Rituximab-containing Chemotherapy Research Articles

The impact of marginalization on diffuse large B-cell lymphoma overall survival: a retrospective cohort study

The aim of this study was to describe the impact of marginalization on DLBCL overall survival (OS) within the Canadian setting. We conducted a population-based retrospective cohort study of adult patients with newly diagnosed DLBCL in Ontario between 1 January 2005 and 31 December 2017 receiving a rituximab-containing chemotherapy regimen with curative intent followed until 1 March 2020. Our primary exposure of interest was the Ontario Marginalization Index (ON-Marg). The primary outcome was 2-year OS, accounting for patient age, sex, cancer characteristics, comorbidity burden, and rural dwelling status. While two-year overall survival was inferior for individuals in the most deprived marginalization quintile (70.4% Q5 vs. 76.0% Q1), after adjustment for relevant covariates neither the composite ON-Marg nor any of its dimensions had a significant effect. Within the Canadian context, among patients who receive chemotherapy, marginalization may not have a significant association with overall survival when accounting for key patient covariates, lending support for preserved outcomes.

Primary Extranodal Diffuse Large B-cell Lymphoma Presenting in the Lips: A Case Report and Literature Review.

Approximately 30-40% of malignant lymphomas are classified as diffuse large B-cell lymphoma (DLBCL), with 30% of DLBCL cases manifesting as extranodal lymphomas. Among these extranodal DLBCLs, primary DLBCL in oral lesions, particularly in the lips, is rare. While the treatment methods, chemotherapy assessment, and prognosis for nodal and extranodal DLBCLs are generally similar, diagnostic challenges can lead to delayed therapeutic intervention. We herein present a recent case of primary extranodal DLBCL in the lips that was swiftly diagnosed and managed using rituximab-containing chemotherapies. Our experience underscores the important role that hematologists play in identifying the possibility of oral hematological tumors, thereby allowing for a rapid diagnosis and timely intervention.

Addition of High-Dose Methotrexate to Initial Chemotherapy Improved Treatment Outcome of Patients with Newly Diagnosed Intravascular Large B-Cell Lymphoma: A Multicenter, Retrospective Study

[Introduction] Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of diffuse large B-cell lymphoma characterized by selective growth of lymphoma cells in the lumina of small vessels. Although the clinical outcomes of IVLBCL before rituximab era were dismal, a retrospective analysis published in 2008 showed improved outcomes for patients treated with rituximab-containing chemotherapy (R-chemo). Furthermore, a recent multicenter, single-arm, phase II trial conducted in Japan (PRIMEUR-IVL study) supports the usage of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone combined with high-dose methotrexate (HD-MTX) and intrathecal chemotherapy (IT), with a 2-year Overall survival (OS) of 92% and 2-year progression-free survival (PFS) of 76% in a selected population with newly diagnosed IVLBCL. However, this trial did not include a control arm, making it difficult to evaluate whether the addition of HD-MTX improves the treatment outcome. Thus, with the largest cohort (we already reported at ASH 2022), we retrospectively evaluated the efficacy of the HD-MTX in real-world settings. [Methods] Patients with histopathologically proven newly diagnosed IVLBCL according to the 2008 World Health Organization criteria between January 2010 through February 2022 from hospitals participating in the North Japan Hematology Study Group were included. Survival analysis was limited to patients with serum creatinine < 2.0 mg/dL and aged 20-79 years, following the eligibility criteria of the PRIMEUR-IVL study. PFS was defined as the time from the start of treatment to the first of progression, relapse, or death from any cause. Patients undergoing upfront autologous stem-cell transplantation (auto-SCT) were censored at the time of transplantation. [Results] A total of 110 IVLBCL cases were identified. Eighty-six patients with serum creatinine < 2.0 mg/dL, aged 20-79 years, received chemotherapy. Eighty-five of 86 patients (98.8%) received R-chemo. Thirty-six of 86 patients (41.9%) received HD-MTX during the initial therapy (w HD-MTX group), and 50 patients (58.1%) did not (w/o HD-MTX group). Fifty-six patients (65.1%) received IT. Six patients (7.0%) received upfront auto-SCT. Complete response (CR), no change (NC), and primary refractory disease were noted after initial therapy by 62 (72.1%), 11 (12.8%), and 11 (12.8%) patients, respectively. The disease progression after achieving NC was noted in 3 patients (3.5%). Fourteen patients (16.3%) experienced a relapse after achieving CR. Eight of 28 recurrences (progressions or relapses) were neurolymphomatosis forms, and 7 were central nervous system (CNS) recurrences. Twenty-five patients (29.1%) died, and 21 were due to disease progression. Compared clinical characteristics of the w HD-MTX group with the w/o HD-MTX group, the proportion of patients older than 60 years, male sex, poor performance status (ECOG PS > 1), elevated serum LDH, Ann Arbor stage III-IV and 2 or more extra-nodal lesions were not significantly different. The number of patients who received IT was significantly higher in the w HD-MTX group (77.8% vs. 56.0%, P = 0.042). Median follow-up duration for censored cases was 47.1 months (range, 7.4-130.7 months) in w HD-MTX group and 33.0 months (range, 1.78-140.5 months) in w/o HD-MTX group. Two-year PFS and OS were 73.1% (95% CI, 54.5-85.0) and 85.0% (95% CI, 67.5-93.5), respectively, in the w HD-MTX group and 54.7% (95% CI, 38.6-68.3) and 69.2% (95% CI, 53.2-80.6), respectively, in the w/o HD-MTX group (log-rank test, P = 0.016 and P = 0.005, respectively; Fig. a, b). The w HD-MTX group and the w/o HD-MTX group showed no significant difference in the cumulative incidence of CNS recurrence at 2 years (8.7%; 95% CI, 2.2-21.0 vs. 6.6%; 95% CI, 1.7-16.5, Gray test, P = 0.98). In univariate analysis, male gender, the addition of IT, and the addition of HD-MTX were significantly associated with PFS and OS ( Table). Multivariate analysis demonstrated that the addition of HD-MTX was independently associated with both PFS and OS. No HD-MTX-related deaths occurred in the w HD-MTX group. Adverse events related to HD-MTX were observed in 24 of 36 patients (66.7%), with grade 3 or 4 non-hematological adverse events in 3 patients (8.3%). [Conclusion] In conclusion, this largest retrospective study showed that the addition of HD-MTX to initial chemotherapy improved the treatment outcome of patients with newly diagnosed IVLBCL.

