Primary Hodgkin Lymphoma Research Articles

Interaction between ERAP Alleles and HLA Class I Types Support a Role of Antigen Presentation in Hodgkin Lymphoma Development.

Simple SummaryHodgkin lymphoma (HL) is a common lymphoma in young adults derived from B cells. Emerging evidence suggests that antigen presentation by the malignant B cells is critically involved in HL pathogenesis. In fact, genetic variants of the antigen presenting Human Leukocyte Antigens (HLA) are strongly associated with HL susceptibility. Interestingly, the endoplasmic reticulum aminopeptidase (ERAP)1 and ERAP2 genes, that code for enzymes that process antigens, also appear to be associated. In this study, we show that genetic variants of ERAP genes strongly affect expression levels of ERAP1 and ERAP2. In addition, we find that certain ERAP variants interact with specific HLA class I types in HL patients. This suggests that mechanisms that determine the repertoire of antigens that are presented to the immune system, affect the chance of developing HL. Our findings therefore support a prominent role of antigen presentation in HL susceptibility.Genetic variants in the HLA region are the strongest risk factors for developing Hodgkin lymphoma (HL), suggesting an important role for antigen presentation. This is supported by another HL-associated genomic region which contains the loci of two enzymes that process endogenous proteins to peptides to be presented by HLA class I, i.e., endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2. We hypothesized that ERAP and HLA class I type interact in HL susceptibility, as shown previously for several autoimmune diseases. We detected ERAP1 and ERAP2 expression in tumor cells and cells in the microenvironment in primary HL tissue samples. Seven ERAP SNPs and ERAP1 haplotypes showed strong associations with RNA and protein levels of ERAP1 and ERAP2 in LCLs and HL cell lines. Analysis of HLA class I types, ERAP SNPs and ERAP haplotypes by direct genotyping or imputation from genome-wide association data in 390 HL patients revealed significant interactions between HLA-A11, rs27038 and the rs27038 associated ERAP haplotype, as well as between HLA-Cw2 and rs26618. In conclusion, our results show that ERAP and HLA class I interact in genetic susceptibility to HL, providing further evidence that antigen presentation is an important process in HL susceptibility and pathogenesis.

Primary intracranial Hodgkin’s lymphoma after a blunt trauma: A case report

We report a case of 30-year-old immunocompetent man, with a previous history of cranial-facial trauma, who presented with progressive left exophthalmos due to an intracranial left frontal-ethmoidal-orbital mass. Histology of the resected tumor revealed a classical Hodgkin’s Lymphoma (HL). Epstein-Barr virus encoded RNA/EBER was detected in typical Hodgkin and Reed-Sternberg cells. After postoperative radiotherapy and chemotherapy administration, the patient remains free of systemic disease or recurrence on 4 years of follow-up. Intracranial involvement by HL has rarely been described, mostly as a late localization or as a recurrence of a disseminated disease, in a setting of immunosuppression. Primary HL of the central nervous system occurring as an isolated disease is even more uncommon, with only 16 reported cases documented to date. The prognosis of these rare cases appears comforting with appropriate treatment. Tumor resection and, in appropriate cases, treatment with radiation and/or chemotherapy seem to warrant a durable response. For this reason a systemic disease should be excluded in all cases intracranial HL by a comprehensive work-up. To the best of our knowledge, this case represents the first report that documents the association of intracranial HL and local trauma with subsequent intracranial infection.

A Ukrainian multicenter prospective study of thevalue of PET/CT prognostic role in primary patients with Hodgkin’s lymphoma in a real-life cohort

INTRODUCTION In recent years, the positron emission tomography combined with computed tomography (PET/CT) has changed and the treatment approaches in Hodgkins lymphoma (HL) patients have entirely improved. The main idea in several studies is the use of PET/CT and the International Prognostic Score (IPS) protocols in identification of patients within a high-risk group and potential early relapse/refractory disease. MATERIALS AND METHODS This study was based on PET/CT evaluation and treatment strategies of patients from eight Centers of Hematology in Ukraine. The patients included were newly dia-gnosed with HL and were aged 67 years or younger. They received a treatment with ABVD or BEACOPP-14/esc or “switched-regimens” (ABVD + BEACOPP-esc/14, BEACOPP-esc/14 + ABVD). The primary endpoints were to assess a correlation between PET/CT findings at the time of dia-gnosis, response to the therapy and clinical outcome (relapse/death) for patients with early and advanced stages of HL. The secondary endpoints were to evaluate the relationship between IPS and PET/CT findings. RESULTS The study group included 106 patients. The overall response rate (ORR) was 90.5%. The ORR for patients with stages I-II was 96.5% (55/57) vs. 91% (41/45) for stage III-IV patients. In total, the disease progression occurred in 58.3% (7/12) of PET2+ patients and in 13.3% (12/90) of PET2 patients (P < 0.05). No significant difference was found between the event free survival (EFS) rate and IPS for patients with PET2+ vs. PET2, (log-rank test; P = 0.4). The PET3 status was found in 88.8% (79/89) of the study group patients and 1.2% (10/89) had a PET3+ status (P < 0.05). Using the Cox regression, we confirmed a significant correlation between EFS with PET3 Deauville scale (DS) and IPS. Patients with DS 1-2, DS 3 and DS 4-5 had a 1-year event-free survival of 94.4%, 100% and 33%, respectively (HR 0.56; 95% CI 1.07-2.8; P < 0.02). Our multivariable analysis showed no statistically significant correlation between PET2+ and PET3+ status and extranodal involvement or large tumor burden. CONCLUSION The results of using PET/CT in patients with primary HL demonstrated a high prognostic value of PET at the end of the treatment. In addition, we confirmed the predictive role of IPS prognostic model in the treatment outcome depending on PET status.

