Extranodal Involvement Research Articles

Does Prompt Access to Healthcare Impact the Outcomes of Hodgkin Lymphoma? a Comparison between Public and Private Patients Sharing the Same Infrastructure

Introduction: Brazil is considered by the World Bank as a Low/Middle-income country (LMIC). In Brazil, most of the population relies on universal public system, with only about 20% of patients able to afford private healthcare. Patients on the public system tend to have delayed diagnosis and access to treatment, and the impact of delay in cancer patients is unknown. Since 2018, Hospital Israelita Albert Einstein (HIAE), a private hospital in Sao Paulo, runs a public Lymphoma Clinic, receiving around 200 new cases/year. Both centers are less than 10km away, and both share most resources, including laboratory, pathology, imaging, pharmacy and medical team. We aimed to evaluate the difference in progression-free survival (PFS) in Hodgkin Lymphoma patients from both public and private systems sharing the same infrastructure. Methods: Patients with newly diagnosed cHL between January 2018 to January 2022 were included in this retrospective analysis, both from Hospital Israelita Albert Einstein (HIAE, private hospital) and Hospital Municipal da Vila Santa Catarina (HMVSC, public hospital). All biopsies were centrally reviewed at HIAE, and all laboratory and imaging were also done at HIAE. All patients were submitted to interim PET-CT after two cycles of ABVD ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), and response-adapted therapy was defined by assistant physician choice. All patients were also evaluated by PET/CT at the end of therapy. Survival rates were estimated by Kaplan-Meier and differences were assessed by a log-rank test. Univariate associations were derived via Cox model with variables P≤0.05 entered into a multivariable model. Results: There were 120 newly diagnosed cHL (40 in private, 80 in public center) and the median follow-up was 16 months. The median age at diagnosis was 36 years (19 to 81) with a male predominance (60%) and 95% presented with an ECOG performance status of 0-1. There was a significant difference in disease stage between HIAE and HMVSC: 55% (22/40) in private institution were at early stage versus only 20% (16/80) in the public center. Furthermore, 80% of patients in the public center were classified as unfavorable. In advanced stage, we observed 87% (56/64) of extranodal involvement in the public center. The progression-free survival at 2 years was 85% (private) versus 66% (p=0.08) (public). The only risk factor associated with inferior PFS was the number of involved extranodal sites (HR = 2.33, p = 0.004 for each extranodal site involvement). There was only 1 patient in the private institution with more than 1 extranodal site involved. Conclusion: Despite improvement in the Outcomes of HL patients, we showed that delayed diagnosis/access to health care had impacted in the disease presentation of patients, with a trend to inferior PFS in this population, even when confounding factors (such as infrastructure) are eliminated. Patients in the public system presented more often at advanced stage, risk factors, and extranodal involvement. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Zanubrutinib Combined with R-CHOP Regimen in the Treatment of Newly Diagnosed Diffuse Large B-Cell Lymphoma with Extranodal Involvement: A Single-Arm, Prospective Phase II Trial

BACKGROUND About one-third of Diffuse large B-cell lymphoma (DLBCL) arises primarily from extranodal sites, patients with extranodal involvement indicate poor clinical outcomes. It is an urgent need to find new treatments for DLBCL patients with extranodal involvement. METHODS We conducted a single-arm, prospective phase II trial for newly diagnosed DLBCL with extranodal involvement to evaluate the efficacy and safety of Zanubrutinib combined with R-CHOP Regimen.Patients received therapies: R-CHOP(intravenously Rituximab (375mg/m2 on Day0), Cyclophosphamide (750mg/m2 on Day1),Doxorubicin (50mg/m2 on Day1), Vincristine(1.4mg/m2 on Day 1), and oral Prednisone(50mg QD Day1-5) with Zanubrutinib (160mg BID Day 1-21) regimen. RESULTS 17 patients received ZR-CHOP regimen treatments at least 2 cycles, median treatments cycles were 4 cycles. The median age of the patients is 62 year (49-77y).11 patients (65%) were classified as medium and high-risk group according to IPI or aaIPI Prognostic Scoring. 10 patients (59%) had stage III~IV disease, 14 patients (82%) were Non-GCB types, 13 patients (76%) with Ki-67 more than 80% in pathological IHC. 3 patients (18%) were diagnosed as double-expression lymphoma and 2 patients (11%) with p53 positive over 80% in pathological IHC(Table1). At data cut off , the objective response rate(ORR) of 17 patients was 94%(16/17), 5 patients(30%) reached complete remission(CR) , 2 patients (11%) withdrew from the clinical trial for intolerable adverse reactions and 1 patient(6%) died due to progression disease(PD)(Figure1). The most common hematological toxicity events were neutrophil count decreased, thrombocytopenia and anemia, with 3-4 level occurrence rate was 41.2%, 23.5% and 17.6%. The most common non-hematological toxicity events were pneumonia,fatigue and nausea.1 patient had rash after medication and no atrial firilation, tumor lysis syndrome or massive hemorrhage were reported(Table2). CONCLUSIONS Our results showed that Zanubrutinib plus R-CHOP(ZR-CHOP) is a safe and effective regimen for DLBCL patients with extranodal involvement. It indicate that the addition of zanubrutinib to the standard first-line treatment can enable these patients to achieve efficient remission in the early stage and without significantly increasing toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Identification and Verification of Immune-Related Gene Prognostic Signature Based on Ssgsea for DLBCL

Background : Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma (NHL), accounting for about 30% of NHL worldwide and a higher incidence of about 50% in China. The tumor microenvironment (TME) and effective immune surveillance are important in the pathogenesis of lymphoma and are closely related to the prognosis. Patients and methods: In this study, we evaluated the immune cell infiltration of 223 patients with diffuse large B-cell lymphoma (DLBCL) downloaded from GEO using ssGSEA and evaluated the RNA sequencing of these patients, divided the GEO downloaded dataset into high and low immune groups, performed differential gene analysis. Results: 952 genes were found to be upregulated. Then we grouped our patients' sequencing data into high and low immune groups. The same differential gene analysis was performed, and upregulation of 425 genes was found. We discovered 22 duplicated genes among these genes yVenn diagram. and the expression of these 22 genes was differentially expressed in the high and low immune groups. 4 genes associated with poor patient prognosis were identified by one-way COX and LASSO regression (CELF2, KIFC1, MEGF6, S100A9), especially KIFC1. We used such four genes as prognostic features to construct the model, and chose GSE10846 as the Train group and GSE87371 as the Test group to verify the accuracy of the model. In the Train and Test groups, there was a difference in survival between high and low risk groups (p<0.05), indicating that the ROC curves suggest that the model can accurately predict patient survival. The 1-year, 2-year, and 3-year calibration curves also show that our model can accurately predict the survival index our patients. The risk curves and survival status plots indicate that the number of death increases as the risk score increases, in summary indicating that our model is able to accurately predict the prognosis of the disease. Next, we analyzed KIFC1 and found that the expression of KIFC1 differed between high and low immune groups. Correlation analysis showed that KIFC1 was positively correlated with patient risk scores. In the GSE32018 dataset, the expression of KIFC1 in tumor tissues differed significantly from normal tissues, and patients in the high expression group was less likely to survive. Univariate and multivariate analyses showed that KIFC1 could be used as an independent prognostic factor. Clinical correlation analysis showed that KIFC1 correlated with patients' extra-nodal involvement, ECOG grade, and tumor subtype. Conclusion: The results of provide a novel approach to predict the prognosis and survival of DLBCL patients by these genetic features. Also, KIFC1 could potentially be used as a therapeutic target.

