Indolent Mantle Cell Lymphoma Research Articles

Rituximab, gemcitabine and oxaliplatin in relapsed or refractory indolent and mantle cell lymphoma: results of a multicenter phase I/II-study of the German Low Grade Lymphoma Study Group

Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated to be effective and safe in lymphoma patients. We aimed to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with rituximab and gemcitabine and to explore the efficacy and safety of R-GemOx in relapsed or refractory (r/r) indolent and mantle cell lymphoma (MCL). In this single-arm, phase I/II trial, we enrolled 55 patients with r/r indolent lymphoma and MCL not suitable for autologous stem-cell transplantation. Patients received 4 cycles of R-GemOx. In the dose escalation group, 70 mg/m2 of oxaliplatin was applied and interindividually increased by 10 mg/m2 until the MTD was reached together with fixed doses of rituximab and gemcitabine. At the oxaliplatin MTD, an extension cohort was opened. Primary aim was to detect an overall response rate (ORR) greater than 65% (α = 0.05). Oxaliplatin 70 mg/m2 (MTD) was chosen for the extension cohort after 3 of 6 patients experienced a DLT at 80 mg/m2. Among 46 patients evaluable for the efficacy analysis ORR was 72% (33/46), missing the primary aim of the study (p = 0.21). After a median follow-up of 7.9 years, median PFS and OS were 1.0 and 2.1 years. Most frequent grade ≥ 3 adverse events were cytopenias. R-GemOx induces decent response rates in r/r indolent lymphoma and MCL, though novel targeted therapies have largely replaced chemotherapy in the relapse setting. Particularly in MCL, R-GemOx might be an alternative option in late relapses or as bridging to CAR-T-cells. This study was registered with ClinicalTrials.gov on Aug 4th, 2009, number NCT00954005.

Indolent mantle cell lymphoma of renal significance.

Indolent mantle cell lymphoma of renal significance.

Updated Trends in Incidence and Survival of Mantle Cell Lymphoma from 2000 to 2020

While the incidence of non-Hodgkin's lymphoma (NHL) has declined ~1% per year (Y) since 2015, it is not known if this trend holds true for mantle cell lymphoma (MCL). The Surveillance, Epidemiology and End Results (SEER) 17 database includes MCL data collected from 12 US states between 2000 and 2013. However, since the launch of the new SEER 22 database, there has not yet been a study analyzing MCL trends. SEER 22 added seven more years of follow up (up to 2020) compared to SEER 17 (up to 2013), as well as the states of Illinois, Texas, Idaho, Massachusetts, and New York to the 12 states of SEER 17. Here we provide updated trends in MCL incidence and survival using the SEER 22 database, with subset analysis of age, race, and gender. Age-adjusted incidence (per 100,000 Persons/Y) of reported MCL cases were extracted from SEER 22 and tabulated at 5Y intervals (2000-2019). We found an initial increase in MCL incidence from 0.675 (2000-2004) to 0.789 (2005-2009) to 0.833 (2010-2014), followed by a slight decrease to 0.826 (2015-2019) (Fig. 1A). Using the SEER*Stat platform, we calculated the Annual Percent Change (APC) of MCL incidence from 2000 to 2019. The APC is a standard way to statistically characterize trends in MCL rates over time assuming the rates are to change at a constant percentage of the rate of the previous year. While the MCL APC from 2000 to 2014 was +2.02% signaling an annual increase, that for the years 2015 to 2019 was -0.49% indicating an average 0.49% annual decline in MCL incidence since 2015. This decline was found to be statistically significant when compared the 2000-2014 APC. Unsurprisingly, the incidence of MCL in 2020, the first year of the COVID-19 pandemic, declined to 0.767 compared to 0.814 in 2019, translating into a -5.77% percent change (PC). The PC was calculated as follows: PC=100 x [rate (2020)/rate (2019)-1]. This decrease in MCL rate is less pronounced than the -7.76% PC in NHL incidence in 2020. While these remarkable PCs reflect a drop in reporting and delayed/postponed diagnosis during the first year of the pandemic, the MCL incidence is expected to be less affected considering the aggressive nature of this disease prompting immediate diagnosis and medical care. Notably, the PC in diffuse large B-cell lymphoma (DLBCL) incidence in 2020 compared to 2019 was -3.77%, which contrasts with a larger PC of -8.69% in follicular lymphoma (FL). While DLBCL is aggressive and warrants immediate attention, FL is indolent, and diagnosis tended to be postponed during the early months of the pandemic. Collectively, the observed decrease in MCL incidence in 2020 could potentially reflect a real trend in the continuous MCL decline over time. When we included the 2020 data in the APC analysis, the 2014-2020 APC further decreased to -0.89% compared to -0.49% (2014-2019). The initial increase in MCL incidence (2000-2014) can be explained by improved reporting (access to electronic medical records, MCL being reported as MCL rather than NHL) and improved diagnostic identification of MCL (SOX11, CD5-negative MCL, indolent MCL, adoption of colonoscopy leading to early MCL detection). Following the observed peak in 2014, MCL incidence seems to follow the overall NHL downward trend. Subset analysis of age, gender, and race will be included in the presentation. Overall, we observed no major trends, except for an uptrend in the MCL incidence in the Black population potentially reflecting improved access to healthcare. To compare trends in MCL survival, we analyzed the 5Y observed overall survival (OS). Additionally, we calculated the relative survival rate (RSR) as the ratio of the observed OS divided by the expected OS of an age-matched comparable group from the general population. The 5Y observed OS improved over time: 45.2% (2000-2004), 49.1% (2005-2009), 53.8% (2010-2014), and 57.1% (2015-2019). This translated in a marked improvement in the 5Y RSR reaching 65.5% in 2015-2019. Unfortunately, while the 5Y RSR of the Hispanic population improved over time, it continues to be significantly lower than the non-Hispanic populations, reflecting either a disparity in access to healthcare or an overall worse prognosis. This dramatically contrasts with the 5Y RSR of the Black population, which once was among the lowest (47.3%, 2000-2004), became the highest 72.5%, (2015-2019) reflecting not only a better access to healthcare, but also a shift to a previously unrecognized better overall prognosis of MCL in Black patients (Fig. 1B).

How I manage mantle cell lymphoma: indolent versus aggressive disease.