Rosetting T cells in Hodgkin lymphoma are activated by immunological synapse components HLA class II and CD58

AbstractA unique feature of Hodgkin lymphoma (HL) is the presence of CD4+ T cells that surround, protect, and promote survival of tumor cells. The adhesion molecules involved in this so-called T-cell rosetting are important components of the immunological synapse (IS). However, it is unknown whether this synapse is fully assembled and leads to T-cell activation by enabling interaction between the T-cell receptor (TCR) and human leukocyte antigen class II (HLA-II). We established a novel rosetting model by coculturing HLA-II–matched peripheral blood mononuclear cells with HL cell lines and showed IS formation with activation of rosetting T cells. HLA-II downregulation by class II transactivator knockout did not affect the extent of rosetting, but almost completely abrogated T-cell activation. Intriguingly, the level of CD58 expression correlated with the extent of rosette formation, and CD58 knockout or CD2 blockade reduced both rosette formation and T-cell activation. The extension of our findings to primary HL tissue by immunohistochemistry and proximity ligation assays showed interaction of CD2 with CD58 and of TCR-associated CD4 with HLA-II. In conclusion, T-cell rosetting in HL is established by formation of the IS, and activation of rosetting T cells critically depends on the interaction of both TCR-HLA-II and CD2-CD58.

Second Primary Malignancy Risk Among HIV-Uninfected and HIV-Infected Survivors of Hodgkin Lymphoma: A 30-Year Follow-up Population-Based Study

Introduction Second primary malignancy (SPM) is one of the most devastating late complications following Hodgkin lymphoma (HL) treatment. Historically, the most common SPMs in patients treated for HL are solid tumors, which are largely related to radiation exposure during initial therapy. For the last three decades, efforts to address the risk of SPM after HL therapy have focused on reducing exposure to radiation, as well as refining the approach for patients where radiation is indicated. To date, few population-based studies in the United States have quantified the burden of SPMs and evaluated the potential effect of changes in therapeutic management over time. Additionally, to our knowledge, no study has compared SPM risk between human immunodeficiency virus (HIV)-infected and HIV-uninfected HL survivors. Methods We used data from the California Cancer Registry on 21,043 patients diagnosed with primary HL between 1988 and 2015 with follow-up through 2017. We calculated standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs) and absolute excess risks (AERs) to compare SPM incidence in our HL cohort with the expected number of first primary cancer incidence in the general California population, based on patient's age at diagnosis (5-year categories), sex, calendar year (3-year intervals), cancer site, and race/ethnicity. SIRs are presented by HIV status, SPM latency, treatment era, and cancer type. P-values for trends were used to examine whether SPM risk changed over time. Findings Among 20,303 HIV-uninfected patients (median follow-up of 14.1 years), overall SPM risk was increased 1.95-fold compared with the general population (SIR=1.95, 95% CI 1.86-2.04). In 740 HIV-infected patients (median follow-up of 11.7 years), overall risk was increased 2.68-fold compared with the general population (SIR=2.68, 95% CI 2.0-3.40), translating to an 37% higher incidence of SPM in HIV-infected vs. HIV-uninfected patients. The AER (per 10,000 person-years) of SPM was 43.1 in HIV-uninfected and 76.5 in HIV-infected patients, resulting in a 33.4 excess SPM per 10,000 person-years in HL survivors with HIV. Malignancies that contributed the most to overall AER were non-Hodgkin lymphoma (NHL), female breast and lung cancers in HIV-uninfected patients; and Kaposi sarcoma, NHL, anorectal and head &amp; neck (HNC) cancers in HIV-infected patients. Notably, among HIV-uninfected patients, the highest overall risk of SPM occurred ≥20 years after diagnosis (SIR= 2.27, 95% CI 1.99-2.58) (Figure). In contrast, the highest overall risk in HIV-infected patients was observed &amp;lt;2 years after diagnosis (SIR=4.42, 95% CI 2.53-7.19). Radiation used decreased from 46.9% in 1988-1996 to 29.5% in 2007-2015. Among HIV-uninfected patients, there was a trend towards decreased risk over time of overall and selected solid SPMs (lung, female breast, and gastrointestinal cancers) (Table). In an analysis restricted to HIV-uninfected patients who received radiation irrespective of chemotherapy, findings also suggested a declined risk of overall and selected solid SPMs over time: any solid (SIR=2.15 in 1988-1996 and SIR=1.30 in 2007-2015, p&amp;lt;0.0001), lung (SIR=3.69 in 1988-1996 and SIR=1.81 in 2007-2015, p=0.0031), and female breast (SIR=2.95 in 1988-1996 and SIR=0.63 in 2007-2015, p&amp;lt;0.0001). Conclusion Compared with the general population, the risk of developing a SPM following HL treatment was significantly higher among both HIV-uninfected and HIV-infected patients, with the absolute excess risk greater for those with HIV infection. There were different temporal patterns and types of SPM between HIV-uninfected and HIV-infected patients. These findings prompt the question on whether earlier and/or more intensive cancer screening should be pursued for HIV-infected survivors. The trend towards decreased risk for selected solid SPMs among HIV-uninfected patients, especially lung and female breast cancers, suggest that strategies to reduce radiation in HL survivors may be working. Despite promising trends in this group, the observation that SPM risk was highest ≥20 years after initial therapy further highlights the need for long-term surveillance and survivorship care in this at-risk population. Disclosures Rosenberg: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Wun:Glycomimetics, Inc.: Consultancy.

