Central Nervous System Prophylaxis Research Articles

Serum Proteome Profiling Reveals Inflammatory, Molecular and Prognostic Information Beyond the Ctdna in Aggressive B-Cell Lymphomas

Introduction Large B-cell lymphomas (LBCL) constitute a group of aggressive B-cell lymphomas, which have striking genetic heterogeneity, variable tumor microenvironment (TME), clinical presentation and treatment outcome. Although LBCL patients are treated with a curative intent, their survival is suboptimal, and the current prognostic tool, the International Prognostic Index (IPI), cannot capture the biological heterogeneity of the disease. We studied serum proteome in a uniformly treated cohort of the patients with LBCL to characterize host response to lymphoma and to identify clinically relevant circulating proteins. Materials and methods We applied proximity extension assay of 1463 proteins (Olink Proteomics) to pretherapeutic serum samples of 109 patients with primary LBCL and five healthy volunteers. The LBCL patients included in the study were 21-65 years of age and had clinically high-risk disease (age adjusted IPI ≥ 2) and/or site-specific risk factors for central nervous system (CNS) progression. Patients were treated in a Nordic phase II protocol with a dose-dense immunochemotherapy and early CNS prophylaxis. The findings from the serum proteome profiling were correlated with clinical and molecular data (gene expression, n = 48; multiplex immunohistochemistry, n = 39) from tumor tissue and circulating tumor DNA (ctDNA) from concurrent plasma samples (n = 91). Results Unsupervised analysis of the pre-treatment serum protein levels revealed a subgroup of patients (n=24, 22%) with a distinct protein profile compared to the other patients and healthy volunteers (Figure 1A). The patients with this profile had elevated levels of inflammatory proteins, such as interferon gamma (IFNg) related T-cell response markers. Clinically, the patients with the inflamed serum protein profile had more often B-symptoms and lymphoma infiltration in the bone marrow, and dismal survival as compared to the patients with the non-inflamed profile (overall survival, HR 4.31, 95%-CI 1.71-10.88, P < .01, Figure 1B). In addition, T-cell/histiocyte rich large B-cell lymphoma and activated B-cell (ABC) molecular subtype were more common entities in these patients. Lymphomas in the inflamed serum cohort were characterized by a higher proportion of tumor-infiltrating T-lymphocytes and macrophages expressing immune checkpoint molecules, such as programmed death-ligand 1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM3) and lymphocyte-activation gene 3 (LAG3). In liquid biopsy, a striking association between the inflamed serum protein profile and high plasma ctDNA levels was discovered (P < .0001). However, the profile associated with poor outcome independently of ctDNA levels (P < .01). Integrative analysis of ctDNA and serum proteins revealed synergistic potential for tumor profiling that extended beyond inflammatory markers. For example, circulating protein levels of tumor protein 53 (TP53) associated with p53 mutations, TP53 expression in the lymphoma tissue and high tumor burden. Moreover, high levels of serpin family A member 9 (SERPINA9) and TNF receptor superfamily member 13B (TNFRSF13B) characterized germinal center B-cell like/EZB and ABC/MCD diffuse large B-cell lymphomas, respectively. Conclusions Our findings reveal an inflamed serum protein profile, which reflects host response to lymphoma, correlates with TME features, extends beyond ctDNA characteristics, and translates to poor outcome. Moreover, by integrating serum protein and plasma ctDNA profiling we uncover new associations that broaden the opportunities of liquid biopsies in LBCL. Together, our data establish a novel interaction between lymphoma and the host. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Role of Prophylactic Chemotherapy for the Prevention of Central Nervous System Relapse in Patients with Large B Cell Lymphoma: A Meta-Analysis

Introduction: Central nervous system (CNS) relapse in large B cell lymphoma (LBCL) is a rare, but catastrophic event associated with poor prognosis without an effective standard prophylactic strategy. Intravenous and/or intrathecal chemotherapy have been proposed for patients at high risk for CNS relapse (i.e., CNS-IPI of 4 or greater) with mixed results due to the lack of prospective trials comparing different approaches. Large retrospective cohort studies have challenged the value of CNS prophylaxis. We performed a systematic review and meta-analysis (MA) assessing the role of chemoprophylaxis in preventing CNS relapse for LBCL patients treated with chemoimmunotherapy. Methods: A systematic literature review was conducted using the major online databases, including English language studies published from 2011 until 2022. Data were pooled from the studies with a comparator group using the random effects model to report odds ratio (OR) and 95% confidence intervals (95% CI). Data from single-arm studies were pooled using the random effects model to report the pooled proportion with 95% CIs. Results: There were 16 studies included in the MA (12 retrospective and 4 prospective) assessing the role of CNS prophylaxis in a total of 11,530 patients. The incidence of CNS relapse appeared to be higher among patients who received CNS chemoprophylaxis (n=2108) compared with patients without chemoprophylaxis(n=9422) (OR 1.70, 95% CI 1.10-2.61) (figure 1). Among the single-arm studies, the pooled proportion of the incidence of CNS relapse, isolated CNS relapse and secondary CNS relapse was 5% (95% CI 4%-7%), 5% (95% CI 4%-7%), and 1% (95% CI 0%-2%), respectively. Results are confounded by the retrospective design of most studies, different types of chemoprophylaxis and heterogeneous patient population. Discussion: This systematic review and MA demonstrated consistent rates of CNS relapse as seen in prior large cohorts, and did not show evidence for the use of chemoprophylaxis in patients with LBCL to prevent CNS relapse. Given the scarcity of high quality data due to the absence of prospective trials and the lack of motivation by multiple stakeholders to develop these type of studies, the totality of evidence grouped in this MA constitutes one of the most robust datasets arguing against chemoprophylaxis for prevention of CNS relapse in patients with LBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Radiotherapy for Secondary CNS Lymphoma: Patterns of Utilization and Clinical Outcomes