Mantle cell lymphoma (MCL) is a mature B-cell lymphoma with a variable clinical course and historically poor prognosis. Management is challenging in part due to the heterogeneity of the disease course, with indolent and aggressive subtypes now well recognised. Indolent MCL is often characterised by a leukaemic presentation, SOX11 negativity and low proliferation index (Ki-67). Aggressive MCL is characterised by rapid onset widespread lymphadenopathy, extra-nodal involvement, blastoid or pleomorphic histology and high Ki-67. Tumour protein p53 (TP53) aberrations in aggressive MCL are recognised with clear negative impact on survival. Until recently, trials have not addressed these specific subtypes separately. With the increasing availability of targeted novel agents and cellular therapies, the treatment landscape is constantly evolving. In this review, we describe the clinical presentation, biological factors, and specific management considerations of both indolent and aggressive MCL and discuss current and potential future evidence whichmay help move to a more personalised approach.

CD5-Negative Mantle Cell Lymphoma Defines a Distinct Disease Entity Characterized By an Indolent Clinical Course Irrespective of Known Prognostic Markers

Introduction: Mantle Cell Lymphoma (MCL) is an aggressive CD5-positive B-cell malignancy with a median survival of 3 to 5 years. A small subset of patients present with an indolent disease and can be managed on a “watch and wait” approach. Indolent MCL remains ill-defined, but is classically associated with hypermutated IGHV, non-nodal presentation, and absence of SOX11 expression. Up to 10% of MCL lack CD5 expression, but there has been limited attention given to its clinical and biological implications. We performed an extensive review of all reported cases of CD5-negative MCL to further characterize this disease subset.Patients and Methods: A systematic literature search was performed and included studies published from June 1994 to July 2017 in Pubmed, Embase, and Web of Science. We used the key words CD5 negative, CD5-, mantle cell lymphoma, and MCL. Data was tabulated regarding 20 variables: t(11;14)(q13;32), cyclin-D1, CD5, CD10, CD19, CD20, CD23, BCL2, BCL6, and Ki-67 (higher or lower than 30%), IGHV mutation status (mutated defined as >3% discordance with germline), SOX11, morphology, initial site of diagnosis, gender, age, light chain expression, presence of leukemic phase, stage, and overall survival (OS). Data was reported as percent and total number of cases with available data of each variable, and compared to historic data on CD5-positive MCL (referred to as conventional MCL). We used the Kaplan-Meier method to study OS, and log-rank test to compare OS between disease subsets.Results and discussion: 140 of 818 screened articles included CD5-negative MCL cases. After exclusion of duplicates and non-English articles, 70 sources were included. Additionally, we included 2 cases identified at our institution. Data of 323 cases of CD5-negative MCL was collected (Figure 1A). Conventional and CD5-negative MCL shared certain similarities: both had a median age of diagnosis between 60 and 70 years, showed male predominance, and presented as stage IV disease. They shared overexpression of cyclin-D1 (100%, 241/241), possessed the t(11;14)(q13;32) (96%, 107/111: 107 of 111 cases with available data on translocation), were CD19-positive (86%, 32/37), CD20-positive (97%, 107/110), BCL2-positive (98%, 44/45), CD10-negative (91%, 77/85), CD23-negative (84%, 91/109), and BCL6-negative (71%, 29/41). Presence or absence of leukemic phase was reported in 31 cases, 14 of those were positive for circulating MCL cells (45%). Lymph node was frequently the initial site of MCL diagnosis (59%, 57/97). Majority of cases showed the classical MCL morphology with small to medium sized lymphoid cells (59%, 61/104). The proliferation marker Ki-67 was reported in 82 cases, 48 (59%) of which were <30%.There were considerable clinical and biological differences between CD5-negative and conventional MCL. Most notably, the median OS (mOS) of 79 CD5-negative MCL cases with available follow-up was >14 years (Figure 1B), which compares very favorably to the historic survival of conventional MCL. SOX11, an MCL-specific biomarker that is positive in 90% of conventional cases was expressed in only 44% (11/25) of CD5-negative MCL cases. Lack of SOX11 expression in MCL predicts an indolent MCL subset. Surprisingly, OS was not significantly different between SOX11-positive and SOX11-negative CD5-negative MCL (Figure 1C, P=0.88). SOX11 stains were performed by expert hematopathologists at Tulane (2 cases) or other reliable institutions. Akin to SOX11 expression, λ light chain restriction and unmutated IGHV, two variables known topredict worse outcomes in conventional MCL, did not significantly impact OS in CD5-negative MCL. Similarly, higher Ki-67 expression (>30%) did not affect OS of CD5-negative MCL. Variables more prevalent in CD5-negative MCL compared to conventional MCL included κ light chain restriction (70%, 26/37) and IGHV hypermutation (79%, 15/19). Though sample size is limited, our survival analysis highly suggests that lack of CD5-expression might in fact represent an independently good prognostic marker in MCL.Conclusion: Lack of CD5 appears to improve survival in MCL independently of other favorable prognostic markers such as IGHV hypermutation, absence of SOX11 expression, low Ki-67, and κ restriction. Reasons for this indolent behavior remain unknown. Our analysis indicates that CD5-negative MCL deserves deeper investigation to further understand its biological implications. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