The Role of Lymphomas in Subsequent Primary Cancers in People with HIV/AIDS: An Australian National Population-Based Data Linkage Study

Background Despite combination antiretroviral therapy (cART), the incidence of lymphomas remains elevated in persons with HIV/AIDS (PWHA). While the risk of subsequent primary cancers (SPCs) in the general population is well understood, these data are lacking for PWHA. Underlying aetiologic factors in PWHA, including oncogenic viruses and immunodeficiency, may have a differential impact on SPCs. We conducted a nationwide data linkage study in order to examine the role of lymphoma in SPCs in PWHA in two ways. First, we determined the incidence of and risk factors for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) (including chronic lymphocytic leukaemia) in PWHA previously diagnosed with an initial cancer of any type. Second, we assessed the incidence and features of SPCs of any type in PWHA after a primary HL or NHL. Methods Since 1982 Australia has had compulsory disease notification of all new HIV infections and all invasive cancers. We conducted a probabilistic data linkage study between the Australian National HIV Registry, the Australian Cancer Database and National Death Index to identify PWHA diagnosed with an initial cancer, followed by at least one SPC between 1982 and 2012. Follow up commenced from 90 days post the date of first cancer diagnosis at or following HIV diagnosis, and ended on 31 December 2012 or death, whichever came earlier. A SPC was defined as a cancer of diverse site and histology to the first cancer and diagnosed more than 90 days later (in order to mitigate ascertainment bias). The incidence of SPC was compared using Poisson regression. Risk factors considered included: age, sex, HIV exposure modality (such as male-to-male, intravenous drug, etc.) and CD4+ cell count at HIV diagnosis (&amp;lt;50, 50-199, 200-499, &amp;gt;500 cells/µL). Incidence was also compared across various eras corresponding to HIV treatment advances: 1982-1995 (pre-cART); 1996-1999 (early-cART); 2000-2004 (availability of protease inhibitors for HIV); and, 2005-2012 (availability of fusion inhibitors for HIV and rituximab for CD20-positive lymphomas). Results Out of 28,696 PWHA, 3,548 were identified with a first cancer. Among them, 229 SPCs were identified over 27,398 person-years (PY) of follow-up. The crude incidence of SPCs was 8.36 per 1000 PY (95% CI 7.34-9.51). Of 229 SPCs, 88 were lymphomas, comprising 42 diffuse large B cell, 4 Burkitt, 3 T cell, 2 primary effusion, 3 low grade lymphomas and 5 HLs; 29 NHLs were not sub-classified in the Database. The majority of first cancers in the group with SPCs were Kaposi sarcoma (KS) (55%). The incidence of lymphoma as an SPC decreased from 8.10 to 0.79 per 1000 PY from 1982-1995 to 2005-2012 (p=0.003). Median time from first cancer diagnosis to the diagnosis of a lymphoma SPC was 2.0 years (interquartile range (IQR): 0.8-4.0). Median age at diagnosis of a lymphoma SPC was 39 years (IQR: 34-49). The risk of a lymphoma SPC decreased with older age, from 10.68 per 1000 PY in those under 35 to 1.28 per 1000 PY in those above 55 (p=0.003). CD4 count at HIV diagnosis and HIV exposure modality were not associated with the risk of a lymphoma SPC. The incidence of a SPC after lymphoma as a first cancer (n=39) was 5.60 per 1000 PY, versus 9.30 per 1000 PY when the first cancer was not lymphoma (n=190, p=0.004). KS was the most common SPC after an initial lymphoma (49% of cases). Only two myeloid SPCs occurred. Median time to diagnosis of SPC after an initial lymphoma was 2.6 years (IQR: 1.1-6.7). Risk of a SPC after a first lymphoma increased significantly from 4.12 per 1000 person-years in those diagnosed with HIV in the 1982-1995 pre-cART era, to 33.15 per 1000 person-years in patients diagnosed with HIV between 2009-2012 (p=0.005). Conclusion The incidence and spectrum of SPC in PWHA is increasingly important as overall and cancer-specific survival of these patients continues to improve. The incidence of lymphomas as SPC in PWHA has decreased over time, which may be a function of improved HIV treatment and reduced susceptibility to immunosuppression-related lymphoma. However, PWHA diagnosed with lymphoma as a first cancer are experiencing increasing incidence of SPCs, occurring after relatively short intervals. Longer survival is likely contributing to this effect. Importantly, therapy-related cancers do not appear prominent, suggesting HIV-specific factors may play a role. These findings emphasise the importance of SPC surveillance tailored to this special population. Disclosures Di Ciaccio: Janssen: Honoraria.

Role of Circulating Myeloid-Derived Suppressor Cell (MDSC) in Hodgkin Lymphoma (HL) Progression: Updated Prospective Study