Introduction: Secondary CNS lymphoma (SCNSL) is a challenging clinical scenario observed in 2-5% of non-Hodgkin lymphoma patients, without well-defined standard of care. We sought to understand the indications and outcomes of patients with SCNSL referred for radiotherapy (RT) at a tertiary cancer center. Methods: We analyzed 93 consecutive patients with SCNSL of aggressive B cell histology who received brain RT at Memorial Sloan Kettering Cancer Center between 1999-2021. Overall survival (OS) was estimated using the Kaplan-Meier method. Time to intracranial progression was estimated for patients with brain imaging at least 30 days after treatment start using competing risk analysis with death as a competing risk. Outcomes were considered from the start of RT. Patients were further analyzed by treatment intent and by the presence of leptomeningeal disease (LMD), defined radiographically or by cerebrospinal fluid analysis. Results: Median age was 63 (interquartile range [IQR]: 51-70). 9% of patients had CNS involvement at initial diagnosis. Histologies included diffuse large B cell (76%), mantle cell (7%), post-transplant lymphoproliferative disorder (7%), Burkitt (5%), Richter's transformed CLL (4%), lymphoblastic lymphoma (1%). 55% of patients received R-CHOP and 12% received R-EPOCH as initial therapy, and 25% received CNS prophylaxis. 21 (23%) patients received RT as their initial SCNSL treatment. Of the 72 (77%) patients who received CNS-directed systemic therapy for SCNSL prior to brain RT, 88% received a methotrexate (MTX)-based regimen. Median time interval between MTX and RT was 32 days (IQR: 15 - 82). 86 (92%) of patients received whole brain (WBRT) and 7 (8%) received partial brain RT. Median RT dose was 30 Gy (IQR: 23.4-30). 3 patients received craniospinal irradiation (CSI). Median OS for the entire cohort was 2.9 months. Median OS differed by RT treatment intent as follows: consolidation after complete response to systemic therapy (61.7 months, n=8), RT bridging to hematopoietic cell transplantation (HCT) (not reached, n=7), RT bridging to CAR-T (5.7 months, n =3), RT salvage after progression or intolerance of systemic therapy (2.5 months, n = 54), RT as initial SCNSL treatment typically in an emergency or palliative setting (1.2 months, n=21) (p < 0.0001). Across the full cohort, median OS was longer for patients without evidence of LMD at the time of RT (6.3 vs. 1.7 months, p < 0.0001). Among patients with LMD at SCNSL diagnosis, those who cleared LMD by the time of RT had longer median OS than those with persistent LMD (8.3 vs. 2.2 months, p = 0.014). The estimated 3-year risk of intracranial failure after salvage RT was 35 ± 11% for patients without LMD and was not evaluable for patient with LMD at salvage as all patients' treatment failed or the patients died by 4 months. Conclusion: SCNSL remains a clinical challenge and patients referred for brain RT have overall poor prognosis. However, the subset of patients who receive RT as consolidation or bridge to HCT can achieve long term survival. The presence of LMD at RT is prognostic for inferior survival. For SCNSL patients without LMD, intracranial disease control after salvage RT is possible. Alternate treatment strategies including broader consideration of CSI for persistent LMD are warranted. Further identification of clinical, anatomic, and molecular subtypes of SCNSL that impact treatment response will help to clarify optimal treatment strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Grade B Cell NHL Outcomes: Real World Experience from the UK

Incidence of non-Hodgkin lymphoma (NHL) is increasing; it is already the sixth most common malignancy in UK (Cancer Research UK NHL incidence statistics 2022). It can present in aggressive or indolent form. Whilst for those with chemo-sensitive disease prognosis is good, with 5 year overall survival (OS) >50%, those with relapsing/refractory (R/R) forms have consistently poor outlook. Historically only 30-40% of these tolerate/respond to salvage therapy with <30% of those who respond able to proceed to consolidation with autologous stem cell transplant (ASCT). Despite this ~50% will relapse (Crump et al, Blood 2017 doi: 10.1182/blood-2017-03-769620). Recent treatment advances seek to address this area of unmet need. CAR-T cell therapy is presented as a highly effective solution for this cohort of patients. The pivotal studies leading to licensing and widespread adoption of these therapies drew comparison from SCHOLAR-1 which pooled data from 2 phase 3 clinical trials and 2 observational cohorts enabling data on 636 patients with refractory NHL to be analysed. There are challenges with this dataset and notably it does not include UK patients. We analysed patient level data for a UK NHL cohort and compare these to other, more historical data sets. 165 patients were identified. Diagnoses included primary DLBCL, DLBCL-transformed follicular lymphoma and PMBCL. Demographics: 92 male, 73 female; median age 64 (24-86yrs). Stage at diagnosis: I 10.3%, II 13.3%, III 21.2%, IV 54.5%, unknown <1%. IPI: 0- 2.4%, 1 - 13.3%, 2 - 27.3%, 3 - 26.7%, 4 - 18.8%, 5 - 3.6%, unknown 7.8%. C-MYC present in 20.7% of those where evaluated (24/116); of those 41.7% (10) double hit, 12.5% (3) triple hit. Cell of origin available for 54.5% (ACB 36.7%, GCB 63.3%). >90% considered suitable for intensive therapy; PS: 0 - 43%, 1 - 33.9%, 2 - 12.7%, 3 - 9.1%, 4 - <1%, unknown 4.2%. Nearly 2 thirds required >1 line treatment: 1 - 37%, 2 - 33.3%, 3 - 20.6%, 4 - 6.1%, 5 or greater - 3%. First line: 57.6% (95/165) 6-8 cycles R-CHOP (22% also received CNS prophylaxis - HD or intrathecal methotrexate, 16.8% additional radiotherapy (IFRT)); 10.3% abbreviated R-CHOP +/- IFRT; 9.7% dose attenuated R-CHOP, 16.4% R-CODOX-M/R-IVAC, 4.8% R-mini-CHOP, 1.8% non-intensive regimes and <1% IFRT alone. Best response was CR 52.7%, PR 11.5%, SD 13.3%, PD 11.5%, not available 10.9%. 63% (104/165) required second line treatment; time to treatment ranged from <6 months (27.9%), 6-12 months (32.7%), >12 months (37.5%), unknown in 2 cases. PS at first relapse: PS 0 - 36.6%, 1 - 45.5%, 2 - 7.1%, 3 - 7.1%, 4 - <1%. 35.6% with refractory disease had improvement in PS with treatment despite suboptimal response. 7.1% were considered too frail for further treatment. Second line therapy was primarily platinum based +/- IFRT +/- HD Mtx 71.2%; other intensive regimes included R-IVE, R-DHAP, R-ESHAP, R-CHOP and MATRIX (11.5%), less intensive regimes included R-lenalidomide, R-BP, R-miniCHOP, R-CVP, IFRT and R-CEPP (17.3%). Best response was CR 24.0%, PR 18.3%, SD 7.7%, PD 44.2%, not evaluated 5.8%. 31.7% proceeded to ASCT, 6 required >1 line of salvage therapy prior to ASCT. Exclusion basis: refractory disease 26.3%, declining PS and suboptimal response 7.5%, age only (>72years) 8.75%, frailty (PS > 2 - treatment induced/ comorbidities) 16.25%, age and frailty 13.75%, failed harvest 6.25%, patient choice 6.3%. 22 (66.6%) achieved CR after ASCT. 45 had suboptimal response to ≥2 lines intensive therapy but maintained fitness and would have been eligible for CAR-T. 47% (49/104) of those requiring salvage therapy proceeded to third line, 38.8% had refractory disease requiring treatment within 12months of first salvage treatment. 14.3% (7/49) had received ASCT. 57.1% (28/49) received intensive therapy, 18.4% (9/49) proceeded to ASCT. 42.9% were treated non-intensively. This UK dataset, analysing real world experience, highlights the challenge of high grade NHL. Whilst OS is: 2 year 63%, 5 year 29.1% with an additional 4.2% and 27.9% alive but <2 and <5 years from diagnosis respectively, for those with R/R disease OS is significantly reduced: 2 year 35.8%, 5 year 21.8%. CR rate after first line is 53.9%. However, 63% of patients required second line treatment; 4.8% relapsed >12months, 33.3% refractory; objective response rate (ORR) 42.3% (CR 24.0%), 35.8% alive at 2 years, 21.8% at 5 years. This is comparable to results from the referenced SCHOLAR-1 study supporting it as a reference point for new therapies.