SOX11 and CD43 Biomarkers in Mantle Cell Lymphoma

Recently, mantle cell lymphoma (MCL) has been recognized as a heterogeneous clinical and biological entity, as molecular genetics highlighted different pathways of cell survival and progression. Histological diagnosis may be challenging due to atypical MCL variants, immunophenotyping or absence of cyclin D1 (D1), encountered in 10% of cases. SOX11 is a neural transcription factor, involved in blocking mature B cell differentiation and its overexpression is associated with poor prognosis. It is overexpressed in most conventional MCL (cMCL) and in MCL lacking D1 overexpression, but not detected in other mature B cell lymphomas or normal lymphoid cells. Recently, its overexpression has been considered as a specific biomarker for MCL diagnosis.Development of novel targeted therapy approaches renders monitoring of minimal residual disease (MRD) essential to assess treatment effectiveness. Amongst methods developed to monitor MRD, allele-specific oligonucleotide quantitative PCR for BCL1 or IgH, is the most sensitive and commonly used approach. Given the role of SOX11 and BCL1 in the pathophysiology of MCL, we developed an easy set up single step quantitative PCR (qPCR) to assess both markers simultaneously, which was tested on a large panel of MCL patients at diagnosis and MRD monitoring.A reverse transcription qPCR protocol was carried out to quantify SOX11, cyclin D1 and D2 overexpression simultaneously, using specific primers, Taqman probes and B2M house keeping gene (LC480, Roche). RNA was extracted from peripheral blood (PB), bone marrow (BM) and lymph nodes (LN). Sensitivity was determined using 6 fold dilutions starting with 1:10 from 30 subjects with normal lymphocytes. A retrospective study on a total of 170 samples for 145 patients between 2002 and 2017 was conducted. Samples were chosen based on morphology, immunophenotyping and histopathology if available. All samples were CD20+, 162 were CD5+ and 165 were CD10-. All patients had provided an informed written consent in accordance with the declaration of Helsinki. We tested 93 patients with MCL at diagnosis, 79 cMCL and 14 indolent mantle cell lymphoma (iMCL). To assess specificity 52 patients with other lymphoid proliferations CD5/20+, CD10- were studied. 20 samples from 5 patients SOX11+/D1+ were available for MRD monitoring.Sensitivity of the method achieved 1.10-4. At diagnosis, tumor cells ranged between 11-97% of total lymphocytes in PB and 1-91% in BM. SOX11 and D1 overexpression was correlated with the tumor burden. 79/79 cMCL patients (100%) overexpressed SOX11 and D1 (SOX11+/D1+), 2 cMCL were CD5-, SOX11+/ D1+ and 2 cMCL were CD10+, SOX11 +/ D1+. All 14 iMCL patients were (SOX11-/D1+). Sox 11 was not detected in normal lymphocytes or in other lymphoproliferative diseases. 5 patients presented with the blastoid variant, overexpressed SOX11, but only 4 overexpressed D1 and tumor infiltration rate at diagnosis was over 83% in PB. MRD follow up showed negativity of both markers for 2 patients at complete remission. SOX11 overexpression was detected before cyclin D1 in 2 patients at relapse, prior to clinical manifestations. Persistent SOX11 and D1 overexpression was observed for 1 splenctomized patient. Time to treatment was found to be 0.6 vs 18 months in 18 cMCL and 12 iMCL patients respectively (p= 0.0006). CD43 was evaluated for 27 patients, 4 blastoid variants and 23 cMCL. 100% of blastoid variants were positive for CD43, but only 43.4% of cMCL were positive for CD43 (p=0.0368). Overall survival curve for CD43 positive patients showed a median of 2.3 years survival (p=0.0285). This was not reached for the CD43 negative MCL.We developed a feasible single step sensitive method to quantify SOX11, D1 and D2 in MCL which allows differential diagnosis with other lymphoid proliferations. A parallel correlation was found between SOX11, D1 and clinical status of MCL during diagnosis and follow up. As histopathology is unsuitable for MRD evaluation, both markers could be used to assess MRD, though SOX11 is preferred to D1 as it lacks the D1 background overexpression. Considering the higher sensitivity of molecular MRD compared to conventional evaluating procedures, its integration in guided treatment strategies is warranted. To the best of our knowledge, this is the first report stating the association of CD43 with adverse prognosis in MCL which might be interesting as a prognostication marker and a target for a novel immunotherapy development. [Display omitted] DisclosuresTroussard:ROCHE: Honoraria; GILEAD: Honoraria; JANSSEN: Honoraria; ABBVIE: Honoraria.

50. Personalized medicine in practice: Comprehensive cytogenomic profiling of a lung adenocarcinoma leads to re-classification of a concurrent lymphoma

Through the use of comprehensive genomic characterization, a personalized medicine approach has the potential to improve diagnosis, ameliorate prognostication and identify actionable molecular alterations. Herein, we describe a 77-year old patient under surveillance for untreated CLL, diagnosed via flow cytometry and further characterized by cytogenetic and molecular studies. In a peripheral blood specimen, FISH analyses identified trisomy 12 in 77% of nuclei and loss of TP53 in 9% of nuclei and was negative for all other markers tested including: loss of 13q14 and/or ATM and IGH-CCND1 rearrangement. Concurrent molecular studies detected a TP53 p.V157F mutation. PET-CT scan for surveillance of patient's CLL incidentally identified multiple bilateral pulmonary nodules, concerning for primary lung cancer. A pulmonary wedge resection confirmed the presence of a lung adenocarcinoma which was profiled using a targeted Next-Generation Sequencing (NGS) panel. This analysis revealed an actionable EGFR mutation (in frame exon 19 deletion), two TP53 mutations (p.P152Q and p.V157F) as well as an IGH-CCND1 rearrangement. Follow-up immunohistochemistry (IHC) studies performed on the intrapulmonary nodules showed positive staining for cyclin D1 (CCND1) and negative staining for SOX11. Together, the presence of the TP53 p.V157F in the lung resection, IGH-CCND1 rearrangement and IHC positivity for CCND1 were most suggestive of an infiltration of an extra-nodal mantle cell lymphoma (MCL) within the lung adenocarcinoma. Genomic characterization of this tumor led to the identification of a CCND1-IGH rearrangement, pathognomonic of MCL, which was misdiagnosed at the onset of the disease due to a cytogenetically cryptic event. This led to the re-evaluation of the patient's heme disorder which was reclassified as a CCND1-positive, SOX11-negative indolent MCL. This further highlights the importance of holistic genomic characterization for accurate classification of neoplasms and disease management.

Third Generation CD20 Targeted CAR T-Cell Therapy (MB-106) for Treatment of Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Third Generation CD20 Targeted CAR T-Cell Therapy (MB-106) for Treatment of Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Recent advances in the first-line treatment of mantle cell lymphoma

: Mantle cell lymphoma (MCL) is a rare B-cell lymphoma, with a median survival of only three to four years. In recent years, the development of new drugs and therapeutic strategies appeared to have improved the outcomes. This review focused on the most important new strategies for untreated MCL patients. Given the heterogeneous clinical evolutions between patients, several prognostic factors have been identified. These factors, as well as the identification of indolent and aggressive MCL, are useful to propose a risk-adapted therapeutic strategy. The prognostic impact and the practical applications of minimal residual disease (MRD) will be addressed. Overall, induction by combining rituximab with cytarabine, followed by consolidation with autologous stem cell transplant had been shown to have benefits for MCL younger patients. However, almost all MCL patients will relapse over time. The addition of rituximab as maintenance therapy for these patients had been shown to improve overall survival. Achievement of complete response with negative MRD and/or negative PET scan while reducing toxicity would be the future therapeutic objective. In this perspective, targeted therapies, alone or in combination as induction or maintenance therapy, are currently being tested earlier in the disease course.

