ALBERT

Description: INTRODUCTION: Circular RNAs (circRNAs) are covalently closed endogenous RNA molecules with tissue- and disease specific expression patterns, that are emerging as potential diagnostic and prognostic biomarkers. These molecules exert diverse regulatory functions, and several studies have reported prognostic relevance and functional significance of circRNAs in cancer. However, no studies have yet examined the role of circRNAs in Mantle Cell Lymphoma (MCL). We have previously shown that the Nanostring nCounter technology enables specific, sensitive and accurate quantification of circRNAs in formalin-fixed, paraffin-embedded (FFPE) tissue samples from patients (Dahl et al, 2018). Here, we quantified circRNA expression in MCL tumors to address whether certain circRNAs could serve as prognostic markers in MCL. Samples were obtained from patients treated in the two Nordic clinical trials MCL2 and MCL3, all treated with immuno-chemotherapy and autologous stem cell transplant, which due to the improved prognosis observed with this regimen, remains the current standard of care. MATERIALS AND METHODS: We profiled the genome-wide circRNA expression in MCL using high-throughput RNA-sequencing (RNA-seq) of 14 diagnostic MCL samples, from which high-quality RNA from lymph nodes with MCL tumor infiltration was available. Based on these data, we designed assays for analyses of 41 differentially expressed circRNAs and quantified the expression using the NanoString nCounter technology. We examined the prognostic potential of individual circRNAs in a training cohort of 75 patients (MCL2) and confirmed these results in an independent, but similarly treated, validation cohort of 90 patients (MCL3). RESULTS: The total cohort consisted of 165 previously untreated MCL patients

Description: SGN-30 is a monoclonal antibody directed against the CD30 antigen expressed on some hematologic malignancies. Based on encouraging phase I data, a multicenter phase II study was conducted treating patients with refractory or recurrent CD30-positive ALCL with an ECOG performance status of ≤ 2. Thirty-nine patients (24M, 15F) with ALCL were enrolled, with a median age of 57 (range 23–82) and a median of 3 prior therapies (range 2–5). Nine patients had previously received a stem cell transplant. Eighty-five percent of tumors were negative for ALK, a poor prognostic factor. SGN-30 was administred at 6 mg/kg/wk (90 minute infusion, premedications were not required) for 6 consecutive weeks. After 24 patients were enrolled, the dose was escalated to 12 mg/kg/wk in subsequent patients. (Patients with stable disease or objective response were eligible to receive additional cycles of SGN-30. Five patients received ≥ 2 cycles of SGN-30.) Response assessments, as determined by CT scans, were performed 2 weeks after the last infusion. Best response is shown below: CR PR SD PD Pending Eval ORR *Both CRs have ongoing durations of 〉365 days; both patients received additional cycles of SGN-30. **PRs had durations of 27, 53, 139 and 167 days; two additional patients have ongoing durations of 86+ and 25+ days. ***Three SDs have ongoing durations of 96+, 365+, and 365+ days. Two additional patients had SD for 71 and 174 days. 2* 6** 5*** 24 2 21% Three drug-related toxicities ≥ Grade 3 were reported (each was considered possibly related to SGN-30): 1) lymphopenia, 2) catheter related infection and 3) urticaria. No other significant hematologic or biochemical toxicities have been observed. There was one definitely related serious adverse event (Grade 2) in a patient who experienced a transient exacerbation of his cutaneous lesions after 2 doses of SGN-30 but achieved a partial response after continuing on study. This phase II study represents one of the largest prospectively designed trials in relapsed/refractory ALCL and demonstrates good tolerability and clinically meaningful antitumor activity of SGN-30, especially in ALK negative patients who have a particularly poor prognosis.

Description: Background There is a consensus that younger patients with mantle cell lymphoma (MCL) should receive intensive immunochemotherapy regimens including high-dose cytarabine, rituximab and high-dose chemotherapy with stem cell support, but the optimization of treatment for elderly or unfit patients, as well as patients with localized or indolent disease, remains a challenge. Methods Our study is based on data from the Swedish and Danish Lymphoma Registries from the period of 2000-2011, in Sweden supplemented by review of patients´ records. The Lymphoma Registries comprise 〉95% of all diagnosed lymphoma patients in Sweden and Denmark. Results 1389 patients were diagnosed with MCL, confirmed by positive cyclin-D1 and CD5 staining, in Sweden and Denmark between 2000 and 2011. In this population based cohort, we could confirm the prognostic impact of MIPI, but in addition, male sex was associated with inferior overall survival (OS) in multivariate analysis (HR 1.4, p65 years, chlorambucil (n=132) was superior to CVP (n=35) (HR 1.8, p=0.003), when adjusted for MIPI and rituximab, but there was no significant difference between CHOP (n=311) and CHOP+Cytarabine (n=84). Rituximab (HR 1.5, p