Decisional Role of Interim PET in Relapsed/Refractory Classical Hodgkin Lymphoma Treated with Begev Chemotherapy As First Salvage

Achievement of complete response (CR) before autologous stem cell transplantation (ASCT) is one of the main predictive factors of outcome in patients (pts) affected by relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) eligible to high-dose chemotherapy. The predictive role of interim PET during salvage treatment is well established in pts treated with IGEV or ICE but has not been investigated in pts receiving BEGEV (Bendamustine, Gemcitabine and Vinorelbine) as first salvage treatment. With the aim to investigate the predictive value of PET after 2 cycles of BEGEV (PET2) in terms of CR rate and survival, we retrospectively collected data of consecutive R/R cHL pts eligible to ASCT treated from 2011 to 2021 in 3 Italian centres. PET scans were locally evaluated using Deauville Score (DS), considering a score 1-3 negative and consistent with CR. Early relapse was defined as a relapse occurring ≤12 months from the end of first-line therapy. Survival functions were calculated from the date of initiation of BEGEV chemotherapy. Ninety-four cHL R/R pts receiving BEGEV as first salvage therapy were included. Fifty-one (54.3%) pts were male. First-line therapy consisted in 2 to 6 ABVD chemotherapy cycles accordingly to clinical stage followed by consolidation radiotherapy (RT) in 24 (25.5%) pts. At relapse, median age was 37 years (range: 18-71 years), 51 (54.3%) pts were in stage III-IV, 16 (17%) pts had B symptoms and 34 (36.2%) pts had extranodal involvement (EI). Fifty-one (54.3%) pts were primary refractory, 23 (24.5%) pts had an early and 20 pts (21.3%) a late relapse. PET2 was performed in 86 (91.5%) pts, and resulted negative in 61 (70.9%) and positive in 25 (29.1%) pts (DS 4 in 17 and DS 5 in 8 pts). PET after 4 BEGEV cycles (PET4) was performed in 82 (87.2%) pts and resulted negative in 63 (67%) and positive in 19 (20.2%) pts (DS 4 in 10 and DS 5 in 9 pts). Complete response after 4 BEGEV was achieved in 55/61 (90.2%) PET2 negative pts and 7/25 (28%) PET2 positive pts. Considering pts evaluable for both PET2 and PET4, PET2 positive pts had a statistically lower probability to achieve CR at PET4 when compared to PET2 negative pts (Odds ratio: 0.07, CI 95%: 0.02-0.29; p<0.00001). Autologous SCT was performed in 81 (86.2%) pts, following BEGEV in 56 pts (69.1%) and after further salvage treatments in 25 (30.9%). A post-ASCT consolidation strategy was performed in 24 (29.6%) pts, and consisted in RT in 18 pts and brentuximab-vedotin in 6 pts. Ten pts received an allotransplant: in 3 cases allotransplant was planned in a tandem modality, while in 7 cases was performed after further salvage treatments for post-ASCT relapse or progression. With a median follow-up of 36.4 months (interquartile range: 20.1-50.0), 3-years overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) for the whole study population were 91.7%, 61.6% and 53.9%, respectively. No significant differences in OS were detected according to PET2 result. Conversely, both 3-years PFS and EFS were significantly superior in PET2 negative vs PET2 positive pts: 3-years PFS was 61.6% (CI 95%: 52.1-72.9) in PET2 negative and 43.6% (CI 95%: 27.9-68.4) in PET2 positive pts (p=0.0004) (Figure 1), while 3-years EFS was 71% (CI 95%: 59.8-84.3) and 23.3% (CI 95%: 11.3-48.1), (p<0.001). Univariable analysis of PFS was performed using Cox regression model and evaluating adverse risk factors at relapse (primary refractory and early relapse vs late relapse, presence of EN involvement and B-symptoms) and demonstrated a significantly inferior PFS for pts with EI (HR 1.94, CI 95% 1.01-3.74, p=0.47) and primary refractory disease or early relapse (HR 2.02, CI 95%: 1.01-4.04, p=0.047), but not for pts with B symptoms (HR 1.05, CI 95%: 0.43-2.51, p=0.9). Multivariate Cox regression model of PFS evaluating presence of EI at relapse (HR 1.55 , CI 95%: 0.74-3.25, p=0.240), time to relapse (primary refractory and early relapse vs late relapse, HR 0.84 (CI 95%: 0.36-1.96, 0.683) and PET2 result, identified PET2 positivity as the only predictive factor for PFS (HR 3.24, CI 95%: 1.55-6.77, p=0.002). In conclusion, R/R cHL pts with PET2 positive during BEGEV salvage treatment had a lower probability to achieve CR after 2 additional BEGEV cycles and a significantly inferior PFS, and could benefit from early exposure to new therapeutic strategies before ASCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Progression of Disease within 5 Months of Adult T-Cell Leukemia-Lymphoma (ATL5) As a Clinical Endpoint for High-Risk Mortality Outcomes in the Real-World Setting: A Multinational Cohort Analysis

Introduction Adult T-cell leukemia-lymphoma (ATL) is an aggressive hematological malignancy associated to poor outcomes. Most of these patients experience a rapid and aggressive disease course characterized by early progression and death. Previous studies have identified clinical and laboratory factors of prognostic value. However, their incorporation in the clinical setting has not been validated due to unstandardized management practices. Risk stratification based on time to progression has not been explored in patients with ATL. Therefore, we develop a clinical endpoint to evaluate whether patients that relapse early have a higher risk of death. Methods We designed a multicenter retrospective cohort study among treated patients with a serological and pathology confirmation of ATL. Included patients with acute or lymphomatous ATL subtypes received systemic treatment (e.g., chemotherapy; zidovudine plus interferon). The training cohort consists of patients from endemic regions treated in tertiary care centers across Latin America and the United States. A validation set of 193 patients from Japan was used for reproducibility. Our exploratory analysis identified that at least 20% of relapsed patients experienced this event within 5 months after diagnosis in both training and validation cohorts. Therefore, we used a 5-month landmark for patients with ATL (ATL5) to define early progression. Median follow-up (reverse Kaplan-Meier) was 48 and 40 months in the training and validation cohorts, respectively. Overall survival was defined from date progression for early-ATL5, and from the 5-month landmark for non-early-ATL5 (reference group). Patients that died without relapse within 5 months (n=62 training, n=54 validation) or those alive with less than 5 months of follow-up time (n=13 training, n=3 validation) were excluded from the analysis. We plotted Kaplan-Meier curves and used the log-rank test to compare groups across the datasets. Univariate and multivariate Cox regression analyses were employed to model the effect of ATL5 on all-cause mortality. Missing values were added as a missing category in the adjusted models. Results Of the 253 patients in the training cohort, 38% (n=96) relapsed within 5 months after diagnosis, and 62% (n=157) did not (reference group). There were 96 (38%) with acute (early-ATL5: n=55, reference: n=41) and 157 (62%) with lymphoma (early-ATL5: n=41, reference: n=116) ATL subtype. The median age at diagnosis was similar between both groups (early relapse: 55 years, reference: 54 years; p=0.831). Patients with early-ATL5 had poor performance status (ECOG 2-4 68% vs. 49%, p=0.009), higher frequency of acute ATL (57% vs. 26%, p<0.001), B symptoms (83% vs. 63%, p=0.034), advanced stage (III-IV 97% vs. 84%, p=0.002), hypercalcemia (51% vs. 35%, p=0.023), and higher values of lactate dehydrogenase (96% vs. 77%, p<0.001). Overall survival at 3 years was poorer among patients with early-ATL5 (12% vs. 30%; p=0.0001; Figure 1A). The univariate Cox analysis identified a hazard ratio (HR) of 2.02 (95% confidence interval [CI] 1.49-2.74) for early progression. After adjusting for ATL subtype, cancer stage, skin involvement, ECOG score, extranodal involvement, and hypercalcemia, patients with early-ATL5 remained with a higher risk of death (adjusted HR: 2.02, 95% CI 1.43-2.86). In the validation cohort, the 23 (12%) patients with early progression were deceased within 18 months after the landmark basal time (Figure 1B). The risk of death was higher among individuals with early-ATL5 in the validation set (adjusted HR: 1.84, 95% CI 1.14-2.95, Figure 1B). Conclusions Patients with ATL who relapse within 5 months after diagnosis had a higher risk of death. Treatment of ATL varies between and within countries, limiting the comparison and validation of current prognostic factors. Therefore, we developed a time-based marker to evaluate the prognosis of these patients. Our findings remain robust in the validation set, suggesting that ATTL5 is a clinically relevant endpoint in the real-world setting. Future studies should validate its applicability in prospective studies and determine its relevance for risk-based treatment in clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Two Sides of the Same Transdifferentiated Coin: A Case Vignette and Review of the Literature Exploring the Relationship between B Cell Non-Hodgkin Lymphoma, Histiocytic Sarcoma and Interdigitating Dendritic Cell Sarcoma