Rituximab Combined with Chemotherapy and Acalabrutinib Prior to Autologous Stem Cell Transplantation in Mantle Cell Lymphoma: The Rectangle Trial

INTRODUCTION In the European MCL Network Triangle study (Dreyling, ASH 2022) the addition of ibrutinib to frontline rituximab-containing chemotherapy and subsequent maintenance therapy improved failure-free survival in young, fit patients with mantle cell lymphoma (MCL). Ibrutinib was administered with R-CHOP, but not with R-DHAP, during the induction phase. Continuous, uninterrupted Bruton Tyrosine Kinase (BTK) inhibition could maximize the benefit of front-line therapy given that responses develop over time. Acalabrutinib has less off-target BTK inhibition than ibrutinib. We hypothesize that combining continuous acalabrutinib with R-CHOP may result in a tolerable, outpatient, highly active regimen producing favorable outcomes. METHODS NCT04566887 is a phase II, single-arm, open-label study conducted across 5 academic centres in Canada. Patients ≥ 18 years of age with previously untreated MCL, ECOG performance status 0-2, adequate organ function and considered fit for autologous stem cell transplantation (ASCT) were included. Patients received 6 cycles of R-CHOP at standard doses plus acalabrutinib 100 mg twice per day orally. Responding patients proceeded with ASCT and maintenance rituximab and acalabrutinib for a total of 2 years. The primary endpoint was the complete response (CR) rate after 6 cycles of induction with centrally reviewed PET/CT using the Lugano Criteria (Cheson, 2014). The total sample size was n=54 and the study completed accrual in May 2023. We present the results of the first 43 patients who have completed response assessment according to local investigators after 6 cycles of induction. RESULTS The median age was 62 years (range 38 - 69), 26 (60%) were male, 42 (98%) had performance status 0-1, 33 (78%) Ann Arbor stage IV, 35 (81%) bone marrow involvement, 6 (14%) high risk MIPI, 7 (16%) blastoid/pleomorphic morphology, 11 (26%) Ki67 ≥30%. All patients completed 6 cycles of induction and proceeded to ASCT. The overall response rate was 100%, and 39 (91%) patients achieved a CR. All patients started maintenance acalabrutinib + rituximab, although none have yet completed two years of protocol maintenance therapy. With a median follow up of 11.8 months (range 3.4 - 25.3) by the reverse Kaplan-Meier method, the 12-month PFS was 94% (95% CI 78.1 - 98.5), shown in Figure 1, and OS 95.5% (95% CI 71.9 - 99.3). Three subjects have developed PD so far, all with adverse clinical and biological factors: Baseline high-risk MIPI and Ki67 70%; biopsy at relapse TP53 positive by immunohistochemistry (IHC)Baseline intermediate risk MIPI and Ki67 60%; biopsy at relapse with pleomorphic morphology, TP53 positive by IHC, Ki67 100%Baseline high risk MIPI, Ki67 ≥30%, and blastoid morphology. Table 1 lists common grade 3-4 adverse events (AE) during induction and maintenance. There were no grade 5 AE. Neutropenia was the most common AE during induction and maintenance. Most infections were respiratory. Cardiovascular toxicity was uncommon. CONCLUSIONS Acalabrutinib + R-CHOP is associated with a 91% CR rate with low rates of grade 3-4 AE expected for this combination. All patients have proceeded to ASCT and subsequent maintenance therapy. Maintenance therapy in this setting is associated with additional toxicity, particularly cytopenias and infections.

Whole Exome Sequencing Analysis of Diffuse Large B-Cell Lymphoma That Progressed to Central Nervous System

Background: Recent sequencing analyses have identified distinct genetic subtypes of diffuse large B-cell lymphoma (DLBCL). The MCD subtype, characterized by MYD88 L265P and CD79B gene mutations, is frequently found in DLBCL that progresses to the central nervous system (CNS), known as secondary CNS lymphoma (sCNSL) (Ollila, Blood 2021). In addition, the MCD subtype is also frequently found in primary CNS lymphoma (PCNSL) (Radke, Nat commun 2022). Therefore, we hypothesized that specific genetic alterations that are present in the initial DLBCL tumors are associated with their progression to the CNS. We aimed to investigate i) the clinical impact of genetic subtypes of DLBCL and ii) genomic mutations that may be associated with sCNSL. To this end, genetic alterations in DLBCL samples at diagnosis that later developed into sCNSL were evaluated using whole-exome sequencing (WES). Methods: A total of 44 patients with DLBCL who developed sCNSL after receiving standard rituximab-containing chemotherapy between 2009 and 2020 were identified from five institutions. sCNSL was diagnosed on the basis of imaging and/or pathological findings. Genomic DNA (gDNA) was extracted from formalin-fixed, paraffin-embedded tumor samples obtained at the initial diagnosis of DLBCL. Finally, 26 of the 44 samples with sufficient gDNA were subjected to WES at BGI Genomic Co. Ltd. Single-nucleotide variants and short indels were detected using Mutect2 and filtered as described in Figure 1. Genetic subtypes were determined using the LymphGen algorithm (https://llmpp.nih.gov/lymphgen/index.php). The association between the clinicopathological features and genetic subtypes was also evaluated. In addition, recurrently mutated genes (>10% in our cohort) were identified and their alteration frequencies were compared with those in a representative general DLBCL cohort (N=574, available in the article by Schmitz, NEJM 2018) and PCNSL cohort (N=30, whole genome sequencing performed, available in the article by Radke, Nat Commun 2022) (Figure 1a). Results: The median age of the 26 patients was 69 years (range, 34-87). At the time of CNS progression, 54, 27, and 19% of the patients had parenchymal CNS disease, extraparenchymal CNS disease, and both, respectively. Immunohistological analysis showed that the non-germinal center B-cell-like (GCB) type, as defined using the Hans algorithm, and dual expression of MYC and BCL2 (DEL) were identified in 65% and 69% of patients, respectively. The median overall survival (OS) from CNS relapse was 16 months (95% confidence interval, 2-30). WES analysis showed that the median mean coverage depth of the 26 samples was 140 (range, 53-299). The median mapping rate was 94% (range, 80-99). As expected, the most frequently mutated genes in our cohort were MYD88 (50%), PIM1 (50%), BTG2 (31%), and CD79B (31%), corresponding to the MCD subtype. The LymphGen algorithm classified the 26 samples into MCD (n=12, 46%), EZB (n=5, 19%, including one with a composite feature of ST2), BN2 (n=1, 4%) and “not classified” (n=8, 31%) (Figure 1b). The CNS-IPI risk, DEL status, and CNS relapse sites did not differ among the genetic subgroups. In addition, univariate analysis showed that non-GCB status, DEL status, and genetic subtype at initial diagnosis did not influence OS. Next, we shortlisted 38 genes whose mutations were identified in three or more samples (>10%) of our cohort as well as in >10% of the PCNSL cohort (by Radke, Nat Commun 2022). We further selected genes that were less frequent (<3%) in the general DLBCL cohort and identified several genes, such as MUC16 and FAT4, that were more enriched in PCNSL and our sCNSL cases (Figure 1a). Metascape analysis (https://metascape.org/gp/index.html#/main/step1) revealed that the top three enriched processes associated with these genes were sensory organ development, cell adhesion via plasma membrane adhesion molecules, and morphogenesis of epithelium. Conclusion: Our study confirmed that MCD was a major genetic subtype of DLBCL that developed sCNSL. We identified recurrently mutated genes that were common in both sCSNL and PCNSL but not in the general DLBCL cohort; these genes may be associated with CNS progression. Validation of our results and investigation of the functions of these genes will help to understand the mechanisms of CNS relapse and develop more accurate markers to predict sCNSL. *Suzuki T and Yokomori R equally contributed to this study.

