Hodgkin Lymphoma Progression Research Articles

SATB1 and p16 Expression and Prognostic Value in Croatian Hodgkin Lymphoma Patients: A Unicentric Study.

Hodgkin lymphoma (HL) is a rare lymphoid neoplasm in which Hodgkin/Reed-Stenberg (HRS) cells are admixed with a population of non-neoplastic inflammatory cells and fibrosis. Dysregulated expressions of cell cycle regulators and transcription factors have been proven as one of the hallmarks of HL. In that context, SATB1 and p16 have been reported as potential regulators of HL progression and survival. However, to date, no studies have assessed the expression levels of SATB1 and p16 in HL in Croatian patients or their prognostic values. Therefore, we investigated the expression pattern of SATB1 and p16 in paraffin-embedded lymph node biopsies using standard immunohistochemistry. We found that 21% of the patients stained positive for SATB1, while 15% of the patients displayed positive staining for p16. Furthermore, we aimed to understand the prognostic value of each protein through the analysis of the overall survival (OS) and progression-free survival (PFS). SATB1 showed a significantly positive correlation with better OS and PFS, while p16 expression had no impact. Interestingly, when patients were stratified by a combination of the two studied markers, we found that patients in the SATB1+/p16- group tended to have the best prognosis in HL, according to statistical significance. In conclusion, SATB1 and p16 might be potentially useful as diagnostic and prognostic markers for HL.

Safety, efficacy, and affordability of ABVD for Hodgkin lymphoma in Malawi: a prospective cohort study

ABVD (doxorubicin, bleomycin, vinblastine, and dexamethasone) is a proven, curative regimen for Hodgkin lymphoma (HL). Prospective data describing HL treatment in sub-Saharan Africa are limited. We aimed to fill this knowledge gap, using data from Malawi. We report a prospective observational cohort of HL (aged 15) from a single, tertiary referral centre in Malawi. We enrolled patients with pathologicially confirmed Hodgkin lymphoma between June 1, 2013, and Dec 31, 2021 with follow-up censored on May 31, 2022. Patients were treated with ABVD and concurrent antiretroviral therapy if HIV-positive and were followed up for 5 years. The primary outcome was overall survival; secondary outcomes included progression-free survival, response assessment, and adverse events. Microcosting of HL diagnosis, treatment, and follow-up was embedded. We enrolled 38 patients with a median age of 27 years (interquartile range 19-46); eleven (28%) were HIV-positive. Of 35 patients treated with ABVD, 24 (71%) had stage III/IV, nine (26%) unfavourable limited stage, and two (6%) favourable limited stage. Among HIV-infected individuals, mean CD4 count at HL diagnosis was 179cells/uL and ten (91%) had HIV RNA < 400 copies/mL. Grade 3/4 neutropenia occurred in 24 (68%) patients and caused treatment delay in 16 (46%). Of ten deaths, seven were due to HL, two possible treatment-related toxicity, and one uncertain. 2-year overall survival was 82% (95% CI 70-96%) and 2-year progression-free survival was 64% (95% CI 50-83%). PFS appeared better for HIV-positive patients (HR 0.23 (95% CI 0.05-1.02)) after controlling for stage and performance status (p=0.05). We estimated $2708 (2022 USD) for HL diagnosis, treatment, and follow-up in our cohort. Our findings suggest that treatment with ABVD is safe, efficacious, and affordable for HL in Malawi. Outcomes are worse than in high-income countries due to HL progression. Future studies are needed to understand outcome inequities and to assess efficacy of therapies for patients with relapsed or refractory HL in Malawi. National Institutes of Health, Lineberger Comprehensive Cancer Center.

Patterns of Progression on Immune Checkpoint Inhibitor Therapy for Relapsed Hodgkin Lymphoma: Implications for the Potential Role of Radiation Therapy

<h3>Purpose/Objective(s)</h3> Radiation therapy (RT) is increasingly utilized for patients with stage IV epithelial cancers experiencing oligometastases or oligoprogression, and often in combination with immune checkpoint inhibitors (ICI). ICIs are an approved treatment for relapsed Hodgkin lymphoma (HL) with a high overall response rate, yet most patients eventually progress. We examined patterns of HL progression during or following ICI therapy, using FDG-PET scans to identify patients who may benefit from comprehensive RT. <h3>Materials/Methods</h3> This retrospective study included patients with HL treated with an ICI from 2013 – 2022. We reviewed the pre-ICI FDG-PET and FDG-PET at progression with the goal of clarifying patterns of failure to define a group of patients who may have been amenable to RT. Optimal RT candidates were patients with ≤5 targetable areas on their pre-ICI FDG-PET and who progressed at only pre-relapse sites (i.e., local relapse). <h3>Results</h3> Eighty-nine patients were identified and 44 progressed during or after ICI – of these, 37 (42% of the total cohort) had adequate imaging for review and were therefore included in this study. For these 37 patients, median follow-up was 5.0 years and 32 (86%) had undergone autologous stem cell transplant prior to initiation of ICI. Nivolumab was the most commonly prescribed ICI (81%). At ICI initiation, 57% had ≤5 sites of disease on FDG-PET. All but one patient experienced local progression after ICI (97%), and 46% had new lesions outside of pre-ICI FDG-PET sites. The number of disease sites at ICI initiation did not predict for local versus distant relapse. Patients with relapse stage I/II nodal only disease at ICI initiation were significantly more likely to have ≤5 pre-ICI sites and only local progression after ICI (our parameters for patients who may potentially benefit from radiation) (HR 11.5, p=0.03). Less than 20% of patients with pre-ICI parenchymal, bone, or splenic disease fell within this parameter. Isolated local progression occurred at a median 261 days after ICI initiation (IQR 112-499), compared to 195 days (IQR 90-369) for those with progression at new sites. Patients who progressed in parenchymal sites had a lower 3-year OS at 38.5%, compared to at least 50% for all other sites (p=0.001). <h3>Conclusion</h3> Patients with relapsed HL experience a variable course on ICI therapy. Patients with relapse stage I/II nodal only disease experience high rates of progression at existing sites only, and may represent an optimal cohort for consolidation RT. Relapse typically occurs more than 90 days after initiation of ICI, indicating that the 90-day timepoint may be an appropriate time to consider integration of radiation if no new sites of disease have developed. This data serves as a potential benchmark for prospective evaluation of integrating RT with ICI to further improve outcomes in patients with relapsed HL, although validation is necessary.