Introduction.Patients with HL normally undergo a risk-adapted treatment based on PET scans. Regardless of HL treatment high efficiency, (80-90% remission), the search of new prognostic markers has been a continued process in recent years. This is related to the disease recurrence in 25-35% of patients in the first 5 years. The studies show that MDSC expands dramatically with tumor growth and causes a tumor immunosuppressed environment. The aim of this study is to investigate the number of MDSC in HL patients' peripheral blood and its correlation with clinical variables when the diagnosis and outcome first set. Methods .43 primary HL patients, (median age: 30, range: 19-78 years; male: 18, female: 25), were included in the study since April, 2018. 58.2% and 41.8% of patients have been diagnosed with early and advanced stages of HL, respectively, and received the ABVD or BEACOPP (14/esc) as a 1st-line treatment regimen. Peripheral blood mononuclear cells (PBMC) were isolated by ficoll density gradient centrifugation treatment, after 2-3 chemotherapy cycles (interim), and at the end of treatment (EOT). We assessed the E-MDSC count (CD33+CD11b+CD14-HLA-DR-) using the anti-human antibodies purchased from Beckman Coulter (Brea, CA, USA). We have also used a routine protocol of metabolic PET assessed according to Deauville criteria of response. Results.83.7% of patients achieved remission (CR/PR) during the follow-up period (median timeline: 18.9 months). We recorded a disease progression in 5 (11.6%) patients during and after the 1st line therapy, (time to relapse - 8 months). In addition, those patients had a high level of MDSC before treatment, which also remained high after interim and EOT-PET. Median of EFS has not been reached and we continue monitoring all patients. The HL patients who achieved remission had an increased E-MDSC percent (median 12.5%) compared to the age and gender control group, (median 2.03%), and the non-responders' one (median 20%). The number of NK-T (CD3+CD16+CD56+) cells increased by 15 % after EOT compared to pretreatment number, 9.2%, p=0.05. PBMC Evaluation at baseline.The E-MSDC count increases significantly with age: 3.1% vs 12.9% in HL patients under 25 years of age vs over 40, respectively p=0.014. Pretreatment MDSC levels were potentially associated with the disease stage: early stages (1A-2A and 2B) vs advanced stages (12% vs 3.9% vs 15%, respectively p=0.07). Our PET imaging tentatively correlated to the above levels. With that, patients with PET 5DS had a higher number of E-MDSC compared to a healthy control group, while the count is reduced in responders during and after treatment (p=0.06). Theoretically, this means that immunosuppression would be reduced and the antitumor immune response of the body would improve. PBMC Evaluation at interim response assessment.At this step, the age was also confirmed as an independent predicting factor in patients under 25 vs &amp;gt; 40, according to the MDSC level (6% vs 11.5%, respectively p=0.008). The level of E-MDSC was higher in patients who failed to achieve CR/PR (p=0.08). PBMC Evaluation at the EOT:90.6% (39/43) and 9.4% (4/43) of patients had a PET-negative and PET-positivestatus at the EOT, respectively (p &amp;lt; 0.05). We found a strong correlation between the EOT-PET and E-MDSC level. With this, patients with EOT-PET-ve had a lower E-MDSC expression vs EOT-PET+ve (12% vs 42% respectively, p=0.0007), which may potentially become a prognostic factor of response prediction. IPS is an important independent prognostic factor positively correlated to the MDSC count at EOT. In our study, patients in the high-risk group (3-4 IPS) had a significantly higher level of MDSC number than the low-risk group (1-2 IPS) and are more likely not to achieve a positive response to treatment (25% vs 18%, respectively p=0.02). Conclusion.The obtained results suggest that the higher level of MDSC number is associated with unfavorable prognosis of HL, reduce response rate. The challenge of strictly prognostic factor application leads to the research of biomarkers in the HL field. The discovery of new prognostic factors will improve an individualized approach to patient treatment and decrease the disease relapse risk. Disclosures No relevant conflicts of interest to declare.

Essential role of the linear ubiquitin chain assembly complex and TAK1 kinase in A20 mutant Hodgkin lymphoma

More than 70% of Epstein-Barr virus (EBV)-negative Hodgkin lymphoma (HL) cases display inactivation of TNFAIP3 (A20), a ubiquitin-editing protein that regulates nonproteolytic protein ubiquitination, indicating the significance of protein ubiquitination in HL pathogenesis. However, the precise mechanistic roles of A20 and the ubiquitination system remain largely unknown in this disease. Here, we performed high-throughput CRISPR screening using a ubiquitin regulator-focused single-guide RNA library in HL lines carrying either wild-type or mutant A20. Our CRISPR screening highlights the essential oncogenic role of the linear ubiquitin chain assembly complex (LUBAC) in HL lines, which overlaps with A20 inactivation status. Mechanistically, LUBAC promotes IKK/NF-κB activity and NEMO linear ubiquitination in A20 mutant HL cells, which is required for prosurvival genes and immunosuppressive molecule expression. As a tumor suppressor, A20 directly inhibits IKK activation and HL cell survival via its C-terminal linear-ubiquitin binding ZF7. Clinically, LUBAC activity is consistently elevated in most primary HL cases, and this is correlated with high NF-κB activity and low A20 expression. To further understand the complete mechanism of NF-κB activation in A20 mutant HL, we performed a specifically designed CD83-based NF-κB CRISPR screen which led us to identify TAK1 kinase as a major mediator for NF-κB activation in cells dependent on LUBAC, where the LUBAC-A20 axis regulates TAK1 and IKK complex formation. Finally, TAK1 inhibitor Takinib shows promising activity against HL in vitro and in a xenograft mouse model. Altogether, these findings provide strong support that targeting LUBAC or TAK1 could be attractive therapeutic strategies in A20 mutant HL.

