selection (SFS) following correlation analysis for feature selection. For TTP, ICARE and CoxNet approaches were utilized. In all models, we used nested cross-validation (CV) (with 10 outer folds and 5 repetitions, along with 5 inner folds and 20 repetitions) after balancing the dataset using Synthetic Minority Oversampling TEchnique (SMOTE). To predict relapse/progression using Delta radiomics between the baseline (staging) and EoT scans, the best performances in terms of accuracy and F1 score (F1 score is the harmonic mean of precision and recall, where precision is the ratio of true positives to the sum of true positives and false positives, and recall is the ratio of true positives to the sum of true positives and false negatives) were achieved with ICARE (accuracy = 0.81 ± 0.15, F1 = 0.77 ± 0.18), RF (accuracy = 0.89 ± 0.04, F1 = 0.87 ± 0.04), and LDA (accuracy = 0.89 ± 0.03, F1 = 0.89 ± 0.03), that are higher compared to the predictive power achieved by using only EoT radiomics features. For the second category of our analysis, TTP prediction, the best performer was CoxNet (LASSO feature selection) with c-index = 0.67 ± 0.06 when using baseline + Delta features (inclusion of both baseline and Delta features). The TTP results via Delta radiomics were comparable to the use of radiomics features extracted from EoT scans for TTP analysis (c-index = 0.68 ± 0.09) using CoxNet (with SFS). The performance of Deauville Score (DS) for TTP was c-index = 0.66 ± 0.09 for n = 50 and 0.67 ± 03 for n = 31 cases when using EoT scans with no significant differences compared to the radiomics signature from either EoT scans or baseline + Delta features (p-value> 0.05). This work demonstrates the potential of Delta radiomics and the importance of using EoT scans to predict progression and TTP from PMBCL [18F]FDG PET-CT scans.

MOLECULAR CHARACTERIZATION CONTRIBUTES TO DIAGNOSIS AND PREDICTS OUTCOME IN PRIMARY MEDIASTINAL LARGE B‐CELL LYMPHOMAS: A LYSA STUDY

Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a unique entity with an unusually good prognosis, except for ∼15% of refractory patients. Routine diagnosis relies on a clinicopathological confrontation. Tools to detect earlier refractory patients are lacking. Methods: We implemented a biological characterization of a multicenter retrospective LYSA cohort that previously reported clinical outcomes of 313 adult PMBL patients treated with first-line ACVBP or CHOP plus anti-CD20 between 2007 and 2017. We centrally reviewed 211 cases with available tumor material at diagnosis and then excluded 17 cases (misclassifications/inadequate material). Next, we applied Gene Expression Profiling (GEP) with a 137-genes RT-MLPA assay (LymphoSign signature) and Next-Generation Sequencing (NGS) with a 45-genes panel. Primary endpoints were progression-free survival (PFS) and overall survival (OS) according to molecular data. Results: We obtained GEP and NGS data for 139 (72%) and 131 (67.5%) cases, respectively. We observed a dominant expression of the PMBL-related driver genes IL4I1, B2M, PDL2, CD23, CD30, MAL, PDL1, and STAT6. Commonly mutated genes were SOCS1 (85.5%), B2M (61.1%), STAT6 (51.9%), IGLL5 (51.1%) and TNFAIP3 (51.1%). After integration of morphologic and available molecular data, 131/194 cases (67.5%) were considered as PMBL bona fide (with typical morphology and molecular profile). Within the PMBL bona fide group, we identified a cluster of 43 cases with overexpression of PDL1/2 genes (PDL1+/PDL2+, cutoff ≥median expression of each gene). As compared with others, PDL1+/PDL2+ cases were as follows: median [range] age of 34 [18–67] years (vs. 33.5 [19–64] years, p = 0.621), male sex: 53% (vs. 35%, p = 0.05), elevated LDH: 95% (vs. 76.3%, p = 0.008), PS 0–1: 79% (vs. 89.6%, p = 0.12), stage III–IV: 55.8% (vs. 39%, p = 0.08), IPI ≥ 3: 37.2% (vs. 18.4%, p = 0.027), extra-nodal involvements: 60% (vs. 45.5%, p = 0.12), metabolic tumor volume (MTV) ≥ 360 cm3: 53% (vs. 25.4%, p = 0.007). Treatments in the PDL1+/PDL2+ group did not differ from other patients: R-ACVBP: 69.8% (vs. 66.2%), R-CHOP14: 18.6% (vs. 20.8%) and R-CHOP21: 11.6% (vs. 14.3%) (p = 0.411). PDL1+/PDL2+ status was associated with poorer PFS (HR = 7, p < 0.001) and OS (HR = 15, p < 0.001, Figure 1). B2M mutations were inactivating and associated with lower PFS (p = 0.006). In a multivariate model including IPI ≥ 3, PDL1/2 status, MTV ≥ 360 and B2M mutations, only PDL1+/PDL2+ status was an independent prognostic factor of adverse PFS (HR = 7.1, 95% CI [1.5;33.1], p = 0.013). The research was funded by: This work was supported by grants from the Ligue Contre le Cancer (Comité de Seine-Maritime, AO_2020), the GIP Cancéropôle Nord-Ouest (N°2021/01 and N°2021/13), Force Hémato (N°02-2020) and CALYM (ANR-2020). Keywords: diagnostic and prognostic biomarkers, extranodal non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Abstract 939: Genomic characterization of PMBCL, cHL and DLBCL utilizing tissue and liquid biopsies