FIVE‐YEAR RESULTS OF A PHASE 2 STUDY OF CNS‐ORIENTED THERAPY WITH R‐CHOP FOR UNTREATED INTRAVASCULAR LARGE B‐CELL LYMPHOMA: FINAL ANALYSIS OF THE PRIMEUR‐IVL STUDY

Introduction: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity of extranodal large B-cell lymphoma characterized by selective growth of lymphoma cells in the lumina of small vessels. The prognosis of IVLBCL is typically poor without timely diagnosis. Based on the promising efficacy of rituximab-containing chemotherapy and a high incidence of secondary central nervous system (CNS) involvement after rituximab-chemotherapy, we conducted the PRIMEUR-IVL study to explore the efficacy of CNS-oriented therapy with rituximab-chemotherapy whose primary analysis demonstrated 2-year progression-free survival (PFS) of 76% and 2-year overall survival (OS) of 92% with a low incidence of secondary CNS involvement of 3%. Patients and Methods: The PRIMEUR-IVL study is a multicenter, single-arm, phase 2 trial at 22 hospitals in Japan for untreated histologically confirmed IVLBCL patients without apparent CNS involvement at diagnosis. The treatment regimen includes three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) followed by two cycles of rituximab with high-dose methotrexate and additional three cycles of R-CHOP. Intrathecal chemotherapy including methotrexate, cytarabine, and prednisolone was administered four times during the R-CHOP phase. We present a preplanned final analysis of the PRIMEUR-IVL study including 5-year PFS, OS and secondary CNS involvement. Results: A total of 38 patients were enrolled, of whom 37 patients were eligible. One patient with a history of testicular lymphoma was excluded. As of July 2021, with a median follow-up of 7.1 years (interquartile range 5.6–8.7), 5-year PFS in all eligible patients was 68% (95% confidence interval [CI] 50%–80%) and OS was 78% (95% CI 61%–89%). Median PFS and OS were not reached. No additional secondary CNS involvement was observed after primary analysis with 3% of cumulative incidence. Severe adverse events after the primary analysis were grade 4 neutropenia (n = 1) and grade 4 myelodysplastic syndrome that did not require specific treatment (n = 1). During the observation period after enrollment, there were a total of eight deaths due to following reasons: primary disease (n = 6), sepsis (n = 1), and unknown sudden death (n = 1). Conclusions: In this 5-year, long-term follow-up analysis of the PRIMEUR-IVL study, frontline treatment of CNS-oriented therapy with standard R-CHOP for untreated IVLBCL patients without apparent CNS involvement provided durable response and clinically meaningful results for PFS, OS, and low incidence of secondary CNS involvement with manageable toxicity. Our result provides one of active treatment for untreated IVLBCL patients. The research was funded by: The Practical Research for Innovative Cancer Control, the Japan Agency for Medical Research and Development (AMED), Japan, JP19ck0106511 and the National Cancer Center Research and Development Fund, 23-A-17 and 26-A-4. The research was supported by the Center for Supporting Hematology-Oncology Trials (C-SHOT). Keyword: chemotherapy Conflicts of interests pertinent to the abstract K. Shimada Honoraria: AstraZeneca, Chugai, Eisai, Kyowa Kirin, Symbio M. Yamaguchi Honoraria: AbbVie, Bristol Myers Squibb, Chugai, Janssen, Kyowa Kirin, Meiji Seika, MSD, Nippon Shinyaku, SymBio, Takeda Research funding: AstraZeneca, Chugai Pharma, Genmab, Incyte, Eisai, Takeda, Nippon Shinyaku, Otsuka, Asahi Kasei, Kyowa Kirin, Chugai H. Nagai Honoraria: Kyowa Kirin, Takeda, Chugai, Bristol Myers Squibb, Eisai, Novartis, Janssen, Mundi Pharma, Lilly, AstraZeneca, Ono, Meiji, AbbVie, Nippon Shinyaku, GSK, Sumitomo Pharma, Genmab, CSL Behring Research funding: Kyowa Kirin, Takeda, Chugai, Bristol Myers Squibb, Janssen, AstraZeneca, Ono, AbbVie, Nippon Shinyaku, Daiichi-Sankyo, Zenyaku Kogyo, Solasia J. Takizawa Honoraria: Chugai, Kyowa Kirin N. Fukuhara Honoraria: Chugai, Genmab, AbbVie, Takeda, Eli Lilly, AstraZeneca, Meiji Seika, Ono, Janssen, Bristol-Myers Squibb, Eisai, Kyowa Kirin, Symbio, Novartis Research funding: Chugai, Genmab, AbbVie, Takeda, Eli Lilly, Incyte, Chordia Therapeu D. Ennishi Honoraria: Eisai, Kyowa Kirin, Chugai Research funding: Nippon Shinyaku, Chugai Y. Minami Consultant or advisory role: Takeda, Novartis Honoraria: Bristol-Myers Squibb, Novartis, Pfizer, Daiichi Sankyo, Astellas Research funding: CMIC, Bristol-Myers Squibb, Novartis, Takeda, Chugai, Ono Y. Atsuta Consultant or advisory role: Meiji Seika, JCR Pharmaceuticals, Kyowa Kirin Honoraria: Novartis, AbbVie H. Kiyoi Honoraria: Novartis, Astellas, AbbVie, Chugai Research funding: Zenyaku Kogyo, Nippon Shinyaku, Chugai, Astellas, Kyowa Kirin, Takeda, Sumitomo Pharma, Sanofi, Eisai, Ono, FUJIFILM, Kyowa Kirin, Otsuka, Perseus Proteomics, Daiichi Sankyo, CURED, Bristol-Myers Squibb, AbbVie

Iterated cross validation method for prediction of survival in diffuse large B-cell lymphoma for small size dataset

Efforts have been made to improve the risk stratification model for patients with diffuse large B-cell lymphoma (DLBCL). This study aimed to evaluate the disease prognosis using machine learning models with iterated cross validation (CV) method. A total of 122 patients with pathologically confirmed DLBCL and receiving rituximab-containing chemotherapy were enrolled. Contributions of clinical, laboratory, and metabolic imaging parameters from fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scans to the prognosis were evaluated using five regression models, namely logistic regression, random forest, support vector classifier (SVC), deep neural network (DNN), and fuzzy neural network models. Binary classification predictions for 3-year progression free survival (PFS) and 3-year overall survival (OS) were conducted. The 10-iterated fivefold CV with shuffling process was conducted to predict the capability of learning machines. The median PFS and OS were 41.0 and 43.6 months, respectively. Two indicators were found to be independent predictors for prognosis: international prognostic index and total metabolic tumor volume (MTVsum) from FDG PET/CT. For PFS, SVC and DNN (both with accuracy 71%) have the best predictive results, of which outperformed other algorithms. For OS, the DNN has the best predictive result (accuracy 76%). Using clinical and metabolic parameters as input variables, the machine learning methods with iterated CV method add the predictive values for PFS and OS evaluation in DLBCL patients.