WHO classifies Histiocytic Sarcoma (HS) and Interdigitating Dendritic Cell Sarcoma (IDCS) as separate, unrelated, entities under histiocytic/dendritic cell neoplasms. We do not fully understand the pathogenesis of HS and IDCS, yet both have been shown to transdifferentiate from B cell non-Hodgkin lymphomas. Diagnosis is challenging and requires application of a wide variety of immunohistochemical studies, flow cytometry and molecular analysis. We present a case of HS which evolved from CLL/SLL and presented as a diagnostic challenge due to unusual features overlapping with what is typically seen in IDCS. An 82-year-old male with a history of CLL/SLL presented with right infiltrative tonsillar mass and cervical lymphadenopathy. Biopsy of the lymph node revealed two abnormal populations of cells : Twenty percent of cells were consistent with CD20+ kappa surface light chain restricted CLL/SLL cells. Eighty percent of cells were histiocytic cells with an abnormal immunophenotype showing expression of CD4, CD43, fascin, HLA-DR, PU.1, (weak) S100 and CD1a without CD163, lysozyme, CD34, CD117, CD21, CD23 or CD14. Expert consultation favored the diagnosis of HS with transdifferentiation from CLL/SLL. PCR for IgH gene rearrangement, performed on separate HS-rich and CLL-rich areas of the biopsy detected identical clonal peaks. Next generation sequencing detected pathogenic KRAS mutations (p.G12D, p.A146P) and likely pathogenic BCOR (p.K839fs*17) and FBXW7 (p.R465S) mutations. While HS was the favored diagnosis, some immunophenotypic features were unusual, including diffuse fascin immunoreactivity, weak S100, and CD1a immunoreactivity which raised the possibility of so-called IDCS. While clonal evolution of HS and IDCS from B cell Non-Hodgkin lymphomas has been reported, there is a paucity of literature on these entities. We suggest that there may be a pathogenic relationship between these two neoplasms that has yet to be elucidated due to their rarity and diagnostic challenge. Few clinical laboratories can perform the breadth of markers required for diagnosis. Both neoplasms have varied clinical presentations with nodal or extranodal involvement and portend poor prognosis. Review of the literature shows significant overlap in immunophenotypic and genomic characteristics of IDCS and HS, suggesting they may be related manifestations of the same neoplasm. A case report has described the initial presentation of IDCS that subsequently developed into HS, although sampling may have been an issue. We identified 11 cases, including our case in the literature presenting with positive histiocytic and dendritic cell markers referred as hybrid dendritic-histiocytic sarcomas or histiocytic sarcoma with interdigitating dendritic cell differentiation. Immunohistochemical analysis of these cases showed positivity rates of S100 (100%), lysozyme (82%) and CD1a (18%). One case in the literature described fascin immunoreactivity, as was observed in our case. Four of six cases had CD163 immunoreactivity. A hybrid neoplasm with overlapping features of follicular and interdigitating dendritic cells has also been reported, further confounding our understanding of these neoplasms. Large studies analyzing genomic features of these neoplasms have shown recurrent mutations in RAS-MAPK pathway, as was seen in our case. Further studies of the relationship between HS, IDCS should include gene expression profiling of these entities which may also yield therapy targets. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TPL2, a New Prognostic Factor and a Potential Therapeutic Target in ABC-DLBCL

Background: Activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL) is a subtype of DLBCL, characterized by the constitutive activation of NF-κB and JAK/STAT3 pathways on the background of the chronic active BCR signaling. Being featured by mutations in MYD88 and/or CD79B, it potentially comprises the MCD/C5 subtype in the recent genetics-based categorization. In light of the inferior prognosis of this subtype to germinal center B-cell (GCB) like DLBCL, identification of subtype-specific strategies has been sought. Tumor progression locus 2 (TPL2) is an intracellular serine/threonine kinase that is reported to be activated downstream of TLRs/MYD88 signaling and to play roles in oncogenesis. However, the involvement of TPL2 in B-cell malignancies is less defined despite relatively higher transcript expression than in solid tumors. Results: To address the impact of TPL2 protein levels on DLBCL phenotypes, we performed an IHC analysis on 79 FFPE samples of DLBCL diagnosed and treated at our institution (48 non-GCB and 31 GCB according to Hans algorithm). When divided into two groups, one with strong TPL2 expression (TPL-high) and the other with no/weak expression (TPL2-low), the ratio of TPL2-high did not differ between non-GCB and GCB (67% vs 64%). However, TPL2-high had a significantly higher percentage of positive B symptom (42% vs 11%, p=0.005) and extra-nodal involvement (75% vs 52%, p=0.047) compared to TPL2-low, and these trends were observed more specifically in non-GCB. Moreover, it is noteworthy that TPL2-high showed a significantly lower overall survival in non-GCB (p=0.037), but did not in GCB (p=0.999) (Figure 1). Intriguingly, the analysis combined with pSTAT3 (Y705) staining revealed that TPL2-high accompanied by positive pSTAT3 tended to display particularly poor prognosis in non-GCB. Then, we analyzed the mechanism by which TPL2 is involved in the tumorigenesis of ABC-DLBCL using TMD8, a well-described ABC-DLBCL cell line with MYD88L265P and CD79BY196 mutations. A specific TPL2 inhibitor significantly affected the cell proliferation of TMD8 cells, whereas did not on the cells with GCB phenotype. Of note, TPL2 inhibitor induced G1 cell-cycle arrest via downregulation of CyclinE and CDK2 and upregulation of p27 in western blot analysis, which was confirmed by quantitative PCR. Next, we investigated the downstream signaling of TPL2 in ABC-DLBCL. Western blot analysis revealed that TPL2 inhibitor as well as genetic TPL2 knock down suppressed the activation of NF-κB components and STAT3, and the expression of c-MYC. These results implied the involvement of TPL2 in IL-6/IL-10 autocrine loop and resultant JAK/STAT3 activation. As expected, treatment with TPL2 inhibitor downregulated IL-6/IL-10 mRNA by quantitative PCR and accordingly decreased the levels of IL-6/IL-10 in the cell culture supernatant of treated TMD8 cells. Therefore, we speculated that TPL2 promoted the oncogenic activation of NF-κB and STAT3 pathways via IL-6/IL-10 upregulation in ABC-subtype. Lastly, we evaluated the physiological function of TPL2 by western blot analysis using 293T. Although an overexpression TPL2 alone did not elicit NF-κB and STAT3 activation, when co-expressed with MYD88L265P TPL2 obviously activated these pathways, whereas dominant negative TPL2 failed to demonstrate those effects even with MYD88L265P co-expression. These findings indicated that TPL2 could possibly exert its tumorigenicity in MYD88L265P-dependent manner in ABC-DLBCL. Conclusion: In association with the importance as an unfavorable prognostic factor, our results suggested that TPL2 might mediate the crosstalk between the oncogenic MYD88L265P and the activation of NF-κB and STAT3 pathways, coordinately contributing to the tumorigenesis of ABC-DLBCL. From this standpoint, TPL2 could emerge as a new therapeutic target in ABC-DLBCL. Figure legend Overall survival of non-GCB (A) and GCB (B) DLBCL patients, with regard to the TPL2 expression: TPL2-low (red line) or TPL2-high (black line). Overall survival was determined by the Kaplan-Meier method and compared by using the log-rank test. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characteristics and Outcomes of Adult Patients with T Prolymphocytic Leukemia: A Real World Study of the French Innovative Leukemia Group (FILO)