Abstract Background: Primary mediastinal large B-cell lymphoma (PMBCL), arising from thymic medullary B cells, shares molecular features with classic Hodgkin lymphoma (cHL), including activation of JAK/STAT and Nuclear Factor Kappa B (NF-ƙB) pathways, as well as PD-L1 mediated immune evasion. Much of the molecular characterization relied on availability of tissue samples. Cell-free DNA (cfDNA) has emerged as a promising non-invasive approach for molecular profiling in lymphomas. In this study, we characterized the molecular features of PMBCL and cHL in the Chinese population utilizing both tissue-based and liquid biopsies. Methods: Tissue and/or plasma samples from a total of 35 PMBCL patients, 52 cHL patients and 81 DLBCL patients that were subjected to targeted next-generation sequencing (NGS) using a 475 cancer-related gene panel were included in the analysis. Results: Analysis of matched tumor and plasma samples from 38 cHL patients revealed 152 (28.10%) overlapping genetic alterations, with a higher number of mutations detected in the plasma compared to tissue (Total=472 vs. 221; Median=11 vs. 3 per patient, P&amp;lt;0.01). Of these, 320 (59.15%) were unique to the plasma, whereas 69 (12.15%) were only found in the tissue. Mutant allele frequencies (MAFs) were also lower in the tissue than in the plasma, with a median of 1.71% vs 2.99% (P&amp;lt;0.01). In 18 PMBCL patients, who had paired plasma and tumor samples, similar number of genetic alterations were detected (Total=347 vs. 411; Median=19.5 vs. 21 per patient, P=0.09). Of these, 273 (56.29%) alterations were shared variants, 74 (15.28%) were unique to the plasma sample and 138 (28.45%) were unique to the tissue. MAFs were higher in the tissue compared with the plasma (23.35% vs. 8.78%, P&amp;lt;0.01). Comparisons of mutational profiles among PMBCL, cHL, and DLBCL showed similar mutational profiles between PMBCL and cHL. The most frequently detected genetic alterations in PMBCL and cHL were STAT6 (68.57% vs. 40.38%), SOCS1 (57.14% vs. 57.69%), ACTB (48.57% vs. 23.08%), B2M (48.57% vs. 42.31%), and TNFAIP3 (34.29% vs. 40.38%). On the contrary, the frequencies of STAT6 (68.57% vs. 6.17%, P &amp;lt;0.01), SOCS1 (57.14% vs. 18.52%, P&amp;lt;0.05), and ACTB (48.57% vs. 9.88%, P&amp;lt;0.05) were markedly different comparing PMBCL and DLBCL. Meanwhile, the more common genetic alterations in DLBCL, such as MYD88 (33.33% vs. 0.00%, P&amp;lt;0.01), BCL6 (33.33% vs. 11.43%, P=0.06), BCL2 (20.99% vs. 2.86%, P&amp;lt;0.05), and CDKN2A (24.69% vs. 2.86%, P&amp;lt;0.05) were rarely detected in PMBCL patients. Conclusion: Our findings support that ctDNA in PMBCL and cHL may be an attractive source of genetic materials to assess tumor genomics and guide treatment decisions, especially in cHL with only 1% Hodgkin and Reed/Sternberg (HRS) cells. We also demonstrate for the first time in the Chinese population that PMBCL and cHL shared comparable mutational profiles, which were different from that of DLBCL. Citation Format: Xiaonan Wang, Lu Shen, Liuqing Zhu, Jiani C. Yin, Haimeng Tang, Yang Shao. Genomic characterization of PMBCL, cHL and DLBCL utilizing tissue and liquid biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 939.

Incidence and risk factors for central nervous system relapse in patients with primary mediastinal large B-cell lymphoma in the rituximab era.

Central nervous system (CNS) involvement is rare in primary mediastinal large B-cell lymphoma (PMLBCL). We aimed to evaluate the incidence of CNS relapse as first treatment failure event and the effect of the induction chemotherapy regimen, central nervous system - international prognostic index (CNS-IPI) and other clinical and laboratory variables on the risk of CNS relapse in 564 PMLBCL patients treated with immunochemotherapy. Only 17 patients (3.0%) received CNS prophylaxis. During a 55-month median follow-up only 8 patients experienced CNS relapse as first event, always isolated. The 2-year cumulative incidence of CNS relapse (CI-CNSR) was 1.47% and remained unchanged thereafter. The CI-CNSR was not affected by the chemotherapy regimen (R-CHOP or R-da-EPOCH). None of the established International Prognostic Index factors for aggressive lymphomas predicted CNS relapse in PMLBCL. The 2-year CI-CNSR in patients with versus without kidney involvement was 13.3% versus 0.96% (p<0.001); 14.3% versus 1.13% with versus without adrenal involvement (p<0.001); and 10.2% versus 0.97% with versus without either kidney or adrenal involvement. CNS-IPI was also predictive (2-year CI-CNSR in high-risk vs. intermediate/low-risk: 10.37% vs. 0.84%, p<0.001). However, this association may be driven mainly by kidney and/or adrenal involvement. In conclusion, in PMLBCL, CNS relapse is rare and appears to be strongly associated with kidney and/or adrenal involvement.