Increased expression of matrix metalloproteinases 2 and 9 as poor prognosis factor for Hodgkin's lymphoma patients

ObjectiveThe aim of our study was to evaluate the expression of MMP-2 and MMP-9 as a prognostic factor in patients diagnosed with Hodgkin Lymphoma (HL). MethodsIn the present study, 45 paraffin biopsies from patients up to 19 years old diagnosed with HL were used in two referral hospitals in the state of Pernambuco, Brazil. Risk groups were classified into favorable and unfavorable, according to Ann Arbor. The expression of matrix metalloproteinases 2 and 9 and their inhibitors was performed by immunohistochemistry (IHC). Data were analyzed using the GraphPad Prism 5 program. ResultsMMP-2 intensity pattern was stronger (>10% of the total field) in patients with stage III/IV and B symptoms. MMP-2 showed an association with the risk group (p = 0.0388). That is, the stronger the MMP-2 marking, the greater the unfavorable risk. However, for MMP-9 there was no difference in the stronger intensity pattern in relation to stages I/II and III/IV, only in the presence of B symptoms. MMP-9 showed an association with B Symptoms (p = 0.0411). Therefore, patients with B symptoms have higher MMP-9 expression. ConclusionOur results suggest that MMP-2 expression is associated with HL progression. While MMP-9 expression is related to the clinical worsening of these patients. However, further studies are needed to evaluate the exact role of these proteins in hematologic malignancies.

Autologous hematopoietic stem cell transplantation in children with relapsed or refractory Hodgkin lymphoma

The majority of patients with Hodgkin lymphoma (HL) are cured, which represents one of the best cure rates in oncology. However, the prognosis is not as favorable in case of relapsed or refractory (RR) disease. Autologous hematopoietic stem cell transplantation (auto-HSCT) is an effective way to consolidate remission in patients with RR HL. Despite the many years of experience and the availability of results of randomized trials confirming the efficacy of high-dose chemotherapy in adults, the role of auto-HSCT in children with HL has not been studied as extensively, and there are only a limited number of publications on the subject. As is the case with the majority of other pediatric tumors, RR HL is a rare entity, which is why it is so difficult to study it. Here we share the experience of the R. M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation in auto-HSCT in children and adolescents with HL. The study was approved by an Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint-Petersburg State Medical University. We included 54 patients with RR HL who had undergone auto-HSCT during the period from 2007 to 2021. Refractory disease (n = 29; 54 %) was diagnosed in case of HL progression either during first-line therapy or in the first 3 months after the completion of the treatment. Relapsed disease was diagnosed in 25 (46 %) children. Early HL relapse (&lt; 12 months since the start of therapy) was evident in 18 (72 %) patients, while late HL relapse (≥ 12 months since the start of therapy) occurred in 7 (28 %) children. The median number of lines of therapy before auto-HSCT was 3 (1–6). The first line of treatment was chemotherapy in accordance with the GPOH-HD (n = 27; 50 %), BEACOPP (n = 19; 35 %), or other protocols (n = 8; 15 %); the second line involved the use of IEP/ABVD (n = 14; 27 %), DHAP (n = 12; 23%), ICE (n = 13; 25 %), or other combinations (n = 13; 25%); and third-line treatment consisted of DHAP (n = 9; 29 %), a combination of brentuximab vedotin and bendamustine (n = 8; 26%), immune checkpoint inhibitors (ICIs) (n = 7; 22.5 %) or other regimens (n = 7; 22.5 %). ICIs were used for remission induction prior to auto-HSCT in 14 (26 %) patients. Response was assessed using the Lugano classification. Status before transplantation: complete remission (CR) – 21 (39 %) patients, partial remission (PR) – 30 (56 %), disease stabilization – 2 (3.5 %), disease progression – 1 (1.5 %). The BEAM conditioning regimen was used in 17 (31 %) patients, and the BeEAM regimen – in 32 (59 %) patients. The 3-, 5- and 10-year overall survival (OS) was 88% (95 % confidence interval (CI) 74–95), 80% (95 % CI 62–90) and 63% (95 % CI 34–81) respectively. The 10-year progression-free survival (PFS) was 46% (95 % CI 24–65). The median follow-up was 3.3 (0.1–12.3) years. The long-term PFS in children with CR and PR was 72% (95 % CI 41–89) and 33 % (95 % CI 8–61) respectively (p = 0.067). A total of 9 (16.7 %) patients died during follow-up. The main cause of death was progressive HL (n = 6), while some patients died in the early post-transplant period due to infections (n = 3; 5.6 %). The median time to relapse or progression after auto-HSCT was 6 (1–77) months. Out of 17 (31 %) patients with relapsed or progressive HL after auto-HSCT, 9 (53 %) children are alive at a median follow-up of 2.3 (0.7–9) years. Considering that our study included patients who had been more extensively pre-treated (the median number of lines of therapy – 3) than patients in the majority of other studies (the median number of lines of therapy – 2), it can be assumed that our results are superior to historical data. The improvement of transplantation outcomes observed over time can be attributed to better supportive treatment and probably, to the use of immunotherapy. According to the Center for International Blood and Marrow Transplant Research (CIBMTR), it is crucially important that long-term survival in children with RR HL be monitored closely since it can be drastically different from results obtained during the first years of follow-up - due to late relapses and complications of the received treatment. The 10-year survival rates show that the RR HL problem is yet to be resolved. With the help of auto-HSCT, approximately half of children and adolescents with RR HL can be cured. One of the most important favorable prognostic factors in these patients is the achievement of CR before transplantation. The use of immunotherapy for remission induction before auto-HSCT is also promising.

Elderly Hodgkin Lymphoma - Multicenter Retrospective Data Analysis from the Czech Hodgkin Lymphoma Registry