Long-Term Activity of Combining CNCT19 with HDT/ASCT in Refractory Large B-Cell Lymphoma: Two-Year Follow-up of a Prospective Phase 1/2 Clinical Trial

Background: We have previously reported the preliminary results of a phase 1/2 clinical trial of administrating CNCT19 (a second-generation anti-CD19 CAR T-cell) following high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT) in large B-cell lymphoma (LBCL) patients with diseases refractory to first-line and/or subsequent lines of chemotherapy. Eight of 10 (80%) patients achieved complete response (CR), and the estimated proportion of progression-free survival (PFS) and overall survival (OS) at 12 months was 66.7% and 77.1%, respectively (Wei liu et al. ASH 2019, 2020). Here we reported this study's updated enrollment, efficacy, and follow-up. This trial was registered at www.chictr.org.cn as ChiCTR1900025419. Methods: Patients with LBCL with a history of refractory to first-line rituximab-containing anthracycline-based chemotherapy and/or subsequent salvage chemotherapy were eligible for this study. Conditioning regimen of GBC/M (Gemcitabine 600 mg/m2/h, infused for 3 hours with loading bolus of 75 mg/m2, day -7, -3, busulfan 105 mg/m2, day -7 until -5, cyclophosphamide 45mg/kg or melphalan 60 mg/m2, day -3, -2) was administered once the CNCT19 product was available. Autologous stem cells were infused on day 0, and CNCT19 cells were infused on day +3 (±1 day). Cytokine release syndrome (CRS) and CAR-T-cell-related encephalopathy syndrome (CRES) were graded according to the CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group criteria. Results: From December 2017 through May 2021, 21 subjects were consecutively enrolled in this study. CNCT19 cells were successfully manufactured for 20 subjects and administered to 18 subjects. The median age was 44 (range 23 to 64), and 56% were male. Patients included 11 (67%) with diffuse large B-cell lymphoma (not otherwise specified), 4 (22%) with high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangement, 2 (11%) with primary mediastinal large B-cell lymphoma and 1 (6%) with transformed follicular lymphoma. The median number of lines of prior therapy was 3 (range, 2 to 5). Eighty-nine percent of patients had a history of refractory to first-line immunochemotherapy of R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, prednisone) or R-DA-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and adriamycin), and 72% were refractory to subsequent platinum-based salvage therapy. TP53 deletion and/or mutation were detected in 7 of 11 (64%) patients. The median dose of infused stem cells was 2.6×106 (range, 1.8~8.7×106) per kilogram of body weight and the median dose of infused CNCT19 cells was 2×106 (range, 1.6~4.0×106) per kilogram of body weight. The CRS occurred in 16 patients (89%), and all were low grades (grade 1, 83%; grade 2, 6%). CRES occurred in two patients on day 5 and day 6 after CNCT19 infusion, respectively. Both of the ICANS were grade 4 and resolved completely after glucocorticoids treatment. We did not observe any unexpected toxicity or treatment-related death throughout the therapy. The median times to neutrophil and platelet recovery were ten days (range, 8 to 30 days) and 16.5 days (range, 8 to 265 days) after stem cells reinfusion, respectively. As of July 26, 2022, the median follow-up from CNCT19 infusion to the data-cutoff date was 28.2 (95% CI 16.9-39.1) months. The best overall response rate was 94.4%, with a best CR rate of 72.2%. The median PFS, duration of response (DOR), disease-free survival (DFS) and OS were not reached, and the probability of 2-year PFS, DOR, DFS and OS were 59.3% (95% CI 32.5%-78.4%), 63.5% (95% CI 35.9%-81.8%), 74.1% (95% CI 39.1%-90.9%) and 64.2% (95% CI 36.2%-82.4%), respectively. Of the patients who were in durable response at three months or six months post CNCT19 infusion, 66.7% and 83.3% were in ongoing response at the date of data cutoff, respectively. Conclusions: CNCT19 could be safely administered following HDT/ASCT in patients with relapsed or refractory LBCL. The strategy of combining CAR T-cell therapy with HDT/ASCT might improve response rate and prolong survival compared to CAR T-cell therapy alone.

Elevated FDG Uptake in the Lung Is a Characteristic Finding of Intravascular Large B-Cell Lymphoma

[Introduction] Intravascular large B-cell lymphoma (IVBCL) is a rare subtype of extra-nodal diffuse large B-cell lymphoma (DLBCL), characterized by preferential growth of lymphoma cells within the lumina of small vessels. Clinical presentation of IVBCL is highly variable, and it often includes organ dysfunction related to obstruction of blood vessels. Up to 80% of IVBCL cases experienced hypoxemia at initial presentation, suggesting a high rate of respiratory involvement. In recent years, some IVBCL cases with diffuse pulmonary uptake on 18F-fluorodeoxyglucose (FDG) PET/CT have been reported from Asia and Western countries. It may also reflect the pulmonary infiltration of IVBCL; however, there are no reports of detailed studies with a large number of IVBCL cases. [Methods] We retrospectively evaluated patients with histopathologically proven newly diagnosed IVBCL according to the 2008 World Health Organization criteria between January 2010 through February 2022 from hospitals participating in the North Japan Hematology Study Group (NJHSG). PET/CT images were reviewed by an experienced nuclear medicine physician (S.W.). In addition to the general PET/CT evaluation, the ratio of the lung to mediastinum standardized uptake value (SUV) peaks (L/M ratio) was calculated to assess the degree of FDG accumulation in the lungs objectively. Lung SUV peaks were measured uniformly about 1 cm medial to the right lower lobe pleura, and mediastinum SUV peaks were measured in the left atrium. The L/M ratio of 226 advanced stage DLBCL cases diagnosed within the same periods was also calculated and compared with IVBCL cases. [Results] We identified fifty-one IVBCL patients (age 30-89 years, median 65 years; 56.9% male) who performed PET/CT at diagnosis, and 29 of whom also underwent after chemotherapy. IVBCL was diagnosed via skin biopsy in 31 (60.8%) cases, bone marrow biopsy in 15 (29.4%) cases, and lung biopsy in 8 (15.7%) cases. Hypoxemia were observed in 25 (49.0%) patients. Twenty-eight (54.9%) patients had poor performance status (ECOG score ≥2). Elevated LDH level was observed in 48 (94.1%) cases (median, 631 IU/L; range, 147-4907 IU/L). Diffusely elevated FDG uptake was seen at the lung in 28 (54.9%) patients, bone marrow in 40 (78.4%), and spleen in 32 (62.7%). Chest CT evaluation revealed that ground-glass opacity lesion corresponding to the areas of FDG accumulation on PET was observed in 14 of 28 patients. At diagnosis, the median L/M ratio was significantly higher in IVBCL patients than in DLBCL patients (IVBCL: median, 0.903; range, 0.22-2.583 vs. DLBCL: median, 0.421; range, 0.177-0.639, P < 0.0001, Fig.). ROC analysis revealed that the cutoff value of the L/M ratio of 0.649 predict IVBCL diagnosis. Area under curve was 0.916 (95% CI: 0.859-0.974). Thus, we classified patients with a threshold of 0.649 for the definition of "high” or "low” levels of the L/M ratio. At the time of diagnosis, 38 of 51 (74.5%) IVBCL cases were classified as having a high L/M ratio. The L/M ratio decreased to low levels in all patients who underwent FDG PET/CT after chemotherapy (median, 0.471; range, 0.269-0.647, Fig.). The high L/M ratio was significantly correlated with diffuse FDG uptake in the lung (P < 0.0001), bone marrow (P = 0.0507) and spleen (P < 0.001) and the presence of hypoxemia (P < 0.01). Surprisingly, 14 of 26 (53.8%) patients who did not present with hypoxemia showed high L/M ratio. Fifty (98%) patients received rituximab-containing chemotherapy. Of the patients treated, 13 (26%) patients experienced a relapse, and 9 (18%) patients eventually died. The 2-year overall survival (OS) was 84.6 % (range, 70.3-92.4 months). Median follow-up duration was 48.8 months (range, 4.7-140.5 months) in survivors. The L/M ratio did not stratify the prognosis significantly (L/M high: 2-year OS, 82.3%; 95% CI, 64.6-91.6 vs L/M low: 2-year OS, 90.9%; 95% CI, 64.6-91.6, P = 0.7). [Conclusion] To our knowledge, this is the largest study to assess pulmonary PET/CT findings in newly diagnosed IVBCL cases. A high L/M ratio was found in about 75% of patients with IVBCL while not in advanced stage DLBCL. Given that the L/M ratio decreased after treatment, the high L/M ratio reflects pulmonary infiltration of lymphoma cells. In cases of suspected IVBCL, FDG-PET can be a good indicator of whether to perform a lung biopsy, even in patients without hypoxemia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hemophagocytic lymphohistiocytosis as an onset of diffuse large B-cell lymphoma: A case report.