Central Nervous System Relapse in Patients with Primary Mediastinal Large B-Cell Lymphoma: Incidence and Risk Factors in the Rituximab Era

Background: Central nervous system relapses (CNSR) are uncommon in primary mediastinal large B-cell lymphoma (PMLBCL) with a reported incidence of 2.3-3.8% in the Rituximab era. Clinical risk factors for CNSR have been recognized in diffuse large B-cell lymphoma (DLBCL), but may not be applicable in PMLBCL, a pathobiologically distinct entity with constitutive activation of NFκB and JAK-STAT pathways and Programmed Death (PD) Ligand 1 and 2 overexpression. Aim: To evaluate the incidence of first CNSR events without prior systemic progression and explore prognostic associations with baseline characteristics, CNS-IPI, and induction immunochemotherapy. Methods: This is a retrospective study of a multinational cohort of 596 adult PMLBCL patients treated with R-CHOP or DA-EPOCH-R immunochemotherapy with or without radiotherapy between 2000 and early 2022. The cumulative incidence of first CNSR (CI-CNSR) was estimated considering the competing risks of death from any cause or prior systemic disease relapse/progression. Results: Baseline characteristics are shown in Table 1. Only 17 patients (2.9%) received CNS prophylaxis [high-dose methotrexate (HD-MTX) 9, intrathecal MTX±other 7, both 1]. Kidney and/ or adrenal involvement at diagnosis was highly correlated with advanced stage, ≥2extranodal sites and high CNS-IPI (4-6) (p<0.001), with the vast majority of the latter also having kidney and/or adrenal involvement. With a 55-month median follow-up [interquartile range (IQR) 32-97 months], all 10 first CNSR events(9 isolated and 1 associated with systemic relapse) were recorded within 2 years of diagnosis [median time7.5 months, IQR 6-8, range 5-13 months], for a 2-year CI-CNSR of 1.78% (95% CI 0.9-3.2%). Two of 10 CNSR cases had received CNS prophylaxis with HD-MTX. All CNSR were parenchymal and only 2/8 were successfully salvaged (2 still under treatment). Four patients with CNSR had kidney involvement (plus adrenal in 2/4). Two of seven patients with both kidney and adrenal involvement and 2/ 17 with kidney infiltration only relapsed in the CNS. Kidney [subhazard ratio (SHR) 15.4, p<0.001], adrenal (SHR 13.6, p=0.001), any kidney or adrenal involvement (SHR 12.5, p<0.001), and high CNS-IPI (4-6, SHR 13.0, p<0.001) were associated with CNSR in univariate analysis. All 4 patients with high CNS-IPI who experienced CNSR (out of 35), had also kidney and/or adrenal involvement. Looser but significant associations were observed with high IPI (2-5; SHR 6.3, p=0.009), advanced stage (III/IV; SHR 5.5, p=0.007), impaired performance status (≥2; SHR 6.6, p=0.005), and ≥2 extranodal sites (SHR 5.4, p=0.009) but not chemotherapy backbone (R-CHOP or DA-EPOCH-R), CNS prophylactic therapy, age, gender, B-symptoms, LDH elevations or other baseline labs, serositis or PMLBCL-specific prognostic indices (stage IV/ extranodal plus bulky or high LDH≥2x). Conclusion: In PMLBCL, CNSR is rare and appears to be primarily associated with kidney and/or adrenal involvement. CNS-IPI is also strongly prognostic but highly correlated with kidney and/or adrenal involvement. No late (>2 years) occurrences were seen and 9/10 relapses were isolated in the CNS. No inferences regarding the value of primary CNS prophylaxis can be made. Even in this very large series multivariate is not reliable due to the small number of events. A larger multinational effort is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cell-Free DNA for Genomic Analysis in Primary Mediastinal Large B-Cell Lymphoma.

High-throughput sequencing of cell-free DNA (cfDNA) has emerged as a promising noninvasive approach in lymphomas, being particularly useful when a biopsy specimen is not available for molecular analysis, as it frequently occurs in primary mediastinal large B-cell lymphoma (PMBL). We used cfDNA for genomic characterization in 20 PMBL patients by means of a custom NGS panel for gene mutations and low-pass whole-genome sequencing (WGS) for copy number analysis (CNA) in a real-life setting. Appropriate cfDNA to perform the analyses was obtained in 18/20 cases. The sensitivity of cfDNA to detect the mutations present in paired FFPE samples was 69% (95% CI: 60–78%). The mutational landscape found in cfDNA samples was highly consistent with that of the tissue, with the most frequently mutated genes being B2M (61%), SOCS1 (61%), GNA13 (44%), STAT6 (44%), NFKBIA (39%), ITPKB (33%), and NFKBIE (33%). Overall, we observed a 75% concordance to detect CNA gains/losses between DNA microarray and low-pass WGS. The sensitivity of low-pass WGS was remarkably higher for clonal CNA (18/20, 90%) compared to subclonal alterations identified by DNA microarray. No significant associations between cfDNA amount and tumor burden or outcome were found. cfDNA is an excellent alternative source for the accurate genetic characterization of PMBL cases.