Overall Survival, Adverse Events, and Economic Burden in Medicare-Insured Patients with Mantle Cell Lymphoma Receiving Cancer-Directed Therapy

Background: Most data on overall survival (OS) and adverse events (AEs) in patients with mantle cell lymphoma (MCL) are from controlled trials in academic centers; data from real world management and outcomes in patients with MCL are sparse. We therefore conducted a population-based retrospective cohort study of patients with MCL in the Medicare database to assess treatment patterns, OS, AEs, and economic burden. Methods: Patients with MCL who received any systemic cancer-directed treatment from 2013 to 2015 were selected from the nationwide Medicare claims database and followed through 2016. The date of the first observed systemic therapy defined each patient's index date. Patients were included if they (a) were ≥ 18 years of age at the index date; (b) had ≥ 12 months of continuous Medicare enrollment before the index date (baseline period); and (c) had no evidence of prior MCL-directed treatment (systemic therapy and/or SCT) at any time before the index date (i.e., during at least the previous 12 months). An observed line of therapy was defined as all agents received on or within 35 days after the first claim for a systemic therapy drug; the observed therapy line was considered ended upon switch to another regimen or a gap ≥ 90 days after the last treatment. OS was estimated by the Kaplan-Meier method from the index date (start of first observed line of therapy) until the last follow-up or death. We also calculated rates of occurrence for hematologic and nonhematologic AEs often associated with the most commonly observed regimens (irrespective of observed line of therapy). The occurrence of AEs was defined based on the presence of at least one claim containing an AE-specific diagnosis code during the treatment, regardless of any history of the AE before treatment initiation. All-cause health care costs were assessed from Medicare's perspective. Multivariable models were fitted to assess the association between number of AEs and average costs during the first observed therapy. Results: We analyzed 1,465 patients who met the inclusion criteria (median age=74 years; 68% male; 93% white). Across all observed lines of therapy, ibrutinib monotherapy (Ibr) (n=588 [40%]) was the most frequently used regimen, followed by bendamustine/rituximab (BR) (n=527 [36%]). Ibr recipients had a median age of 75 years, median Charlson Comorbidity Index (CCI) score of 4.0, and were followed for a median duration of 15 months; 52% died during the study period. BR recipients had a median age of 75 years, median CCI score of 3.0, and were followed for a median duration of 21 months; 28% died during the study period. In Ibr recipients, median OS was 22 months (95% CI = 16.9-28.6) and 24-month OS was 47% (95% CI = 42.9%-50.5%). In BR recipients, median OS was not reached while OS at 24 months was 73% (95% CI = 69.4%-76.0%). The occurrence of common AEs during Ibr and BR therapies are presented in Tables 1 and 2. The average per patient per month costs, among all patients, were $2,501 (SD = $2,818) during the baseline period and $12,604 (SD = $14,437) during the period after initiation of the first observed MCL-directed systemic therapy. Multivariable analysis showed that the patients with 3 or more AEs had nearly 4 times higher monthly per patient costs (cost ratio = 4.12, 95% CI = 3.53-4.82) compared with those with 0-2 AEs. Conclusions: Two-year survival rates observed in this study are comparable to those reported in clinical trials (47% for Ibr in the relapsed disease setting [Wang, 2015, Blood]) and nearly 75% for BR in patients with relapsed indolent disease and MCL [Rummel, 2016, Lancet]). Rates of AE occurrence in Ibr- and BR-treated patients in this study highlight the substantial burden and susceptibility to AEs among Medicare patients in the real-world setting. These findings also demonstrate a substantial increase in the economic burden from the baseline period to the period after MCL treatment initiation and as the number of AEs increased. Disclosures Kabadi: AstraZeneca: Employment, Equity Ownership. Goyal:RTI Health Solutions: Employment. Nagar:RTI Health Solutions: Employment. Davis:RTI Health Solutions: Employment. Le:AstraZeneca: Employment, Other: Stocks. Wang:Dava Oncology: Honoraria; Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Kite Pharma: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Acerta Pharma: Consultancy, Research Funding. Kaye:RTI Health Solutions: Employment.

A Phase I/II Trial of Intratumoral CpG, Local Low-Dose Radiation, and Oral Ibrutinib in Patients with Low-Grade B-Cell Lymphoma

Background: In situ vaccination for the treatment of cancer aims to trigger an immune response locally that propagates systemically. We have shown that local treatment with intratumoral CpG (a TLR9 agonist) and low-dose radiation can elicit antitumor immune responses and global tumor shrinkage in patients with low-grade lymphoma (Brody, J Clin Oncol, 2010; Frank, Cancer Discov, 2018). Ibrutinib is a small molecule that compromises B cell survival by inhibiting Bruton's tyrosine kinase (BTK) but also modulates T cell phenotypes by inhibiting interleukin-2-inducible T-cell kinase (ITK). Specifically, there is evidence for ibrutinib-induced skewing of CD4 T-cells toward a Th1 phenotype, which would be expected to promote anti-tumor immunity (Dubovsky, Blood, 2013). In a mouse model of lymphoma, systemic ibrutinib plus intratumoral CpG was curative of systemic disease in all treated mice, an effect that was fully T-cell dependent (Sagiv-Barfi, Blood, 2015). Study Design: To test the hypothesis that ibrutinib will enhance the efficacy of in situ vaccination via its effects on T-cells, we initiated a phase I/II clinical trial combining oral ibrutinib (560mg), intratumoral CpG (SD-101, 3mg) and local low-dose radiation in patients with recurrent low-grade lymphoma (NCT02927964). Patients with follicular lymphoma, marginal zone lymphoma, or indolent mantle cell lymphoma relapsed or refractory to at least one line of prior therapy and with at least one superficial disease site accessible for injection and one independent measurable disease site are eligible. Patients with significant autoimmune disease, recent stroke or intracranial hemorrhage, and those requiring anticoagulation with vitamin K antagonists or chronic treatment with strong CYP3A inhibitors are excluded. The primary outcome of the study is determination of safety of the combination treatment. Secondary outcomes include overall response rate, progression-free survival, and correlative studies of tumor and blood immune populations. Fourteen patients have been enrolled thus far, with a goal enrollment of 21-30 patients. Treatment consists of two consecutive days of low-dose (2 Gy) radiation to the chosen treatment site, followed by 5 weekly injections of CpG into that same site. Daily oral ibrutinib is begun one day after the second CpG injection. CT scans are performed at 3, 6, 12, 18, and 24 months. Common Terminology Criteria for Adverse Events (CTCAE) are used to track treatment-emergent safety events, and Lugano criteria (Cheson, J Clin Oncol, 2014) are used to assess response to therapy. Correlative Studies: Fine needle aspirates (FNAs) are obtained from CpG-injected and non-injected sites pre-treatment and at weeks 2 and 6. Peripheral blood samples are obtained pre-treatment and weeks 2, 4, 6, and at all response assessment timepoints. When available, tumor cells from an excisional biopsy pre-treatment are viably preserved. FNAs and peripheral blood samples from pre-treatment and at weeks 2 and 6 are being analyzed by both flow cytometry and single cell RNA sequencing. For patients for whom viably preserved tumor cells are available, these are co-cultured with autologous peripheral blood T cells in an in vitro immune response assays to test for tumor-specific T-cell activation. Summary: This innovative study combines in situ vaccination and ibrutinib-induced T-cell modulation and incorporates serial sampling of multiple tumors and peripheral blood using minimally invasive procedures, analyzed by methods that allow for deep profiling of treatment-induced changes. This study is ongoing and currently accruing at the Stanford Cancer Center. Disclosures Khodadoust: Corvus Pharmaceuticals: Research Funding. Levy:Spotlight: Membership on an entity's Board of Directors or advisory committees; 47 Inc: Membership on an entity's Board of Directors or advisory committees; XCella: Membership on an entity's Board of Directors or advisory committees; Immunocore: Membership on an entity's Board of Directors or advisory committees; Walking Fish: Membership on an entity's Board of Directors or advisory committees; Five Prime: Membership on an entity's Board of Directors or advisory committees; Corvus: Membership on an entity's Board of Directors or advisory committees; Quadriga: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; GigaGen: Membership on an entity's Board of Directors or advisory committees; Checkmate: Membership on an entity's Board of Directors or advisory committees; Teneobio: Membership on an entity's Board of Directors or advisory committees; Sutro: Membership on an entity's Board of Directors or advisory committees; Dragonfly: Membership on an entity's Board of Directors or advisory committees; Nurix: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Abpro: Membership on an entity's Board of Directors or advisory committees; Apexigen: Membership on an entity's Board of Directors or advisory committees; Nohla: Membership on an entity's Board of Directors or advisory committees.