A 53-year-old male presented with a 1-month history of hyperpyrexia. The clinical manifestations revealed hemophagocytic lymphohistiocytosis (HLH). Although a lymph node biopsy could not be obtained, a bone marrow biopsy revealed the activated B-cell subtype of diffuse large B-cell lymphoma (DLBCL). After being treated with HLH-1994 (dexamethasone and etoposide), a rituximab-containing chemotherapy and target agents involving bortezomib, the patient achieved remission. To understand the molecular profile of patient, next-generation sequencing and MYD88 L265P mutation examinations were performed, and the patient was determined to be positive for the MYD88 L265P mutation. Reports of DLBCL with plasmacytic differentiation and a MYD88 innate immune signal transduction adaptor L265P mutation concurrent with HLH are rare. Early recognition, precise diagnosis and timely therapy are pivotal in improving patient prognosis. Furthermore, molecular profiling enables researchers to develop potential therapies aimed at the activated NF-κB and endoplasmic reticulum stress signaling pathways. The present study highlights this pathogenesis and provides suggestions for further individualized therapeutics.

Time trends in primary therapy and relative survival of diffuse large B-cell lymphoma by stage: a nationwide, population-based study in the Netherlands, 1989\u20132018

It is unclear whether survival in diffuse large B-cell lymphoma (DLBCL) continues to increase in an era where rituximab-containing chemotherapy reigns for almost two decades. Therefore, we evaluated trends in primary therapy and relative survival (RS) among Dutch DLBCL patients diagnosed between 1989 and 2018. Analyses were performed separately according to the stage I (N = 6952) and stage II–IV disease (N = 20,676), stratified by calendar period and age (18–64, 65–74, and ≥75 years). The use of chemotherapy ± radiotherapy increased over time across all age and stage groups. As of the mid-2000s, >95% of chemotherapy-treated patients received chemoimmunotherapy, irrespective of age and stage. Overall, RS increased significantly over time across all age groups, especially after 2003 when rituximab-containing chemotherapy had become the standard of care. However, RS increased less pronounced between 2003–2010 and 2011–2018 than between 1989–2002 and 2003–2010. These findings were congruent across all studied stage groups. Five-year RS across the three age groups during 2011–2018 was 96%, 84%, and 67% for stage I DLBCL and 75%, 60%, and 46% for stage II–IV DLBCL. Collectively, survival in DLBCL increased modestly beyond the initial introduction of rituximab, with apparent survival differences across age and stage that warrant novel treatment approaches.

Incidence and Characteristics of CD20 Monoclonal Antibody-Induced Interstitial Pneumonitis

Background:CD20 monoclonal antibody therapy is the backbone of treatment for B-cell non-Hodgkin lymphoma. Several studies have described an association between the use of rituximab and non-infectious interstitial pneumonitis, with estimates ranging from 3.9% to 8.4%. 1-3 However, several novel CD20 monoclonal antibodies have been introduced in the past decade, with obinutuzumab gaining FDA approval in 2013, ofatumumab first approved in 2014, and rituximab/hyaluronidase human approved as a subcutaneous route of rituximab in 2017. While the use of these agents has rapidly increased in clinical practice, the incidence of pneumonitis with these agents is not well known. Thus, we have performed a retrospective review of patients with B cell lymphoma treated with CD20 monoclonal antibody therapy to determine the incidence and characteristics of pneumonitis with these novel agents.Methods:We evaluated all patients at the University of North Carolina at Chapel Hill with B-cell lymphoma who were treated with CD20 monoclonal antibody therapy from 2014 to 2020. We performed individual chart review to verify the presence of interstitial pneumonitis, as defined by presence of respiratory symptoms (cough, dyspnea, fever, chest pain) in addition to imaging findings (pulmonary opacity on chest X-ray and/or ground glass opacities on chest computed tomography (CT)) without alternative cause (CHF with pulmonary edema, COPD flare, infectious cause including bacterial, fungal or viral pneumonia/bronchitis). We extracted demographic data, comorbid conditions, tobacco use history, and timing of pneumonitis related to CD20 monoclonal antibody exposure. We determined rates of pneumonitis based on agent and chemotherapy backbone.Results:We identified 18 cases of chart-confirmed interstitial pneumonitis over a six-year period, out of 2,207 patients treated with CD20-monoclonal antibody therapy. Seven (39%) were current or former smokers, with a median of 30 pack-years smoked. Five (29%) had a history of hypersensitivity reaction to rituximab infusion. Pneumonitis developed after a median of 4 cycles, and 16 days from the most recent CD20 monoclonal antibody infusion. Ten (56%) had diffuse large B-cell lymphoma, 4 (22%) had mantle cell lymphoma, and 1 (6%) each had follicular lymphoma, chronic lymphocytic leukemia, hairy cell leukemia, and Waldenstrom's macroglobulinemia. Eight cases (44%) occurred among patients being treated with R-CHOP, 2 (11%) were treated with BR, 2 (11%) were receiving single agent rituximab, although several other regimens were represented. Most cases occurred in patients being treated with infusional rituximab, but the rate remained quite low (14/1654, 0.8%). Four occurred in patients receiving subcutaneous rituximab hycela out of 167 treated patients (2.4%), less than prior estimates of pneumonitis with monoclonal antibody therapy. Most cases of pneumonitis were treated with steroids (n=15, 83%), although none required infliximab or anti-TNF agents, and no cases of pneumonitis were fatal. Most notably, we did not identify any cases of pneumonitis among patients treated with ofatumumab (n=51) or obinutuzumab (n=58).Conclusion:This retrospective review reinforced the safety of novel anti-CD20 agents, with low rates of interstitial pneumonitis among patients treated with infusional or subcutaneous rituximab. Cases that did occur were effectively treated with steroids, and there were no fatalities associated with pneumonitis. Ofatumumab and obinutuzumab were not associated with any cases of interstitial pneumonitis.Bibliography1. Katsuya H, Suzumiya J, Sasaki H, et al. Addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy has a high risk of developing interstitial pneumonia in patients with non-Hodgkin lymphoma. Leuk Lymphoma. 2009;50(11):1818-1823. doi:10.3109/104281909032587802. Salmasi G, Li M, Sivabalasundaram V, et al. Incidence of pneumonitis in patients with non-Hodgkin lymphoma receiving chemoimmunotherapy with rituximab. Leuk Lymphoma. 2015;56(6):1659-1664. doi:10.3109/10428194.2014.9630753. Liu X, Hong X-N, Gu Y-J, Wang B-Y, Luo Z-G, Cao J. Interstitial pneumonitis during rituximab-containing chemotherapy for non-Hodgkin lymphoma. Leuk Lymphoma. 2008;49(9):1778-1783. doi:10.1080/10428190802270886 [Display omitted] DisclosuresGrover: Novartis: Consultancy; Genentech: Research Funding; ADC: Other: Advisory Board; Kite: Other: Advisory Board; Tessa: Consultancy. Dittus: BeiGene: Other: Advisory Board; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding.