Introduction: The proportion of elderly Hodgkin lymphoma (HL) patients (age ≥ 60 years) ranges between 15% and 35%. Outcome of this group of patients (pts) is significantly inferior compared with younger pts. Management of therapy is still unclear, standard treatment is not yet defined, especially with concomitant cardiac and/or pulmonary diseases. Purpose of this study was to analyze treatment and outcome of elderly HL pts prospectively registered in Hodgkin Lymphoma Project in the Czech Republic.Patients and methods: The proportion of elderly patients in the Czech HL Registry was 11%. We analyzed 151 pts ≥ 60 years (y) with classical HL diagnosed between 1995 and 2016. Median age was 67y (60-84), 72.2% of them were 60-70y old and male gender represented 54% (82 pts). Histological subtype mixed cellularity occured most frequently (50%). Advanced clinical stage (CS) was confirmed in 67.3% pts. CS in 1 pt remained unknown. Chemotherapy (CT) alone was used in 103 (68.2%) of pts (initial/intermediate stages 15 pts, advanced stages 87 pts, CS unknown 1 pt). Combined modality of treatment (CT and radiotherapy, RT) was used in 42 pts (intial/intermediate stages 30 pts, advanced stages 12 pts). Anthracycline - based CT received 81.5 % of pts (119 pts). Three pts (2%) were treated with RT alone, 2 pts (1.3%) with CT+ other treatment and 1 pt was without treatment after surgery exstirpation.Results: The median follow-up was 4.2 years. Treatment response was evaluable in 138 (91.4%) pts. Overall response rate (CR+PR) after the first-line treatment was observed in 125 (82.8%) pts, with 99 (65.7%) CR. Stable disease was observed in 1 (0.7%) pt and primary disease progression in 12 (7.9%) of pts. Relapses occured in 10% and 1 pt underwent high dose CT and autologous stem cell transplantation in the 1st relapse (age 61y). Median PFS and OS was 8.7y and 10.3y, respectively. Four - year PFS and OS was 69.5% and 71.6%, respectively. Overall 59.6% pts are alive and 61 (40.4%) of pts died: HL progression 17 pts, toxicity of treatment 15 pts, secondary malignancy 8 pts, others causes 12 pts. The cause of death in 9 pts remained unknown.Univariate Cox regression analysis identifies age ≥ 75y (p=0.033), failure of CR achievement (p<0.001), no anthracycline based CT (p=0.018), low albumin level < 4.0g/dl (p=0.016), lymphopenia <8% (p=0.006), CIRS score > 3 (p=0.037) as risk factors for OS. All mentioned factors without CIRS score predicted a significantly shorter PFS. CIRS > 3 and lymphopenia <8% were independent factors for shorter OS and PFS in multivariate analysis (Table 1, Figure 1).Conclusions. Long-term survival of our pts depended on the CIRS score and lymphopenia. Interestingly, 4 IPS factors (sex, hemoglobin, leucocytes, GHSG advanced stage), ADL (activity of daily living) and performance status WHO/ECOG were not significant for survival in univariate analysis. Prospective clinical studies are still needed to determine an optimal effective regimen with low toxicity in elderly pts.This work was supported by grant awarded by AZV 16-29857A, Ministry of Health in Czech Republic and Research project P 27/2012 awarded by Charles University in Prague, Third Faculty of Medicine, Prague, Czech Republic [Display omitted] DisclosuresBelada:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants , Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants , Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants , Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau.

Long non-coding RNA NEAT1 regulates Hodgkin's lymphoma cell proliferation and invasion via miR-448 mediated regulation of DCLK1.

To explore whether long non-coding RNA nuclear enriched abundant transcript 1 (lncRNA NEAT1) could regulate Hodgkin's lymphoma (HL) cell proliferation and invasion through miR-448, which could target doublecortin like kinase 1 (DCLK1) and mediate DCLK1 expression. Expressions of NEAT1, miR-448 and DCLK1 were evaluated by qRT-PCR or Western blot assay. Cell Counting Kit-8 (CCK-8) and transwell assay were utilized to detect cell proliferation and invasion capability in L428 cells respectively. The target relationship between NEAT1, miR-448 and DCLK1 was confirmed by Luciferase reporter assay. QRT-PCR results showed that NEAT1 expressed higher in HL tissues and cell lines than that in controls. In vitro experiments, NEAT1 downregulation could decrease cell proliferation and invasion capability in L428 cells. NEAT1 directly interacted with miR-448 and negatively regulated it. Moreover, DCLK1 was confirmed as a target of miR-448. DCLK1 expression was increased in L428 cells and positively regulated by NEAT1. NEAT1 overexpression upregulated the protein level of DCLK1 in L428 cells according to Western blot analysis. Additionally, DCLK1 overexpression could reverse the suppression on cell proliferation and invasion capability induced by NEAT1 knockdown or miR-448 overexpression. NEAT1 might be contributed to HL progression by promoting cell proliferation and invasion capability via miR-448 mediated DCLK1 expression.

Construction of relapse-related lncRNA-mediated ceRNA networks in Hodgkin lymphoma.

IntroductionHodgkin lymphoma (HL) is a type of lymphoma common throughout the western countries. However, the detailed mechanisms and special biomarkers of HL remain to be further investigated. Emerging studies have shown that long non-coding RNAs play a key role in human cancers.Material and methodsIn the present work, we constructed relapse-related lncRNA-mediated ceRNA networks in HL. Additionally, we constructed co-expression networks for these relapse-related lncRNAs. We also constructed a relapse-related lncRNA-miRNA-mRNA network to study the potential mechanism of these lncRNAs. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to explore functions of DEGs in Hodgkin lymphoma.ResultsA total of 18 lncRNAs were found to be dysregulated between early relapse and late relapse HL. Six lncRNAs (PCBP1-AS1, HCG18, GAS5, PSMD6-AS2, PRKCQ-AS1, SNHG6), 116 mRNAs and 121 miRNAs were included in the ceRNA network. Bioinformatics analyses revealed that these lncRNAs were significantly involved in regulating immune system processes, responses to chemical stimuli and responses to stress. Among them, HCG18 and PCBP1-AS1 were identified as key lncRNAs in HL relapse.ConclusionsOur results for the first time constructed the key relapse-related lncRNA-mediated ceRNA networks in Hodgkin lymphoma progression. We trust that this work will provide a new therapeutic and prognostic target for HL.

Does the Incidence of Treatment-Related Toxicity Plateau After Radiation Therapy: The Long-Term Impact of Integral Dose in Hodgkin's Lymphoma Survivors

BackgroundConventional radiation therapy (RT) has produced unprecedented cure rates in patients with Hodgkin's lymphoma (HL) but exposed large volumes of nontargeted tissue to radiation (integral dose). ObjectiveOur goal was to report the effects of integral radiation dose on health outcomes in patients with at least 20 years of potential follow-up time. Methods and MaterialsWe reviewed the medical records of 365 patients who were treated with RT for HL between 1965 and 1995. All patients were confirmed to have received primary RT with curative intent at our institution for de novo HL. Serious adverse events were classified as HL progression or death, grade ≥3 treatment- or staging-related acute or late effects, second malignancies, or cardiovascular events. ResultsThe minimum potential follow-up time was 20 years, and the actual median follow-up time 22 years (range, <1-49 years) for all patients and 27 years (range, 5-49 years) for surviving patients. The overall survival rates at 5, 10, 20, 30, and 40 years were 86%, 76%, 64%, 44%, and 27%, respectively. The observed-to-expected ratio for second malignancy was 3.6 (95% confidence interval, 2.9-4.4). Grade ≥3 cardiovascular events occurred in 31% of all patients (n = 112). At the time of the most recent follow up, serious adverse events occurred in 70% of the entire cohort (n = 256) and 58% (n = 103), 77% (n = 103), and 93% (n = 50) among those with a potential 20, 30, and 40 years of follow up, respectively. ConclusionsWith increased survivorship, the long-term impact of the integral radiation dose may result in clinically significant adverse events, which suggests the importance of surveillance and affirms advances in both chemotherapy and RT that minimize the integral dose in future patients with HL.