Combination of Phosphodiesterase 4 (PDE4) Inhibitor Roflumilast and R-CHOP As First-Line Therapy for High-Risk Diffuse Large B Cell Lymphoma Patients

BACKGROUND PDE4 inhibition is a biologically well-informed strategy with activity in B-cell malignancies including diffuse large B-cell lymphoma (DLBCL) (PMID: 15331441, PMID: 26503641). Roflumilast (R) is a PDE4 inhibitor, currently FDA-approved for COPD (PMID: 26338438 ). Building on preclinical and clinical activity of R in B-cell lymphomas, both alone and in combination with other agents (PMID: 27756749); a phase 1 evaluation was conducted, adding R to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with untreated high risk DLBCL. METHODS: This is a single center, phase 1b, open label, non-randomized, single arm, investigator initiated trial (IIT) of R + R-CHOP (RR-CHOP) for treatment naïve high-risk DLBCL patients. Key eligibility criteria included: non-GCB DLBCL (Han's algorithm), NCCN-IPI risk score of ≥ 2, Ann Arbor stage II-IV; key exclusion criteria include active CNS involvement and documented history of severe depression (a specific concern related to the use of PDE4 inhibitors). Patients received R-CHOP every 21 days for 6 cycles and R PO daily (500 mcg), throughout the 18-week treatment period. Paired germline-tumoral exome sequence was completed for 70% of patients enrolled in the trial, and DLBCL genetic subtype defined by the probabilistic classification tool LymphGen (PMID: 32289277). Primary end point was assessment and grading of adverse events (AE) according to the CTCAE version 4.03 criteria. Eligible patients were included in the intent-to-treat analysis. Secondary end points were estimation of complete response (CR) as per Lugano criteria, progression free survival (PFS), overall survival (OS) and their relationship to DLBCL genetic subtypes. RESULTS: Ten patients met eligibility criteria for enrollment. Sixty percent were male, 50 % were Hispanics (HI), median age at diagnosis was 59 years old (y.o) (33 y.o-79 y.o), 50% were stage 2, and 50% were stage 3-4; 50% received CNS prophylaxis given high risk and 70% had International Prognostic Index (IPI) scores of 3 to 5. Standard doses of R-CHOP were able to be delivered safely, with addition of 500 mcg of R on daily basis. Regarding hematologic adverse events (AE); 1 patient (10%) experienced neutropenia grade 3, and two patients (20%) had neutropenia grade 2. Anemia occurred in 2 patients (20%), all grade 1-2. Regarding non-hematologic AE; anorexia occurred in 40% of the cohort, all grade1; diarrhea occurred in 50%, all grade 1; headache occurred in 60%, with 40% being grade 2, and 20% being grade 3, with the latter judged to be unrelated to RR-CHOP by the investigators. Forty percent had grade 1 increase of BNP; 40% of patients had nausea, 30% being grade 1-2, and 10% being grade 3; and 40% experienced weight loss, all grade 1-2. Of 10 enrolled patients, 9 were found evaluable for assessment of efficacy, with 66% achieving CR, 22% partial response and 11 % stable disease. At 50 months of follow up, PFS was 60% at 1 year (y) and 50% at 2 y. Median PFS was not reached. OS was 100% at 1 y and 86% at 2 y, with a median OS of 38.9 months. (Figure 1 and Figure 2). The recommended R dose for phase 2 is 500 mcg PO daily. LymphGen assigned the DLBCLs in this cohort to the A53, MCD, EZB and B2N subtypes. Notably, 3 of the 3 DLBCLs in our cohort classified as MCD or A53 DLBCLs, which normally predict poor outcome, reached CR and are long term responders. Examination of 461 primary DLBCLs (NCBI dbGaP Genomic Variation in DLBLC cohort) uncovered significantly higher PDE4B expression in in the MCD subtype, suggesting that addition of R may be particularly beneficial in this DLBCL subset. CONCLUSION: Phosphodiesterase Inhibition in DLBCL is a well biologically informed strategy with the potential to enhance and perhaps optimize the duration of responses to R-CHOP. On this difficult to treat subgroup of non-GC DLBCL, with known subpar outcomes, RR-CHOP demonstrated to be safe, with manageable AEs that did not differ from what we have historically seen with R-CHOP alone. Early efficacy data from this combination shows 10% improvement compared to our own institutional historical controls of treatment naïve non-GC DLBCL patients treated with R-CHOP. Based on this data, we are pursuing a phase 2 multisite IIT of RR-CHOP in patients with newly diagnosed high risk DLBCL. Despite the small size cohort, our data suggest that tailoring this strategy to the poor outcome MCD/A53 genetic subgroups may increase the likelihood of success. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prophylaxis strategies containing high dose intravenous methotrexate on preventing CNS relapse for patients with diffuse large B-cell lymphoma at intermediate to high risk: A study based on 12 cohorts in the rituximab era

During the Rituximab era, high dose intravenous methotrexate (HD) and intrathecal methotrexate (IT) are recommended prophylaxis in preventing central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) patients. However, the optimal CNS prophylaxis strategies remained uncertain. This meta-analysis research explored the findings of previous studies and highlighted the efficacy of HD and/or IT on CNS prophylaxis of DLBCL patients at intermediate to high risk. Specifically, it aims to answer the following research questions: (1) Is there a difference on CNS relapse rate between HD and IT cohorts? (2) Is there a correlation between CNS prophylaxis and survival? This meta-analysis research performed an in-depth examination of pertinent studies available in PubMed, Embase, and Cochrane databases. The primary endpoints included: CNS relapse rate and 2-year or 3-year survival rate. The findings of the qualified studies were reviewed and analyzed using 5.3 version of the Review Manager software. After thorough analysis of 12 studies involving 5950 DLBCL patients, it was revealed that in comparison with IT alone, HD with or without additional IT (HD ± IT) significantly reduced the risk of CNS relapse (Risk Ratio (RR)= 0.41, 95 % CI (0.24–0.68), P = 0.0007). Besides, the efficacy of HD alone was comparable to HD + IT (RR = 1.08, 95 % CI (0.19–6.32), P = 0.93), which was also considered to be more optimal than IT alone on CNS prophylaxis (RR = 0.39, 95 % CI (0.15–1.06), P = 0.06).Based on these results, IT alone or no-prophylaxis were viewed as a group of inadequate prophylaxis. Comparing to HD ± IT, the 3-year survival rate of inadequate prophylaxis group was lower (RR = 1.17, 95 % CI (1.03–1.32), P = 0.01). The results of this study reveals that in the Rituximab Era, prophylaxis strategies containing HD is better than IT alone or no-prophylaxis on preventing CNS relapse of DLBCL patients with intermediate to high risk.