PF526 STRUCTURAL AND FUNCTIONAL VARIABILITY OF THE TUMOR B‐CELL RECEPTOR INDICATES A ROLE FOR ENVIRONMENTAL INFLUENCES ON BEHAVIOR OF MANTLE CELL LYMPHOMAS

Background:Mantle cell lymphoma (MCL) is a mature CD5+ B‐cell tumor defined by common phenotypic and genetic features resulting in overexpression of cyclins (most commonly cyclin D1) and subsequent alterations of cell cycle progression. However, MCL has a heterogeneous course ranging from relatively indolent to very aggressive. In CLL, variability of B‐cell receptor (BCR) structure and function, consequent to antigen engagement, has provided key information on the variability of CLL behavior and clinical course. MCL typically express immunoglobulin M (IgM) and IgD. The association of IGHV status with different clinical outcome (Navarro, 2012; Walsh, 2003) and the sensitivity to BCR‐associated kinase inhibitors suggest the functional importance of BCR signaling in MCL.Aims:Our aim was to investigate the hypothesis that BCR surface IgM (sIgM) levels and function are variable and that its variability may be consequent to environmental influences acting on the BCR binding site.Methods:Peripheral blood mononuclear cells from 26 MCL patients were investigated. BCR structure was analyzed by IGHV‐D‐J transcript sequencing to characterize the antigen‐binding site, and by immunoblotting of the tumor sIgM, following EndoH or PNGase digestion, to investigate the functional status of the effector site. SIgM/D expression was determined on MCL cells by immunophenotype using F (ab’)2 anti‐IgM/D. SIgM/D levels were measured after culture of MCL cells at 0 (baseline), 24, 48 and 72 hours. MCL samples with sIgM levels increasing &gt;20% over baseline in vitro were defined “recoverers”. SIgM signaling capacity was measured by calcium mobilization assay and by phosflow of SYK and BTK following anti‐IgM stimulation.Results:Analysis of the tumor IGHV revealed an enrichment of MCL cases with mutated IGHV (M‐IGHV, homology to germline&lt;98%, 11/21), possibly reflecting selection of patients with a more indolent course in this cohort. SIgM levels were extremely variable (n = 26, MFI range 47–2597, median 810) while sIgD levels were low (MFI range 1–252, median 25). Interestingly, sIgM levels increased during ‘antigen‐free’ in vitro culture in 9/17 samples (53%). Analysis of the “recoverers” revealed that 6/9 expressed M‐IGHV (66%), while the remaining 3 cases expressed sIgM using unmutated IGHV4–39 (1/3) and IGHV3–21 (2/3), known to associate with a more indolent course in MCL (Walsh, 2003). Baseline sIgM levels in the “recoverers” were significantly lower (range 47–1534, median 325) than the non‐recovering group (range 119–2282, median 1272; p = 0.027). SIgM levels associated with signaling capacity, measured by calcium mobilization (r = 0.635, p = 0.009) and phosflow (pSYK[Y525]; r = 0.933, p = 0.007 and pBTK[Y223]; r = 0.952, p = 0.001). Immunoblotting of the tumor sIgM by EndoH and PNGase digestion revealed immature glycans in a recovering MCL with low sIgM baseline levels but not in a non‐recovering MCL with high sIgM. This provides further support of prior exposure of the “recovering” MCL sIgM to environmental influences in vivo (Krysov, S 2010, Drennan, 2018).Summary/Conclusion:Our data on this selected cohort indicate that sIgM levels are variable and correlate with their signaling capacity. The evidence that a group of MCL with M‐IGHV or IGHV3–21, that express relatively low levels of sIgM with ability to recover in vitro, suggests selective influences on the BCR of these MCL. This process may be prominent in indolent MCL, where genomic aberrations are less frequent. The evidence in these MCL with recovering sIgM claims analogies with CLL, in which variable antigen‐driven anergy plays a role in clinical behavior.

A Systemic Review of CD5-Negative Mantle Cell Lymphoma Identifies Potential Clinical and Biological Implications