The Impact of Marginalization on Diffuse Large B-Cell Lymphoma Overall Survival: A Retrospective Cohort Study

Introduction: While health disparities in diffuse large B-cell lymphoma (DLBCL) have been previously noted, literature systematically describing the impact of social determinants of health (SDOH) on DLBCL overall survival (OS) is sparse. Furthermore, existing data largely examine SDOH of health in isolation, not accounting for key covariates or disease-related variables. Marginalization, which accounts for various SDOH, is a process of systemic discrimination and exclusion. Given the paucity of literature to date, we examined how marginalization influences DLBCL OS in the Canadian setting. The objectives of this study were: 1) To describe the impact of marginalization on DLBCL OS and 2) To identify which dimensions of marginalization, if any, impacted OS.Methods: We conducted a population-based retrospective cohort study of adult patients with newly diagnosed DLBCL in Ontario between January 1, 2005 to December 31, 2017 receiving a rituximab-containing chemotherapy regimen for curative intent, followed until March 1, 2020. Our primary exposure of interest was the Ontario Marginalization Index (ON-Marg), an administrative database tool which combines demographic indicators into four distinct marginalization dimensions: residential instability (% renters and % living alone), material deprivation (% low income and % lone parent families), dependency (% seniors and % employment), and ethnic concentration (% recent immigrants and % visible minority). Our primary outcome was 2-year OS, defined as time from the date of first rituximab-based treatment to date of death or completion of follow-up. Survival curves were generated using Kaplan-Meier methods, and Cox regression analyses were used to identify covariates that were independently associated with OS. Our final model adjusted for age (as increments of 10 years), sex, and comorbidity burden as measured by aggregate diagnostic groups (ADGs).Results: A total of 10,344 patients were diagnosed with DLBCL and treated with a rituximab-containing regimen in Ontario between January 1, 2005 and December 31, 2017. The median age was 67 (IQR, 55-75) and 46% were female. Of patients who had staging data (49%), 54% were advanced stage at diagnosis, and the median number of cycles of chemoimmunotherapy received was 6 (4-6). Median number of ADGs was 10 (8-12), indicating a moderate-to-high burden of comorbidities within this cohort, and 13% of patients resided in a rural area. Cohort characteristics and mortality rates per ON-Marg quintile (Q5 = most marginalized) are provided in Table 1. Overall, group characteristics were evenly distributed, except that the most marginalized group had a higher proportion of patients residing in urban settings and nearer to treatment hospitals. Two-year overall survival was 73.2%. After controlling for relevant confounders, material deprivation (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.02 - 1.10, p=0.003) and ethnic concentration (HR 1.05, 95% CI 1.01 - 1.09, p=0.013) contributed to increased risk of all-cause mortality. Residential instability and dependency had no significant effect. Increasing age (HR 1.29, 95% CI 1.25 - 1.33, p<0.0001) and increasing number of ADGs (HR 1.028, 95% CI 1.025 - 1.031, p<0.0001) were also associated with increased risk of all-cause mortality, while female sex was found to be protective (HR 0.89, 95% CI 0.83 - 0.97, p=0.005).Discussion: To our knowledge, no study has examined the impact of marginalization and collective SDOH on DLBCL outcomes. We found that increased material deprivation and ethnic concentration conferred increased mortality. While Canada's largely single-payer system and previously documented healthy immigrant effect may have been expected to attenuate effects of income and immigration, our study suggests otherwise. Possible explanations may include barriers to healthcare access for patient subsets, who may have less support for treatment. Structural factors such as systemic racism, health literacy, and caregiver burden must also be taken into account. These factors require further evaluation to inform targeted interventions and establish support for increased access to timely care amongst this patient population. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Worse outcome and distinct mutational pattern in follicular lymphoma with anti-HBc positivity

AbstractEpidemiological studies have demonstrated the association between hepatitis B virus (HBV) infection and B-cell non–Hodgkin lymphoma (NHL), mainly for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). We studied a cohort of 121 patients with FL for HBV infection status, clinical features, and gene mutational profile. Anti-HBc was detectable in 16 patients (13.2%), although all had undetectable HBV DNA. Anti-HBcore+ (anti-HBc+) cases presented with older age at diagnosis than anti-HBc− cases (68.1 vs 57.2 years; P = .007) and higher β2-microglobulin (56.3% vs 28.9%; P = .04). All patients included in the study fulfilled criteria for treatment and received therapy with rituximab or rituximab-containing chemotherapy. There were no episodes of HBV reactivation or HBV hepatitis during treatment and/or maintenance. Remarkably, anti-HBc+ patients had significantly lower 10-year progression-free survival (PFS; 12.9% vs 58.3%; P < .0001) and overall survival (OS; 22.0% vs 86.2%; P < .0001), that remained at multivariate analysis. Gene mutational profiling of all cases showed that anti-HBc+ cases had higher incidence of ARID1A mutations and absence of EP300 mutations, 2 key epigenetic regulators in FL. Overall, our study shows that FL patients with resolved HBV infection have a worse outcome independently of other well-known clinical risk factors and a distinct gene mutational profile.

Clinicopathologic Analysis of Primary Adrenal Diffuse Large B-Cell Lymphoma: A Reappraisal of 23 Japanese Patients Based on EBV Association and PD-L1 Expression in Tumor Cells.

Primary adrenal diffuse large B-cell lymphoma (PA-DLBCL) is rare. We investigate 23 Japanese patients with PA-DLBCL to understand the clinicopathologic features and biological behavior of this disease. The 17 males and 6 females had a median age of 74 years (range: 40 to 86 y). Tumor cells harbored Epstein-Barr virus-encoded small RNA (EBER) in 9 (39%) samples, including samples from the 2 patients with methotrexate-associated B-cell lymphoproliferative disorder. Programmed cell death ligand 1 (PD-L1) expression was detected in tumor cells of 6 (26%) samples, including 1 EBER+ and 5 EBER- samples. Four (17%) patients exhibited an intravascular proliferating pattern, and all 4 patient samples showed positive staining for PD-L1 in tumor cells. Among those patients, 3 showed intravascular proliferating pattern accompanied by a diffuse extravascular proliferation of tumor cells, and 1 patient was diagnosed with intravascular large B-cell lymphoma. We divided the 23 patients into 3 groups: EBER+ (n=9, 39%), EBER-PD-L1+ (n=5, 22%), and EBER-PD-L1- (n=9, 39%). A comparison of the outcomes among the 3 groups showed significant differences in overall survival (P=0.034). The EBER+ group had the worst prognosis, and the EBER-PD-L1- group had the best prognosis. We also compared the outcomes among the 3 groups that received rituximab-containing chemotherapies. Both the overall survival and progression-free survival were significantly different among these groups (P<0.001 and P=0.002, respectively). In conclusion, we evaluated 3 types of PA-DLBCL and found that each had unique clinical, pathologic, and prognostic features. Our results suggested that immune senescence, iatrogenic immunodeficiency, and immune evasion contribute to the development of PA-DLBCL.

