Post-rituximab Era Research Articles

Outcomes and toxicities in patients with diffuse-large B cell lymphoma involving the gastrointestinal tract and digestive organs.

Diffuse large B-cell lymphoma (DLBCL) involving the gastrointestinal (GI) organs is rare, and real-world outcomes after combined modality therapy (CMT) with systemic therapy (ST) and radiotherapy (RT) are not well-characterized, particularly in the contemporary era. We characterized outcomes in a large cohort of GI-DLBCL patients treated with ST alone or CMT. Patients with GI-DLBCL treated at a single institution were retrospectively reviewed. Kaplan-Meier and Cox regression models estimated survival. Multivariable analyses were conducted using the Cox proportional hazards model. Of 204 patients, gastric involvement was most common (63%). Most presented with early-stage disease (61%). All patients received ST and 65 patients (32%) received RT, 88% as part of first-line CMT. Median dose was 36 Gy (IQR 30.6-39.6) in 18 fractions (IQR 17-22). Median follow-up was 46 months. Five-year overall survival (OS) and progression-free survival (PFS) was 88% and 84%, respectively; complete response (CR) rate was 82%. Improved OS associated with low IPI (p=0.001), fewer chemotherapy lines (p<0.001), early stage (p<0.006), and CR (p<0.001). Survival did not differ by RT receipt (p>0.25). Only early stage and CR correlated with improved OS on multivariable analysis. Stomach-directed RT vs. RT to other sites correlated with improved PFS and OS (p<0.04). Patients with early stage DLBCL treated with CMT in the post-rituximab era had equivalent OS vs. ST alone, even with fewer chemotherapy cycles (p<0.02; median of 4 with RT vs. 6 cycles without). Fifty patients had bulky disease (≥7.5 cm), of whom 18 (36%) had early stage disease. Among patients with bulky disease, 5 (10%) developed relapse at the initial site of disease bulk. Four of the 5 patients did not receive consolidative radiation. Among these 4 patients, 3 relapsed only in their initial site of bulky disease. Of 191 patients with luminal GI-DLBCL, n=4 (2.1%) developed perforation; only one received RT. Acute Grade 3 toxicities were reported in 41.2% of patients, and 12 (5.8%) patients had late Grade 3 toxicities, 99% attributed to chemotherapy. GI-DLBCL patients have favorable outcomes after CMT with minimal late toxicity. CMT may be offered with abridged systemic regimens with equivalent outcomes. Stomach directed-RT may mitigate relapse risk associated with incomplete disease response or bulky disease.

Outcomes and Toxicities in Patients with Diffuse Large B-Cell Lymphoma of the Gastrointestinal Tract.