Introduction T-prolymphocytic leukemia (T-PLL) is a rare T-cell neoplasm of aggressive clinical course and poor outcome. Treatment with the monoclonal antibody to CD52-alemtuzumab (alem) has considerably improved outcomes, yet with transient responses. Bendamustine (benda) showed encouraging results, particularly in alem-refractory patients (pts). Allogeneic hematopoietic stem cells transplantation (Allo-HSCT) has been reported to be effective in T-PLL, yielding durable remissions and improved overall survival (OS). New approaches using well-tolerated therapies and drugs that target such growth and survival signals as that the JAK/STAT pathways or BCL2 have recently been tested in small series of pts ineligible to intensive therapy. Methods The present multicenter study aimed at evaluating clinical and biological characteristics, as well as outcome of a cohort of 157 T-PLL pts over 18 years old (yo) treated in any of 24 centers of the French Innovative Leukemia Organization (FILO) between 03/1997 and 05/2022. OS, relapse, progression and progression-fee survival (PFS) were evaluated. Molecular analyzes searched for JAK1, JAK3, STAT5B, IL2RG, NOCH1, NOTCH2, EZH2, TET2 and TP53 mutations/deletions in 39 pts. Results Pts characteristics are shown in Table 1. The median age at first therapy was 72 yo (range 30-94). Neuro-meningeal and extra-nodal involvement were present at diagnosis and first relapse in respectively 4.6% / 10.5% and 5.9% / 14.3% of pts. At diagnosis, 12% of pts had hemoglobin <100 g/L, 32.6% thrombocytopenia <100x109/L and 43% lymphocytosis >40x109/L. Flow cytometric immunophenotyping showed pan-T antigens expression (CD2,CD3, CD5, CD7) in nearly all pts (table). Alpha-beta TCR was present for 64/73 pts (87.7%) and CD25 for 17/42 (40.2%). The TPLL was CD4+ for 73/98 pts (74.5%), CD8+ for 7/93 (7.5%), double positive (CD4+/CD8+) for 15/93 (16.1%) and double negative (CD4-/CD8-) for 3/92 (3.2%). Cytogenetics/FISH showed recurrent changes involving chromosome 14 in 69/95 (72.6%) pts [inv(14) and t(14;14) in 47/69 (68.1%) and 7/69 (10.3%)] and complex karyotype in 67/95 (70.5%). C-MYC gain, ATM and TP53 deletions/mutations were identified in respectively 22.6%, 27.5% and 16.4% of the pts analyzed at diagnosis, while JAK1, JAK3, and STAT5B were mutated in 15.4 %, 64.3% and 21.4% of tested cases. Additional results will be presented at the meeting. Pts received 1 to 5 lines of treatment (median 1). In first line, 45/127 (35.4%) evaluable pts received alem 30 mg IVx3 per week, after ramp-up (median:6 cycles; 1-10), with for 7 of them a previous sequence of benda (90 mg/m2 on day 1 [D1]). Thirty pts (23.6%) received first line benda 90 mg/m2 on D1 then 2x6 cycles every 28 days (median 3; 1-6), 15 (11.8%) received pentostatin, 11 (8.6%) had a CHOP-like regimen. Best supportive care was provided to 21 pts (16.5%). No treatment was proposed to 3 indolent pts (2.3%). Various schedules were applied to the remaining pts. Post-CR Allo-HSCT was performed for 20 pts (15.7%). Median follow-ups are 9.5 months (0.03-217) for the whole cohort (Figure1) and 11.8 (0.03-221) for Allo-HSCT recipients. Median OS are respectively 12.5 (8.4-17.5) and 23.2 months (5.82-not reached [NR]). The median PFS of the whole cohort is 2.6 months (0-217). Median OS for patients treated with alem or benda in first line are respectively 14.1 (8.4-25.4) and 7.8 (4.3-21) months, while OS for pts who had a benda bridge is 8 months (3.22-NR). The overall response rate (ORR) after first line is 42.7 % (CR 25.6%, partial response [PR] 17.1%). ORRs after first line alem or benda are respectively 53.5% (CR 41.9%, PR 11.6%) and 35.7% (CR: 14.3%, PR 21.4%). In univariate analysis, platelets<100x109/L (HR: 1.95 [1.28-2.95]; p=0.002%) and complex karyotype (HR: 2.08 [1.19-3.63]; p=0.010) statistically significantly appear to impact survival. Conclusion This large study demonstrates that alem therapy significantly improves the survival of T-PLL pts. Consolidation by Allo-HSCT should however be performed for all eligible patients achieving CR. Other therapeutic agents should be reserved for relapse. Prospective trials are needed to define the most effective therapeutic strategy and improve clinical responses to frontline therapy. New approaches using well-tolerated targeted therapies involving growth and survival signals are needed for the majority of patients unable to receive intensive chemotherapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Autologous Stem Cell Transplantation for Treatment with Curative Intent in Adult Patients with Acute Lymphoblastic Lymphoma

Introduction Lymphoblastic lymphoma (LBL) is a rare, aggressive lymphoma that is often classified as a subtype of acute lymphoblastic leukemia (ALL). There is no consensus on the best treatment approach. It is often treated on ALL-type protocols involving prolonged courses of multiagent chemotherapy regimens; the reported long-term disease-free survival is 45-65%. In British Columbia, we take an alternative approach of consolidating initial response to induction chemotherapy with autologous stem cell transplantation (AutoSCT). We present our experience with this treatment pathway. Methods We identified 35 patients who received treatment with curative intent for LBL at our centre over the 15-year-period between January 2007 and January 2022 from our database. We excluded one patient who declined AutoSCT, one who received ALL-type chemotherapy and one who had upfront allogeneic stem cell transplantation (AlloSCT) due to complex karyotype. We collected data pertaining to demographics, disease characteristics, treatment course and outcome on the remaining 32 patients by review of clinical documents and laboratory and radiology reports. The primary outcome was event-free survival (EFS), defined as time from diagnosis to disease progression, relapse or death. Surviving patients were censored at the last follow up. We used Kaplan-Meier method to estimate survival and log-rank test and cox-hazard model for comparison of survival. Statistical analysis was performed using STATA® version 16.1 (Texas, USA). Results The median age was 35 years (range 18-64). 27/32 (84%) had T-LBL. Bone marrow, CSF and extranodal involvement was seen in 7 (22%), 3 (9%) and 24 (75%) patients respectively. The majority of patients (30/32, 94%) received induction chemotherapy on the NHL 98-01 protocol (consisting of doxorubicin, cyclophosphamide, vincristine, prednisone, and asparaginase). 16/32 (50%) achieved complete remission and 15/32 (47%) partial response post-induction. 28/32 (88%) proceeded to AutoSCT; four patients had early disease progression, preventing AutoSCT. 21/28 (75%) required bridging chemotherapy - most commonly high dose cytarabine (3000 mg/m2 on days 1-6). Nearly all patients (26/28, 93%) received conditioning with VP16-CyTBI (etoposide 1800/m2 on day -7, cyclophosphamide 50mg/kg on days -6 to -4 and TBI 200cGy BID on days -3 to -1) pre-AutoSCT. Two received BEAM (carmustine, etoposide, cytarabine, melphalan); both died from disease relapse post-AutoSCT. The stem cell source was bone marrow in 54% and peripheral blood in 46%. During treatment, all but one had febrile neutropenia and 12/21 (63%) had positive microbiology. Three patients were treated for invasive fungal infection, although only one had a confirmed diagnosis. 5/32 (16%) developed C. difficile infection. 14/32 (44%) patients had unplanned hospital admissions with an average length of stay of 21 days. 5/32 (16%) required ICU admission, two at initial presentation and two post-AlloSCT. Significant viral infections were seen only in the AlloSCT setting. After a median follow-up of 43 months (range 3-166), 16/32 (50%) patients remained alive, all but one in remission. The estimated 5-year EFS was 46% (95% CI 27-63). 13/28 (46%) patients relapsed post-AutoSCT; the median time to relapse was 10 months (range 3-57). At relapse, eight patients presented with ALL (one with concomitant CSF involvement, one with testicular involvement); three had mediastinal disease; one transformed to mixed phenotype leukemia, myeloid/lymphoid; and one had isolated CSF involvement. 3/13 (23%) who relapsed post-AutoSCT went on to receive AlloSCT following salvage chemotherapy; all died in remission from an infection at 1, 3, and 22 months post-AlloSCT respectively. All other deaths were with relapsed disease. There was no statistically significant difference in EFS by stem cell source (p=0.25). EFS was significantly longer in patients with T-LBL compared to those with B-LBL (HR 0.23, 95% CI 0.08-0.74, p=0.007; graph 2). Discussion Autologous stem cell transplantation with TBI-based conditioning for treatment of T-LBL is a viable treatment approach with acceptable tolerability and survival outcome. It also offers the advantage of a shorter treatment course compared to ALL-type chemotherapy. Further research is required to make direct comparison between these two distinct therapeutic approaches and provide guidance on the best practice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcome after 3rd Line Treatment for Diffuse Large B-Cell Lymphoma: A Danish Population-Based Study