S101: GENETIC AND EPIGENETIC FACTORS DRIVING PRIMARY MEDIASTINAL B-CELL LYMPHOMA PATHOGENESIS AND OUTCOME

Background: Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive lymphoma affecting predominantly young female patients. Previous studies in this rare entity have focused on single genes or were limited in cohort size. Aims: To unravel the underlying genetic pathogenesis and its impact on outcome, we embarked on a comprehensive large-scale genetic investigation. Methods: Specimens of 486 previously untreated PMBCL patients were analyzed by paired tumor/normal whole-genome (WGS, n=14), whole-exome (WES, n=78) and targeted sequencing (TS, n=486). To understand the consequences of highly recurrent mutations in the chromatin-modifying gene ZNF217, we conducted functional and multi-omics analyses in CRISPR/Cas9 engineered cell lines. Results: WGS/WES revealed a complex genomic landscape in PMBCL with a median of 85 structural variants, a mutational burden of 5 mutations/Mb, 12 mutated coding candidate driver genes (CDG) and 4 focal somatic copy-number aberrations per sample (Fig.1a). Besides known targets, significant breakpoints were identified in genes previously not implicated in B-lymphomagenesis such as TOX and TP73 (36% and 21%). In addition, non-coding mutations clustered within the PAX5 enhancer region. With the identification of 50 recurrently mutated CDGs, we significantly expand the repertoire of known PMBCL drivers. The 10 most frequently mutated CDGs were SOCS1 (86%), B2M (67%), ITPKB (64%), ACTB (58%), STAT6 (58%), IGLL5 (56%), TNFAIP3 (53%), NFKBIE (49%), GNA13 (47%), and ZNF217 (36%), respectively. The operative mutational processes were attributed to aging, AID/APOBEC activity, defective MMR, and an unexpected infidelity of DNA-Polymerase ε. Next, we performed TS in 486 samples using a PMBCL-specific 106-gene panel. Recurrent lesions in 25 epigenetic modifiers were found in >90%, with ZNF217 being among the most frequently mutated genes (Fig.1b). After knockdown of ZNF217 in Karpas1106P and L428 cells, we demonstrated altered proliferation, migration, and apoptosis. Using mass spectrometry, we showed that ZNF217 is acting in a LSD1, CoREST and HDAC containing histone modifier complex. Accordingly, knockout of ZNF217 led to global changes in chromatin accessibility with an enrichment of differentially accessible motifs for crucial lymphoma-associated transcription factors, especially of the NF-κB, BATF/AP1, and IRF family, but also of CTCF, a major regulator of global 3D chromatin architecture. Resulting gene expression was characterized by changes in interferon-responsive genes and inflammation-associated transcription (Fig 1c). Clinical data were available for 329 cases, including 84 cases from clinical trials. Multivariate analysis using an IPI-corrected Cox regression model was performed. The estimated 5-year PFS and OS were 77% and 86%. Among the genetic lesions with the strongest association for poor outcome, we identified patients with mutatedCD58 having a significantly shorter survival (PFS: HR 2.96; p<.001; OS: HR 2.55; p=.006). In contrast, mutated DUSP2 indicated longer survival (PFS: HR 0.28; p=.002; OS: HR 0.15; p=.011) (Fig1d). Notably, DUSP2 mutated patients (25%) showed a similar outcome for CR rate, PFS and OS when comparing CHOP-like and intensified treatment regimens, suggesting no further benefit from treatment intensification in this very-low risk patient population. Image:Summary/Conclusion: Here, we present the genetic landscape of PMBCL highlighting a previously underappreciated role of chromatin modifying genes, identify novel treatment targets and provide a solid basis for guiding precision medicine approaches.

Brentuximab vedotin and nivolumab alone and then combined with rituximab, cyclophosphamide, doxorubicin, and prednisone for frontline therapy of patients with primary mediastinal large B-cell lymphoma.

TPS7589 Background: Primary mediastinal large B-cell lymphoma (PMBL) is a rare and distinct subtype of diffuse large B-cell lymphoma and affects primarily young adults. PMBL has a unique genomic profile that has similarities to classic Hodgkin lymphoma with CD30 expression and genomic alterations in the programmed T-cell death-ligand 1 (PD-L1) locus 9p24.1. The trial CheckMate-436, including relapsed/refractory PMBL patients treated with nivolumab (antibody that binds to immune checkpoint PD-1) and brentuximab vedotin ((BV) anti-CD30 antibody-drug conjugate) 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 with or without radiotherapy, the outcome of patients having rr-PMBL treated with intensive regimens is generally unfavorable. The discovery of new frontline regimens to decrease chemoresistance and toxicities represents an urgent unmet clinical need for PMBL patients. Methods: We are conducting a phase II, open-label, single-center clinical trial 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 with an urgent need for cytoreductive treatment will be excluded. 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. 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). 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, the safety of the combination, and patient-reported outcome. Exploratory analyses include assessing molecular response by sequencing cell-free DNA and Multiplexed ion beam imaging to analyze the tumor microenvironment. The trial is actively accruing at MD Anderson Cancer Center, and 2 out of 40 patients have been enrolled. Clinical trial information: NCT04745949.