Description: Purpose: A few patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who start on standard primary treatment with R-CHOP do not complete the recommended 6-8 cycles for reasons related to toxicity, however, this group has seldom been formally studied. We set out to describe the outcome of DLBCL patients failing to complete at least 6 R-CHOP cycles for reasons other than non-response, and to investigate determinants of such failure. Methods: We identified patients diagnosed with DLBCL in Sweden 2007-2014 who started primary treatment with R-CHOP (i.e., received at least one cycle) with the aim to receive 6 or 8 cycles, in the national Swedish Lymphoma Register (N=2,155). The analysis covered 5 out of 6 health care regions (70% of all patients diagnosed nationally). Overall survival by number of cycles was estimated using Kaplan-Meier curves (with censoring at stable disease or progression at first interim evaluation to avoid inclusion of patients who switched therapy due to non-response). Univariable and multivariable logistic regression was used to estimate odds ratios (OR) with 95% confidence intervals (CI) for the association between baseline clinical and demographic characteristics and failure to complete full R-CHOP treatment (i.e., receipt of less than 6 cycles compared with 6 cycles or more). Baseline characteristics included age, sex, calendar period of diagnosis, performance status, Ann Arbor stage, serum-lactate dehydrogenase, hemoglobin level, number of extranodal disease locations, and international prognostic index (IPI) score. In the logistic regression analysis, patients with early tumor progression (stable or progressive disease at interim or final evaluation) were excluded. Results: Among the 2,155 patients who started on R-CHOP, 399 (18.5%) failed to complete 6 cycles. Of these, 137 patients (6.4%) received only 1 or 2 cycles, and 262 (12.2%) received between 3 and 5 cycles. Only 42 patients stopped prematurely due to evidence of non-response whereas the majority (357 out of 399 patients, 89%) did so for other reasons related to toxicity and early death. Patients who failed to complete 6 cycles were older than other patients (median age 77 versus 68 years), more often had a WHO performance status of 2 or more (33% versus 12%) and more often were diagnosed with stage IV disease (40% versus 33%). Number of received R-CHOP cycles strongly correlated with survival (Figure 1). Among patients 65 years of age or younger, 5-year OS varied from 18% (95% CI 4-42%) following 1 extranodal location remained significantly associated with failure to complete 6 cycles of R-CHOP for reasons other than non-response. Conclusion: A surprisingly large proportion of patients diagnosed with DLBCL intended for treatment with 6-8 R-CHOP cycles fail to complete the treatment at the population-based level for reasons unrelated to non-response. Failure to complete at least 6 R-CHOP cycles was associated with poor survival, especially for patients receiving 1-2 cycles only, but also for those receiving 3-5 cycles. Old age and poor performance status most strongly predicted such failure. Figure 1: Kaplan-Meier curve of overall survival of patients with DLBCL diagnosed in Sweden 2007-2014 by number of administered R-CHOP cycles overall (top panel) and by age at diagnosis above or below 65 years (bottom panels). Disclosures Ekstrom Smedby: Janssen Pharmaceuticals: Other: The Department have recieved partial funding from Janssen Pharmaceuticals. Harrysson:Janssen Pharmaceuticals: Other: The Department have recieved partial funding from Janssen Pharmaceuticals. Ekberg:Janssen Pharmaceuticals: Other: The department has received partial funding from Janssen Pharmaceuticals. Eloranta:Janssen Pharmaceuticals: Other: S Eloranta is currently employed as a project coordinator and her salary is funded via a public-private real world evidence collaboration between Karolinska Institutet and Janssen Pharmaceuticals.

Description: Mantle cell lymphoma (MCL) is defined pathologically by the detection of CD20, CD5, and most importantly cyclin D1 (CCND1). Its distinction from other lymphomas is important for prognosis and appropriate therapy, but occasional cases may fail to express CCND1 and morphologic simulators may express CD20 and CD5 but not CD23. In this study, we show that the transcription factor Sox11 is specifically expressed in the nucleus of MCL compared with other lymphomas and benign lymphoid tissue. Although the role of Sox11 presently is not known in lymphocyte ontogeny, it is normally expressed in the developing central nervous system in the embryo and shows sequence homology with Sox4, a transcription factor crucial for B lymphopoiesis. Sox11 mRNA is increased in gliomas compared with healthy brain tissue, suggesting a role in malignant transformation and/or cell survival. Our novel finding of specific overexpression of Sox11 mRNA and nuclear protein in both cyclin D1–positive and – negative MCL may be useful for the diagnosis of MCL as a complement to cyclin D1 and also suggests a functional role for Sox11 in MCL.