Outcomes of high‑dose methotrexate for CNS prophylaxis in diffuse large B‑cell lymphoma with an intermediate or high CNS‑International Prognostic Index: A single‑center retrospective cohort study.

Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is rare (2-5% of cases), but is a devastating complication with a poor survival rate. The administration of high-dose methotrexate (HDMTX) for CNS prophylaxis in patients with DLBCL is controversial and variable in the literature. The present study aimed to evaluate the clinical outcomes of HDMTX CNS prophylaxis in patients with intermediate and high CNS-International Prognostic Index (IPI) DLBCL using real-world data. An observational retrospective cohort study was conducted of all patients with intermediate and high CNS-IPI DLBCL treated at Princess Noorah Oncology Center (King Abdulaziz Medical City, Jeddah, Saudi Arabia) between January 2010 and December 2020. Patients were treated with HDMTX either intravenously or intrathecally, according to the physician's evaluation of the patient. Data on patient clinical characteristics, CNS relapses, risk factors and survival rates were obtained from hospital records. Data were analyzed using Student's unpaired t-test and the χ2 test to compare the two subgroups, the Kaplan-Meier survival method with log-rank test to calculate and compare the survival rates, and regression analysis to determine the risk factors for CNS relapse and death. The study included 358 patients (n=32 with HDMTX CNS prophylaxis and n=326 without CNS prophylaxis). Patients in the CNS prophylaxis group had a significantly higher CNS relapse rate than those in the non-CNS prophylaxis group (12.5% vs. 1.8%; P=0.008). Patients who received CNS prophylaxis were younger and had an advanced stage of disease, with extranodal involvement and a high serum lactate dehydrogenase level at presentation. CNS prophylaxis was significantly associated with CNS relapse, while relapsed disease was associated with the risk of death (all P<0.05). In conclusion, the present study found that patients with intermediate and high CNS-IPI who received HDMTX CNS prophylaxis did not have fewer CNS relapses; however, those without CNS relapse had higher survival rates. In addition to CNS prophylaxis, Stage of DLBCL and IPI were significantly associated with CNS relapse. Future randomized control trials are needed to evaluate the efficacy of HDMTX CNS prophylaxis in patients with DLBCL.

Low Incidence of Central Nervous System (CNS) Relapse of Diffuse Large B-Cell Lymphoma despite Limited Use of Intrathecal Prophylaxis

Diffuse large B cell lymphoma (DLBCL) is the commonest sub type of non-Hodgkin's lymphoma (NHL) accounting for 30–50 % of NHL cases. Around 2% to 10% of patients with diffuse large B-cell lymphoma (DLBCL) experience central nervous system (CNS) relapse after initial therapy which is associated with a poor prognosis and most often a fatal outcome. The incidence of CNS relapse can vary from <1% in younger, good-risk patients, to around 30% in patients with multiple risk factors, however, the relapse risk was reported to be lower in the rituximab era in some studies. Moreover, optimal modality of CNS prophylaxis remains to be defined, with both systemic and intrathecal (IT) chemotherapy being widely used. As the incidence of CNS relapse and type of prophylaxis used varies in different reports, it is important to study this risk in different populations to implement optimal prophylaxis strategies. The Objectives of this study was to evaluate the incidence of CNS relapse in DLBCL patients at our institution and to study risk factors and the type and role of CNS prophylaxis. We retrospectively analyzed patients diagnosed with DLBCL at King Khalid University Hospital, Riyadh, from January 2011 to June 2019. Data were collected from computerized hospital information system and from the files of the patients. Variables studied included age at diagnosis, stage at diagnosis, international prognostic index (IPI) and CNS-IPI score, site(s) of extra-nodal involvement, type of chemotherapy received, CNS prophylaxis and CNS relapse. CNS prophylaxis was administered on the basis of presence of high-risk features like presence of ≥2 extranodal sites, involvement of bone marrow, bone, testes, nasopharynx and paranasal sinuses. Patients with presence of CNS involvement at diagnosis and primary CNS lymphoma were excluded. A total of 101 patients were diagnosed with DLBCL during the study period. There were 58 males and 43 females with a median age of 56 (range: 16-87) years. Ann Arbor stage of I-IV was assigned in 9, 21, 17 and 50 patients, respectively. The lung was the most common extranodal site involved in 27 (26.7%) patients, and liver and bone marrow involved in 20 (19.8%) patients each. Gastrointestinal tract was involved in 9 (8.9%) patients, kidneys in 5 (4.95%), breast in 4 (4%), and testis and adrenal in 2 (2%) patients each. Twenty-five (24.75%) patients had high risk CNS-IPI score, 44 (43.5%) had intermediate risk score and 32 (31.7%) had low risk score. Ninety-four (93%) patients received R-CHOP chemotherapy while rest of the patients received other types of chemotherapy, mostly a milder regimen (R-CVP), because of comorbidities and poor performance status. Sixteen patients received CNS prophylaxis, which was IT methotrexate (MTX) ± cytarabine/hydrocortisone in all patients. Nine of 25 (36%) patients with high-risk CNS-IPI score did not receive CNS prophylaxis. After a median follow up of 36 months (range 4-114), 2 (2%) patients developed CNS relapse and died shortly after this diagnosis. Both the patients with CNS relapse had high risk CNS-IPI score and did not receive CNS prophylaxis. CNS relapse of DLBCL was uncommon in this patient population despite limited use of IT CNS prophylaxis in high-risk patients. Low incidence of CNS relapse in many high-risk patients despite limited use of IT prophylaxis may be related to rituximab use and/or other factors. Our data indicate that IT CNS prophylaxis may be adequate for DLBCL patients at high risk of CNS relapse.