Diffuse large B-cell lymphoma (DLBCL) involving the gastrointestinal (GI) tract is rare and long-term outcomes are not well defined. Combined modality therapy (CMT) with radiotherapy (RT) in addition to systemic therapy in this setting is not commonly pursued. We aim to characterize outcomes in patients with GI DLBCL treated with systemic therapy, with or without RT. Patients diagnosed with DLBCL of the GI tract (with or without mesenteric involvement) treated at a single institution from 1988-2022 were retrospectively reviewed on an IRB-approved protocol. Clinical and treatment data were collected including adverse events (AE; acute vs late defined as before or 4 weeks after therapy end). Kaplan-Meier and Cox regression models were used to estimate survival. Of 207 patients, 62% were male and median age at diagnosis was 63 (IQR 52-73). Gastric involvement was most common (n = 130, 63%), followed by small intestines (n = 48, 23%) and colon/rectum (n = 24, 12%). Most presented with early-stage disease (n = 124, 60%), with a median IPI score of 1. All patients received chemotherapy. Of 182 treated with CHOP/EPOCH, 36 (20%) were treated in the pre-rituximab era while 146 (80%) received rituximab. 66 patients (32%) were treated with RT, 89% as part of first line CMT. 50 cases (76%) received consolidative RT, while 10 (15%) targeted residual gross disease and 4 (6%) targeted distant sites. Median dose and fractionation were 36Gy (IQR 30.6-39.6) in 18 fractions (IQR 17-22). Over half (n = 132, 64%) developed grade 3+ acute chemotherapy AEs, and the most common were anemia (n = 64), febrile neutropenia (n = 40), and neutropenia (n = 20). Grade 3+ late chemotherapy AEs occurred in 14 patients (7%). Acute grade 3+ radiation AEs were uncommon (n = 2, 3%; colitis, emesis). No grade 3+ late radiation AEs were noted. Median follow-up was 46 months (IQR 16-97). 169 (81.6%) had a complete response (CR), with 154 (91%) after first line chemotherapy, 9 (5%) after second line, and 6 (4%) after RT. CR was defined by PET (62%), endoscopy (22%), CT (9%), or other methods (7%). The 5-year progression-free survival for those treated with one line of chemotherapy with or without RT was 95%. Median overall survival (OS) was not reached. Improved OS was associated with early-stage disease (p = 0.003), low IPI (p = 0.001), fewer chemotherapy lines (p<0.001), and CR (p<0.001). OS did not differ by gender, age, immunophenotype, GI site, SUVmax, or RT. Patients with early stage DLBCL treated with RT in the post-rituximab era received fewer chemotherapy cycles compared to those treated without RT (p = 0.02; median of 4 (IQR 3-6) vs 6 cycles (IQR 4-6)), with no OS difference. GI DLBCL patients have favorable outcomes after CMT with minimal late toxicity. CMT with RT to the GI tract is well tolerated with no OS difference compared to chemotherapy alone, and may mitigate risks from additional chemotherapy cycles for selected early-stage patients.

Hexokinase II expression as a prognostic marker in diffuse large B-cell lymphoma: pre- and post-rituximab era.

We aimed to assess HKII expression and its prognostic significance in diffuse large B-cell lymphoma (DLBCL) patients. The HKII protein level was determined by immunohistochemistry in 159 newly diagnosed DLBCL patients, and its relationship with overall response rate, progression-free survival (PFS), and overall survival (OS) was analyzed. HKII was expressed in 95 DLBCL patients (59.7%). HKII-positive patients had poorer outcomes than negative patients for 5-y PFS (68% vs. 84%, p = 0.029) and 5-y OS (78% vs. 94%, p = 0.05). When only patients without no bulky disease, B symptoms, or extranodal involvement who had low IPI scores were considered, those with positive HKII had worse 5y-PFS and 5y-OS (p < 0.05). Multivariate analysis indicated that HKII status was an independent prognostic factor of OS. In subgroup analysis, HKII expression was associated with inferior OS in the CHOP group (p = 0.017). In CHOP group patients without bulky disease or extranodal involvement who had low LDH and low IPI scores (p < 0.05), positive HKII was associated with worse PFS and OS. No differences in PFS and OS, or any independent prognostic factors, were found in the RCHOP group. In DLBCL, HKII is valuable as a prognostic biomarker and may be useful as a tool for assessing disease risk.

Ibrutinib Associated with Rituximab-Platinum Salt-Based Immunochemotherapy in B-Cell Lymphomas: Results of a Phase 1b-II Study of the LYSA Group.