Description: Background Despite the advent of rituximab (R)-based chemoimmunotherapy, outcome for patients with high-risk diffuse large B-cell lymphoma (DLBCL) continues to be suboptimal, and the risk of central nervous system (CNS) progression is high. In a previous Nordic phase II study with dose-dense chemoimmunotherapy followed by systemic CNS prophylaxis, the CNS progression rate was lower than expected (4.5%), but all events occurred within 6 months after initiation of therapy (Holte et al., Ann Oncol 2013). Hence, in the present study, systemic CNS prophylaxis was moved to the beginning of therapy and CNS targeted therapy was further intensified by adding intrathecally administered liposomal AraC. Methods Inclusion criteria are age 18-65 years, primary DLBCL or grade 3B follicular lymphoma without clinical or radiological signs of CNS disease and cytology negative cerebrospinal fluid (CSF), age adjusted IPI 2-3, WHO performance score ≤3, and/or site specific risk factors for CNS recurrence. Treatment consists of two courses of high dose (HD)-Mtx in combination with R-CHOP14, four courses of R-CHOEP14 and a course of HD-AraC with R. In addition, liposomal AraC is administered intrathecally in courses 1, 3 and 5. All courses are administered with support of pegfilgastrim. Indications for radiotherapy are bulky masses at diagnosis and localized PET positive residual disease not eligible for biopsy. Primary endpoints are failure-free survival at 3 years, and CNS progression rate at 18 months. A secondary aim is to elucidate if CSF cytology negative/flow cytometry (FC) positive cases carry an increased risk of CNS progression with the present regimen. Results Of the accrued 84 patients by July 22, 2013, 70 had a complete set of baseline data. Median age was 55 years (range 20-64). The majority presented with DLBCL (96%), advanced-stage disease (94%), elevated LDH (94%), B-symptoms (67%), and 49% with 〉1 extranodal site. Seven CSF-samples were FC positive. Data on toxicity, response and relapse rates were registered for 45 patients. One toxic death due to pneumonia was reported. Grade 4 hematological toxicity and infections were observed in 78% and 11% of the patients, grade 3-4 mucositis and gastrointestinal toxicity in 27% and 42%, and grade 3 arachnoiditis in 2.2% of the patients. CR, CRu, PR and PD rates at the end of chemoimmunotherapy were 69.0%, 14.3%, 14.3% and 2.4 %, respectively. After a median follow up time of 19 months, four patients have relapsed, two of whom with fatal CNS manifestations. Conclusions Preliminary results indicate highly satisfactory response rates and reasonable toxicity despite intensive therapy. HD-Mtx in combination with R-CHOP in the beginning of therapy and further intensification of treatment with CNS targeted liposomal AraC seem feasible and safe. ClinicalTrials.gov Identifier: NCT01325194 Disclosures: Leppa: Amgen: Research Funding; Mundipharma: Honoraria, Research Funding. Holte:Mundipharma: Honoraria, Research Funding; Amgen: Research Funding.

Description: Eskelund et al examined clonal hematopoiesis (CH) in a cohort of patients with mantle cell lymphoma (MCL) treated with first-line chemotherapy and autologous stem cell transplantation. In young, good-risk MCL patients, CH after first-line therapy arises almost entirely from preexisting clones, stabilizes after a period of expansion posttransplantation, and does not negatively impact survival.