ABCL-455 Multicenter Retrospective Analysis of Single-Route Prophylaxis in Aggressive B-Cell Lymphomas

Relapses involving the central nervous system (CNS) are uncommon among patients with diffuse large B-cell lymphoma (DLBCL) but carry very poor prognosis. Prophylaxis is heterogeneously prescribed around the time of frontline therapy, with no clear standard of care in terms of recipient selection or route of administration. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline chemoimmunotherapy between 2013-2019. Primary endpoint was CNS relapse rate. Secondary endpoints included PFS, OS, and treatment-related toxicities following frontline and salvage therapies. Prophylaxis was administered intrathecally (IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7 %) had CNS relapse, after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4 vs 6.8%, p=0.40), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected versus observed CNS relapse rates were nearly identical (5.8 vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. Median OS following CNS relapse was 6.2 months (IQR 2.9-24.6) and was significantly shorter among patients achieving less than CR to first salvage therapy (HR 3.39, 95% CI 1.76-6.54, p=0.0003). Additional analyses of outcomes following CNS relapse will be presented. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated; treatments following CNS relapse were heterogeneous, with poor outcomes for the vast majority of patients. Reconsideration of SCNSL prophylaxis and treatment strategies is of critical need.

ABCL-398 Primary Breast Diffuse Large B-Cell Lymphoma: An Indian Experience

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare site of localized extranodal DLBCL. It represents 0.5% of all primary malignant neoplasms of the breast and around 2% of extranodal lymphomas. There is a paucity of data regarding the clinicopathologic characteristics, cell of origin, response, and outcome of treatment with uniform treatment protocol in patients from India diagnosed with PB-DLBCL. This was a retrospective study of 18 consecutive cases of PB-DLBCL registered at All India Institute of Medical Sciences between 2006 and 2021 treated with uniform 3x weekly cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) ±rituximab (R) with involved-field radiotherapy. The patients were classified as germinal center B-cell-like or activated B-cell (ABC) type using the Hans classification. The median age was 43 (21-67) years with a male:female ratio of 1:17. All the patients presented with a breast lump with a median tumor size of 5 cm. The right side was involved in 11 (61.1%) cases. Eight patients were diagnosed with lumpectomy, 9 patients with biopsy, and one patient with mastectomy specimen. Out of 18 patients, Ann Arbor: Stage I was seen in 6 (33.3%) patients, Stage IIE in 11 (61.1%) patients, and Stage 1V in 1 (5.5%) patient. B-symptoms and bulky disease were seen in 6 (33.3%) and 7 (38.8%) patients, respectively. Cell of origin data were available in 14 patients, and 11 (71.4%) were ABC in origin. Low- and intermediate-risk International Prognostic Index was seen in 42% and 48% of patients, respectively. The median number of chemotherapy cycles was 4 (3-6), rituximab was used in 10 (55.5%) cases, and CNS prophylaxis with intrathecal methotrexate was used in 10 (55.5%) cases. The complete response rate was 83.3%. After a median follow-up of 42 months, the 3-year progression-free survival and overall survival were 75% and 88%, respectively. The most common site of relapse (n=3) was parenchymal brain disease. Multimodality combination therapy (chemotherapy, immunotherapy, and radiation) can give good survival with PB-DLBCL but adding high-dose methotrexate to existing protocol needs further exploration.

AML-394 Tagraxofusp in Blastic Plasmacytoid Dendritic Cell Neoplasm With/Without Central Nervous System Involvement and Intrathecal Chemotherapy as Primary Treatment or Prophylaxis: An Italian Experience

The precise frequency of central nervous system (CNS) involvement in blastic plasmacytoid dendritic cell neoplasm (BPDCN) is currently unknown. Recent data suggest it may be ~10% at baseline and 30% at first relapse. CNS is a 'sanctuary' for systemic treatment and can lead to disease recurrence even after the achievement of a complete response (CR) at the medullary and skin level. Ensuring complete meningeal disease clearance is essential, and combining intrathecal (IT) chemotherapy with systemic treatment is a promising approach. Tagraxofusp (TAG, SL-401) is a first-in-class therapy targeting CD123, a molecule that is overexpressed in BPDCN. TAG, available in the US and Europe, is the only approved drug for patients with BPDCN. To determine whether CNS prophylaxis/treatment impacts the prognosis and efficacy of systemic TAG treatment in patients with BPDCN. Retrospective single-center chart review. Patients with BPDCN, with (CNS+) or without (CNS-) CNS involvement. Patients received TAG intravenous infusions at 12 mcg/kg daily on days 1-5 of a 21-day cycle. Intrathecal (IT) chemotherapy (cytarabine and dexamethasone ± methotrexate) was administered in combination with TAG at each cycle as prophylaxis (CNS-) or primary-intention treatment (CNS+). Assessments included CNS response, tumor response, survival, and adverse event (AE) monitoring. Data were collected on 5 patients (n=3 CNS+, n=2 CNS-); all received TAG as first-line therapy. The median number of TAG cycles was 3 (range 1-4). All 3 patients with CNS+ disease achieved CNS complete response (CR), and none reported CNS relapse. In patients receiving CNS prophylaxis, 1 patient received TAG plus HSCT and is in CR after 29 months; another received high-dose chemotherapy, achieved a good partial remission after TAG, and remains alive after 4 months with HSCT shortly planned. No AEs associated with IT chemotherapy were reported. These preliminary results confirm the feasibility of IT chemotherapy in combination with systemic TAG therapy. Baseline CNS involvement did not appear to impact the efficacy or safety profile of TAG. IT chemotherapy and TAG effectively cleared and controlled CNS involvement. IT prophylaxis should be considered in patients with BPDCN who receive CD123-targeted therapies.

AML-173 Pseudotumor Cerebri (PTC) in Patients With Acute Leukemia (AL)

Pseudotumor cerebri (PTC) is characterized by headache, vision changes, and fundus papilledema. Primary PTC is often seen in obese women (childbearing age) and secondary with medications such as all-trans retinoic acid (ATRA). We analyze clinical presentation, and outcomes of PTC in patients with acute leukemia (AL) treated at a general hospital. Single-center retrospective study. We reviewed cases of AL patients with PTC at Memorial Hermann Hospital, Texas Medical Center between January 2013 and April 2022. Three (2.3%) of 127 patients (AML=85, APL=29, ALL= 13) had PTC. Fit non-APL patients received induction chemotherapy (IC) with purine analogs-cytarabine-anthracycline. Unfit patients received a hypomethylating agent and venetoclax. APL patients received IC with arsenic trioxide and ATRA. Patients suspected of having APL were started on ATRA, and discontinued with a negative PML-RARA FISH test. We describe the incidence, risk factors, clinical presentation, and outcomes of AL patients with PTC. Mean age was 42 years. Mean BMI was 42. All were white women. Two had AML, and one Philadelphia chromosome-positive ALL. AML patients received 3 doses of ATRA discontinued after negative PML-RARA FISH. One AML patient had PTC at presentation. The other developed PTC 3 months later. One AML patient had PTC 30 years before being treated for 6 months with acetazolamide; PTC recurred 3 months after her diagnosis. All patients had headaches, blurry vision, and papilledema with brain MRI showing optic sheath distension, globe flattening, and papilla cupping, all features suggestive of PTC. In two, the opening lumbar puncture pressures were elevated at 30 and 35 cm H2O. Cerebrospinal fluid cytology and flow cytometry were negative for leukemia. Two patients (AML=1, ALL=1) received intrathecal (IT) chemotherapy for CNS prophylaxis. All patient's symptoms improved with acetazolamide. LP done for IT chemotherapy helped to alleviate symptoms. No patient with APL (29 patients) developed PTC during treatment with ATRA. PTC is a rare diagnosis that can complicate the clinical course of AL patients. In addition to ATRA-induced PTC, clinicians should consider primary PTC, seen most often in morbidly obese women of childbearing age.