Simple SummaryPatients with relapsing/refractory B-cell lymphoma who respond to a platinum salt-based salvage regimen can be cured after therapy intensification followed by autologous stem cell transplantation. The Bruton tyrosine kinase inhibitor ibrutinib, given alone or in association with other molecules, has proven effective in numerous B-cell lymphomas. The aim of the current study was to evaluate the safety of the combination of ibrutinib, rituximab, dexamethasone, and cytarabine with either cisplatin (R-DHAP) or oxaliplatin (R-DHAOx), with ibrutinib given based on a prespecified dose-escalation design. The concomitant combination of ibrutinib and R-DHAP resulted in limiting hematological, infectious, and renal toxicities. As a result, the maximum ibrutinib dose could not be administered. On the other hand, when the ibrutinib administration schedule was combined with R-DHAOx, ibrutinib dosing could be increased up to the maximum prespecified dose but with relevant toxicities. Despite a strong rationale for combining ibrutinib with either R-DHAP or R-DHAP/Ox, this approach was limited by significant toxicities.In the post-rituximab era, patients with relapsed/refractory non-Hodgkin B-cell lymphoma (R/R B-NHL) responding to a platinum salt-based salvage regimen can potentially be cured after intensification followed by autologous stem cell transplantation, with the quality of the response to salvage predicting survival. The Bruton tyrosine kinase inhibitor ibrutinib, given as monotherapy or combined with other molecules, has proven effective in numerous B-cell lymphomas. To evaluate the safety of the combination of ibrutinib, rituximab, dexamethasone, and cytarabine with either cisplatin (R-DHAP) or oxaliplatin (R-DHAOx), we conducted a multicenter Phase 1b-II study in transplant-eligible R/R B-NHL patients, with ibrutinib given using a 3-by-3 dose-escalation design. The combination of R-DHAP and ibrutinib (given from Day 1 to Day 21 of each cycle) was associated with dose-limiting hematological, infectious, and renal toxicities, while we were unable to reach a dose to recommend for Phase II. R-DHAOx could only be combined with a daily dosage of 280 mg ibrutinib when administered continuously. R-DHAP combined with intermittent ibrutinib administration (from Day 5 to Day 18) was found to be highly toxic. On the other hand, when this administration schedule was combined with R-DHAOx, ibrutinib dosing could be increased up to 560 mg but with relevant toxicities. Despite a strong rationale for combining ibrutinib and R-DHAP/R-DHAOx, as both target lymphoma B-cells by different mechanisms, this approach was limited by significant toxicities.

Treatment Patterns and Outcomes in Patients with Relapsed/Refractory Follicular Lymphoma Who Received Third Line Therapy at the Christie NHS Foundation Trust in the UK

Background: There are limited data on real-world treatment patterns and outcomes for follicular lymphoma (FL) in the relapsed/refractory (r/r) setting, with shorter response durations reported after each relapse (Link et al, 2019; Rivas-Delgado et al, 2019 and Batlevi et al, 2020). We examined treatment patterns for patients with FL initiating third line (3L) therapy at a single institution by time period in the post-rituximab era (2004-2010 and 2011-2020), and clinical outcomes for the overall cohort receiving therapy between 2004 and 2020.Methods: This is a retrospective, observational study of patients with FL who initiated 3L therapy between 2004 and 2020 in routine clinical practice at The Christie NHS Foundation Trust, UK. We selected patients aged ≥18 years at 3L initiation, with histologically documented FL Grade 1−3a treated with two prior lines of systemic therapy including an anti-CD20 monoclonal antibody and an alkylating agent, and at least one year of follow-up after initiating 3L therapy; follow-up ended June 2021. We excluded patients with grade 3b FL or transformation to high grade lymphoma any time before 3L treatment. Overall response rate (ORR) and complete response (CR) to 3L therapy was calculated, and overall survival (OS), progression free survival (PFS) and time to next treatment (TTNT) were estimated using the Kaplan-Meier (KM) method with 3L therapy initiation date as the index date.Results: Overall, 41 patients met all eligibility criteria; 11 and 30 patients received 3L therapy between 2004-2010 and 2011-2020, respectively. Median age at index date was 59 years and 53.7% were male; 73.2% had grade 1 or 2 FL; 78.1% had advanced stage (III/IV) FL at diagnosis. Median follow-up was 33.9 (IQR: 14.5, 63.0) months, and median time from diagnosis to 3L treatment was 60.2 (IQR: 29.4, 89.1) months. The most common regimen in 3L was rituximab plus bendamustine (R-benda) followed by rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab used as a single agent (R-mono). Treatment patterns differed by time period (Table 1). R-benda was more commonly used between 2011 and 2020. The most common sequence was rituximab plus cyclophosphamide, vincristine and prednisone (R-CVP) followed by R-CHOP and R-benda (Figure 1). ORR to 3L treatment was 61.0%, CR 29.3%. Median OS, PFS and TTNT with 95% confidence interval (CI) were 70.0 (30.2-NR), 19.2 (9.5-34.7) and 11.8 (9.0-27.6) months after 3L initiation, respectively. Two- and five-year OS rates were 79% and 50%, and two-year PFS rate was 37%.Conclusions: Patients with r/r FL treated in the routine 3L setting have highly variable treatment patterns and unfavorable outcomes, representing a continued unmet medical need. This study is limited by its small size and evolving treatments, warranting a larger study of more recently treated 3L patients to evaluate the impact of modern treatment pathways and novel therapies on clinical outcomes for r/r FL. [Display omitted] DisclosuresLinton: University of Manchester: Current Employment; BeiGene: Research Funding; Hartley Taylor: Honoraria; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptitude Health: Honoraria; Celgene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Julian: Genentech, Inc.: Current Employment, Current holder of stock options in a privately-held company. Gibb: The Christie NHS Foundation Trust: Current Employment; Takeda: Honoraria, Research Funding, Speakers Bureau. Li: Genesis Research: Current Employment. Liu: Genesis Research: Current Employment. Shewade: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Radford: BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company.