Introduction: Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) with a median survival of 3 to 5 years. MCL is characterized by the translocation t(11;14)(q13;32) which results in the overexpression of cyclin-D1 and ultimately an uninhibited G1/S cell cycle transition. MCL has a distinctive immunophenotype among B-cell NHL, characterized by a strong expression of the pan B-cell markers CD19 and CD20, absence of CD10 and CD23, overexpression of the anti-apoptotic protein BCL2, and aberrant expression of the T-cell marker CD5. However, up to 10% of MCL lack CD5 expression and remain ill-characterized. Whether this absence of CD5 expression impacts MCL biology and clinical course remains unknown. We performed a systematic review of all reported cases of CD5-negative MCL and analyzed their biological and clinical characteristics.Patients and methods: A systematic literature search was performed and included studies published from 1st June 1994 to 1st June 2016 in PubMed, Embase, and Web of Science. We used the key words CD5 negative, CD5-, mantle cell lymphoma, and MCL. Data was tabulated regarding the following 16 variables: t(11;14)(q13;q32), cyclin-D1, CD5, CD10, CD19, CD20, CD23, BCL2, BCL6, Ki-67 (higher or lower than 30%), IGHV mutation status (mutated IGHV >3% discordance with germline), male to female ratio, light chain expression (kappa or lambda), presence of a leukemic phase, stage, and overall survival (OS). Data was reported as percent and total number of cases with available data of each variable.Results and discussion: 68 out of 470 screened articles included CD5-negative MCL cases. After exclusion of duplicates, 50 sources (46 full articles and 4 abstracts) were included. Data of 222 cases of CD5-negative MCL were collected.To a degree, reviewed cases of CD-5 negative MCL shared similarities to classic MCL. Both sub-types had a median age at diagnosis of approximately 65 and presented as stage IV disease 70% of the time. Both subtypes overexpressed cyclin-D1 (100%, 222/222), possessed the t(11;14)(q13;q32) (93%, 49/53: 49 of 53 cases with available data on the translocation), were CD-19 positive (100%,18/18), CD20-positive (100%, 58/58), BCL2-positive (97%, 34/35), CD10-negative (93%, 42/45), and CD23-negative (95%,56/59). Presence or absence of leukemic phase was reported in 16 cases, 8 of those were positive for circulating MCL cells (50%). The proliferation marker Ki-67 was reported in 22 cases, 7 (32%) of which were >30%.CD5-negative MCL deviated from the classic MCL presentation in a number of clinical and biological variables. Most importantly, the median OS of 47 cases with available follow-up was greater than 16 years (Figure 1), which compared very favorably to the historic survival of 3 to 5 years in classic MCL. Interestingly, the number of affected males was less than expected in the CD5-negative group. Male-to-female ratio was 2:1 (74 males and 36 females of 110 cases with available gender data), which is lower than the expected 3:1 ratio.From a biological standpoint, the CD5-negative MCL cohort had more kappa than lambda-restricted cases (62%, 13 of 21 available light chain data), and more mutated than unmutated IGHV (61% mutated, 11 of 18 cases with available IGHV data). Classically, lambda-restricted MCL and unmutated IGHV are more commonly seen and were associated with worse clinical outcomes. In addition, we observed BCL6 expression in 23% of CD5-negative MCL cases, which is higher than expected (6 of 26 cases with BCL6 available data).Conclusions: To our knowledge this is the most comprehensive review of CD5-negative MCL. Lack of CD5 expression was associated with important clinical and biological differences compared to classic MCL. The higher survival observed in our analysis suggest that CD5 can potentially be incorporated in identifying a subset of a more indolent MCL that might benefit from a watch and wait approach. Currently, treatment in MCL can be differed in a subset of patients with an indolent presentation characterized by leukemic-only disease with absence of lymphadenopathy, mutated IGHV, and lack of SOX11 expression. SOX11 data was not available in our cohort, and only 18 patients had available IGHV mutation data. While the exact role of CD5 in MCL remains unknown, our findings highlight the need for a deeper investigation of CD5-negative MCL at the genetic, phenotypic, and clinical levels. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The discovery and the development of bendamustine for the treatment of non-Hodgkin lymphoma

ABSTRACTIntroduction: Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies. The treatment strategy for patients with NHL had remained unchanged until the advent of the era of molecular targeting agents. Although rituximab-containing chemotherapy has improved the response rates and survival of patients with B-cell NHL (B-NHL), several subtypes of B-NHL, especially indolent B-NHL and mantle cell lymphoma (MCL), remain incurable. Therefore, novel treatment modalities for B-NHL, especially for indolent B-NHL and MCL, are needed. Bendamustine is an old, but unique, multifunctional cytotoxic agent that exhibits structural similarity to alkylating agents and purine analogs.Areas covered: The basic aspects and preclinical development of bendamustine are summarized, followed by a discussion of the clinical development of bendamustine-based treatments for indolent B-NHL and MCL.Expert opinion: Bendamustine monotherapy or the use of bendamustine in combination with rituximab is highly effective against various types of hematological malignancies, especially relapsed or refractory indolent B-NHL, and exhibits an acceptable toxicity profile. Furthermore, bendamustine plus rituximab might be a promising treatment option for patients with untreated indolent B-NHL. Therefore, bendamustine has the potential to play an important role in the treatment of malignant lymphoma.

A Phase I Study of BKM120 (Buparlisib) and Rituximab in Patients with Relapsed or Refractory B-Cell Non-Hodgkins Lymphoma (NHL)

Introduction: BKM120 is a potent and highly specific oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor. Several PI3K inhibitors have single agent activity in relapsed or refractory B-cell NHL. We are conducting a phase I trial of the combination of BKM120 and rituximab to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), tolerability and preliminary efficacy in patients with relapsed or refractory NHL. Methods: Patients ≥ 18 years with relapsed or refractory B-cell NHL including follicular lymphoma (FL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma/waldenstrom's macroglobulinemia (LPL/WM), mantle cell lymphoma (MCL), and activated B cell subtype diffuse large B cell lymphoma (ABC DLBCL) who have received at least one prior therapy were eligible. Additional eligibility included ECOG Performance Status 0-2, adequate renal and liver function, absolute neutrophil count (ANC) ≥ 750/mm3, platelets ≥ 50,000/mm3, INR ≤ 2.0, and fasting glucose &lt; 120 mg/dL. Prior autologous or allogeneic transplant was allowed if patient did not require immunosuppressive therapy for GVHD. Prior treatment with a pan-selective PI3K inhibitor was not allowed but prior therapy with a selective PI3K inhibitor, Bruton's tyrosine kinase inhibitor or other B-cell receptor targeting agent was allowed. Patients with active moderate or severe major mood or psychiatric disorders were excluded given mood-associated toxicities. Treatment consisted of escalating doses of BKM120 (mg/day) days 1-28 and standard rituximab dosing at 375 mg/m2 days 2, 8, 15, and 22 of cycle 1 and then day 1 of cycles 3, 5, 7, 9, 11 for 28-day cycles. A standard 3+3 dose escalation schema was followed. DLT was defined during cycle 1 and included: treatment delays &gt; 28 days for toxicity; grade 5 toxicity: grade 3 febrile neutropenia &gt; 7 days; grade 4 febrile neutropenia or infection; grade 3 or 4 somnolence, cognitive changes, altered mood, anxiety, or confusion; grade 2 somnolence, cognitive changes, altered mood, anxiety, or confusion that does not resolve to ≤ grade 1 within 14 days; other grade 3 or 4 non-hematologic toxicity with the exception of grade 3 nausea, vomiting, diarrhea, or electrolyte abnormalities that are reversible within 72 hours of holding treatment. Patients without toxicity were allowed to continue treatment until disease progression. To further evaluate safety, preliminary efficacy and correlatives, an expansion cohort of an additional 12 patients to be treated at the MTD was planned, 6 patients with indolent NHL or MCL and 6 patients with ABC DLBCL. Response was assessed by CT or PET/CT after cycles 2, 4, 6, and then every 3 months while on therapy. Results: From August 2014 until July 2015, seven patients were enrolled in this trial. The median age was 67 (range 52-71). Histologies included FL (n=5) and MZL (n=2). Three patients were treated at dose level (DL) 1 (BKM120 80 mg/day). No DLT's occurred. Four patients have been treated at DL2 (BKM120 100 mg/day). One patient experienced a DLT consisting of grade 3 maculopapular rash. The rash occurred cycle 1 day 15 and resolved with interruption of therapy which was continued on day 22 at a reduced dose of BKM120 at 80 mg without any recurrence. The rash was confounded by the simultaneous initiation of allopurinol. Grade 3 toxicities occurred in 2/7 (29%) patients, including grade 3 maculopapular rash in one patient (DLT) and grade 3 hyperglycemia in one patient. Patients have received a median 3 cycles of therapy to date (range 1-9) and six remain on therapy. At DL1, two patients with FL achieved a partial response (PR). At DL2, one patient with FL achieved a PR. Overall response rate for the 5 evaluable patients is 60%. The other two evaluable patients had best response of stable disease. One patient discontinued study to pursue alternative therapy. Conclusions: Combined therapy with the pan-PI3 kinase inhibitor BKM and rituximab in patients with relapsed or refractory B-NHL has been well tolerated, with only one DLT of maculopapular rash that resolved with therapy interruption and did not recur at a lower dose. Patients continue to enroll at the current and final dose level of BKM120 mg administered at 100 mg daily with standard rituximab dosing, with a planned expansion cohort at the MTD. While the number of patients treated has been small, preliminary efficacy has been observed including all enrolled FL patients assessable for response achieving a PR. Disclosures Maddocks: Pharmacyclics: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Research Funding. Cohen:BMS, Janssen: Research Funding; Celgene, Pharmacyclics, Millennium, Seattle Genetics: Consultancy. Christian:Seattle Genetics: Consultancy, Research Funding; Novartis: Other: IDSM; Celgene: Consultancy; Pharmacyclics: Research Funding; Acerta: Research Funding; Janssen: Research Funding; Immunomedics: Research Funding. Blum:Janssen: Research Funding; Pharmacyclics: Research Funding; cephalon: Research Funding; Celgene: Research Funding.