Real-life Experience With Rituximab-CHOP Every 21 or 14 Days in Primary Mediastinal Large B-cell Lymphoma.

Primary mediastinal large B-cell lymphoma (PMLBCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL), whose prognosis has greatly improved since the incorporation of the anti-CD20 monoclonal antibody rituximab into current therapeutic regimens. Evidence, however, on the optimal time interval between consecutive chemoimmunotherapy (CIT) cycles is still scarce. This study aimed to evaluate the efficacy outcomes of the more commonly administered 3-weekly regimens to the biweekly ones in a PMLBCL patients' population, who were mostly treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP-21) or R-CHOP-14. We retrospectively studied our cohort of consecutively treated PMLBCL patients, focusing on their treatment density, in order to determine possible differences in treatment outcomes. CIT, in the form of both R-CHOP-21 as well as R-CHOP-14 (or similar regimens), is highly active in PMLBCL, with low rates of early treatment failure. In our cohort of patients, R-CHOP-14 did not result in a meaningful improvement of freedom from progression (FFP) or overall survival (OS). Both R-CHOP-14 and R-CHOP-21 are probably equally effective in PMLBCL, yet further, prospective, randomized studies are warranted to clarify whether dose-dense regimens can be associated with better disease control and long-term results.

Identification of Very Low-Risk Subgroups of Patients with Primary Mediastinal Large B-Cell Lymphoma Treated with R-CHOP.

R-CHOP can cure approximately 75% of patients with primary mediastinal large B-cell lymphoma (PMLBCL), but prognostic factors have not been sufficiently evaluated yet. R-da- EPOCH is potentially more effective but also more toxic than R-CHOP. Reliable prognostic classification is needed to guide treatment decisions. We analyzed the impact of clinical prognostic factors on the outcome of 332 PMLBCL patients ≤65 years treated with R-CHOP ± radiotherapy in a multicenter setting in Greece and Cyprus. With a median follow-up of 69 months, 5-year freedom from progression (FFP) was 78% and 5-year lymphoma specific survival (LSS) was 89%. On multivariate analysis, extranodal involvement (E/IV) and lactate dehydrogenase (LDH) ≥2 times upper limit of normal (model A) were significantly associated with FFP; E/IV and bulky disease (model B) were associated with LSS. Both models performed better than the International Prognostic Index (IPI) and the age-adjusted IPI by Harrel's C rank parameter and Akaike information criterion. Both models A and B defined high-risk subgroups (13%-27% of patients [pts]) with approximately 19%-23% lymphoma-related mortality. They also defined subgroups composing approximately one-fourth or one-half of the patients, with 11% risk of failure and only 1% or 4% 5-year lymphoma-related mortality. The combination of E/IV with either bulky disease or LDH ≥2 times upper limit of normal defined high-risk but not very-high-risk subgroups. More importantly, their absence defined subgroups comprising approximately one-fourth or one-half of the pts, with 11% risk of failure and minimal lymphoma-related mortality, who may not need more intensive treatment such as R-da-EPOCH. By analyzing the impact of baseline clinical characteristics on outcomes of a large cohort of patients with primary mediastinal large B-cell lymphoma homogeneously treated with R-CHOP with or without radiotherapy, we developed novel prognostic indices which can aid in deciding which patients can be adequately treated with R-CHOP and do not need more intensive regimens such as R-da-EPOCH. The new indices consist of objectively determined characteristics (extranodal disease or stage IV, bulky disease, and markedly elevated serum lactate dehydrogenase), which are readily available from standard initial staging procedures and offer better discrimination compared with established risk scores (International Prognostic Index [IPI] and age-adjusted IPI).

Retrospective evaluation of patients with primary mediastinal large B-Cell lymphoma: Real life experience

Aim: Primary mediastinal large B-cell lymphoma (PMBCL) is a type of lymphoma that forms approximately 3 % of non-Hodgkin lymphomas that often encounter with mass. The aim of this study was to present the epidemiological characteristics, response rates of the treatment and the survival of PMBCL patients in our single center. Materials and Methods: Patient demographics, treatment regimens, survival rates of PMBCL patients were retrospectively analyzed. Results: There are 15 patients in our study. Most of the patients were female (n:9, 60%). The median age at the time of diagnosis was 35.4. Nine patients applied with a bulky lesion in the mediastinum. Most of the patients have been treated with DA-EPOCH-R (dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine and prednisone with rituximab) (n:13, 87%) and 2 (n:2, 13%) patients have been treated with R-CHOP (doxorubicin, cyclophosphamide, vincristine and prednisone with rituximab) regimens for 6 cycles. Eight patients (53.3%) received involved-field radiotherapy on the mediastinum. After the first-row chemotherapy, total remission rate was 93.3%. Thirteen (87%) of the patients were still in remission and alive. The median follow-up time in our study was 43 months (13 -81). Mean disease-free survival was 67.43 months and overall survival was 72.87 months. The overall and disease-free survival rate was 86.7 % and 80%. Conclusions: In our study, most patients responded to the treatment and are still being followed in remission.