Validation of POD24 as a robust early clinical end point of poor survival in FL from 5225 patients on 13 clinical trials

AbstractObservational studies and stand-alone trials indicate that patients with follicular lymphoma (FL) who experience disease progression within 24 months of front-line chemoimmunotherapy (POD24), have poor outcomes. We performed a pooled analysis of 13 randomized clinical trials of patients with FL in the pre- and postrituximab eras to identify clinical factors that predict POD24. Logistic regression models evaluated the association between clinical factors and POD24. Cox regression evaluated the association between POD24 as a time-dependent factor and subsequent overall survival (OS). A landmark analysis evaluated the association of POD24 with OS for the subset of patients who were alive at 24 months after trial registration. Patients without progression at 24 months at baseline had favorable performance status (PS), limited-stage (I/II) disease, low-risk FL International Prognostic Index (FLIPI) score, normal baseline hemoglobin, and normal baseline β2 microglobulin (B2M) level. In a multivariable logistic regression model, male sex (odds ratio [OR], 1.30), PS ≥2 (OR, 1.63), B2M (≥3 mg/L; OR, 1.43), and high-risk FLIPI score (3-5; OR, 3.14) were associated with increased risk of progression before 24 months. In the time-dependent Cox model and the 24-month landmark analysis, POD24 was associated with poor subsequent OS (hazard ratio, 4.85 and 3.06, respectively). This is the largest pooled analysis of clinical trials data validating POD24 as a robust indicator of poor FL survival and identified clinical predictors of early death and progression that can aid in building comprehensive prognostic models incorporating clinical and molecular predictors of POD24.

Validation of POD24 As a Robust Early Clinical Endpoint of Poor Survival in Follicular Lymphoma: Results from the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) Investigation Using Individual Data from 5,453 Patients on 13 Clinical Trials