Abstract A15: Clinico-pathologic and molecular characteristics of primary extranodal germinal-center B-cell like diffuse large B-cell lymphoma (EN GCB-DLBCL)

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and in 30-40% cases can present or relapse at extranodal sites. Primary extranodal DLBCL (EN-DLBCL) is defined as disease presenting as clinically dominant extranodal masses with no or only minor nodal disease. EN-DLBCL is predominantly of the activated B-cell (ABC) and less commonly of germinal center B-cell (GCB) like DLBCL subtype. We aimed to identify genetic characteristics of EN GCB-DLBCL to gain insights into extranodal tropism and aggressive clinical behavior. Methods: Patient data was collected via retrospective chart review. Inclusion criteria consisted of pathologically confirmed diagnosis of GCB-DLBCL by the Hans algorithm, extra-nodal involvement at diagnosis or relapse, and availability of next-generation sequencing (NGS). Overall (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. Results: Fifteen patients were identified. The median age at diagnosis was 64 years (range 33-89) and majority were men (62.5%). Two patients had purely nodal disease at presentation that relapsed at EN sites, while the remainder (13/15) had predominantly EN disease. EN sites included central nervous system [CNS] (n = 5), bone marrow (n = 4), epidural (n=4), bone (2), paranasal sinus (1), testes (1), stomach (n = 2), lung/pleura (n=2), and liver (n=3). Nine patients had disease in multiple EN sites. All patients had advanced stage disease and median IPI score was 3 (range 3-4). On FISH/cytogenetic analysis, two patients had MYC and four patients had BCL2 rearrangements. Copy gains in BCL6, BCL2 and MYC were seen in 2, 1 and 4 patients respectively. No patients had evidence of MYC and BCL2 and/or BCL6 rearrangements (double hit). TP53 deletion was seen in 1 patient. On NGS, prominent gene mutations identified were KMTD2 (8/15, 53%), TP53 (5/15, 33%), TNFRSF14 (4/15, 27%), and evidence of aneuploidy with abnormalities in chromosome 12 (5/15, 33%), chromosome 6 (4/15, 27%), and chromosome 8 (4/15, 27%), including both losses and gains of function. Notably, MYD88 (3/15, 20%), CARD11 (2/15, 13%), and IRF4 (2/15, 15%) mutations, representative of BCR/TLR4 pathway activation and NF-kB signaling were seen at initial presentation. All patients were treated with chemo-immunotherapies incorporating CNS prophylaxis and 2 patients received salvage CAR T-cell therapy. Median OS was 1.3 years and median PFS was 11.3 months. Nine patients (63%) progressed, with CNS relapses in 5 and of these, 7 patients died. Conclusions: This study shows that EN GCB-DLBCL is molecularly similar to EN ABC-DLBCL; specifically, activation of NF-kB pathway signaling through gene mutations involving the MCD (MyD88/CD79B) cluster is prominent, and this potentially enables extranodal tropism. The complex karyotype and TP53 mutations may contribute to chemoresistance and aggressive disease biology. Our results provide valuable molecular information and can aid in personalizing treatment strategies for this uncommon, aggressive DLBCL subset. Citation Format: Akshat Patel, Brian Lue, Kiran A Kumar, Farrukh T Awan, Jeffrey Gagan, Weina Chen, Praveen Ramakrishnan Geethakumari. Clinico-pathologic and molecular characteristics of primary extranodal germinal-center B-cell like diffuse large B-cell lymphoma (EN GCB-DLBCL) [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A15.

Prophylactic Central Nervous System Irradiation Is Not Indispensable in Adult Patients with Acute Lymphoblastic Leukemia: A Multicenter Retrospective Cohort Study

Objective:Studies comparing the efficacy and safety of prophylactic regimens for central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL) are scarce in adults. This multicenter retrospective study aimed to compare the efficacy of prophylactic regimens with and without CNS irradiation on the development of CNS relapse during follow-up.Materials and Methods:This was a multicenter comparative cohort study. A total of 203 patients were included from four tertiary care centers in Turkey. Patients were divided into two groups according to whether they received CNS irradiation or not. The groups were analyzed retrospectively regarding patient and disease characteristics, with the main focus being CNS relapse.Results:While 105 patients received chemotherapy-based prophylaxis, 98 patients received additional CNS irradiation. These groups were statistically comparable in terms of demographic characteristics and risk factors for CNS involvement. In the irradiation group, patients were younger and had more stem cell transplants. In a median of 23.8 (11.1-62.4) months, there was no difference between the two groups regarding CNS relapse-free survival (log-rank p=0.787).Conclusion:Craniospinal irradiation may not be indispensable for every adult patient with ALL, similarly to pediatric patients. It is crucial to avoid the long-term toxicities of radiation, especially in patients with long life expectancy. Craniospinal irradiation may be reserved for therapeutic use in cases of CNS relapse and prophylaxis for some high-risk patients.

Diffuse large B-cell lymphoma: a consensus practice statement from the Australasian Lymphoma Alliance.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for 30-40% of lymphoma diagnoses. Although aggressive, cure is achievable in approximately 60% of cases with primary chemoimmunotherapy, and in a further substantial minority by salvage therapy and autologous stem cell transplantation. Despite promising activity in early phase clinical trials, no intensified or novel treatment regimen has improved outcomes over R-CHOP21 in randomised studies. However, there remain several areas of controversy including the most appropriate prognostic markers, central nervous system prophylaxis and the optimal treatment for patients with high-risk disease. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice.