Overexpression of survivin in pediatric Hodgkin lymphoma tumor cells: Characterization of protein expression and splice-variants transcription profile

Survivin is abundantly expressed during fetal development but absent in most differentiated adult tissues; an exception being components of the immune system, such as B and T lymphocytes. Beyond acting as a master regulator of the cell cycle, survivin acts as an inhibitor of apoptosis and is overexpressed in almost all carcinoma types; however, its expression in lymphomas is lesser-explored. Survivin's role in carcinogenesis was subjected to its sub-cellular localization and splice transcripts expression, namely wild-type survivin, survivin-∆Ex3 and survivin-2B. To assess survivin's expression and sub-cellular localization in Epstein Barr virus positive and negative biopsies from treatment naïve pediatric patients with Hodgkin lymphoma (HL), samples were stained for survivin protein by immunofluorescence. The proportion of survivin+ cells was calculated, survivin sub-cellular localization assessed and its fluorescence intensity quantified. Transcription profile of survivin mRNA variants was studied by RT-qPCR. Survivin was overexpressed in the nucleus of tumor cells, and also in a greater proportion of tumor cells, in comparison with the non-tumoral infiltrating cells. Although a higher expression of survivin was observed in advanced clinical stages, no correlation was found between the expression level of survivin and a proliferation marker, or event-free survival. Instead, survivin was related to apoptosis inhibition in tumor cells. Additionally, survivin's transcriptional variants displayed similar expression levels. Present results suggest that although survivin is overexpressed in Hodgkin's tumor cells, it may not play a central role in the progression of classic HL, or act as a suitable progression biomarker, as suggested for most carcinomas.

A Simple Model for Predicting Post-Autologous Stem Cell Transplantation Outcome in Patients with Relapsed/Primary Refractory Hodgkin Lymphoma

Introduction: Current Hodgkin lymphoma (HL) therapies result in 80-90% progression-free survival (PFS). However, about 10-20% of patients with advanced disease relapse. The standard treatment for primary progressive or relapsed disease is salvage chemotherapy. For patients responding to this treatment, high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is recommended. In a recently published study, an addition of post-transplant therapy has improved PFS. However, as this approach is associated with additional toxicity and increased financial burden, precise identification of patients who could benefit from this strategy is crucial. Our study provides outcome data of an unselected group of HL patients and suggests a model identifying individuals at high risk of disease progression in whom post-ASCT therapy could be advantageous.Methods: This retrospective study included 92 HL patients with a median age of 31years (18-66) at diagnosis and 36 years (20-67) at time of transplant, who underwent ASCT at Rambam and continued follow-up until 08/01/2017.Results: At a median follow-up of 48 months (0-195) for patients with an uneventful course and 6 months (1-33) for those who progressed, the relapse rate was 41%. The Kaplan Meyer plot for event-free survival (EFS) is presented in Fig 1. In group 1, including patients with negative PET-2 during first-line therapy, who had stage I-III HL at relapse, that occurred at ≥3 months from the end of therapy (n=43), a 5-year EFS was 0.82. In group 2, including patients with the parameters similar to those in group 1, but in whom PET-2 had not been performed (n=16), a 5-year EFS was 0.71. In group 3, incorporating patients with stage I-III HL at relapse that occurred at <3 months from the end of therapy or those with positive PET-2 (n=15) a 5-year EFS was 0.52. Group 4, comprising patients with stage IV disease at relapse (n=18), had a 5-year EFS of 0. In a bivariate analysis, HL stage IV at relapse (HR 2.56, 95% CI 1.06-6.15; p=0.036), positive PET-2 during first-line therapy (HR 2.41, 95%CI 1.1-5; p<0.02) and PET positivity post-salvage therapy (HR 2.39, 95%CI 1.24- 4.6; p=0.009) were associated with increased risk of disease progression after ASCT. The factors associated with improved prognosis were: age ≥40 years at transplant (HR 0.27, 95% CI 0.11-0.66; p=0.004) and relapse at ≥6 months from the end of therapy (HR 0.31 95% CI 0.11-0.92; p=0.035). In multivariate analysis, disease progression was associated with HL stage IV at relapse (HR 11.8, 95% CI of 4-34; p=0.000), PET-2 positivity or HL progression at <3 months from the end of therapy (HR 3.5, 95%CI 1.3-9.7; p=0.015).Conclusions: The current study suggests a 3-risk-factor model for prediction of post-ASCT HL progression, including stage IV disease at relapse, PET-2 positivity at first-line treatment or HL progression at <3 months from the end of therapy. Upon verification of our findings in an independent cohort, the suggested model could be employed in decision making regarding preemptive post-ASCT use of new therapeutic approaches, including biological and checkpoint inhibitor therapies, in HL patients who are at an increased relapse risk. [Display omitted] DisclosuresZuckerman:Cellect Biotherapeutics Ltd: Consultancy.

Second Autologous Stem Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma after a Previous Autograft: A Registry Study of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation

Patients with relapsed or refractory (R/R) Hodgkin Lymphoma (HL) after first autologous stem cell transplantation (ASCT1) may be offered several therapeutic options. New agents such as brentuximab vedotin or checkpoint inhibitors have recently been approved for the treatment of these patients, however, their efficacy to provide long-term control or cure is still unknown. Thus, a significant proportion of patients are still considered candidates for a second hematopoietic stem cell transplantation, usually an allogeneic transplantation. A second ASCT (ASCT2) has historically been considered as an option only in a small group of patients so the published experience is scarce.We retrospectively evaluated the outcome of 56 adult patients (25% female/75% male) with R/R HL registered in the EBMT database who received an ASCT2 between 2005 and 2014. Planned tandem ASCT were excluded. The median age at ASCT2 was 33 years (range, 19-71) and most patients (n=46, 87%) had a Karnofsky performance score ≥80%. Forty (73%) and 9 (16%) patients were in complete remission (CR) and partial remission (PR), respectively, at day 100 after ASCT1. Twenty-six (46%) relapsed within 12 months after ASCT1. Patients received a median of 1 (0-5) treatment lines between ASCT1 and ASCT2. Of note, only 2 patients received brentuximab vedotin after ASCT1 and none of the patients in our series received checkpoint inhibitors as salvage after ASCT1. The median interval from relapse/progression to ASCT2 was 9.7 months (1.7-89.3). At the time of ASCT2, 38 (69%) patients had chemosensitive disease (20 of them CR; and 18 PR). Most patients (n=43, 77%) received BEAM as the conditioning regimen for ASCT1, whereas preparative regimens for ASCT2 were more heterogeneous (BEAM or similar in 27, 48%; CBV or similar in 8, 14%; and others in 21, 37%). The median time to neutrophil (>0.5x109/L) and platelet (>20x109/L) recovery after ASCT2 were 11 (IQR 9-12) and 12 (IQR 10-15) days, respectively. Best response at day 100 following ASCT2 included CR in 29 (52%) patients and PR in 7 (12%); 3 (5%) had stable disease, and 3 (5%) progressed. Twenty-nine (52%) patients are currently alive, with a median follow-up for surviving patients of 73 months (2-153). Causes of death were HL progression (n=21, 79%), ASCT2 toxicity (n=3, 11%), secondary neoplasia (n=1, 3.7%), and unknown (n=2, 7%). The 4-year non-relapse mortality (NRM) was 5% (95% CI 1-14%). The 4-year cumulative incidence of disease progression/relapse was 69% (95% CI 54-80%). The 4-year overall survival (OS) and progression free survival (PFS) were 63% (95% CI 51-77%) and 25% (95% CI 16-41%). In univariate analysis, HL relapse within 12 months of ASCT1 was associated with a worse 4-year OS (44% vs. 79%, p=0.016) and PFS (16% vs. 33%, p=0.033). Chemosensitivity at ASCT2 predicted for better outcomes (4-year OS 78% vs. 30%, p=0.002; PFS 34% vs. 6%, p=0.004).Our series is the largest thus far reported of ASCT2 for patients with R/R HL after ASCT1. NRM is lower than that observed after allogeneic transplantation in this setting; however, relapse remains a major issue, especially for patients who relapse in less than one year after ASCT. For this population, a second ASCT should not be considered, whereas ASCT2 in patients with long response duration after ASCT1 might be appropriate in selected cases. The role of ASCT2 for those patients treated with new drugs such as brentuximab vedotin and checkpoint inhibitors deserves further investigation. DisclosuresMartinez:BMS: Research Funding; Takeda: Consultancy. Sureda:BMS: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria; Merck: Consultancy, Honoraria.

Hodgkin Lymphoma-Derived Extracellular Vesicles Change the Secretome of Fibroblasts Toward a CAF Phenotype.

Secretion of extracellular vesicles (EVs) is a ubiquitous mechanism of intercellular communication based on the exchange of effector molecules, such as growth factors, cytokines, and nucleic acids. Recent studies identified tumor-derived EVs as central players in tumor progression and the establishment of the tumor microenvironment (TME). However, studies on EVs from classical Hodgkin lymphoma (cHL) are limited. The growth of malignant Hodgkin and Reed–Sternberg (HRS) cells depends on the TME, which is actively shaped by a complex interaction of HRS cells and stromal cells, such as fibroblasts and immune cells. HRS cells secrete cytokines and angiogenic factors thus recruiting and inducing the proliferation of surrounding cells to finally deploy an immunosuppressive TME. In this study, we aimed to investigate the role of tumor cell-derived EVs within this complex scenario. We observed that EVs collected from Hodgkin lymphoma (HL) cells were internalized by fibroblasts and triggered their migration capacity. EV-treated fibroblasts were characterized by an inflammatory phenotype and an upregulation of alpha-smooth muscle actin (α-SMA), a marker of cancer-associated fibroblasts. Analysis of the secretome of EV-treated fibroblast revealed an enhanced release of pro-inflammatory cytokines (e.g., IL-1α, IL-6, and TNF-α), growth factors (G-CSF and GM-CSF), and pro-angiogenic factors such as VEGF. These soluble factors are known to promote HL progression. In line, ingenuity pathway analysis identified inflammatory pathways, including TNF-α/NF-κB-signaling, as key factors directing the EV-dependent phenotype changes in fibroblasts. Confirming the in vitro data, we demonstrated that EVs promote α-SMA expression in fibroblasts and the expression of proangiogenic factors using a xenograft HL model. Collectively, we demonstrate that HL EVs alter the phenotype of fibroblasts to support tumor growth, and thus shed light on the role of EVs for the establishment of the tumor-promoting TME in HL.

Proteomic Identification of Plasma Biomarkers in Children and Adolescents with Recurrent Hodgkin Lymphoma.

The treatment of paediatric Hodgkin lymphoma (HL) has steadily improved over the years, so that 10- years survival exceed 80%. The purpose of this study was to identify prognostic markers for relapsed HL that might contribute to optimize therapeutic approaches. To this aim we retrospectively analysed differential protein expression profiles obtained from plasma of children/adolescents with HL (age ranging from 10 to 18 years) collected at diagnosis. We examined the protein profiles of 15 HL relapsed (R) patients compared with 14 HL not relapsed (NR) patients treated with the same LH-2004 protocol. Two dimensional difference in gel electrophoresis (2D-DIGE) revealed significant differences (fold change > 1.5; Student's T-test p<0.01) between R and NR patients in 10 proteins: α-1-antitrypsin chain a, apolipoprotein A-IV precursor; inter-α-trypsin inhibitor heavy chain; antithrombin-III; vitronectin; fibrinogen α, β and γ chains, complement C3, and ceruloplasmin. An up-regulation of fibrinogen α (spots 78, 196, 230, 234, 239) and β (spots 98, 291, 296, 300) chains together with a lower level of α-1-antitrypsin (spots 255, 264, 266, 272, 273) were found in R patients, and this difference was validated by immunoblotting. The functional role(s) of these proteins in the coagulation and inflammation associated with paediatric/adolescent HL progression and relapse deserves further investigations.

Quality of life among patients after Hodgkin lymphoma treatment: a 3-year prospective study

The purpose of the study was to investigate the quality of life among patients after Hodgkin lymphoma treatment to estimate demographic, clinical, psychosocial risk factors of unfavorable prognosis depending on the occurrence of cardiovascular events.Materials and methods. Population sample was 38 patients after Hodgkin lymphoma treatment. All patients received the interviewer, 35 patients (92.1% of all respondents) answered the questions and were included to the study. Clinical visits have been conducted each month for 3 years after enrollment, during which cardiovascular events have been recorded.Results: During observation period progression of Hodgkin lymphoma was proved in 8 patients, 3 persons were excluded for poor follow-up. Thirty four cumulative clinical events occurred in 12 patients (50%) within the follow-up, with their distribution being as follows: 2 cardiovascular deaths, 16 cardiac arrhythmias, 6 cardiac ischemic events, 1 stroke, 4 chronic heart failures and 5 hospital admissions for cardiovascular reasons. 3 deaths were not related with cardiovascular pathology or cardiovascular reasons. 3 deaths were not related with cardiovascular pathology.Patients who had cardiovascular events reported significantly worse physical functioning after anthracyclines with cumulative dose ≥326 mg/m2, after mediastinal radiotherapy. There were significant lower level of vitality in patients with cardiovascular events (p<0.001), in patients with advanced stages and mediastinal radiotherapy. After second-line treatment (MINE) patients had much worse physical functioning (p<0.001) that was associated with quality of life outcomes. There were significant differences in mental health, (р<0.001), role-psychological (р<0.03) scales. The lower level of mental health was associated with disease stages, doses of radiotherapy.Conclusion: The general health perceptions and vitality levels of Hodgkin lymphoma survivors depends on passed courses of chemotherapy, appearance of cardiovascular events during 3 years.