Abstract IA28: Disparities in late effects incidence among adolescent and young survivors of lymphoma

Abstract IA28: Disparities in late effects incidence among adolescent and young survivors of lymphoma

Response rates, long term outcomes and toxicity profile of gemcitabine and vinorelbine based outpatient chemotherapy regimen in primary progressive and relapsed childhood Hodgkin lymphoma

This study aimed to determine response rates, overall survival (OS), event-free survival (EFS) and toxicity profile of an outpatient chemotherapy regimen based on gemcitabine and vinorelbine (GV) for relapsed childhood Hodgkin lymphoma (HL). This was a retrospective study that included 41 patients up to the age of 18 years with relapsed HL. Twelve patients (29%) had primary progressive disease (PPD), 6 (15%) had early relapse (ER) and 23 (56%) had late relapse (LR). The overall initial response rate was 83% (LR: 87%, ER: 83%, PPD: 75%. p-value: .2). Three-year combined OS was 80% (LR: 89%, ER: 80%, PPD: 65%. p-value: .07) and EFS 71% (LR: 86%, ER: 62%, PPD: 47%. p-value: .01). There were no toxic deaths. Febrile neutropenia was observed in four patients (9.6%) and lung toxicity in 1 patient (2.4%). This study suggests that outpatient GV is an effective and low toxicity salvage regimen for relapsed childhood HL.

Outcome of elderly patients with classical Hodgkin lymphoma (HL) in British Columbia.

8031 Background: Outcomes in elderly patients (pts) with Hodgkin lymphoma (HL) have traditionally been poor. We evaluated the survival of elderly pts (&gt;60 years [y]) with classical HL in British Columbia (BC). Methods: All pts aged &gt;60 y newly diagnosed with classical HL from 1961 to 2019 were identified in the BC Cancer Lymphoid Cancer Database. Limited stage was defined as non-bulky (&lt;10 cm) stage 1A/IB or 2A (before 2000 1B = advanced stage), with the remainder considered advanced stage. Results: Following exclusions (HIV positive n=4, incomplete data n=21, prior or concurrent other lymphoproliferative disease n=67), 713 pts were identified. With a median follow up of 6.0 y (0.1 - 24.0 y) in living pts, there has been an improvement in 5 y DSS/OS (both p&lt;.001) by decade comparison: 1960s (n=52) 25%/17%; 1970s (n=75) 38%/31%; 1980s (n=90) 51%/43%; 1990s (n=115) 53%/42%; 2000s (n=180) 66%/57%; 2010s (n=201) 63%/53%. To account for advances in diagnosis, staging, supportive care, and therapy in the modern era, we evaluated the outcome of pts diagnosed since 01/1995. A total of 368 pts were treated with curative intent (Table). Most pts received multi-agent chemotherapy (n=359, 98%: ABVD[like] n=351, alkylator-based n=7, CHOP n=1), 8 pts had radiotherapy (RT) alone, and 1 pt had surgery (primary CNS HL). The 5 y DSS, PFS, and OS were 74%, 57%, and 62%, respectively. Increasing age was associated with inferior outcomes (5 y DSS/PFS/OS): 61-70 y (81%/70%/74%), 71-80 y (69%/47%/52%), and &gt;80 y (59%/27%/31%) (DSS p=.011; PFS p&lt;.0001; OS p&lt;.0001). Of 318 pts that received bleomycin, 60 (19%) developed pulmonary toxicity, including 22 cases that occurred after cycles 1 and 2. Overall, 24/368 pts (7%) died of acute treatment toxicity (pulmonary [bleomycin n=10, radiation n=1], infection n=10, cardiac n=3). There was no association between age and developing bleomycin (p=.80) or lethal treatment toxicities (p=.74). Conclusions: The outcome of elderly pts with HL has improved in recent decades. However, treatment related toxicity remains a concern and use of multi-agent chemotherapy, particularly bleomycin-containing regimens, should be undertaken with caution. [Table: see text]

Survival of Patients With Second Primary Hodgkin Lymphoma

IntroductionThe increased risk for second malignancies after Hodgkin lymphoma (HL) diagnosis is well known. However, to our knowledge, no study has investigated the outcomes of patients diagnosed with HL after an antecedent malignancy (HL-2). We aimed to investigate overall survival (OS), disease-specific survival (DSS), and correlates of survival in HL-2 using the Surveillance, Epidemiology and End Results (SEER) database. Patients and MethodsHL-2 patients (n = 821) identified from the 2000-2014 SEER-18 registries were compared to first primary HL patients (HL-1, n = 31,355) from the same registries. Multivariable, propensity score–matched (PSM), and competing risks regression analyses were conducted to assess the effect of antecedent malignancy on survival. ResultsHematologic (n = 309, 37.6%), prostate (n = 169, 20.6%), and breast (n = 76, 9.3%) malignancies were common antecedent malignancies in HL-2. Median latency between antecedent malignancy and HL diagnosis was 39 months. Median ages at HL diagnosis for HL-1 and HL-2 were 36 and 66 years, respectively (P < .001). The 5-year OS and HL-DSS rates for HL-2 versus HL-1 were 53.2% versus 82.7% and 79.1% versus 90.9%, respectively (P < .001). On multivariable analysis, antecedent malignancy was associated with decreased OS (hazard ratio [HR] = 1.27; 95% confidence interval [CI], 1.13-1.42; P < .001). With PSM balancing across covariables, antecedent malignancy was associated with decrements in HL-DSS (HR = 1.46; 95% CI, 1.12-1.92; P = .006) and OS (HR = 2.09; 95% CI, 1.74-2.51; P < .001). ConclusionThe decrement in DSS in HL-2 relative to HL-1 may be related to biological differences in HL, age, and/or other unanalyzed factors. Further study of HL-2 patients is warranted.