P353: FORTY MONTHS UPDATE OF THE GIMEMA LAL2116 (D-ALBA) PROTOCOL AND ANCILLARY LAL2217 STUDY FOR NEWLY DIAGNOSED ADULT PH+ ALL

Background: The outcome of adult Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients greatly improved since the introduction of tyrosine kinase inhibitors (TKIs). A further improvement was achieved with a chemo-free induction/consolidation strategy based on the sequential administration of dasatinib followed by blinatumomab - the D-ALBA GIMEMA LAL2116 trial - with overall survival (OS) and disease-free survival (DFS) rates of 95% and 88% at 18 months (Foa et al, NEJM 2020). Aims: To provide an updated follow-up of the D-ALBA trial and to document the long-term management of previously enrolled patients. Methods: In the D-ALBA trial, after the primary endpoint, patients were followed for 12 months. Data on subsequent treatment and survival are being collected in the ancillary study GIMEMA LAL2217. Results: As reported, 63 patients were enrolled (median age 54 years, 24-82; no upper age limit); the median follow-up is 40 months (0.9-62.5). Since enrollment in the D-ALBA trial, 9 relapses have been documented: 4 hematologic (1 major protocol deviation and 1 in an 82-year old woman who rapidly went off study), 4 at CNS and 1 nodal; median time to relapse was 4.4 months (1.9-25.8). Six deaths were recorded (3 post-allogeneic transplant) in 1st complete hematologic remission (CHR). Of the 58 patients who started blinatumomab, 29 continued treatment with TKI: 21 with dasatinib (85% after receiving all 5 cycles of blinatumomab), 2 switched to imatinib due to intolerance (all after the 5 cycles of blinatumomab) and 5 switched to ponatinib for a molecular minimal residual disease increase or medical decision (66% had received all 5 cycles of blinatumomab). Twenty-nine patients were allografted, including 6 patients in 2nd CHR: 9 from a sibling, 13 from an unrelated donor, 6 from a haploidentical donor and 1 from a cord blood. Six transplants were performed in 2nd CHR. Before transplant, 8 patients received 2 and 3 cycles of blinatumomab, respectively, 5 4 cycles and 6 5 cycles (2 patients were allografted after 1 cycle). Among grafted patients, 6 deaths occurred, 3 of which in cases transplanted in 2nd CHR; thus, the transplant-related mortality in 1st CHR is 10%. When considered in a covariate model, transplant did not impact on both OS and DFS; similar results were obtained also considering allograft only in 1st CHR. It must, however, be underlined that the allografted population was enriched in cases who did not achieve a molecular response (23 pts). Further investigation is ongoing on this aspect. In the updated follow-up, the estimated 48 months OS is 78% (95% CI: 66-92%) and the DFS is 75% (95% CI: 64-87%). DFS was significantly better in patients achieving a molecular response upon induction than in those who did not (100% vs 67%, p=0.016, Fig. 1A), with no events recorded in the group of complete molecular responders and positive-not-quantifiable cases. Furthermore, we confirmed the inferior DFS for patients carrying an IKZF1plus genotype compared to that of cases with no IKZF1 deletions/IKZF1 deletions alone (85% vs 47%, p=0.012, Fig. 1B). Image:Summary/Conclusion: In the updated analysis of the D-ALBA trial and the ancillary GIMEMA LAL2217 study, with a median OS of 40 months, we confirm the reported very favorable outcome. Among the few relapsed cases, we observed a rather high incidence of CNS involvements. These results represent the scientific rationale for the ongoing phase 3 GIMEMA LAL2820 trial, where dasatinib has been substituted by ponatinib, CNS prophylaxis has been increased, and transplant allocation is based on genomic features and minimal residual disease monitoring.

PB2122: THE EFFICACY OF THE STANDARD AND INTENSIVE CHEMOTHERAPY IN ELDERLY PATIENTS WITH DOUBLE- AND TRIPLE-EXPRESSOR LYMPHOMA.

Background: Overexpression of c-myc and bcl-2 and/or bcl-6 in diffuse large B-cell lymphomas, defined as double-expressor lymphoma (DEL) and triple-expressor lymphoma (TEL), are considered to have a poor prognosis. These patients using intensified chemotherapy have been tried to achieve therapeutic efficacy and prolong their prognosis. Although several clinical data have been reported, the requirement of intensive chemotherapy, including dose-adjusted R-EPOCH (DA-R-EPOCH), for DEL and TEL is still controversial. Primarily, there seems to be insufficient analysis in elderly patients over 70 years old, which is the preferred age for malignant lymphoma. Aims: To reveal the efficacy of dose-intensifying regimens in managing DEL and TEL, we analyzed data comparing the outcomes of R-CHOP and DA-R-EPOCH as frontline therapy. Methods: We retrospectively analyzed the 37 of DEL and TEL patients diagnosed from January 2017 to December 2021 using R-CHOP versus more intensified treatment, DA-R-EPOCH. Formalin-fixed and paraffin-embedded tissues were constructed for immunohistochemistry (IHC). Statistical analyses were performed using the Kaplan-Meier method and log-rank test. Univariate and multivariate analyses were conducted via the Cox proportional hazards model, and it took p values lower than 0.05 to be significant. Results: The median age in the patients with DEL and TEL was 71.3 (range, 56-88). Moreover, the patients aged 70 years old over were 56 %. Twelve patients were diagnosed in DEL, and twenty-five patients were TEL, respectively. In DEL and TEL patients, twenty-one patients (60%) are received R-CHOP, and 14 patients (40%) were treated DA-R-EPOCH, respectively. The patients in Stage III-IV were 73%. GCB types were constituted 18 cases (48.6%). Fifteen patients (40.5%) diagnosed with DEL and TEL were received central nervous system (CNS) prophylaxis. The progression-free survival (PFS) was equivalent when comparing the TEL and DEL patients, respectively. Two-years PFS with R-CHOP vs DA-R-EPOCH for the overall population were 52.6% (95% confidence interval [CI], 21.7-76.2) vs 49.6% (95% CI, 14.8-77.3), respectively. The overall response rates and complete response rates for R-CHOP were 93% and 46%, and for DA-R-EPOCH were 90% and 60%, respectively (Figure A). Especially, over 70 years old patients with DA-R-EPOCH showed poor prognosis than DA-R-EPOCH in younger patients, although the PFS with R-CHOP has no difference between aged patients or not (Figure B). Furthermore, the patients with the drug discontinuation or dose reduction in DA-R-EPOCH treatment were tended to indicate poor PFS outcomes than the rest of the patients (Figure C). Image:Summary/Conclusion: Our finding is consistent with the fact that R-CHOP and R-EPOCH showed a similar prognosis in patients with DEL, and the association of aged TEL with intensive therapy confers earlier relapses of this variant DLBCL, requiring more appropriate treatment. It might be considered about the therapeutic approach for DEL and aged TEL patients whether required the intensive therapies or not.

Low lymphocyte-to-monocyte ratio predicts poor outcome in high-risk aggressive large B-cell lymphoma.