Brentuximab vedotin and bendamustine as salvage therapy for primary refractory or relapsed Hodgkin lymphoma: A multicentre experience of the Polish lymphoma research group

Introduction: An optimal therapy for patients with primary refractory or relapsed (R/R) Hodgkin lymphoma (HL) who did not respond to standard salvage chemotherapy has not been established. Brentuximab vedotin (BV) and bendamustine (B) used in monotherapy both have shown to be active in R/R HL and both are included in therapy options in these clinical settings. However, the combination of BV with B (BVB) has been investigated in only few clinical trials. Here, we report our experience of BVB given to patients with R/R HL. Methods: Since March 2015, the patients with R/R HL treated at one of the centers involved in the present retrospective analysis were considered to receive BVB (BV 1.8 mg/kg on day 1 and B 90 mg/m2 on days 1 and 2 of a treatment cycle repeated every 21 days). The choice of BBV as salvage therapy was based on the decision of the responsible physician. Results: Between March 2015 and February 2017, BVB regimen was administered to 24 patients (median age, 33 years; range, 18-60) with primary refractory (n = 8) or relapsed HL (n = 16), who were treated with a median of 3.5 (range, 2-12) prior chemotherapy lines. Ten of 24 patients were given BVB for relapse after autologous stem cell transplant (SCT), and 4 for relapse after allogeneic SCT preceded by autologous SCT. The patients received a median of 2 (range, 1-6) BVB courses. The toxicities of a total 66 BVB cycles were analyzed. The grade 3-4 toxicities were myelosupression and infections. Grade 3-4 neutropenia occurred in 2 (8%) and thrombocytopenia <75 G/L in 3 patients (12%). Two of 66 cycles (3%) in 2 patients (8%) were complicated by pneumonia. There were 2 early deaths, 1 due to progression of HL, and 1 due to pneumonia in a patient treated after allogeneic SCT. The overall response rate was 82%, with 10 (41%) complete and 10 (41%) partial metabolic response assessed by positron emission tomography. After a median follow-up of 12 months (range, 2-24), 20 patients remain alive. Fifteen of them are in complete remission. Four patients have proceeded to autologous SCT and other 4 to allogeneic SCT. The probability of overall survival for the whole group at 18 months is 74% (95% CI, 47-90). The estimated median progression-free survival time is 14 months (95% CI, 10-19) (Figure). Keywords: bendamustine; brentuximab vedotin; Hodgkin lymphoma (HL)

Cost-Effectiveness Analysis of Consolidation with Brentuximab Vendotin Versus Active Surveillance in Individuals with High-Risk Hodgkin Lymphoma Undergoing High Dose Chemotherapy with Stem Cell Rescue

IntroductionAlthough the majority of individuals diagnosed with Hodgkin's lymphoma (HL) are cured with first-line therapy, upwards of 20-30% of patients experience primary refractory disease or relapse after achieving remission. Autologous stem cell transplantation (ASCT) remains a curative option for R/R HL, but approximately 50% will experience HL recurrence followingASCT. A recent randomized double-blind trial (ATHERA) found post-ASCTconsolidation treatment with 16 cycles ofbrentuximabvedotin(BV) decreased the risk of HL progression compared to placebo. However, the impact of BV consolidation on overall survival, quality of life, and health care costs remains to be elucidated.MethodsWe constructed a Markov decision-analytic model from the US societal perspective to compare the costs and clinical outcomes associated with post-ASCTBV consolidation versus active surveillance with BV at time of HL progression. Patients entered our post-ASCTmodel receiving BV consolidation or active surveillance, with 4 additional 3-month health transition states used to model care until death (Figure 1). Results from theATHERAtrial informed the majority of our health state transition probabilities and our cohort characteristics.Rates of HL progression followingASCTwere extrapolated to 5 years using standard parametric modeling of reconstructed individual patient data derived from publishedATHERAresults.Our model also incorporated a number of recently published studies, including long term follow-up data of BV monotherapy in the salvage setting and separate reports supporting the use ofnivolumabfor R/R HL. All drug costs were calculated at 106% of average sales price and administrative costs were derived from the Medicare fee schedule. All future costs and benefits were discounted at 3% annually and a lifetime horizon was used to estimate cumulative healthcare costs and health utilities. Quality-adjusted utility, lifetime costs, and incremental cost-effectiveness ratios (ICERs) were calculated for each post-ASCTstrategy.ResultsReconstructed individual patient data from publishedATHERAresults was best fit using aGompertzdistribution. This parametric model predicted 5-year progression free survival to be 54% for BV consolidation compared to 43% for active surveillance. This reduction in HL progression translated intolonger overall survival (OS) for individuals receiving BV consolidation (mean [median] OS: 30.2 [36.6] vs 28.0 [29.9] years). After quality-of-life adjustments and standard future discounting, BV consolidation was associated with an improvement of 0.98 quality-adjusted-life years (QALYs) compared to active surveillance. However, the strategy of BV consolidation led to significantly higher healthcare costs ($330,833 vs $187,747), with anICERof $146,006/QALYfor BV consolidation compared to active surveillance. Model conclusions were stable on sensitivity analyses, including probabilistic sensitivity analysis where less than 5% of iterations found BV consolidation cost-effective at a level of $100,000/QALY.ConclusionsAlthough consolidation treatment with BV followingASCTappears to reduce the risk of HL recurrence and prolong survival, the strategy is associated with significant health care costs compared to active surveillance. Our analysis suggests the use of BV as consolidation therapy at current US pricing ($137/mg) is unlikely to be cost-effective at a willingness to pay of $100,000/QALY. However, if indication-specific pricing were implemented, our model estimates BV price reductions of 20% to 40% for the post-ASCTconsolidative setting would translate toICERsof $100,000/QALYand $50,000/QALY, respectively. Thus, for effective therapies such as BV, moderate reductions in current prices may produce cost-effective strategies. Ultimately, future indication-specific and value-based pricing has the potential to not only align drug prices to their value, but also continue to reward highly effective and innovative cancer therapy. [Display omitted] DisclosuresZeidan:Ariad: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Gore:Celgene: Consultancy, Honoraria, Research Funding. Ma:Celgene Corporation: Consultancy. Davidoff:PhRMA: Research Funding. Huntington:Celgene: Consultancy, Honoraria; Oncosec Medical: Equity Ownership; Exelixis: Equity Ownership; Johnson & Johnson: Consultancy; Pharmacyclics: Honoraria; Geron: Equity Ownership.