Introduction Follicular lymphoma (FL) is the most common indolent lymphoma with a median survival approaching 20 years. However, there is significant clinical heterogeneity with a subset of patients experiencing transformation, early recurrence or refractory disease. Data from the National LymphoCare Study and others identified that progression of disease within 24 months of diagnosis in patients treated with chemoimmunotherapy (POD24) is associated with poor subsequent overall survival (OS). Using the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) data, we sought to i) evaluate the association between FL international prognostic index (FLIPI) and other baseline factors on progression-free survival within 24 months of trial enrollment (PFS24) and ii) to validate POD24 as an early clinical endpoint in FL. Methods We performed a pooled analysis of 13 randomized clinical trials of patients in both the pre and post rituximab era (total sample size of 5,453, Table). Logistic regression model was used to evaluate the association between FLIPI, gender, and performance status (PS) with PFS24. Cox regression with POD24 as a time-dependent covariate was used to evaluate the association between POD24 and subsequent OS. An additional landmark analysis was conducted to evaluate the association of POD24 on OS for the subset of patients who were alive at 24 months post trial registration. Baseline Beta 2 Microglobulin (B2M) data were available for 9 of the 13 studies (total sample size of 4,361). Additional analyses including B2M along with other baseline factors were conducted on this subset of patients. Results 29% of patients progressed and 2.5% died without progressive disease within 24 months from trial registration. Patients alive without progression at 24 months were younger and more commonly had favorable PS, limited stage, low FLIPI risk score, normal baseline hemoglobin, and normal baseline B2M. A multivariable logistic regression model indicated that being male (odds ratio (OR) = 1.35; 95%CI = (1.19 - 1.52); p = 2 (OR = 1.85; (1.47 - 2.38); p = 3mg/L) (OR = 1.47; (1.25 - 1.75); p Results of the time-dependent Cox model, adjusted for gender and stratified by PS and FLIPI, indicate that POD24 was associated with poor subsequent OS (hazard ratio (HR) = 5.24; (4.63 - 5.93); p Conclusions This pooled analysis of >5,000 patients with FL included in 13 prospective clinical trials is the largest cohort to date validating early progression as a robust indicator of poor FL survival. We identified male gender, poor PS, high FLIPI score, and elevated baseline B2M as predictors of early death and progression. These provide well-defined clinical factors for building comprehensive prognostic models in the future that incorporate clinical and molecular predictors of POD24. Results on maintenance and response to therapy as factors impacting POD24 will be updated in the presentation. Our results confirm POD24 as an early clinical endpoint of poor survival in FL that should be utilized to identify patients for prospective clinical trials. Disclosures Casulo: Celgene: Research Funding; Gilead: Honoraria, Other: travel support; Infinity: Consultancy. Salles: Janssen, Celgene, Novartis, and Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Mundipharma: Honoraria. Hoster: Roche: Other: Travel support, Research Funding. Hiddemann: Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Marcus: Celgene: Other: Support for meeting attendance ; Roche: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Kimby: Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Honoraria; Abbvie: Membership on an entity9s Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pfizer: Research Funding. Vitolo: Mundipharma: Honoraria; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria; Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Nielsen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Foon: Celgene: Employment. Flowers: Burroughs Welcome Fund: Research Funding; Spectrum: Consultancy; Gilead: Consultancy; Onyx: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Research to Practice: Research Funding; Abbvie: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen Pharmaceutical: Research Funding; Acerta: Research Funding; Infinity: Research Funding; Educational Concepts: Research Funding; Clinical Care Options: Research Funding; OptumRx: Consultancy; National Institutes Of Health: Research Funding; Seattle Genetics: Consultancy; V Foundation: Research Funding; Prime Oncology: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Genentech/Roche: Consultancy, Research Funding; Bayer: Consultancy; Millennium/Takeda: Research Funding; TG Therapeutics: Research Funding.

The adhesion molecule ICAM-1 in diffuse large B-cell lymphoma post-rituximab era: relationship with prognostic importance and rituximab resistance.

Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface receptor contributing to lymphocyte homing, adhesion and activation. The prognostic significance of the protein is unknown in diffuse large B-cell lymphoma (DLBCL) in post-rituximab era. We detected expression of ICAM-1 immunohistochemically in 102 DLBCL tissue samples. Overexpression of ICAM-1 was found in 28 (27.5%) cases. In patients with low ICAM-1 expression levels, the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy resulted in an improved overall response rate, progression-free survival (PFS) and overall survival (OS) (P=0.019, 0.01, 0.02). In pre-clinical models, we found that chronic exposure of cell lines to rituximab led to downregulation of ICAM-1 and acquirement of a rituximab resistant phenotype. In vitro exposure of rituximab resulted in rapid aggregation of B-cells regardless of the ICAM-1 expression levels. MTT assay showed knockdown of ICAM-1 could cause rituximab resistance. Neutralization of ICAM-1 did not affect rituximab activity in vitro and in vivo. Our data illustrated that in post-rituximab era, R-CHOP significantly improved the ORR, PFS and OS in ICAM-1 negative subset patients. Downregulation of ICAM-1 may contribute to rituximab resistance, and that rituximab, by promoting cell-cell aggregation, may sensitize cells to the cytotoxic effects of chemotherapy agents.

Estimates and Timing of Therapy Initiation during the First Decade for Patients with Follicular Lymphoma Who Were Observed at Diagnosis

Background: Observation or "wait and watch" (W/W) strategy remains a viable option in the rituximab era for asymptomatic, stage II-IV, low-tumor burden patients with FL grade 1-2, 3A. Studies to date both in pre and post rituximab era have not shown an overall survival benefit from immediate treatment in such low-risk patients.To improve our understanding and to better counsel FL patients on W/W strategy, we sought to estimate the incidence of treatment initiation at landmark time points in our prospectively observed cohort from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). We further evaluate the association between the presence of GELF criteria (MER treatment criteria) at diagnosis and initiation of treatment patterns, transformation rates and cause of death in FL patients managed by W/W. Methods: FL patients on W/W strategy were identified from MER of the University of Iowa/Mayo Clinic Lymphoma SPORE. From 2002-2015, consecutive patients with newly diagnosed FL were offered enrollment. Patients were managed per treating physician and followed prospectively. Baseline clinical and pathological data were abstracted using a standard protocol. Cumulative incidence estimates of treatment initiation for follicular lymphoma were calculated using transformation to large cell lymphoma (as the first event) and death due to any cause as competing risks. Transformation was defined based on biopsy-proven disease. Patients were retrospectively considered to meet treatment criteria at diagnosis if they had the presence of any GELF criteria components per available abstracted data in the MER database. Not all GELF criteria were prospectively assessed and captured for all patients, and thus the MER treatment criteria utilized here will be conservative for formal GELF assessment. Results: A total of 401 FL patients were identified in MER on W/W strategy. Baseline characteristics for W/W patients showed a favorable profile such as normal LDH (89%), low and intermediate FLIPI score in 48% and 35% respectively, no B symptoms (97%), low tumor burden (&amp;lt;4 nodal groups) in 72%, and GELF positive vs. negative in 36% and 64% respectively. At a median follow up of 8 years (IQR 5.9-12), 64% initiated treatment for FL only. Cumulative incidence estimates of treatment initiation at sequential time points were calculated from the initiation of observation (Table1&amp;2). At diagnosis, the likelihood of treatment initiation was 15%, 26%, and 42% in the next 1, 2, and 5 years. The incidence of treatment initiation decreased over time as patients remained treatment-free after diagnosis (Figure 1A [blue curve]). Patients that met MER treatment criteria had increased rates of therapy initiation (33.2% vs. 21.9%) in the next two years and untreated transformation to large cell lymphoma [red curve] (8.7% vs. 4.5%) during the next 5 years (Figure 1B). Despite this, the rate of lymphoma related death at 10 years was similar between groups (met treatment criteria = 6.2% vs. 7.1%) (Figure 1C, [green curve]). Discussion: The longer duration of W/W strategy suggests a decreasing need for treatment over time. We provide time point estimates, which would be helpful for counseling patients. Of note, long-term continuous oncologic assessment and follow-up is necessary since approximately 66% of patients in this mature cohort initiated treatment by 8 years median follow up. MER treatment criteria at diagnosis identified patients with higher rates of transformation and therapy initiation in the first two years but did not identify those with worse lymphoma specific survival. Identification of biological differences in patients with early vs. late or no progression is a critical next step in understanding outcomes in W/W patients. Disclosures Ansell: Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Wang:Incyte: Research Funding; Innocare: Research Funding; Novartis: Research Funding. Witzig:MorphSys: Consultancy; AbbVie: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding. Maurer:Morphosys: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Research Funding. Nowakowski:NanoString: Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy; Kymera: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Autologous stem cell transplant in first remission for transformed indolent non-Hodgkin lymphoma: additional data to guide practice.