Assessing the Role of Radiation Therapy for Primary Mediastinal Large B-Cell Lymphoma in the Setting of PET Avid Disease after Chemotherapy

Most patients with primary mediastinal large B-cell lymphoma (PMBCL) are treated with dose-adjusted rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) without consolidative radiation therapy (RT), and the value of RT is poorly understood. We sought to evaluate the efficacy of RT administered to PMBCL patients with positron emission tomography–computed tomography (PET-CT) positive findings at the time of RT. We conducted a retrospective review of 22 consecutive PMBCL patients who received RT between 2008 and 2018 with residual metabolically active tumor (defined as five-point score [5PS] of 4-5) at the time of RT. Progression-free survival (PFS) and overall survival (OS) were defined from the last day of RT. The median age at diagnosis was 32 years; 68% (n = 15) were female. Frontline DA-R-EPOCH was administered to 86% (n = 19). End of frontline therapy PET-CT revealed 5PS of 4 in 32% (n = 7) and 5PS of 5 in 68% (n = 15). Biopsy was performed in 64% (n = 14), and was positive in 11 (79%) of the patients. RT was given after 1 line of systemic therapy in 59% (n = 13) and after ≥2 lines of therapy in 41% (n = 9). At the time of RT, 23% had a 5PS of 4 (n = 5) and 77% had a 5PS of 5 (n = 17). RT was delivered using a sequential or simultaneous boost to areas of PET-avid disease in 86% of cases (n = 19), with a median dose of 46.7 Gy (R 36-49.8). At a median follow-up of 6.2 years (95% CI 3.0 – 9.5), the 5-year PFS and OS were 54.5% and 76.4%, respectively. The median PFS and OS were not reached. RT resulted in a complete response (CR) rate of 64%; disease progression after RT occurred in 46% (n = 10), all in patients with 5PS of 5, with a median time of 3.0 months (range 0.8 – 6.8). Failures were in-field (n = 2), out-of-field (n = 3), or both (n = 5). PFS was significantly worse for patients with SUVmax>11.6 at the time of RT (p = 0.001), though not affected by RT dose ≥45 Gy (p = 0.47). Patients with a 5PS of 5 had significantly worse PFS compared to patients with a 5PS of 4 at the time of RT (41% vs. 100%, p = 0.04). For these patients with 5PS of 5, the median PFS was 5.3 months (95% CI 1.2 – 9.5), and a pre-RT SUVmax>11.6 was associated with inferior PFS (p = 0.02). In total, 11 patients received stem cell transplant (SCT); in 3 cases RT was given as salvage following SCT relapse. In 8 cases RT was given pre-SCT, with CR achieved due to RT before SCT in 4 patients. Overall, RT was well-tolerated with two cases (9%) of grade 3 toxicity (1 pneumonitis, 1 esophagitis). No cardiac toxicity or secondary malignancies were noted. PMBCL patients with PET avid disease after frontline immunochemotherapy pose a therapeutic challenge. RT achieved a CR in 50% of patients with PET-positive disease, but was less effective for patients with 5PS of 5. Residual SUVmax data may appropriately guide patient selection as higher activity is associated with inferior outcomes.

Ruxolitinib shows activity against Hodgkin lymphoma but not primary mediastinal large B-cell lymphoma

BackgroundThe upregulated expression of the JAK/STAT pathway promotes tumor growth in Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL). Based on the hypothesis that JAK2 is a therapeutic target, we performed a prospective pilot study using ruxolitinib.MethodsRelapsed or refractory patients with HL or PMBCL were eligible for this study, and JAK2 amplification was assessed by fluorescence in situ hybridization. Ruxolitinib was administered orally at a dose of 20 mg twice daily for a 28-day cycle. Treatment was continued for up to 16 cycles or until progressive disease or intolerability. The primary objective was to assess the overall disease control rate comprising complete response (CR), partial response (PR), or stable disease (SD).ResultsWe analyzed 13 HL patients and six PMBCL patients. All responders (one CR, five PR, and one SD) had HL whereas all cases of PMBCL progressed after first or second cycle. The disease control rate for HL was 54% (7/13) with median response duration of 5.6 months. JAK2 amplification was present in six of nine patients tested (four HL, two PMBCL), and three of these HL patients showed PR (n = 2) or SD (n = 1). None of the three HL patients shown to not have JAK2 amplification responded to ruxolitinib. Most treatment-related adverse events were grade 1 or 2 and manageable.ConclusionsRuxolitinib has single-agent activity against HL but does not act against PMBCL with or without JAK2 amplification.Trial registrationThe study population was patients who had relapsed or refractory HL or PMBCL, and patients were registered for our pilot study after providing written informed consent between November 2013 and November 2015 (CilinicalTrials.gov: NCT01965119).