Description: HCL has been considered to be a disease of predominantly young males with, after the introduction of effective treatment, excellent prognosis. However, although very effective, these therapies introduced in the 1980’s are not curative. The Swedish Lymphoma Registry records all patients diagnosed since year 2000, with a 96 % coverage compared to the Swedish Cancer Registry, which is compulsory since 60 years. In contrast, previously published studies include patients highly selected for inclusion in treatment studies or referral to major medical centers. The Swedish registry data confirms the high male to female ratio, with yearly incidences of 5.3 males and 1.1 females per million. However, the median age at diagnosis was 62 years (range 30–92). The incidence in males rise with age as follows: 3 (30–49 yrs), 11 (50–69 yrs), 16 (70–79 yrs), and 20/million (80–95yrs). The 5-year overall survival of these unselected patients was 81%. Age and performance status had strong influence on survival. If HCL was diagnosed before age 60 the 5-year survival was 94%, whereas it was 70% for patients over 60 years. We also performed a 15-year follow-up of patients included in our first cladribine trials in the early 1990’s. The progression-free survival at 10 years was 60% and at 15 years 55%, irrespective of age. However, the 10 year and 15 year overall survivals were 91% and 82% for patients

Description: Background: Peripheral T-Cell lymphomas (PTCLs) constitute approximately 10% of lymphoid malignancies and consist of several distinct entities based on pathologic and clinical characteristics. With the exception of a few subtypes (e.g., ALK-positive anaplastic large cell lymphoma (ALCL) and some primary cutaneous or leukemic forms of PTCL), a majority of PTCLs are aggressive as characterized by poor treatment response, rapid disease progression and poor overall survival. We have shown that landmark timepoints of event-free survival after diagnosis can stratify subsequent overall survival (OS) in diffuse large B-cell and follicular lymphoma. Here we evaluate this approach in newly diagnosed aggressive PTCLs treated with anthracyline-based or related chemotherapy. Methods. Newly diagnosed PTCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012. Clinical data were abstracted from medical records using a standard protocol. For this analysis, we included patients receiving anthracycline-based or other multiagent chemotherapy for the following PTCL subtypes: ALK-negative ALCL (N=24); angioimmunoblastic T-cell lymphoma (AITL, N=34); PTCL, not otherwise specified (NOS; N=60); enteropathy-associated T-cell lymphoma (EATL, N=8); extranodal NK/T-cell lymphoma, nasal type (ENKTL, N=11); and hepatosplenic T-cell lymphoma (HSTCL, N=1). Patients were prospectively followed, and event-free survival (EFS) was defined as time from diagnosis to progression, re-treatment, or death due to any cause. Landmark EFS timepoints were assessed at 12 (EFS12) and 24 (EFS24) months after the date of diagnosis. Subsequent OS was defined as time from a specific endpoint (diagnosis, event or EFS landmark). Replication was performed in a population-based cohort of T-cell lymphomas diagnosed from 2000-2009 from the Swedish Lymphoma Registry. Results. 138 eligible patients were enrolled in the MER from 2002-2012, the median age at diagnosis was 58 years (range, 19-88), 66% were male, 73% had Stage III-IV disease, and 33% had IPI 0-1. At a median follow-up of 47 months (range 11-120), 87 patients (63%) had an event and 70 patients (51%) had died. From diagnosis, only 60 patients were event-free at 12 months (EFS12 45%). Patients who failed to achieve EFS12 had a poor subsequent OS from event (median OS = 6.8 months, 95% CI: 5.3-14.0, figure 1). In contrast, patients who achieved EFS12 had a favorable subsequent OS (median unreached, figure 2). Of the 427 eligible patients in the Swedish registry, the median age at diagnosis was 66 years (range, 18-88), 63% were male, 68% had Stage III-IV disease, and 25% had IPI 0-1. PTCL subtypes were: ALK-negative ALCL (N=89); AITL (N=80); PTCL, NOS (N=183); EATL (N=44); ENKTL (N=24); and HSTCL (N=7). At a median follow-up of 86 months (range 40-158), 333 patients (79%) had an event and 316 patients (74%) had died. From diagnosis, 183 patients were event-free at 12 months (EFS12 44%). Similar to the MER cohort, Swedish patients failing EFS12 had poor subsequent survival (median OS = 3.7 months, 95% CI: 2.9-5.3, figure 1). Swedish patients achieving EFS12 had a favorable subsequent OS (median OS = 89 months, figure 2). Similar results were obtained when conducting landmark analysis at 24 months after diagnosis (EFS24). Conclusion. Relapse and re-treatment events within the first 12 months of diagnosis are associated with very poor OS in PTCL treated with anthracyclines or related chemotherapy, while patients achieving EFS12 have encouraging subsequent OS. Stratifying patients into prognostically distinct subsets using EFS12 may help focus biologic and biomarker studies. EFS12 has potential as an early endpoint for studies of newly diagnosed PTCL. Further investigation of determinants related to post-EFS12 survival is needed. Disclosures Maurer: Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Relander:Respiratorius: Patents & Royalties: valproate for DLBCL.