Low lymphocyte‐to‐monocyte‐ratio (LMR) has been associated with unfavorable survival in patients with diffuse large B‐cell lymphoma (DLBCL). To date, however, the impact of LMR on survival has not been examined in a uniformly treated cohort of patients with high‐risk aggressive large B‐cell lymphoma. We collected peripheral blood absolute lymphocyte counts (ALCs) and absolute monocyte counts (AMC) prior to treatment and calculated LMR from 112 adult patients, who were less than 65 years of age, had age‐adjusted International Prognostic Index 2–3, or site‐specific risk factors for central nervous system (CNS) recurrence, and were treated in a Nordic Lymphoma Group LBC‐05 trial with dose‐dense immunochemotherapy and early systemic CNS prophylaxis (www.ClinicalTrials.gov, number NCT01325194). Median pretreatment ALC was 1.40 × 109/l (range, 0.20–4.95), AMC 0.68 × 109/l (range, 0.10–2.62), and LMR 2.08 (range, 0.10–12.00). ALC did not correlate with tumor‐infiltrating lymphocytes, AMC did not correlate with tumor‐associated macrophages, and neither ALC nor AMC correlated with survival. However, low LMR (<1.72) translated to unfavourable progression‐free survival (PFS) (5‐year PFS 70% vs. 92%, p = 0.002) and overall survival (OS) (5‐year OS, 77% vs. 92%, p = 0.020). In the patients with low LMR, relative risk of progression was 4.4‐fold (95% confidence interval [CI] 1.60–12.14, p = 0.004), and relative risk of death was 3.3‐fold (95% CI 1.18–9.50, p = 0.024) in comparison to the patients with high LMR. We conclude that low LMR is an adverse prognostic factor in uniformly treated young patients with high‐risk aggressive large B‐cell lymphoma.

P1180: ARE EXTRANODAL LIMITED-STAGE DIFFUSE LARGE B-CELL LYMPHOMA MORE AGRESSIVE THAN NODAL FORMS?

Background: Limited-stage diffuse large B-cell lymphoma (DLBCL) is associated with favourable outcomes with overall survival of 70-80% at 10 years. Stage-modified IPI (sm-IPI) predicts the risk of relapse and death based on clinical factors that do not include extranodal (EN) involvement, although in some studies it has been associated with worse outcomes. Aims: To analyse the characteristics and outcomes of limited-stage DLBCL in a single center series and evaluate the prognostic impact of EN involvement. Methods: We conducted a retrospective analysis of consecutive patients with newly diagnosed stage I-II DLBCL treated with curative intent at a single centre from 2015 to 2019. Primary central nervous system (CNS) lymphoma, primary testicular lymphoma, primary mediastinal B-cell lymphoma and transformed lymphoma were excluded. Response to therapy was assessed according to Lugano criteria. Overall (OS) and progression free survival (PFS) were calculated by Kaplan-Meier method and comparisons done by the log rank test. Cumulative incidence of relapse was calculated using competing risk models and Gray test for group comparisons. Cox regression was used to identify prognostic factors for PFS. Results: Of 152 patients identified, 53 (35%) had EN disease and 99 (65%) were nodal (N). The most common EN sites were stomach (30%), sinus/nasal cavity (13%), skin and soft tissue (9%) and breast (9%). Seventy-two (47%) had low risk sm-IPI (45 N; 27 EN). Clinical characteristics were similar between both groups, except for stage (stage I in 50.9% of EN vs 32.3% of N cases) and bulky disease (EN 15.1% vs N 37.4%). All patients received R-CHOP (median 6 cycles; range 1-8). Eight patients, all with EN involvement (3 sinus/nasal cavity, 2 breast, 2 bone and 1 orbit), received CNS prophylaxis. Seventeen out of 152 patients received additional radiotherapy (RT), 71% of whom had nodal involvement; 16/17 were irradiated due to bulky disease and/or treatment with abbreviated immunochemotherapy. Globally, 89% patients had a complete response (CR) to treatment: 85% in the N and 96% in the EN group (p=0.212). Nine patients relapsed at a median of 18 (7-52) months after obtaining CR (6 from the N and 3 from the EN group). The 4-year cumulative incidence of relapse was similar: 11.2% (95%CI 9.0-13.9%) in EN and 6.7% (95%CI 5.9-7.5%) in N group (p=0.778). No gastric lymphomas relapsed. The most common sites of relapse were lymph nodes (3), soft tissue (3) and CNS (2). Nineteen (14 N; 5 EN) patients died at a median of 12 (0-47) months after starting treatment, mostly (52.6%) due to lymphoma progression. With a median follow-up of 43 months, 4-year OS and PFS were 87% and 82%, respectively. No significant survival differences were observed in patients with N or EN presentation with a 4-year PFS of 81.8% and 81.3% (p=0.428), respectively. On multivariable analysis adjusting for RT, sm-IPI and bulky disease, EN involvement was not associated with a decreased PFS compared with N involvement (HR 0.77; 95%CI 0.31-1.90; p=0.570). Image:Summary/Conclusion: Our study corroborates the very favourable outcomes of localized DLBCL. We could not find differences in PFS according to N and EN presentations when controlling for other prognostic factors. These results do not support different treatment strategies for EN disease; however, due to limited sample size the role of RT and the prognostic impact of specific locations cannot be fully ascertained.

High efficacy of intensive immunochemotherapy for primary mediastinal B-cell lymphoma with prolonged follow up

Primary mediastinal B-cell lymphoma (PMBL) is currently curable in 85–95% of patients. Treatment regimens frequently used include RCHOP ± radiotherapy, DAEPOCH-R, or occasionally more intensive protocols. Here we present results of treatment of 124 patients with PMBL over a period between 2004 and 2017 with the use of a protocol designed for aggressive B-cell lymphoma GMALL/B-ALL/NHL2002 including 6 cycles of alternating immunochemotherapy with intermediate-dose methotrexate in each cycle, and reduced total doxorubicin dose (100 mg/m2 for whole treatment). Majority of patients (77%) received consolidative radiotherapy. A median (range) age of patients was 30 (18–59) years, and 60% were female. With a median (range) follow up of 9 (1–17) years, 5-year overall survival (OS) and 5-year progression free survival (PFS) were 94% and 92%, respectively. Positron emission tomography—computed tomography (PET-CT) results at the end of chemotherapy were predictive for outcome: OS and PFS at 5 year were 96% and 94% in PET-CT negative patients, respectively, and 70% and 70% in PET-CT-positive patients (p = 0.004 for OS, p = 0.01 for PFS). Eight (6%) patients had recurrent/refractory disease, however, no central nervous system (CNS) relapse was observed. Acute toxicity included pancytopenia grade 3/4, neutropenic fever, and treatment related mortality rate of 0.8%. Second malignancies and late cardiotoxicity occurred in 2.4% and 2.4% of patients, respectively. Intensive alternating immunochemotherapy protocol GMALL/B-ALL/NHL2002 is curative for more than 90% of PMBL patients and late toxicity in young patients is moderated. The attenuated dose of doxorubicin and intermediate dose of methotrexate may contribute to low incidence of late cardiotoxicity and effective CNS prophylaxis.