2 Gy x 2 for Palliation of Indolent Mantle Cell Lymphoma

Indolent non-Hodgkin lymphomas such as follicular and marginal zone lymphoma are highly radiosensitive, and low-dose radiation of 2 Gy x 2 has been well established as an effective palliative regimen for these patients. Mantle cell lymphoma is also known to be radiosensitive and, while often aggressive, can also behave in a similar indolent fashion. We sought to review our experience using 2 Gy x 2 as palliative treatment for indolent mantle cell lymphoma. A total of 14 consecutive patients treated to 25 sites of disease from 2006 to 2014 were retrospectively analyzed. Median age was 69 (range 55-80). Two patients had stage II disease, 3 had stage III, and 9 had stage IV. Thirteen patients (93%) had received prior chemotherapy. Treated sites included the head/neck/axilla (n=14), abdomen/pelvis/groin (n=8), and thorax/mediastinum (n=3). The primary endpoints were response and local relapse rates, which were determined by clinical exam and PET-CT imaging. Mean follow-up was 20 months (range 2-69 months). After 2 Gy x 2, overall local response rate was 88%. Complete response was achieved in 68% of the treated sites, partial response in 20%, stable disease in 8%, and progression in 4%. Symptomatic response or break from chemotherapy was achieved in 94% of patients. Two patients experienced acute grade 1 toxicity (dry mouth), and there was no late toxicity from radiation therapy. Thirteen sites (52%) eventually developed local relapse, with a median time to local relapse of 10 months. At 20 months, the freedom from local relapse rate was 49%. In this series, low-dose radiation with 2 Gy x 2 was effective and well-tolerated for the palliative treatment of indolent mantle cell lymphoma.

A Rare Presentation of Tracheal Crystal-Storing Histiocytosis as Early Manifestation of Subglottic Mantle Cell Lymphoma

SESSION TITLE: Pulmonary Manifestations of Systemic Disease Student/Resident Case Report Posters II SESSION TYPE: Student/Resident Case Report Poster PRESENTED ON: Tuesday, October 27, 2015 at 01:30 PM - 02:30 PM INTRODUCTION: Mantle Cell Lymphoma (MCL) is a B cell malignancy. Crystal-Storing Histiocytosis (CSH) is a rare, benign entity suggesting the presence of underlying lymphoproliferative disorders. Neither is commonly identified in the trachea. We present a woman with significant dyspnea with CSH in the distal trachea, and co-existing subglottic MCL. CASE PRESENTATION: A 68 year old female avid biker, with a 25 year history of relapse-free CLL, with multiple prior therapies and splenectomy, presented with a six month history of progressive dyspnea, unable to climb 4 stairs. CT angiogram was negative for PE or progressive adenopathy, but upon re-review demonstrated stable thickening of the distal trachea, present since 2009. PFTs suggested a fixed large airway obstructive process. Echocardiogram was negative, and exercise ECG was limited by dyspnea without evidence of cardiopulmonary abnormality. Bronchoscopy revealed an infiltrative process markedly narrowing the subglottic area, as well as a separate lesion involving the distal trachea. Two days after bronchoscopy she was admitted with stridor, placed on steroids and underwent subglottic debulking with dramatic symptomatic improvement. Pathology revealed MCL in the subglottic region and CSH in the distal trachea. Bone marrow biopsy revealed no involvement, and PET CT only demonstrated FDG avidity in the subglottic and distal tracheal areas. She was initiated on rituximab and bendamustine with good response. DISCUSSION: MCL represents 7% of all adult forms of non-Hodgkins Lymphoma with a median age of onset in the 60s. Most patients are in advanced stages at diagnosis primarily presenting with lymphadenopathy, though MCL can present in a single non-lymphoid organ. The disease is typically aggressive with a median survival of 3 years, though a smaller subset of patients survives for years with stable disease. Though CSH is benign, it usually represents the presence of underlying hematologic malignancies, and when discovered necessitates exploration for the malignant source. Lung involvement of CSH is well described. To our knowledge, this is the first case report of CSH associated with MCL, and the first of CSH in the trachea. CONCLUSIONS: It is likely, upon re-review, that our patient has had indolent MCL throughout the course of her disease and not CLL. Her subglottic lesion likely represents a symptomatic recurrence of MCL. Presumably the stable thickening in the distal trachea, previously thought to be inflammation induced from intubation, had long been CSH from her underlying MCL. Had her subglottic lesion been identified first, the distal tracheal lesion would have been considered a metastatic lesion, and the rare CSH-MCL association would have been missed. Reference #1: Guddati AK, et al. Primary mantle cell lymphoma of the trachea. Medical oncology 2012; 29:2385-2387 Reference #2: Lee JS, et al. A challenging diagnosis: crystal-storing histiocytosis in plasma cell myeloma. American journal of clinical pathology 2015; 143:300-304 DISCLOSURE: The following authors have nothing to disclose: Amanda McCambridge, Finbar Foley, Ryan Kern, Timothy Call, Eric Olson No Product/Research Disclosure Information

Autoimmune haemolytic anaemia in mantle cell lymphoma : an insidious complication associated with leukemic disease

Autoimmune haemolytic anaemia in mantle cell lymphoma : an insidious complication associated with leukemic disease

TCL1 expression predicts overall survival in patients with mantle cell lymphoma.