Can We Improve the Predictive Value of Interim PET/CT Using a New Prognostic Model for Advanced Hodgkin Lymphoma?

Introduction: The treatment of advanced Hodgkin lymphoma (HL) has undergone many changes in recent years. The original International Prognostic Score (IPS) introduced by Hasenclever et al (1998) was based on a cohort of 1618 patients (pts) mainly treated with MOPP-ABV or ABVD between the years 1983 and 1992. One third (33%) of those pts also underwent involved field radiation therapy (IFRT). Staging was based on CT. The 5-y freedom from progression (FFP) results ranged between 84% and 42%, depending on the presence of 0-≥5 risk factors. The IPS has been validated in a number of studies and settings. Currently, staging is based on baseline PET/CT, which upgrades the disease stage in 15% and downgrades it in 5% of pts compared to CT scan. Positive interim PET/CT (PET-2) is predictive of an inferior prognosis in pts with early and advanced HL. Based on these findings, several studies have used a positive PET-2 as an indication for therapy escalation. However, the majority of relapses still occur in pts with negative PET-2, highlighting the need for additional prognostic markers. We evaluated baseline factors and lab results in a prospectively collected database of pts enrolled in a multicenter clinical trial (NCT00392314) where treatment was modified based on PET-2 results. The current study aimed to develop a model for refined prediction of HL progression risk in advance-disease pts with negative PET-2, using baseline risk factors.Methods: Pts with advanced classic Hodgkin lymphoma (HL) were stratified according to their baseline IPS; treatment was modified according to PET-2 results. Pts with IPS 0-2 initially received 2 ABVD cycles and those with IPS ≥ 3 received 2 cycles of escalated BEACOPP (EB). In the former group, if PET-2 was positive without evidence of disease progression, therapy was escalated to EB with involved site radiation therapy (ISRT) given to residual masses. If PET-2 was negative in both IPS strata, 4 additional ABVD cycles were administered. We evaluated whether traditional IPS parameters continued to predict relapse when treatment was modified based on PET-2 results, and assessed the need for new cutoffs based on ROC curves using univariate and multivariate Cox proportional hazard models.Results: Of 185 enrolled pts, 33 (18%) experienced disease progression and 27 (15%) had a positive PET-2. The 5-y PFS for the whole group, PET-2 negative and PET-2 positive subgroups was 80%, 82% and 68%, respectively (p=0.07). Eight of 33 (28%) relapsed pts had a positive Deauville score (≥3). On univariate analysis of traditional IPS parameters, male gender, age >45, stage IV disease were not found to be associated with a significantly increased hazard ratio (HR) for progression. New cutoffs for lymphocyte count and albumin level predictive of relapse were determined. The following parameters were significantly (P<0.006) associated with lower PFS on univariate analysis: albumin <3.5gm/dL, hemoglobin <10.5 gm/dL, lymphocyte count <1400 or <11% of white blood cell (WBC) count. On multivariate analysis, albumin <3.5gm/dL, lymphocyte count <1400 or <11% of WBC remained significantly associated with relapse, with adjusted HRs of 2.2 (95% CI 1.1-4.5; P<0.03) and 2.6 (95% CI 1.1-6.2; P<0.025), respectively. Hence, a score was constructed using 0, 1 or 2 of these factors. Pts with 0-1 or 2 new risk factors and negative PET-2 had a relapse rate (RR) of 10% and 42%, respectively (HR=4.7; 95% CI 4.7-11), while in pts with positive PET-2 the RR was 30% (Table 1). However, one should bear in mind that pts with IPS 0-2 initiated therapy with ABVDx2 and those with IPS≥3 initiated therapy with EBx2.Conclusions: The current analysis, using data prospectively collected during a phase II study but analyzed retrospectively after pts had been stratified by IPS, suggests a scoring model that could refine the IPS-based identification of pts at a higher risk for disease progression, even if their PET-2 is negative. The findings imply that pts with 2 new risk factors (19% of pts) may need to initiate more intensive therapy than ABVD. However, given the retrospective nature of the analysis, its results should be interpreted with caution. The model needs to be verified in an independent cohort of pts with advanced HL using uniform treatment protocols. [Display omitted] DisclosuresBairey:Janssen: Consultancy.

Five-Year Survival Data Demonstrating Durable Responses from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin Lymphoma

Background: Classical Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The standard of care for patients (pts) with relapsed or refractory (R/R) HL is salvage chemotherapy followed by high dose chemotherapy and autologous stem cell transplant (auto-SCT). Approximately 50% of these pts will experience relapse or progression of HL after auto-SCT. For these individuals, outcomes have historically been poor, with median overall survival (OS) from time of relapse ranging from 10.5 to 27.6 mos (Crump, 2008; Fanale, 2013). A pivotal phase 2 study evaluated brentuximab vedotin, a CD30-directed antibody-drug conjugate, in pts with R/R HL after auto-SCT (ClinicalTrials.gov #NCT00848926). Primary results and 3-year follow-up data have been previously reported (Younes, 2012; Gopal, 2015). Here, we summarize final data from the 5-year follow-up period.Methods: Pts received 1.8 mg/kg brentuximab vedotin once every 3 wks as a 30-min outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Assessments of response and durability of response per an independent review facility (IRF) have been previously reported. Following a protocol amendment that removed the requirement for routine CT scanning during the follow-up period, disease status was only assessed per the investigator. Survival and disease status were assessed every 3 mos for 2 yrs and then every 6 mos through Year 5. CT scans were required if progression was suspected clinically. At the time of the amendment, 18 patients were still being assessed for progression; these patients had been in long-term follow-up for a median of over 30 months.Results: The enrolled population of 102 pts (53% female) was heavily pretreated and had a median age of 31 yrs (range, 15-77 yrs). Pts received a median of 9 cycles (range, 1-16) of brentuximab vedotin. Per investigator, the ORR to brentuximab vedotin was 72% and complete remission (CR) rate was 33%. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events of Grade 3 or higher that occurred in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia.At study closure, which occurred approximately 5 yrs after the last patient's end-of-treatment visit, the median observation time for all enrolled patients from first dose was 35.1 mos (range, 1.8 to 72.9). The estimated 5-year overall survival rate was 41% (95% CI: 31 %, 51%) and the median OS was 40.5 mos (95% CI: 28.7, 61.9 [range, 1.8 to 72.9+]). Median OS by best clinical response was CR (n=34): median not reached; partial remission (PR, n=39): 39.4 mos; and stable disease (SD, n=28): 18.3 mos. The median PFS was 9.3 months overall, but was not reached in CR pts. Of the 102 enrolled patients, 15 remained in follow-up and in remission at study closure. Among these 15 pts, 6 received consolidative allo-SCT and 9 have received no further therapy since completing brentuximab vedotin.Conclusions: These end-of-study results demonstrate that single agent brentuximab vedotin can induce durable remissions and long-term survival in a subset of heavily pretreated patients with relapsed/refractory HL, particularly in pts that achieve CR. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with AVD (doxorubicin, vinblastine, and dacarbazine) versus ABVD (A, bleomycin, VD) for frontline treatment of advanced HL (ECHELON-1 trial, ClinicalTrials.gov #NCT01712490). [Display omitted] DisclosuresChen:Seattle Genetics: Consultancy, Research Funding; Genentech: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Gopal:BMS: Research Funding; Piramal: Research Funding; Emergent/Abbott: Research Funding; Millenium: Honoraria, Research Funding; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; BioMarin: Research Funding; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi-Aventis: Honoraria; Merck: Research Funding. Smith:Seattle Genetics: Research Funding; Celgene: Consultancy, Speakers Bureau. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Rosenblatt:Seattle Genetics: Research Funding. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Engert:Takeda Millenium: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Larsen:Seattle Genetics Inc.: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Fong:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Janssen: Honoraria; Novartis: Research Funding; Incyte: Honoraria; Takeda Millenium: Honoraria; Celgene: Honoraria; Bristol Meyer Squibb: Honoraria; Curis: Research Funding; Bayer: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria; Johnson and Johnson: Research Funding.