Autologous stem cell transplant in first remission for transformed indolent non-Hodgkin lymphoma: additional data to guide practice.

Prognostic significance of interim PET/CT response for the treatment of advanced-stage marginal zone lymphoma in the post-rituximab era

There are still controversies about the use of interim positron emission tomography/computed tomography (PET/CT) in indolent non-Hodgkin lymphoma due to the variable fluorodeoxyglucose (FDG) avidity. Therefore, this study aimed to evaluate the roles of interim PET/CT in marginal zone lymphoma (MZL), a representative indolent lymphoma. We analyzed the data of 146 MZL patients. All were treated with rituximab-containing immunochemotherapy. Interim PET/CT scan was performed after 2–3 cycles of therapy, and the response was assessed using the Deauville 5-point scales (5-PS) and a semi-quantitative assessment using the SUVmax reduction rate (ΔSUVmax). Progression-free survival (PFS) was well stratified according to a visual assessment of interim PET/CT using 5-PS (p < 0.001). Particularly, there was a significant difference in PFS between patients with interim score 1–2 and those with score 3. However, ΔSUVmax did not predict the survival outcome using 59.8% of the optimal cutoff value. In the multivariate analysis, failure to achievement of grade 1–2 in interim PET/CT was significantly associated with inferior PFS (HR, 2.154; 95% CI 1.071–4.332; p = 0.031). The interim PET/CT response based on the 5-PS is useful for predicting PFS of patients with MZL in the post-rituximab era.

Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups

Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1–3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.

Prognostic Nomogram and Predictive Factors in Refractory or Relapsed Diffuse Large B-Cell Lymphoma Patients Failing Front-Line R-CHOP Regimens.

Background: The clinical course of relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) is variable, with limited efficacy data of second-line treatment in a post-rituximab real-world context. Hence, we explored the predictors and constructed a nomogram for risk stratification in this population.Patients and methods: Among 296 r/r DLBCL patients pretreated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) at the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College between 2006 and 2017, 231 were included for nomogram construction. After randomization, we constructed the prognostic nomogram in the primary cohort (n=161) based on a multivariate analysis and confirmed it in the validation cohort (n=70). Additionally, we explored predictive factors for second-line therapy using a ordinal regression analysis.Results: Four independent prognostic factors including rituximab in the second-line setting, initial Eastern Cooperative Oncology Group (ECOG) performance status (PS), response to front-line treatment, and invasion on progression/recurrence were used to construct the nomogram. The nomogram had a C index of 0.70 with AUC values of 0.73 and 0.71 for the primary and validation cohorts, respectively. Subsequently, three risk groups (low, intermediate, and high) were determined with median overall survival (OS) of 38.0, 25.0, and 7.0 months, respectively. Additionally, we conducted a multivariate ordinal regression analysis and identified prior response to front-line treatment (odds ratio=4.50, 95% CI: 1.84-11.27, p=0.001) and bulky disease at diagnosis (odds ratio=0.36, 95% CI: 0.182-0.702, p=0.003) were two independent factors for second-line treatment efficacy.Conclusions: The established predictors for treatment efficacy and the novel nomogram for survival in r/r DLBCL patients could potentially be applied for risk stratification and treatment guidance in the post-rituximab era.