Background: Outcomes of patients with relapsed/refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) are generally poor. There are no generally accepted standard treatment for patients with disease recurrence after first salvage therapy. Several novel therapies are being evaluated for patients in the 3rd line setting in single arm trials, but the efficacies of these therapies must be contextualized with efficacy data on existing treatments. Aim To report the outcomes for R/R DLBCL following 3rd line therapy in a population-based setting. Methods This study was based on the Danish population-based lymphoma registry (LYFO). Adult patients (≥18 years) diagnosed with DLBCL between January 2012 - December 2019 were identified using LYFO and had their medical records reviewed by local investigators. All patients who were treated with rituximab and anthracycline based therapy (R-CHOP/CHOEP) in first or second line, and that received 3rd line treatment after January 2015 were included. Patients with primary CNS lymphoma and post-transplant lymphoproliferative disease were excluded. The endpoints were overall survival (OS) and progression-free survival (PFS) measured from the initiation of 3rd line therapy. Refractory disease was defined as initiation of 3rd line therapy within 12 months after beginning of 2nd line irrespective of response after 1st line therapy. Outcomes were described for all patients and stratified by clinicopathologic features associated with high-risk disease. Results A total of 3,752 patients diagnosed with DLBCL in the period were screened and 196 patients were included. At time of 3rd line therapy, median age was 72 years (range 20-95), median time since last treatment was 6 months (range 0.5-64.8) and 145 patients were classified as refractory. Most patients had advanced stage disease (63%), extranodal involvement (63%) and/or elevated LDH (62%). 32% had ECOG score ≥2 and 23% had an IPI score ≥4. 18 (6%) patients had CNS involvement. 3rd line treatment regimens were best supportive care BSC) (20%), ICE/DHAP/GDP (14%), other types of chemotherapy (i.e GemOX, CCVP, PREBEN, Bendamustine etc.) (46%), radiotherapy alone (9%), or treatment in clinical trials (11%). Only 42% received rituximab as part of 3rd line treatment. 5% received allogenic and 4% received autologous bone marrow transplant (BMT). CAR-T was not available to any of the patients in the cohort. For the entire cohort the 2-year OS and PFS were 22% (95% CI 16-28) and 12% (95% CI 7-17) respectively, and the median OS was 6 months (95% CI 4.8-7.8). Patients with high IPI (4-5) had worse outcomes than low IPI (0-1) with 2-year OS of 13% (95% CI 6-28) versus 40% (95% CI 40-95). Young patients (< 70 years) had 2-year OS and PFS of 27% (95% CI 18-41) and 16% (95% CI 9-28), which was significantly better than the OS of 19% (95% CI 13-28) and PFS of 9% (95% CI 5-17) observed in patients older than ≥ 70 (p = 0.03) (Figure 1). 27 Patients were treated with ICE/DHAP/ GDP with a median age of 66 (range 20-81) and most had a ECOG score <2 (63%). Only 7 patients achieved complete remission, and two achieved partial remission but OS was significantly better than patients treated with "other” treatments (p=0.04) or BSC (P<0.001) (Figure 2). Only 7 (26%) of patients treated with ICE/DHAP/GDP were consolidated with autologous BMT and none with allogenous BMT. Patients classified as refractory, had poor 2-year OS of 19% (95% CI 13-27). Of the 14 that were in remission for more than 24 months after 3rd line therapy, 4 had received consolidation with allogenic BMT. Conclusion We report granular real-world data on 3rd line therapy for DLBCL in a Danish population-based cohort. Outcomes were dismal as half of all patients were dead within 6 months of 3rd line therapy and only 22% survived more than 2 years. This study highlights the major unmet need for novel therapeutics in regions where CAR-T is not yet readily available. Updated results will be available at the time of ASH. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Characteristics and Outcomes of Follicular Lymphoma Patients with Extranodal Involvement: Analysis of a Series of 1090 Cases in China

Clinical Characteristics and Outcomes of Follicular Lymphoma Patients with Extranodal Involvement: Analysis of a Series of 1090 Cases in China

Brentuximab Vedotin Combined with Chemotherapy in Newly Diagnosed, Early-Stage, Unfavorable-Risk Hodgkin Lymphoma: Extended Follow-up with Evaluation of Baseline Metabolic Tumor Volume and PET2

INTRODUCTION: While the majority of patients with early-stage (ES), bulky Hodgkin lymphoma (HL) can be cured with modern approaches, approximately 15% of patients with bulky HL relapse. Improving upfront approaches while minimizing long-term adverse effects remains integral. We previously reported the results of a multicenter pilot study of 4 cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD) followed by 1 of 4 approaches if positron emission tomography (PET)-4 negative. The treatment program was highly active and well-tolerated. We now present extended results and prognostic evaluation of baseline metabolic tumor volume (MTV) and PET2 results. METHODS: Full methodology has been published (Kumar et al., J. Clin Oncol. 2021). Briefly, patients with untreated HL were enrolled into 1 of 4 sequential cohorts. In cohort 1 (C1), eligible patients had any of the following unfavorable (UF) risk factors: bulky mediastinal mass, ESR ≥ 50 mm/h or ≥ 30 mm/h if B symptoms, extranodal involvement, > 2 lymph node sites, or infradiphragmatic disease. The same criteria applied to C2, except for bulk being defined by the Memorial Sloan Kettering (MSK) definition (maximal transverse or coronal diameter of the largest mass > 7 cm). In C3 and C4, all patients were required to have MSK criteria bulk. All cohorts received BV-AVD x 4. Patients with a PET-negative response after 4 cycles received 30-Gy involved site radiation therapy (ISRT) in C1, 20-Gy ISRT in C2, 30-Gy consolidative-volume RT (CVRT) in C3, and no RT in C4. For 84 patients at MSK, baseline MTV was measured using the 41% maximum standard uptake value (SUV) threshold method. Interim PET after 2 cycles was interpreted using the 5-point scale with scores ≤ 3 considered negative. Survival data was updated through July 1, 2022. Progression-free (PFS) and overall survival (OS) probabilities were estimated by the Kaplan-Meier method and compared for various features using the log-rank test, with a p-value of ≤ 0.05 statistically significant. RESULTS: Of 117 patients enrolled, 116 completed chemotherapy. With a median followup of 4.6 years (6.7, 5.3, 4.5, and 3.3 years for C1-4), there were 8 progression events and 2 deaths. Since original publication, 1 further progression occurred amongst a patient in C4. The median PFS and OS have not been reached in either group. The overall 4-year PFS and OS were 93% and 98%, respectively. The 4-year PFS for C1-4 was 93%, 96%, 90%, and 93%, respectively (p=0.78). Next, outcomes were compared by MTV and PET2. Among 84 patients assessed for baseline MTV, median MTV was 150 (range 13-827) cm3. Using the median MTV to stratify patients, overall 4-year PFS in the MTV-high (n=43) versus MTV-low (n=41) group was 91% versus 100%, respectively (p=0.047). Fourteen patients (12%) had positive PET2. Four-year PFS in the PET2 positive versus negative group was 79% versus 95%, respectively (p=0.02). By MTV and PET2, 4-year PFS for the MTV-low/PET2-negative (n=36), MTV-low/PET2-positive (n=5), MTV-high/PET2-negative (n=38), and MTV-high/PET2-positive (n=5) groups was 100%, 100%, 95%, and 60%, respectively (p=0.001) (Figure 1). Within these 4 groups, there were 4 progression events, 2 within the MTV-high/PET2-negative group and 2 within the MTV-high/PET2-positive group. The 2 patients in the MTV-high/PET2-negative group had Deauville score (DS) 2 on PET2 and then developed DS4 on PET4; 1 received salvage R-ICE (concomitant CD20 expression) followed by autologous transplant (autoSCT), and 1 received salvage pembrolizumab-GVD followed by autoSCT. The 2 patients within the MTV-high/PET2-positive group had DS4 on PET2 and PET4. One patient received salvage augmented ICE followed by radiation and autoSCT. The other patient had a negative biopsy of PET4 disease and completed CVRT, but relapsed 2 months later and received salvage augmented ICE and autoSCT. All 4 of these patients remain without disease after a median follow-up post autoSCT of 65 (28-86) months. CONCLUSIONS: We report extended followup of short-course BV-AVD followed by various doses/fields of RT, including no RT, in ES, bulky HL. The BV-AVD program remains highly active and well-tolerated, including in the absence of consolidative RT for certain patients. Baseline MTV and PET2 identifies an unfavorable cohort at higher risk of treatment failure. Trials in ES, bulky HL should evaluate stratified treatment paradigms using baseline MTV and PET2. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hypomagnesemia and Prognosis in Newly Diagnosed Diffuse Large B Cell Lymphoma