The Prognostic Role of Interim PET after First Chemotherapy Cycle and PET Sequential Evaluation of Response to ABVD in Hodgkin Lymphoma Patients - the Polish Lymphoma Research Group (PLRG) Observational Study

Background: Several studies confirmed the predictive role on treatment outcome of interim-PET after 2nd ABVD cycle (iPET2) in Hodgkin lymphoma (HL). We hypothesized that interim PET after 1st cycle (iPET1) might define chemosensitivity with a better accuracy than iPET-2. To test this hypothesis, PLRG launched in 2008 a prospective multicenter observational study aiming at assessing the prognostic role of iPET1 and the dynamic of sequential PET response to ABVD.Methods: Adult pts with newly diagnosed early (stage I-IIA) and advanced (stage IIB-IV) consecutively enrolled in 11 Polish centers were risk-stratified by the EORTC/GELA criteria and treated according to the ESMO guidelines: ABVD x 3-4 cycles + IFRT in early stage, ABVD x 6 ± consolidation RT in advanced stage disease. Patients were scanned with iPET1 and iPET2 and no treatment change was permitted based solely on iPET results, with the exception of clinical or radiological evidence of overt HL progression. After the first interim analysis (52 pts enrolled, 2010), which demonstrated that all the iPET1 negative patients had also a negative iPET2, the protocol was amended, limiting the iPET2 scans only to pts with iPET1 Deauville score 5,4,3. Quality control for PET-CT was supervised by the Italian-Polish core lab using a standard methodology. PET scans were interpreted locally according to the Deauville 5-point scale: Score 1 to 3, was considered a negative (-), score 4 to 5 a positive (+) scan. Subsequently all PET scans were uploaded to the web platform WIDEN® for central review and Italian-Polish expert panel (EP) scored them afresh. Discorcondant cases were discussed in a joint review session with all the five EP members. Binary and overall concordance rates were calculated using k Cohen's and alpha Krippendorf's coefficients, respectively. Negative (NPV) and positive predictive values (PPV) of iPET1 were calculated using time to progression free survival (PFS) event.Results: Between 2008 and 2014, 346 pts were registered. 35 pts were excluded from the analysis for absence/poor quality of images resulting in 108(35%) assessable pts with early and 203(65%) with advanced HL. Median age at diagnosis was 31(18-80) years. iPET1 was scored 1-3 in 87/108(81%), and 4-5 in 21/108(19%) of pts with early and in 133/203(65%), and 70/203(35%) with advanced stage, respectively. Out of 91pts with positive iPET1, 83 pts underwent iPET2, which remained (+) in 41/83(49,4%) pts. In 22 pts treatment was escalated. 11 of those pts, in whom the treatment escalation was decided solely on positive iPET were excluded from the analysis; the remaining had symptoms or CT evidence of progression. After a median follow-up of 40,2 (3,2-90,2) months 300 pts (103 "early" and 197 "advanced") were evaluable. 65(21,7%) of them (9 in early and 56 in advanced group) had a PFS event: in "early" group 9(9%) showed disease progression (4 with iPET1(-) and 5 with IPET1(+)) and 1 of them died. In advanced stage 49(25%) pts showed disease progression (16 with iPET1(-) and 33 withiPET1(+)) out of whom 13 died; 7 additional pts died without HL progression: 4 from toxicity and 3 from unrelated events. At 36 months NPV and PPV of iPET1 was 93% and 45% in "early" and 81% and 52% in "advanced" group, respectively. The dynamic of response to ABVD was assessed in 189 pts who underwent both iPETs. All 116 pts with iPET1(-) remained (-) in iPET2-(fast-responders). Out of 83pts with IPET1(+) 39 (47%) became iPET2(-)-(slow responders); the rest (34pts: 41%) remained iPET2(+)-(no responders). PFS for fast-responders @36 months was 85%, for slow-responders 80% (log rank p=0,36) and for no-responders 25% (log rank p=0,0000). The EP changed the local iPET1 score in 27 cases: in 14 from (+) to (-) in 13 from (-) to (+). The inter-observer-agreement among reviewers on evaluating a positive vs. negative interim PET scans was good, Fleiss' kappa = 0.73, comparable to that found in analogous studies (IVS, HD0607).Conclusion: iPET1 fails to better identify chemosensitivity in ABVD-treated HL compared to iPET2. PPV of iPET1 is substantially inferior to the published results for iPET2. However NPV of iPET1 is comparable to iPET2 and therefore might guide early treatment de-escalation strategies. DisclosuresZaucha:Roche: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Knopinska-Posluszny:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Teva: Other: travel, accommodation, Speakers Bureau. Walewski:Mundipharma; Roche; Takeda: Honoraria, Other: Travel expenses; Amgen; Boehringer Ingelheim; Celgene; Janssen-Cilag; Mundipharma; Roche; Takeda; Teva: Consultancy; Bayer (Inst); Bayer/Onyx (Inst); Boehringer Ingelheim (Inst); Celgene (Inst); Celltrion (Inst); Gilead Sciences (Inst); GlaxoSmithKline (Inst); GlaxoSmithKline (Inst); Mundipharma (Inst); Pfizer (Inst); Roche (Inst); Roche/Genentech (Inst); Seattle Geneti: Research Funding.