Progress in the application of rituximab in treating primary mediastinal B-cell lymphoma

Primary mediastinal large B-cell lymphoma (PMBCL) is morphologically similar to diffuse large B-cell lymphoma (DLBCL) and nodular sclerosis Hodgkin lymphoma. For most PMBCL patients, chemotherapy plus consolidation radiotherapy showed that the latter could improve PMBCL responsiveness and progression-free survival (PFS), and its combined use with chemotherapy demonstrated higher therapeutic efficacy. Recent clinical studies suggested that rituximab and anthracycline chemotherapy regimens could increase PMBCL treatment efficacy, reduce early treatment failure, enhance PFS and overall survival, and improve prognosis. Although rituximab combined with some high-intensity chemotherapy without radiotherapy have achieved good results, many studies still support the use of post-immunochemotherapy consolidation mediastinal radiotherapy. Based on the results of a few studies with a small sample size, patients who were assessed as complete metabolic remission by PET following high-intensity immunochemotherapy may omit consolidation radiotherapy. However, these results will need to be further confirmed by large-sample multicenter clinical trials. Consolidation radiotherapy is recommended for patients with poor prognostic factors or PET score>3. Key words: B-cell lymphoma/rituximab; B-cell lymphoma/radiotherapy; Prognosis

The treatment of primary mediastinal large B-cell lymphoma: a two decades monocentric experience with 98 patients

BackgroundThe purpose of this study is to investigate the most suitable first-line approach and the best combination treatment for primary mediastinal large B-cell lymphoma (PMLBCL) as they have been matter of debate for at least two decades.MethodsOur single centre experience in the treatment of 98 de novo PMLBCL patients over the last 20 years is reviewed. All patients received MACOP-B chemotherapy. Thirty-seven received both rituximab and mediastinal radiotherapy; 30 were irradiated after chemotherapy, although not receiving rituximab and 20 received rituximab without radiotherapy consolidation. Eleven patients received chemotherapy only.ResultsSixty-one (62.2%) patients achieved a complete response after MACOP-B (with or without rituximab); among the 27 (27.6%) partial responders, 21 obtained a complete response after radiotherapy. At the end of their scheduled treatment, 82 patients (83.7%) had a complete and 6 a partial response (6.1%). Eleven patients relapsed within the first 2 years of follow-up. The 17-year overall survival is 72.0% (15 patients died); progression-free and disease-free survival are 67.6% and 88.4%, respectively. A statistically significant difference in overall and progression-free survival was noted among treatment groups, although no disease-free survival difference was documented.ConclusionsOur data indicate that a third-generation regimen like MACOP-B could be considered a suitable first-line treatment. Mediastinal consolidation radiotherapy impacts on survival and complete response rates and remains a good strategy to convert partial into complete responses. Data suggest that radiotherapy may be avoided in patients obtaining a complete response after (immuno)chemotherapy, but this requires confirmation with further ad hoc studies.

The Efficacy of JAK2 Inhibitor in Heavily Pretreated Classical Hodgkin Lymphoma: A Prospective Pilot Study of Ruxolitinib in Relapsed or Refractory Classical Hodgkin Lymphoma and Primary Mediastinal Large B-Cell Lymphoma

BackgroundJAK2 expression and activity increased in classical Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL) because both of them were reported to have chromosome 9p24.1/JAK2 amplification. Thus, JAK2 has been suggested as a potential therapeutic target in both disease having similar clinical and genetic features, and a previous in vitro and in vivo study showed cHL and PMBCL with JAK2 amplification were sensitive to JAK2 inhibition. However, the efficacy of JAK2 inhibitor has never been evaluated in clinical trials with cHL and PMBCL patients. We performed a prospective pilot proof of concept study with JAK2 inhibitor, ruxolitinib in relapsed or refractory cHL and PMBCL to evaluate the effect of JAK2 inhibition.MethodsThis study enrolled only relapsed or refractory cHL and PMBCL. Subjects should experience at least two times of relapse or treatment failure before enrollment. We enrolled subjects who were more than 18 years and had at least one lesion of FDG-PET positive measureable disease. Ruxolitinib was administered orally at a dose of 20 mg twice a day of a 28-day cycle. Treatment cycles were repeated up to 16 cycles until disease progression or unacceptable toxicity occurred. The primary objective was to assess the overall disease control rate including the achievement of complete response (CR), partial response (PR) and stable disease (SD). Response evaluation was done according to the 2007 Cheson criteria, and the planned number of subjects was 20. Pathology review was done by the Korean Lymphoma Pathology Review Board after the enrollment was completed. The JAK2 amplification in tumor cells was independently analyzed by the Cancer Institute Hospital of Japanese Foundation for Cancer Research without clinical information. Details of the study were registered at ClinicalTrials.gov (NCT01965119).ResultsWe enrolled 20 patients (median age: 43, range: 19 - 76) including 14 cHL and 6 PMBCL between 2013 and 2015. The median number of prior therapies was four (range: 2 - 10). Eight patients underwent autologous stem cell transplantation, and ten patients received involved field radiotherapy during their treatment period. Four cHL (29%, 4/14) and four PMBCL (67%, 4/6) were primarily refractory to induction treatment. At the time of enrollment, 18 patients were refractory to salvage treatment, and two patients relapsed five years after their last treatment. The first response evaluation after the 2nd cycle showed 40% (7/20) of overall disease control rate (1 CR, 6 PR, and 1 SD). However, one cHL case with PR was excluded from the analysis after the final diagnosis was changed to chronic active EBV infection by the pathology review board. The comparison between cHL and PMBCL showed more efficacy of ruxolitinib in cHL because all patients with PMBCL rapidly progressed after 1st or 2nd cycle whereas disease was controlled in seven patients with cHL (1 CR, 5 PR and 1 SD) out of 13 patients with cHL (54%, 7/13). Although the median number of treatment cycle of all patients was two (range: 1-10), six responders received on the average five cycles of treatment (range: 4-10), and the median duration of response was 5 months (range: 4 - 12+ months). The toxicity was manageable without any grade 3 or 4 hematologic and non-hematologic toxicity. Most non-hematologic toxicities including liver enzyme elevation and abdominal pain were grade 1 or 2. The analysis of JAK2 amplification by FISH was done in 9 patients whose tissue sample was available. Among three patients with high amplification (more than 10 signals), only one SD was observed whereas two patients achieved PR out of six cases with low or absent amplification.ConclusionsThe efficacy of ruxolitinib in heavily pretreated patients with relapsed or refractory cHL suggested JAK2 inhibition might be more effective for the treatment of cHL than PMBCL. A phase I/II study with larger study population should be warranted based on our results of pilot study. DisclosuresKim:Celltrion, Inc.: Consultancy, Honoraria.