A Novel Prognostic Model for Primary Gastric Diffuse Large B-Cell Lymphoma in the Rituximab Era, Integrating EBV Harboring on Tumor Cells

Introduction: EBV‐positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) often shows an aggressive clinical course with frequent extranodal disease including gastrointestinal involvement. However, the clinicopathological and prognostic significance of the EBV+ disease among primary gastric DLBCL (gDLBCL) has not been confirmed. Recently targeted therapies using antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have shown great promise in the treatment of relapsed or refractory DLBCL, but there remains a need for reliable methods to identify the candidates for novel immune-therapies.We analyzed the clinicopathological characteristics of gDLBCL and shed the light on the EBV harboring on tumor cells and PD-L1 expression as prognostic indicators for the future clinical trials of PD-1 blockade.Patients and methods: A total of 157 patients previously diagnosed as primary gDLBCL and treated with rituximab-containing chemotherapies were retrospectively examined. All cases were tested for EBV-encoded small RNA (EBER) by in situ hybridization (ISH). The expression of PD-L1 was immunohistochemically evaluated (clone SP142, Spring Bioscience, Pleasanton, CA).Results: Our series consisted of 157 patients: 92 males and 65 females (male: female ratio = 1.4), with a median onset age of 67 years (range, 32-89 years). 66 patients (42%) showed Lugano stage Ⅱ2/ⅡE/Ⅳ, 59 (40%) with high levels of soluble interleukin -2 receptors (sIL-2R >1000U/ml), 45 (29%) with IPI HI/H, and 34 (22%) with B symptoms. 39 patients (38%) had multiple gastric lesions, 19 (12%) with the presence of Bulky mass, and 29 (60%) with Helicobacter pylori infection. 92 patients (61%) had a non-germinal center B-cell immunophenotype (non-GCB). All of 157 patients received multiagent chemotherapy combined with rituximab, with an additional irradiation in 55 (35%). EBV harboring was found on the tumor cells in 12 (7.6%). There was no significant difference in the clinicopathological findings between EBV+ and EBV‐negative (EBV−) subgroups. But, notably, the EBV+ patients had a significantly worse overall survival (OS) than EBV− ones (P=0.004). Multivariate analysis of survival revealed that EBER positivity (P=0.012), the presence of multiple gastric lesions (P=0.014), and IPI HI/H (P=0.017) were adverse independent prognostic factors in gDLBCL. We constructed a prognostic model by combining these prognostic variables as follows: patients with a score of 0 (n=43), no adverse factors; patients with a score of 1 (n=36), one factor; and patients with a score of 2/3 (n=24), two or three factors. The 5-year OS rates for these 3 groups were 100%, 91%, and 43%, respectively. Furthermore, this model significantly stratified gDLBCL patients separately by survival (P <0.001, Figure). Although none of gDLBCL cases expressed PD-L1 on tumor cells, 7 (78%) of 9 cases with EBV+ gDLBCL were positive for PD-L1 in ≥20% of nonmalignant stromal cells in microenvironment (miPD-L1+), which showed a higher frequency than in EBV− ones (78% vs 42%, P=0.13).Conclusions: EBV+ gDLBCL showed a significantly worse prognosis. Our prognostic model appeared to well define the clinical outcome of gDLBCL patients. PD-L1 expression in nonmalignant stromal cells was a common feature of EBV+ gDLBCL. They could be good candidates to benefit from anti-PD-1/PD-L1 therapy. A novel prognostic model by integrating EBV harboring on tumor cells may serve as a risk‐stratification for future clinical trials in which high‐risk patients can be treated with newly developing immune-therapies to improve their outcomes. [Display omitted] DisclosuresShimada:Kyowa Hakko Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria.

Impact of the Double Expression of MYC and BCL2 on Outcomes of Primary Refractory Diffuse Large B-Cell Lymphoma Following R-CHOP Chemoimmunotherapy

Impact of the Double Expression of MYC and BCL2 on Outcomes of Primary Refractory Diffuse Large B-Cell Lymphoma Following R-CHOP Chemoimmunotherapy

A Nationwide Real-World Analysis for the Effectiveness of Rituximab Maintenance in Patients with Follicular Lymphoma in Taiwan

IntroductionFollicular lymphoma (FL) is the most frequent type of indolent lymphoma in western countries, but the incidence is lower in Asia. Several clinical trials have demonstrated the advantage of progression-free survival for rituximab maintenance (R-maintenance) in FL in western countries. Nevertheless, the clinical benefits of R-maintenance in Asian FL patients are still uncertain. In this study, we aimed to demonstrate this clinical benefits in Taiwan FL patients by utilizing our nation-wide database, i.e. Taiwan Cancer Registry Database (TCRD) and National Health Insurance Research Database (NHIRD).MethodsFrom 2009 to 2012, 836 patients with newly diagnosed FL were identified in TCRD. Their cancer-specific information was obtained from TCRD, the claim-based information (including demographic, medical resource utilization and treatment pattern) was retrieved from NHIRD, and survival information was ascertained by the National Death Registry Database.The study population was further restricted to those patients with stage II-IV disease and receiving 4-8 cycles of rituximab-containing multi-agent chemotherapy as induction, and the patients who died or received chemotherapies again within 180 days after the end date of the induction were excluded for suspected refractory cases to frontline treatments. Total 396 patients were included. Their demographics, clinical parameters and outcome (overall survival (OS) and time to next treatment (TTNT)) were subjected for analysis.ResultsAmong the 396 targeted patients, 260 underwent R-maintenance, and 136 did not receive any R-maintenance or other therapies (identified as the observation group) after rituximab containing induction therapies. Compared with the observation group, those patients receiving R-maintenance had similar distribution in age, gender, Ann Arbor stage, Charlson Comorbidity Index and practice setting. However, those with R-maintenance underwent less intensive induction chemotherapies (less R-CHOP receiving rate; 53.5% in R-maintenance, versus 66.2% in observation; p value 0.0150) and less cycles of rituximab-containing induction therapies (the rate of receiving 7-8 cycles induction therapies, 25.8% in R-maintenance, versus 41.9% in observation; p value 0.0010).The patients receiving R-maintenance had a significantly better OS in univariate analysis (hazard ratio (HR), 0.43; 95% confidence interval (CI), 0.20-0.91; Figure a) and even in multivariate analysis (HR, 0.42; 95% CI, 0.19-0.91) after potential confounding are adjusted. In multi-variate analysis, elder age (more than 60 years) and stage IV disease also showed negative impacts on OS. On the other hand, the TTNT was similar in the R-maintenance and observation groups (multivariate analysis, HR, 0.96; 95% CI, 0.65-1.42; Figure b), and other factors neither did not alter TTNT significantly.ConclusionOur study is the first real-world study which demonstrates the overall survival benefit of R-maintenance in newly diagnosed FL patients after induction therapy in Asian population. [Display omitted] DisclosuresTien:Celgene International Sàrl: Research Funding. Ko:Celgene International Sàrl: Research Funding.