Comparative pathologic analysis of mediastinal B-cell lymphomas: selective expression of p63 but no GATA3 optimally differentiates primary mediastinal large B-cell lymphoma from classic Hodgkin lymphoma

BackgroundInterpretation of mediastinal biopsy is often challenging even for experienced pathologists especially when a hematolymphoid neoplasm is suspected. Primary mediastinal large B-cell lymphoma (PMLBCL) and classic Hodgkin lymphoma (CHL) represent two major types of mature B-cell lymphomas of the mediastinum. Although PMLBCL and mediastinal CHL share many clinicopathologic characteristics, their treatment strategies and responses are remarkably different. We therefore aimed to find distinctive histologic or protein markers to better differentiate these two lesions.MethodsSearch for primary mediastinal B-cell lymphomas found 52 consecutive cases from 3 university hospitals of Korea during 2005 to 2012. Among them, 32 cases that were available for additional immunohistochemistry (IHC) assessment were enrolled in this study. These cases consisted of the following: CHL (N = 13), PMLBCL (N = 16), and B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma and CHL (gray zone lymphoma, N = 3). Along with the clinicopathologic findings, the expression of p63, GATA3 and cyclin E was investigated by IHC in the three categorized lesions mentioned above.ResultsMost clinical features overlapped between PMLBCL and CHL except for the increased disease progression and mortality found in PMLBCL. In the pathologic review, the presence of epithelioid granuloma favored a diagnosis of CHL, whereas reticulated or alveolar patterns of fibrosis were characteristic of PMLBCL. For protein markers, p63 was predominantly positive in PMLBCL (15/16) compared with CHL (2/13), which indicates that p63 is a marker of the highest diagnostic accuracy when calculated by the area under the ROC curve. GATA3 was expressed in the majority of CHL cases (10/13) compared with PMLBCL (0/16), while the expression of cyclin E was only rarely present in a minor population of PMLBCL.ConclusionsP63 expression in tumor cells, even focal expression, and no GATA3 is the most helpful feature in distinguishing PMLBCL from mediastinal CHL.

Role of Circulating Myeloid-Derived Suppressor Cell (MDSC) in Hodgkin Lymphoma (HL) Patients: Prospective Study

Introduction. MDSC's are a heterogeneous population of bone marrow-derived myeloid progenitors including macrophages, granulocytes, dendritic cells and immature myeloid cells, which expand dramatically with tumour growth, and there are several clues have an important role in the disease progression. Recent studies have also highlighted interim PET as the most important prognostic factor for HL. The interim PET positivity may indicate that there is a reactive microenvironment promoting tumor cells survival. In this study we analyzed the prognostic significance of MDSC count together with PET in HL patients. Methods . The 29 primary HL patients (median age: 33, range 19-61 years; males: 15, females: 14) were included in the study from Apr 2018 until now. 62% of patients were diagnosed with early stages of HL, while 38% - with advanced stages. ABVD or BEACOPP (14/esc) were administered as a 1st-line therapy. Peripheral blood mononuclear cells (PBMC) were isolated on ficol density gradient from peripheral blood before treatment, interim after 2-3 chemotherapy cycles and after the end of treatment (EOT). The percentage of E-MDSCs subtype and lymphoid populations was measured by flow cytometry using CD11b, CD33, CD14, HLA-DR, CD34, CD45, CD3, CD4, Cd8, CD16, CD56 antibodies. Metabolic PET-CT imaging was performed to routine protocols using Deauville criteria for response assessment. Results. 93% of patients achieved remission (CR/PR) during follow-up period (median 11.6 months). All pts are still in follow-up. The count of E-MDSC was increased in HL patients (median 12.5%) compared to matched for sex and age healthy controls (median 11%) and was higher in non-responders (median 19.7%). We also found that E-MSDC count in HL patients significantly increases with age - 6.5% in patients under 40 years vs 19.8% in patients 40+ years, p=0.007. No significant correlations were found between the frequency of MDSC and clinicopathological factors, including gender, Ann Arbor Stage, B symptoms, IPI scores. The number of NK-T (CD3+CD16+CD56+) cells increased on 6.73 % after EOT compared to before treatment, p=0.009. Theoretically, this means that immunosuppression is reduced and the antitumor immune response of the body is improved. 93.1% (27/29) and 6.9% (2/29) of patients had 1-3 and 4-5 DS of the EOT, respectively (p &lt; 0.05). We recorded one early relapse (11months) after the 1st line therapy - patient had high level of MDSCs before treatment and it remained high after iPET and EOT-PET. Additionally, pts with iPET 4DS have a greater number of E-MDSCs compared to healthy control and, when complete remission is achieved, their values return to be equal to healthy control. We found strong significant association between EOT-PET and level of E-MDSC after treatment. Thus, pts with EOT-PET-ve had lower expression E-MDSC vs EOT-PET+ve (3% vs 29% respectively, p=0.0007). May be in future it can be new prognostic factor for predict to relapse. Conclusion. Patients with HL have high level of expression MDSC. Biomarkers research and HL biology at its basis may potentially rise up to the challenge of sole clinical prognostic factors application. This potentially area for research but are as yet unproven and in need have prospective validation. Disclosures No relevant conflicts of interest to declare.

Skuteczność brentuksymabu vedotin w czwartej linii leczenia chorego na pierwotnie opornego chłoniaka Hodgkina

Patients with relapsed or primary resistant Hodgkin lymphoma (HL) who do not qualify for high-dose chemotherapy with a transplant of autologous hematopoietic stem cell transplantation (auto-HSCT) have poor prognosis. The use of new drugs such as brentuximab vedotin, anti-PD-L1 antibodies enables remission and sustained response in this difficult to treat group of patients. Brentuximab vedotin is a conjugate of anti-CD30 and auristatin E antibodies. The drug was registered by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2012 to treat patients with recurrent or resistant HL. In Poland, this drug is available in the National Health Fund drug program for patients after autologous peripheral blood stem cell transplantation or after at least two lines of chemotherapy, when auto-HSCT is not a valid treatment option. This case illustrates the effectiveness of brentuximab vedotin in the fourth line of primary resistant HL treatment.