Magnesium (Mg) is an essential element that is involved in cellular metabolism. Hypomagnesemia occurs due to inadequate diet and urinary losses which can be induced by platinum-based chemotherapy. We previously demonstrated that low serum Mg (<1.7 mg/dL) occurred in 14% of patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant and was associated with increased non-relapse mortality. In this study we investigated whether the pre-treatment serum Mg levels in patients with DLBCL are predictive of event-free survival (EFS) and overall survival (OS). We obtained frozen pretreatment serum from 408 patients using the resources of the Iowa/Mayo Lymphoma SPORE Biospecimens Core and analyzed the serum Mg level (normal range, 1.7-2.3 mg/dL) in the Mayo Clinic Core Laboratory. Fourteen patients (4%) had low serum Mg (<1.7 mg/dL) and 95 (23%) had serum Mg levels <2.0 mg/dL. Low/low normal (<2.0 mg/dL) levels were associated with higher stage at diagnosis (p = 0.027), more extranodal involvement (p < 0.001), higher lymphoma international prognostic index (IPI) score (p = 0.006), and shorter OS (HR, 1.4; 95% CI, 0.97-2.03, p = 0.07) and EFS (HR, 1.33; 95% CI, 0.95-1.87, p = 0.09) compared to those with serum Mg levels (≥2.0 mg/mL). In a multivariate analysis of EFS/OS, the low serum Mg was not independent of the IPI. Conclusions: Hypomagnesemia is uncommon in DLBCL patients prior to treatment but is associated with high-risk disease. Since low Mg is one of few actionable prognostic factors, we recommend that nutritional counseling be included in the pretreatment evaluation of these patients. The feasibility and efficacy of replacing Mg to normal levels in lymphoma patients is the focus of our ongoing trial (NCT05294367). Panel A: Overall survival of patients with diffuse large B-cell lymphoma by pre-therapy serum magnesium levels. Panel B: Event free survival of patients with diffuse large B-cell lymphoma by pre-therapy serum magnesium levels. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characterization of a Large Cohort of Patients with Nodal Marginal Zone Lymphoma Shows Prolonged Survival, Time-to-Treatment, and Time-to-Transformation

INTRODUCTION: Nodal marginal zone lymphoma (nMZL) is a rare lymphoma accounting for < 2% of all non-Hodgkin lymphomas. As 1 of 3 recognized MZL subtypes, nMZL has only been formally recognized by the World Health Organization Classification in the last 2 decades. Consequently, characterization is limited. Therefore, we reviewed a large cohort with the goal of defining characteristics, survival, and time-to-event descriptions. METHODS: Using a search of the Memorial Sloan Kettering (MSK) Lymphoma Outcomes Database, we identified patients with nMZL between 1/1/2001-6/1/2021. Only patients with a histological diagnosis based on pathology review at MSK were included. Patients with splenic involvement were included if presentation was predominantly nodal on radiographic review. Patients with nodal and extranodal involvement that was indistinguishable between nMZL and non-nodal MZL were excluded. Data were collected by chart review. Baseline Follicular Lymphoma International Prognostic Index (FLIPI) scores were calculated to evaluate impact on prognosis. Management strategies were classified into 1 of 5 categories (observation, radiation, rituximab/anti-CD20 monotherapy, chemoimmunotherapy, or other). Active treatment was considered any non-observation treatment. The primary objective was to determine the progression-free (PFS) and overall survival (OS) of the entire cohort, as estimated by the Kaplan-Meier method and compared for various features using the log-rank test. Time-to-1st and 2nd active treatment, as well as time-to-transformation, was evaluated by cumulative incidence function with death as a competing risk; 3 patients with transformed disease at initial presentation were excluded from time-to-transformation analyses. RESULTS: We identified a total of 187 patients with nMZL. The median age at diagnosis was 62 (interquartile range: 50-69). Among those evaluable for baseline FLIPI (n=139), 61 (44%), 35 (25%), and 43 (31%) had scores of 0-1, 2, and ≥ 3. Initial management strategies varied; the most common approaches were observation (n=89, 48%) and chemoimmunotherapy (n=44, 24%), followed by rituximab/anti-CD20 monotherapy (n=26, 14%), radiation (n=18, 9.6%), and other (n=14, 5.3%), which predominantly consisted of chemotherapy prior to widespread use of anti-CD20 therapy. Forty-eight patients (28%) never required therapy. Patients who received observation as first management were more likely to have stage I/II (p<0.001) and FLIPI 0-1 (p=0.008) in comparison to others. Among survivors, the median follow-up time was 70 months (m) (range 7-252); for the entire cohort, median PFS was 48 m (95% CI 36-87) and median OS was not reached (157 m-not reached). Overall 5-year PFS and OS was 47% (40%-56%) and 91% (87%-95%), and overall 10-year PFS and OS was 33% (25%-43%) and 76% (68%-85%). PFS and OS varied significantly by baseline FLIPI (Table 1), with 5-year PFS for FLIPI 0-1, 2, and ≥ 3 of 55%, 56%, and 30% (p<0.001), and 5-year OS for FLIPI 0-1, 2, and ≥ 3 of 46%, 40%, and 16% (p<0.001). By first management strategy, non-risk adjusted median 5-year PFS for observation, radiation, rituximab/anti-CD20 monotherapy, and chemoimmunotherapy was 45%, 65%, 34%, and 58% (p=0.049), and 5-year OS was 94%, 100%, 81%, and 90% (p=0.13) (Figure 1). Among patients who ever received treatment (n=139), median time to 1st active treatment was 4.3 m (3.1-11). For those observed initially, the median time to active treatment was 72 m (49-not reached). For those who received at least 2 active treatments (n=60), the cumulative incidence of 2nd active treatment (in the presence of death as a competing risk) at 24 and 60 m was 36% and 46%, respectively. For those initially treated with radiation, rituximab/anti-CD20, or chemoimmunotherapy, the cumulative incidence of 2nd active therapy at 24 m was 6%, 44%, or 34%, respectively (p=0.02). Overall, 26 patients (14%) experienced transformation. For those who transformed after original presentation, cumulative incidence at 24, 60, and 120 m was 4%, 11%, and 14%. CONCLUSIONS: To our knowledge, this is the largest cohort of nMZL with survival and time-to-event analyses. Initial management strategies varied, though observation was chosen in nearly half (48%) of patients, reflecting a commonly indolent presentation. Transformation was uncommon (14%). nMZL frequently has an indolent course and initial expectant observation is often a management option. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes with Immunochemotherapy Plus Radiation Versus Immunochemotherapy Alone in Stage I Diffuse Large B-Cell Lymphoma: A Retrospective Study

Introduction Diffuse Large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma with a prognosis highly dependent on the stage of the disease. The mainstay of front-line therapy for limited-stage DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP-like immunochemotherapy (IC). The impact of combined modality therapy (CMT) with radiation therapy (RT) after IC remains uncertain in the rituximab era. In the pre-rituximab era, studies comparing the efficacy of chemotherapy with or without RT showed heterogenous results. To date, only a few single institutional studies have compared IC versus CMT. The aim of this study is to evaluate the efficacy of standard IC compared to CMT in patients with stage I DLBCL in the rituximab era. Methods Adult patients with stage I DLBCL diagnosed between 2002 to 2015 and seen at Mayo Clinic Rochester were identified. Data were obtained from medical records. All patients were treated with IC (R-CHOP or R-CHOP-like), or IC followed by radiation (CMT). The student's t-test or the Wilcoxon rank-sum test was used to analyze between-group differences, as appropriate. Chi-square or Fisher's exact test was used for categorical variable comparisons. Progression-free survival (PFS) was defined as the time from the date of diagnosis to the date of relapse, death or the date of the last follow-up and was analyzed using the Kaplan-Meier method. Overall survival (OS) was defined as the time from the date of diagnosis to the date of last follow-up or death. Response to treatment was evaluated by treating physicians. Results The study included 123 patients diagnosed with stage I DLBCL with a median follow-up time of 65.9 months for IC arm and 56.2 months for CMT arm. Overall, 78 patients were treated with six cycles of IC, and 45 patients were treated with 2-4 cycles of IC followed by involved-site radiation (2 cycles in 4 patients, 3 cycles in 25 patients, 4 cycles in 16 patients). There were no significant differences in age, sex, or extranodal involvement. In the IC group, 59 patients had cell of origin data available: 44 (56.41%) were GCB subtype and 15 patients (19.23%) were non-GCB subtype. In the CMT group, 21 patients (47%) and 9 patients (20%) had GCB and non-GCB subtypes, respectively. Double-hit lymphoma (defined as rearrangement of MYC together with rearrangement of BCL2 and/or BCL6) was reported in 4 out of 78 patients in the IC arm and 2 out of 45 patients in the CMT arm. There was no significant difference in response rates to frontline treatment between groups. In the IC group, the overall response rate (ORR) was 92% (n=72), and the rate of complete response (CR) was 87% (n=68), partial response (PR) was 5% (N=4), stable disease (SD) was 5% (n=4), and progressive disease (PD) was 5% (n=4). In the CMT group, the ORR was 96% (n=43, all CR); 2 patients achieved SD (4%) and no patients had a PR or PD. With a median follow-up time of 65.9 months for IC arm, 14 patients had died. With a median follow-up of 56.2 months for the CMT arm, 14 patients had died. Median PFS was not reached in the IC group while PFS was more than 10 years in the CMT group (p=0.7851) [Figure 1]. There was no significant OS difference observed in both groups (p=0.2561) [Figure 2]. Conclusion Our study showed no significant difference in OS and PFS between patients with stage I DLBCL treated with IC or CMT. Future research on a larger patient population is needed to evaluate the role of consolidation radiotherapy in early stage DLBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Validation of Angioimmunoblastic T-Cell Lymphoma (AITL) Score in Korean AITL Patients