Mantle cell lymphoma (MCL) has a heterogeneous clinical course. Although most cases show a poor prognosis, a minority has an indolent course. It is difficult to identify indolent MCL cases prospectively. T-cell leukemia/lymphoma protein 1 (TCL1) is expressed by several B-cell lymphomas, including MCL. This study examined the expression of TCL1 and its prognostic relevance for MCL. Clinical data for 162 patients with MCL were collected. Of these, 144 cases with available tissues for tissue microarray construction and immunostaining were included in the analysis. TCL1 staining was quantified using the Nuclear Quant application with Pannoramic™ Viewer v. 1.14. High TCL1 expression was defined as moderate to strong nuclear and/or cytoplasmic staining in 40% or more of the cells. High TCL1 expression was observed in 39 of 144 samples (27.1%). Patients with low TCL1 expression were more likely to present with blastoid/pleomorphic morphology (P = 0.010). Low TCL1 expression was associated with significantly shorter overall survival (OS, P = 0.006). Multivariate analysis identified low TCL1 expression (P = 0.003), high-risk MIPI (P = 0.027), and anemia (P = 0.018) as adverse prognostic factors. Our study suggests that TCL1 expression profile may have a role in the prediction of overall outcome in patient with MCL and call for prospective studies.

Risk of Central Nervous System (CNS) Involvement in Patients with Mantle Cell Lymphoma (MCL): Analysis of Clinico-Biological Factors in a Series of 283 Cases

IntroductionMCL is a mature B-cell neoplasm characterized by t(11;14) (q13;q32) and cyclin D1 (CCND1) overexpression. Molecular studies have revealed other alterations in cell-cycle regulation, DNA damage response and cell survival pathways, with a landscape of somatic mutations being recently identified.CNS involvement is a well known complication, occurring in 4-26% of MCL at five years, with an ominous significance. Although different clinical variables have been identified as risk factors for CNS infiltration, the biological parameters related to this complication have not been extensively studied. The aim of the study was to explore the biological parameters associated with CNS involvement in a multicentre and retrospective series of MCL patients. Patients and Methods285 patients (M:74%; 64 yr) diagnosed of MCL between 1990-2014 (median survival of 4 years) were analysed. In addition to standard clinico-biological variables, IGHV mutational analysis, chromosomal alteration studies and Sanger sequencing of NOTCH1, NOTCH2, TP53, BIRC3, WHSC1, MEF2B, MLL2, TLR2 and PRDM1 were performed. ResultsCNS involvement was observed in 15/285 MCL patients (5.2%), with a 5-yr risk of 9.1% (95%CI: 4.6-13.6), one patient at diagnosis, and at first or second/ulterior progressions in 7 cases each. The clinical, pathological and molecular risk factors identified are detailed in the Table. In addition to what has been already described, CNS involvement was usually observed in MCL cases with a clinical nodal presentation (p=0.05). In fact, no indolent MCL with a non-nodal presentation developed this complication during the follow-up period. No differences were observed in the risk of CNS involvement between patients treated in first-line with conventional or high-dose intense treatment (5-yr risk: 6.1%+/-6% vs. 10.7%+/-10.6%, p=ns).Regarding the biological features, no differences in terms of the IGHV mutational status were observed in cases developing CNS involvement compared to the others (75% vs. 68.7%, using 97% identity cut-off). Similarly, the IGHV gene usage of CNS involved cases corresponded to the more frequent IGHV genes observed in MCL (usually IGHV1-18, IGHV3-23, IGHV4-34, IGHV4-59). Although not significant, a predominance of high number copy number alterations (CNA) (>4) could be observed in the genetic study of MCL cases with CNS involvement as could be expected for the enrichment in blastoid variants (up to 50% of these cases). In fact, we did not observe any case with CNS involvement among those cases with 3 or less CNA. CNS involvement was not related to common poor prognosis genetic alterations such as 9p, 11p and 17p losses, but the presence of 8q gains was associated with a higher risk of CNS involvement (p=0.05). We did not find any significant association between CNS involvement and the large number of oncogenic mutations studied. ConclusionsCNS involvement in MCL is associated with initial aggressive clinico-biological characteristics. Non-nodal MCL cases with a low number of genetic alterations did not present CNS involvement. Finally, the presence of 8q gains was associated with a higher risk of CNS infiltration.TableInitial Clinical FeaturesCategoryN5 yr-CNS involvement(%, 95%CI)HRpPerformance status (ECOG)> 18/5141.5 (+/-28)4.2.003≤ 17/1289.4 (+/-5.5)Nodal diseaseYes14/18513.3 (+/-7.6)6.1.05No1/771.4 (+/-2.7)Hemoglobin (g/L)< 10512/9324.7 (+/-14.7)3.2.05≥ 1053/785.3 (+/-6.3)LDH> ULN4/8927.1(+/-19.4)6.7<.001< ULN11/1375.6 (+/-6.3)B2microglobulin> ULN11/11421.6 (+/-14.9)3.5.04< ULN3/668.7(+/-10)Molecular & Pathological dataHistological variantBlastoid6/5817.3 (+/-13.7)3.5.02Others8/1561.3 (+/-7.2)Ki-67> 30%5/4417.5 (+/-14.9)3.6.06≤ 30%3/616.7 (+/-9.4)SOX11Positive8/1532.9 (+/- 5.7)2.6nsNegative1/422.1 (+/-2.4)IGHV≥97%6/1099.5 (+/-9.6)1.9ns<97%2/496 (+/-8.2)CNA> 42/873.9 (+/-5.7)1.1ns≤ 41/442.3 (+/-4.3)ChromotripsisYes1/1712.5 (+/-22)3.2nsNo2/1061.9 (+/-2.7)8q gainYes2/3013.1(+/-19)7.5.05No2/971 (+/-1.96) CNAcopy number alteration; IGHV: immunoglobulin heavy chain; LDH: Lactate dehydrogenase DisclosuresNo relevant conflicts of interest to declare.