Survival of Patients with Second Primary Hodgkin Lymphoma

Abstract Introduction The increased risk for second malignancies after Hodgkin lymphoma (HL) diagnosis is well known. However, to our knowledge, no study has investigated the outcomes of patients diagnosed with HL after an antecedent malignancy (HL-2). We aimed to investigate overall survival (OS), disease-specific survival (DSS), and correlates of survival in HL-2 using the Surveillance, Epidemiology and End Results (SEER) database. Patients and Methods HL-2 patients (n = 821) identified from the 2000-2014 SEER-18 registries were compared to first primary HL patients (HL-1, n = 31,355) from the same registries. Multivariable, propensity score–matched (PSM), and competing risks regression analyses were conducted to assess the effect of antecedent malignancy on survival. Results Hematologic (n = 309, 37.6%), prostate (n = 169, 20.6%), and breast (n = 76, 9.3%) malignancies were common antecedent malignancies in HL-2. Median latency between antecedent malignancy and HL diagnosis was 39 months. Median ages at HL diagnosis for HL-1 and HL-2 were 36 and 66 years, respectively (P Conclusion The decrement in DSS in HL-2 relative to HL-1 may be related to biological differences in HL, age, and/or other unanalyzed factors. Further study of HL-2 patients is warranted.

Classical Hodgkin Lymphoma Presenting as the Primary Rectal Lesion in a HIV patient on HAART Management

Background: Hodgkin lymphoma involving rectum as primary lesion is very rare. Incidence rates of Hodgkin lymphoma have increased by 7-8 times in HIV patients when compared with the general population. The incidence has increased in the era of highly active anti-retroviral therapy (HAART). Only five cases of primary Hodgkin lymphoma of the rectum are reported in the literature. Case Report: We are presenting a case of primary Hodgkin lymphoma of the rectum in a HIV infected patient on HAART. Conclusion: Hodgkin lymphoma involving the rectum as a primary lesion is very rare and in HIV infected patients is much rarer. Hodgkin lymphoma should be kept in mind in an anorectal growth in HIV patients.

Prognostic Assessment of the PET-CT Role in Primary Patients with Hodgkin Lymphoma: Do We Still Need More Data?

Introduction.PET-CT is the new imaging modality for staging of patients with Hodgkin Lymphoma (HL) with its excellent results in prognostic role for survival rate. Despite this fact, there are still patients in different risk groups who need intensification in treatment or dose de-escalation. In recent years several studies have been activated and published data about baseline, interim (iPET) and end-of-treatment (PET3) PET-CT prognostic role. But somewhere, there are still a lot of controversies. Here we report the results of a multicenter prospective study of iPET and PET3 in HL.Methods.113 patients with the primary HL were evaluated in the study. Between 113 patients 67.2% (76) were females and 32.8% (37) - males, with median age 42.5 years (range - 18 to 67years ). Patients received standart chemotherapy protocols based on risk group - ABVD or BEACOPP-14/esc. Metabolic PET-CT imaging was performed at participating PET centers according to routine protocols. iPET and PET3 with 1-3 and 4-5 scores by Deauville were considered as astatus-negative and status-positive result, respectively.The primary endpoints of the study were evaluated predicting treatment outcome and event free survival (EFS).Results.40.7% (46/113) with early stages were treated by ABVD and 59.3% (67/113) patients with advance stages received BEACOPP-esc/14 and ABVD, respectively (p<0.05).The ORR of 96 patients (CR, PR) was 92%. The maximum follow-up period in this group of patients was 62 months (median 17 months). 98% (111/113) patientsare still followed up.89% (89/100) and 11% (11/100) of patients had 1-3 and 4-5 scores of iPET by Deauville 5-PS scale, respectively (p < 0.05). In total, disease progression was documented in 27.2% (3/11) of iPET-positive patients and 12.3% (11/89) of iPET-negative patients (p<0.05). There was one death from refractory disease.We did not find anysignificantprognostic roleof iPETanddepends on type of regimen in patients from that group to predict the EFS. Thus, 3-year EFS of patients with iPET-positive versus iPET-negative was 57% and 85%, respectively (Log-rank test, p=0.3).95.5% (108/113) and 4.5% (5/113) patients in our cohort had PET3- negative (PET3-) and positive (PET3+) status, respectively (p<0.05). The 2-year EFS rates were 90% and 15% for patients whose PET3 was negative and positive, respectively (Log-rank test, p<0.0001).2-year EFS for pts PET3+ with I-IIA was higher compared in cases with IIB-IVB stages (50% vs 15%,respectively; Log-rank test, p<0.0001). But EFS ratein patients with PET3- depends on stage of disease was similar: 95 % vs 90% in patients with I-IIA vs IIB-IVB, respectively.Conclusion. While performed iPET provides valuable information about the quality of the treatment response, there is still a need for its prospective confirmation as a prognostic factor. Clinical trials are designed to improve upon the current 1st-line therapy, may be more informative, if focused on PET-positive patients after treatment. DisclosuresNo relevant conflicts of interest to declare.