Background: Angioimmunoblastic T cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL), accounting for approximately 2% of all non-Hodgkin lymphoma and 20% of PTCLs. AITL generally displays aggressive clinical course and prognosis is poor with 5-year OS (Overall survival) rate of approximately 40%. The International Prognostic Index (IPI), Prognostic Index for PTCL (PIT), and Prognostic Index for AITL (PIAI) have been widely used for the prognostication of AITL patients. Recently, the international T-cell lymphoma project proposed a novel prognostic score, AITL score based on age, ECOG performance status (ECOG PS), serum CRP level and serum B2-microglobulin (B2-M) level. AITL score demonstrated better discriminant power compared with the IPI, PIT, and PIAI. However, the prognostic significance of AITL score has not been validated. In this study, we aim to validate the prognostic significance of AITL score in Korean AITL patients. Methods: Between March 2001 and August 2021, 98 patients who were newly diagnosed with AITL were identified in the database of the Asan lymphoma Registry, Asan Medical Center, Seoul, South Korea. After excluding patients with no baseline serum β2-microglobulin level (n=13) and CRP (n=4), 81 patients were included in this retrospective analysis. Key baseline characteristics including age, performance status, stage, serum CRP level, serum B2-M level were collected. The upper limit of normal (ULN) of serum CRP level and serum B2-M level are 6 mcg/mL and 2.4 mcg/mL, respectively. Overall survival (OS) was defined as time from diagnosis to any cause of death. Survival curves were estimated by Kaplan-Meier method and compared using log-rank test. In the multivariate analysis, variables exhibiting a potential association with survival (p < 0.5) in the univariate analysis were included. Results: The median age was 61 years (range, 28-83), 47 patients (58.0%) were male, 79 (97.5%) had advanced disease at diagnosis, and 77 (95.1%) had elevated B2-M levels. In addition, two patients (2.5%) had ECOG PS > 2, 31 (38.3%) had extranodal involvement > 1. With a median follow-up duration of 2.0 years, the median OS was 3.6 years. A total 81 patients were found to be evaluable for the prognostic model. There was no significant difference in OS of patients stratified according to the AITL score, with 2-year OS of 44.4%, 59.2%, and 58.4% for patient with low-risk (0-1 risk factor, n=6, 7.4%), intermediate-risk (2 risk factors, n=43, 53.1%) and high-risk (3-4 risk factors, n=32, 39.5%) groups, respectively (p=0.7). The lack of prognostic significance of the AITL score was mainly due to the fact that most of the patients had elevated B2-M (n=77, 95.1%), and serum B2-M had no significant association with OS in the univariate analysis (HR: 2.44, 95% CI: 0.33-17.79, p=0.379). Thus, we reevaluated the prognostic significance of B2-M by using 2 times of the ULN (2 x ULN, 4.8 mcg/mL). Serum B2-M of > 2 x ULN was significantly associated with poor OS in the univariate analysis (HR: 3.38, 95% CI: 1.75-6.50, p<0.001), and its prognostic significance remained in the multivariate analysis (HR: 2.66, 95% CI:1.09-6.49, p=0.031). Thus, we modified the AITL score using 2 x ULN as a cut-off value for B2-M instead of 1 x ULN (modified AITL score). There was a significance difference in OS of patients according to the modified AITL score with 2-year OS rate of 73.5%, 57.2%, and 40.3% for patient with low-risk (0-1 risk factor, n=31, 38.3%), intermediate-risk (2 risk factors, n=24, 29.6%) and high-risk (3-4 risk factors, n=26, 32.1%) groups, respectively (p=0.004). Conclusion: The AITL score failed to be validated in Korean AITL patients due to the fact that most patients had B2-M of > 1 x ULN. Modified AITL score, which adjusted the B2-M cut-off to 2 x ULN provided significant risk stratification of the patients. The optimal cut-off value for B2-M in AITL patients should be validated in future studies.

Outcome of Advanced Stage Diffuse Large B-Cell Lymphoma; Experience from Saudi Arabia

Background Diffuse large B-cell lymphoma (DLBCL) is one of the most common subtypes of non-hodgkin lymphoma, and an aggressive cancer of B-cells. As per the Saudi Cancer Registry, the reported DLBCL prevalence in Saudi Arabia is 15(22.7%) in males and 3(13%) in females (1). CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is the standard of care (2), however, the outcome had displayed significant improvement with rituximab addition. The treatment adjustment is required as per the International Prognostic Index (IPI), based on a patient's profile (age and the associated risk factors)(3,4). There is high mortality in relapsed and refractory cases. The overall survival 0.40 (95% CI, 0.27-0.61), and the progression free survival 0.40 (95% CI, 0.27-0.61) had improved with the addition of rituximab. Methods A retrospective cohort study was employed in year 2016 for patients diagnosed with DLBCL during 2008-2018. The patients were followed up for five years from the treatment till the outcome death or survival. The collected data included demographics, clinical characteristics, ECOG status, Ann Arbor stage, bulky disease, spleen/ extra-nodal involvement, disease status, received line of therapies, and the outcome. Study was approved by the institutional ethical committee (RC14/076). Results A total of 145 consecutive patients were enrolled. The median age was 67 (20-111) years. Little more than half of the sample 80(55%) were males. The B-symptoms were positive in 42(46%). Almost two-thirds 103(71%) had ANN Arbor stage III or IV. 19(22%) had three or more co-morbidities. 58(50.43%) patients had a high-intermediate/ high IPI risk category. Chemotherapy/ Immunotherapy was most common mode of therapy 140(96%), followed by radiotherapy 20(14%). 9(6%) had received stem cell transplantation. First line of therapy was received by 134(92%), followed by second line of therapy19(13%), third line of therapy and above in 9(6.2%). 95(71%) patients had received R-CHOP as a first line of therapy, followed by R-CVP 15(11%), ABVD 3(2.24%), R-bendamustine 2(1.5%), Rituximab 2(1.5%), and others 17(12.68%). The mid treatment evaluation using PET was negative in 16(28%), and post therapy PET evaluation was negative in 44(51%). The five years overall survival was 78%, and five years progression free survival was 74% (figure 1). Conclusion Despite the advanced and high-risk presentation in the majority of patients diagnosed with DLBCL, the 5-year overall survival and progression free survival appears similar or better than what has been reported in literature. This can be attributed to the individualization of therapy based on clinical stage and risk factors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characterizing Mature T-Cell Lymphoma Patients' Outcomes By Race

Background Mature T-cell lymphomas (TCL) are a rare and aggressive group of non-Hodgkin lymphomas with significant geographic variability. Data on TCL patient outcomes by race are limited, and minority populations are often underrepresented in TCL clinical trials in North America and Europe. Herein, we describe outcomes in patients with newly diagnosed TCL from an urban US tertiary care center based on race. Methods We retrospectively identified 125 patients with non-cutaneous and non-leukemic mature TCL diagnosed between 1/1/2009-12/31/2021 from the electronic medical records at the Hospital of the University of Pennsylvania. In a univariate model stratified by self-reported race, we compared baseline patient characteristics at initial presentation, treatment patterns (including first line (1L) therapy, use of CNS prophylaxis and hematopoietic cell transplant (HCT), number of subsequent lines of treatment), and disease outcomes. Multivariate Cox proportional hazards models controlling for race, sex, age, ECOG score, LDH level, initial stage of disease, presence of B symptoms, hemoglobin, platelet count, IPI score, number of sites of extranodal involvement (ENI), histology, and 1L treatments (CHOP, CHOEP, other intensive treatment, radiation only, as well as palliative care), and receipt of HCT were implemented to further investigate the impact of these clinical parameters on overall survival (OS) and progression-free survival (PFS). P-values <0.05 were considered significant. Hazard ratio (HR) is reported with 95% CI in brackets. Results We collected and evaluated data from 94 White patients, 21 Black patients and 10 patients of other races. Patients of other races comprised less than 10% of our cohort and were omitted from the analysis due to inadequate statistical representation. Compared to White patients, Black patients demonstrated comparable baseline characteristics at initial presentation, except for lower incidence of TCL with T-follicular helper phenotype (p=0.013), poor performance status (ECOG ≥ 2; p=0.005), and ≥2 sites of ENI (p=0.002). Treatment patterns for Black and White patients, including 1L chemotherapy, radiation therapy, CNS prophylaxis, HCT, and subsequent lines of treatment were not significantly different. On univariate analysis, response rates to initial therapy, PFS, and OS were similar for Black and White patients (Table 1). On multivariate analysis, race did not significantly impact OS (HR 0.72 [0.29-1.80], p=0.480) or PFS (HR 0.50 [0.17-1.47], p=0.206), though worse outcomes were observed with other established risk factors, including ECOG ≥ 2 (OS HR 3.32 [1.43-7.73], p=0.005), elevated LDH (OS HR 3.25 [1.37-7.71], p=0.008; PFS HR 2.29 [1.00-5.21], p=0.0.049), and low platelet count (OS HR=2.84 [1.22-6.60], p=0.015; PFS HR 2.73 [1.13-6.62], p=0.026). However, advanced stage was associated with better OS (HR 0.22 [0.09 -0.58], p=0.002). For both races, HCT in 1st remission was associated with significantly improved PFS (HR 0.03 [0.03-0.33], p=0.004) but not OS (HR 0.57 [0.14-2.35] p=0.44) (Table 2). Conclusion In this cohort of patients with TCL treated at an urban US tertiary care center with demographics reflective of the national population, we did not find outcomes affected by race despite the higher incidence of poor risk baseline prognostic factors in Black patients. Treatment patterns, including intensive therapy, use of transplant, and number of subsequent therapies, were also not affected by race in our cohort. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CNS Relapse in T-Cell Lymphoma Index: A Risk Score to Predict Central Nervous System Relapse in Patients with T-Cell Lymphomas