Phase 1b Study of Pembrolizumab in Patients with Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Results from the Ongoing Keynote-013 Trial

Phase 1b Study of Pembrolizumab in Patients with Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Results from the Ongoing Keynote-013 Trial

Primary mediastinal large B-cell lymphoma in Japanese children and adolescents.

This is the first case series to describe primary mediastinal large B-cell lymphoma (PMLBL) patients in children and adolescents in Asia. We retrospectively identified 17 PMLBL patients diagnosed between 1991 and 2014; in seven of these cases, the diagnosis was confirmed by central review, representing 1.0% of all NHL and 2.2% of all B-NHL cases registered. All patients were teenagers, including seven adolescents, with a median age of 14years (range 12-18years). Ten patients were male, and seven were female. The 5-year EFS and OS rates were 81.9 and 84.4%, respectively. All seven recent cases remain alive, of which three received rituximab combination therapy. Incidence, characteristics, and outcome varied considerably from those of Western populations. Further studies, including molecular analysis, are warranted.

Primary mediastinal large B-cell lymphoma: transcriptional regulation by miR-92a through FOXP1 targeting.

BackgroundPrimary mediastinal large B-cell lymphoma (PMBL) shares pathological features with diffuse large B-cell lymphoma (DLBCL), and molecular features with classical Hodgkin lymphoma (cHL). The miR-17∼92 oncogenic cluster, located at chromosome 13q31, is a region that is amplified in DLBCL.MethodsHere we compared the expression of each member of the miR-17∼92 oncogenic cluster in samples from 40 PMBL patients versus 20 DLBCL and 20 cHL patients, and studied the target genes linked to deregulated miRNA in PMBL.ResultsWe found a higher level of miR-92a in PMBL than in DLBCL, but not in cHL. A combination of in silico prediction and transcriptomic analyses enabled us to identify FOXP1 as a main miR-92a target gene in PMBL, a result so far not established. This was confirmed by 3UTR, and RNA and protein expressions in transduced cell lines. In vivo studies using the transduced cell lines in mice enabled us to demonstrate a tumor suppressor effect of miR-92a and an oncogenic effect of FOXP1.A higher expression of miR-92a and the down-regulation of FOXP1 mRNA and protein expression were also found in human samples of PMBL, while miR-92a expression was low and FOXP1 was high in DLBCL.ConclusionsWe concluded to a post-transcriptional regulation by miR-92a through FOXP1 targeting in PMBL, with a clinico-pathological relevance for better characterisation of PMBL.

Racial patterns of patients with primary mediastinal large B-cell lymphoma: SEER analysis.

The aim of this study is to investigate the incidence and clinical outcomes of primary mediastinal large B-cell lymphoma (PMBL).Here we did a retrospective analysis using the surveillance, epidemiology, and end results (SEER) database to analyze the incidences and survival of patients with PMBL diagnosed during 2001–2012 among major ethnic groups.During 2001–2012, a total of 426 PMBL patients were identified, including 336 whites, 46 blacks, and 44 others. The incidence rates of female to male ratios in white, black, and other were 1.4938, 1.1202, and 1.7303 respectively, suggesting that the female-prominent disease occurrence was seen only in whites and others, but not in black population. Compared to white, the other had a worse 5-year overall survival (OS); however, factors including age, race, socioeconomic status, and stage associated with OS showed no significant difference among ethnic groups; thus, biology factors should be explored to explain the racial difference in OS.In conclusion, our findings revealed diversities in demographic features and prognosis among different racial groups.