Inflammatory Bowel Disease and Hodgkin's Lymphoma: Two New Observations

Introduction :Malignancies are the second most common cause of death after cardiovascular diseases in patients with inflammatory bowel disease (IBD). Indeed, patients with IBD have an increased risk for developing a variety of extraintestinal malignancies, in particular, lymphomas and mostly non-Hodgkin lymphomas. In the spectrum of lymphoproliferative disorders, Hodgkin lymphoma-type is rare, only a few cases with Hodgkin's lymphoma (HL) in IBD patients have so far been reported. We report two new cases.Case 1 :A 44 year old male presented in 2010 with a history of abdominal pain, intermittent diarrhea, and rectal bleeding. The clinical, endoscopic, and pathologic findings were consistent with ulcerative colitis. Initial medical treatment was Azathioprine (50 mg, three times a day), Prednisolone (50 mg, one time a day), and 5-aminosalicylic acid (800 mg, three times a day). He was also diagnosed as having type 2 diabetes, treated with insulin. The patient was continually treated with Azathioprine through 5 years, with reduced dose (100 mg/d) because of hematological toxicity. In 2016, the patient was readmitted with severe pneumonia. He reported having abdominal pain, weight loss, night sweat, and intermittent fever for three to four months before admission. A computed tomography was performed, showed retroperitoneal, peri-aortic and iliac bilateral lymphadenopathy. Needle biopsy was performed out and histology revealed large cells of Hodgkin's type, and intense staining for CD30 and CD15 all in favor of the diagnosis of HL.Case 2 :The second patient is a 30-year-old man with ileocecal Crohn disease diagnosed at age 23 years. Remission was induced with corticosteroids and maintained by Azathioprine (150 mg/d). Three month before his admission to our unit, he complains from intermittent fever, decline in general condition. Cervical and axillary lymphadenopathy were noted. The lymph node biopsy revealed mixed-cellularity Hodgkin lymphoma. Computed tomography scan revealed stade IIIB disease for both patients. They received 6 cycles of adriamycin, bleomycin, vincristine, and dacarbazine. A complete regression of lymphadenopathy was confirmed by CT and positron emission tomography scan. Presently, the patients remain in remission and without any signs of lymphoproliferative disorder or IBD (on sulfasalazine).Discussion :IBD patients show a trend toward higher risks of developing hematological malignancies. Compared with the general population, there is an increased risk for lymphoma, especially non-Hodgkin lymphoma, with a standardized incidence rate of 1.42 (95% CI, 1.16-1.73). HL is a known rare comorbidity that can emerge in IBD patients. Thiopurines were shown to increase the incidence of lymphoma after kidney transplantation and similar observations have been reported in patients with IBD. In observational cohort, the risk of acquiring lymphomas was significantly higher (4- to 5- fold) in patients with thiopurine exposure; this risk appears to rise with longer duration of therapy and to decrease after drug withdrawal. Most of the thiopurine promoted lymphomas are attributed to the cytotoxic effects of thiopurines on EBV-specific immune cells that prevent the proliferation of EBV-infected B lymphocytes.IBD itself may contribute to the development of lymphoproliferative disorders, particularly primary intestinal HL. Indeed, recent population-based study showed an association between lymphomas and IBD, regardless of the use of thiopurines. In fact, inflammation itself plays a role in lymphomagenesis. Local sites of inflammation may be particularly at risk of lymphoproliferation, due to chronic B-cell stimulation, may also explain the frequency of gastrointestinal lymphoproliferative disorders involving the gastrointestinal tract (26% of cases). The duration of the disease appears also as an independent risk factor for lymphoma.Conclusion :HL can emerge in IBD patients on immunosuppressive therapy and physicians must be aware of this possibility. EBV infection might have an intermediate role between immunosuppressive treatment and lymphoma. Those data should alert clinicians that, not only thiopurine use but also the disease itself could contribute to a higher occurrence of lymphoproliferative disorders. DisclosuresNo relevant conflicts of interest to declare.

Risk of a second neoplasm on long‐term survivors of Hodgkin's lymphoma

AbstractObjectiveAlthough advances in Hodgkin's lymphoma treatment have led to improvements in overall survival (OS), this has been accompanied by an increased risk of second neoplasm (SN) development. We analyzed the incidence and outcome of SN development in patients treated at a single cancer center.MethodsWe collected the following information from the records of 8288 patients diagnosed with primary Hodgkin's lymphoma since 1970: pathological diagnosis of Hodgkin's lymphoma, initial stage, treatment, response type, and outcome. SN was diagnosed in pathological studies, stage and treatment of SN were indicated in all cases, and all patients were followed up until death or last follow up (December 2016). OS was analyzed to determine whether SN had an impact on it. The Kaplan–Meier method was used to determine progression‐free survival and OS. The χ2‐test was used for comparisons between groups.ResultsAfter a median follow‐up period of 19.9 years (range 5.6–40 years), just 89 cases (1.07%) of SN development were found. The most frequent sites were the lung (28%), breast (26.9%), and gastrointestinal tract (18%). There was no significant difference in the development of SN according to age, stage, pathological diagnosis, presence of bulky disease, use of alkylating agents, or radiotherapy administration. No difference in OS was observed between patients who did and did not develop a SN.ConclusionsThe main cause of death was secondary to tumor progression, and SN was observed in a reduced number of patients compared with previous studies. We did not observe any differences between the treatment strategies used in studies of populations white people. We used radiotherapy in a greater number of patients and included extended fields, and radiotherapy was not associated with the development of SN. The main difference between the present study and other studies was the race of the patient cohort; therefore, we propose that race could have had a protective effect in this patient cohort. Further studies that have a non‐white base population are necessary to draw definitive conclusions.