Background: Central nervous system (CNS) relapse (CNSr) in patients with aggressive non-Hodgkin lymphoma is uncommon but carries a high morbidity and mortality. Data in T- and NK-cell lymphomas (TCL) are sparse, though the few small case series describing CNSr in TCL report an incidence up to 9% with median overall survival (mOS) less than 3 months (mo). We previously reported a large (n=75) case series of CNSr in TCL (Abstract #1382, ASH 2021). Herein, we developed a prediction score for CNSr in newly diagnosed patients with TCL. Methods: We retrospectively collected clinicopathologic and treatment data from 19 US academic centers from patients diagnosed with TCL between 1/1/09-1/1/19 who experienced CNSr (CNSr cohort). We combined these data with that from patients diagnosed with TCL without CNSr from a single institution (Penn cohort) to create a training set (T-set) enriched for patients with CNSr. Patients with leukemic or cutaneous TCL subtypes were excluded. We applied a LASSO Cox proportional hazards model to the T-set to create a predictive score for factors associated with CNSr and validated this score in an independent population-based validation set (V-set) from the Swedish Lymphoma Registry, which was not enriched for CNSr. Results: We evaluated data from 91 and 135 patients in the CNSr and Penn cohorts, respectively, which were combined to form the T-set and compared them to the V-set (n=745). Median age in the T-set was lower than in the V-set (60 vs 67; p<0.001). The most common TCL subtypes in the T-set and V-set were peripheral TCL, not otherwise specified (PTCL, NOS; 23% vs 34%, respectively; p=0.002), TCL with T-follicular helper phenotype (23% vs 14%, respectively; p=0.001), and ALK-negative anaplastic large cell lymphoma (18% vs 15%, respectively; p=0.352). CNS prophylaxis, defined as intrathecal therapy or high-dose methotrexate, was more common in the V-set than in the T-set (15% vs 9%, respectively; p=0.012). Rates of stem cell transplantation (SCT) as consolidation in first remission (CR1) did not differ significantly between the T-set and V-set (p=0.140). The median follow-up time was 37.6 mo in the T-set and 95.9 mo in the V-set. The median progression free survival (mPFS) and mOS after diagnosis were 9.8 mo and 33.2 mo in the T-set, respectively, and 8.5 mo and 17.9 mo in the V set, respectively. Within the T-set, mPFS and mOS were shorter for patients in the CNSr cohort vs the Penn cohort (6.0 mo vs 37.1 mo [p<0.001] and 17.3 mo vs 78.1 mo [p<0.001], respectively). In univariate analysis of the CNSr-enriched T-set, CNS prophylaxis, SCT in CR1, or frontline etoposide did not significantly decrease the risk of CNSr. Using several clinicopathologic characteristics, we fitted a LASSO Cox proportional hazards model to the T-set, which selected histology, LDH, stage, B-symptoms, and ≥2 sites of extranodal involvement (ENI) for a weighted risk score of CNSr (Fig. 1A). Variables most strongly associated with CNSr were PTCL, NOS (HR 2.64), enteropathy-associated TCL (HR 2.92), and ≥2 sites of ENI (HR 2.66). We stratified the T-set into tertiles based on weighted scores (x), which was low-risk if x≤0.14, intermediate-risk if 0.14<x ≤1.11, or high-risk if x>1.11. Cumulative incidence of CNSr in each respective group was 19.6%, 55.1%, and 83.7%. When the same cutoffs were applied to weighted scores in the V-set, we confirmed separation into distinct low-, intermediate-, and high-risk groups with cumulative incidences of CNSr of 1.9%, 4.9%, and 7.3%, respectively (Fig. 1B). As the V-set population was not enriched for CNSr, the relative incidence is expectedly lower compared to the T-set. Compared to the low-risk group in the V-set, risk of CNSr was significantly increased in the high-risk group (HR 5.72, p=0.002) and increased with a trend toward significance in the intermediate-risk group (HR 3.35, p=0.057). Conclusions: In a cohort of patients with TCL enriched for CNSr, we were able to characterize several risk factors associated with CNSr and developed a predictive CNSr in T-cell lymphoma Index (CITI) that could stratify patients into 3 distinct risk groups. PTCL, NOS, EATL, and ≥2 sites of ENI had the highest impact on risk of CNSr. The CITI score was validated in an independent population-based cohort. Although CNSr was uncommon even in high-risk patients (7.3%), our data will inform clinical decision making and may allow for identification of patients with TCL at high-risk of CNSr in future studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinicopathologic Determinants of Subcutaneous Panniculitis-like T-Cell Lymphoma (SPTCL) Clinical Outcomes: Analysis of a Pooled Database

Introduction Subcutaneous Panniculitis-like T-cell Lymphoma (SPTCL) is a rare subtype of extra-nodal Peripheral T-cell Lymphoma. SPTCL was initially described as an aggressive T-cell lymphoma frequently associated with hemophagocytic syndrome (HPS) and requiring aggressive multiagent chemotherapy. In 2005, this entity was restricted to SPTCL with αβ phenotype, a less aggressive entity compared to its γδ counterpart, currently known as primary cutaneous γδ T-cell lymphoma. We conducted this analysis to explore the determinants of clinical outcomes in this little-known subtype of Peripheral T-cell Lymphoma. Methods To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 214 cases. Descriptive statistics were calculated. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS) and disease-free survival (DFS). Results A total of 214 patients with confirmed SPTCL diagnosis were identified. The median age was 34 years with a peak incidence between ages 13 and 26. There was a female predominance with F:M ratio of 1.7. Upon presentation, 12% had lymphadenopathy, 12% had hepatosplenomegaly, and 27% had bone marrow involvement. No extra-nodal or extra-cutaneous involvement were reported. The most common clinical presentations were nodular skin changes (87%) followed by constitutional symptoms (57%). Fifteen and ten percent of SPTCL patients had history of immune-deregulatory disorders and immunosuppressive therapies, respectively. HPS occurred in 24% of the cases. Fat necrosis and dermal involvement were noted in 9% and 17%. The median duration of symptoms prior to diagnosis was 4 months. Median DFS of the whole group was 60 months. While the median OS of the whole group was not reached, the mean overall survival was 73 months. OS was not impacted by sex, constitutional symptoms, immunocompromising factors, presence of lymphadenopathy, hepatosplenomegaly, or bone marrow involvement. OS was not impacted by histological or immunohistochemical features though there was a trend for better OS as well as DFS for TIA-1 expressors. OS and DFS declined as age increased from <19 to 20-39 and >40 years. HPS negatively impacted OS and DFS, but with borderline significance with the latter. Attaining complete remission positively impacted both OS and DFS. Stem cell transplant positively impacted OS and DFS, but with borderline significance with the former. Conclusions This study presents a comprehensive clinicopathologic data from a pooled cohort of patients with SPTCL. It describes the clinicopathologic features of SPTCL and identifies major clinical, immunohistochemical, and therapeutic modalities that are major determinants of OS and DFS in this rare disease.