Molecular Definition of Activated B Cell-like (ABC) DLBCL Identifies Patients Who May Benefit from Front-Line Intensive R-HDS Chemotherapy with ASCT

BackgroundDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease in adult patients with respect to clinical presentation, histopathology and molecular-genetic features. While the long-term cure rate after rituximab-containing conventional chemotherapy programs exceeds 80% in young patients with low and low-intermediate risk according to International Prognostic Index (IPI), similar treatments still remain unsatisfactory in patients belonging to high and high-intermediate risk (Pfreundschuh M Lancet Oncol 12:1013-1022, 2011; Coiffier B Blood 116:2040-2045, 2010; Pfreundschuh M Lancet Oncol 7: 379-391, 2006).For these patients the optimization of front-line therapy remains an important objective. Advances in molecular genetics have vastly improved the understanding of the biological diversity in DLBCLs, leading to the discovery of key oncogenic pathways and novel therapeutic targets.In a recently published randomized phase III trial we recruited 246 untreated DLBCL patients with a high-intermediate (56%) or high (44%) IPI score, in order to compare the R-CHOP-14 to the R-HDS plus ASCT therapeutic protocol. In this study the definition of the cell of origin (COO) by immunohistochemistry was unable to discriminate the clinical outcome according to the allocated treatment (Cortelazzo S J Clin Oncol. 2016 33:4015-4022). Herein, we show that a molecular classification of DLBCL may lead to identify patients who most likely benefit from treatment intensification.Methods and PatientsWe were able to run digital multiplex gene expression profiling (Nanostring technology) in 62 of the 246 patients, for whom formalin-fixed paraffin-embedded (FFPE) material was available, to classify them into the molecular COO types: ABC (Activated B Cell), GCB (Germinal Center B Cell) or Unclassified.The Nanostring panel contains 28 genes: 20 genes are used to assign COO subtype according to LST algorithm (Scott D Blood 123: 1214-1217, 2014), the remaining 8 genes are employed to assess MYC and BCL2 expression, to quantify TP53 level, to detect potential therapeutic targets (STAT3, NFKB, PTEN and PKI3CA) and to evaluate macrophages infiltrate (CD68).ResultsFirst of all, we confirmed that the distinction of DLBCL into COO categories by gene expression was more accurate than immunohistochemistry (IHC) determination, which failed especially in classifying non-GCB cases (86% of concordance in GCB cases, 53,6% in ABC plus Unclassified group, 22% considering only ABC). Indeed, considering the entire cohort, the Overall Survival (OS) was significantly different comparing GCB to ABC patients, while IHC failed to identify prognostic subgroups (Figure 1a and 1b).Regarding the effects of the two therapeutic treatments on OS, when we analyzed the 62 patients together or only the GCB group, we observed no significant difference between the two arms. Instead, in ABC group we noticed a clear difference in OS between R-HDS, with 83% of cases that survived, and R-CHOP14, after which only 25% of cases survived.Furthermore we investigated a possible correlation between MYC and BCL2 IHC and Nanostring mRNA expression data, we found no linear relationship but we noticed a positive trend. Moreover BCL2 and MYC expression showed a higher predictive OS value than IHC.ConclusionsOur results suggest that the diagnostic FFPE gene expression assay by Nanostring robustly identifies DLBCL subgroups according to the COO. Moreover, yet preliminary, the molecular definition of the COO is able to identify patients at high risk of poor outcome when treated with R-CHOP and who may benefit by intensified high dose chemotherapy programs or experimental new treatments. [Display omitted] DisclosuresRambaldi:Novartis, Amgen, Celgene, Sanofi: Other: Travel, Accomodations, Expenses; Novartis, Roche/Genentech, Amgen, Italfarmaco: Consultancy. Cesano:NanoString Technologies: Employment, Equity Ownership. Pileri:Takeda Pharmaceuticals: Speakers Bureau.

Cytogenetic Alterations Are Differently Associated with Disease Progression Depending on t(14;18) in Follicular Lymphoma

[Introduction] Follicular Lymphoma (FL) is characterized by indolent clinical behavior and subsequent histological transformation which links to aggressive clinical course and poor outcome. The hallmark of cytogenetic abnormality in FL is the translocation t(14;18)(q32;q21), which is found in more than 75% of cases. Several other cytogenetic abnormalities, which might contribute to disease progression, have been found. However, the prognostic and biological significance of cytogenetic or genomic features of FL has not been fully revealed. Last year we have shown clear evidence that cytogenetic abnormalities, +21 and 3q27, were independent prognostic factor in the rituximab era. Next we evaluated the pattern of chromosomal abnormalities in FL and the relation between cytogenetic and biological feature in this study.[Patients and Methods] Cells from lymph nodes or other sites of disease at diagnosis from 201 patients with FL admitted to our hospital and affiliated hospitals between 2001 and 2013 were cytogenetically analyzed using standard methods of G-banding. Ninety nine (49.3%) men and 102 (50.7%) women with a median age of 59 years (range, 28 - 83 years) were included in the analysis. The median follow up period was 48.3 months. Forty three patients (21.4%) were Stage I or II; 156 patients (77.6%) were Stage III or IV; and 2 patients (1%) were unknown. Eighty patients (39.8%) were follicular lymphoma international prognostic index (FLIPI) low, 55 patients (27.4%) were intermediate, and 43 patients (21.4%) were high; and 23 patients (11.4%) were unknown. The distribution of FL pathological subgroups was as follows: FL Grade 1 - 2, 142 patients (70.6%); FL Grade 3a, 30 (15.0%); and unknown, 29 (14.4%). One hundred and fifty seven patients (78.1%) received Rituximab-containing chemotherapy as an initial treatment.[Result] t(14;18)(q32;q21) was the most common abnormality observed in 119 patients (59.2%). Other numerical or structural abnormalities that were identified in more than 5% of the patients were as follows: +X (17.9%), del(6)(q) / −6 (16.9%), +7 (14.4%), abnormality of 1q12-21 / 1q (12.9%), del(13)(q) / -13 (11.9%), abnormality of 3q27 (10.4%), abnormality of 10q22-24 (10.0%), +12 / dup(12)(q) (10.0%), abnormality of 1p21-22 / 1p(9.0%), +18 (9.0%), del(17)(p) / −17 (5.0%), and the number of cytogenetic aberration higher than 3 (54.7%). Patients with the number of cytogenetics aberration higher than 3 significantly correlated with higher FLIPI grade (p= 0.0028). As is the case with much higher number of aberration (higher than 4, p= 0.0019 and higher than 5, p= 0.0024). The higher number of cytogenetic aberration also showed a trend of good correlation with advanced stage of Ann Arbor system. These suggest that additional chromosomal aberration closely related to disease progression in FL. To investigate the relationship between the disease progression and each cytogenetic abnormality logistic regression analysis was performed. In all cohort +X (Oods Ratio (OR) 2.604, 95%CI 1.184 - 5.751, p= 0.0175) and +12 / dup(12)(q) (OR 3.955, 95%CI 1.397 - 12.22, p= 0.0095) were significant abnormalities for higher FLIPI grade. To evaluate significance of t(14;18) multivariate analysis was performed for both FLs with and without t(14;18) again. In FLs with t(14;18) the same cytogenetic abnormalities, +X (OR 3.293, 95%CI 1.212 - 9.459, p= 0.0216,) and +12 / dup(12)(q) (OR 6.748, 95%CI 1.779 - 33.998, p= 0.0042), were detected as significant factor for disease progression. On the contrary in FLs without t(14;18) quite different cytogenetic abnormalities, such as +5 (OR 4.01e7, 95%CI 2.180 - , p= 0.0144) and +21 (OR 11.065, 95%CI 1.318 - 232.1, p= 0.0267), were chosen. However, these cytogenetic abnormalities did not influence patients' survival except for +21.[Conclusion] In patients with FL disease progression was closely associated with cytogenetic abnormalities, +X and +12 / dup(12)(q) in those with t(14;18). However, in patients without t(14;18) disease progression developed in distinct manner with respect of cytogenetic alteration. Important cytogenetic alterations for disease progression may be different from those for survival in Rituximab era. DisclosuresMurakami:Ono: Honoraria; BMS: Honoraria; Fujimoto: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Celgene: Honoraria.