Prognostic Significance of Interim PET/CT Assessment for the Treatment of Advanced Stage of Marginal Zone Lymphoma in the Post Immunochemotherapy Era

Introduction In aggressive lymphoma, the prognostic value of FDG-PET/CT is well established to assess the response to therapy and predict long-term outcome. However, there are still many controversies for using PET/CT in indolent non-Hodgkin lymphomas because of the low FDG avidity. Therefore, this study was planned to evaluate the roles of PET/CT in marginal zone lymphoma, which is a representative of indolent lymphoma. Method We retrospectively analyzed the data of 136 patients with advanced stage marginal zone lymphoma from 13 independent institutions between January 2008 and January 2018. All of the enrolled patients had Ann Arbor stage III-IV except some patients with stage II with bulky mass or rapid progression. Patients were treated with 6th or 8th cycles of immunochemotherapy which consisted of R-CVP (Rituximab, cyclophosphamide, vincristine, prednisolone) (90.4%), R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) (5.9%), R-B (Rituximab, bendamustine) (3.7%). PET/CT scan was performed at diagnosis, after 2~3 cycles of immunochemotherapy (interim), and at the end of the treatment. Interim PET/CT response was assessed according to Deauville 5-PS (DS) and semi-quantitative assessment based on the rate of reduction in the SUVmax (deltaSUVmax). Results The median age of the patients was 59.5 years (range;28.0~84.0), and 115 patients (84.6%) had stage III-IV. 119 patients (87.5%) had one or more extranodal site involvement, and gastrointestinal tract (25%) was the most commonly involved extranodal site. Fifty-one patients (37.5%) were classified into high risks and 85 patients (62.5%) were with low risks based on IPI. The median SUVmax of the lesion was 4.8 (range; 0.8-23.5) on initial PET/CT. According to Deauville 5-PS in interim PET/CT, 37 patients (27.2%) were defined in score 1, 34 patients (25.0%) in score 2, 31 (22.8%) patients in score 3, 27 patients (19.9%) in score 4, and 7 patients (5.1%) in score 5. The optimal cutoff value for the deltaSUVmax was 59.8 according to the ROC analysis. After median follow up of 35.9 months, performance status, LDH, IPI and interim PET/CT response were significant prognostic factors for progression free survival (PFS) in univariate analysis. Patients who achieved complete metabolic response (DS 1-2) showed significantly longer progression free survival (PFS) than patients with DS 3-5 grade (Figure 1A, 89.3 months vs. 43.9 months, P=0.046). However, the semi-quantitative method using deltaSUVmax did not predict the survival outcome. In regard to post-treatment PET/CT assessment, patients who achieved complete response showed long PFS (Figure 1B, P&lt;0.05). In multivariate analysis, complete metabolic response (DS 1-2) achievement in interim PET/CT was the strong prognostic factor in patients with advanced stage marginal zone lymphoma (HR 2.017, 95% CI 0.981-4.147, P&lt;0.05). Conclusion Deauville 5-PS based interim PET/CT response assessment is useful to predict the survival outcome of advanced stage marginal zone lymphoma in post-rituximab era. Whereas, the semi-quantitative assessment based on deltaSUVmax did not have the prognostic impact. Figure 1. Progression free survival of all patients according to Deauville 5-PS based interim PET/CT response (Figure A, B) and post-transplant PET/CT response (Figure C) Figure 1 Disclosures No relevant conflicts of interest to declare.

Hexokinase II Expression As a Prognosis Marker in Diffuse Large B-Cell Lymphoma (DLBCL) Pre- and Post- the Incorporation of Rituximab to Standard CHOP Chemotherapy

Purpose: The results of the prospective multicenter phase III Collaborative trial in relapsed aggressive lymphoma (CORAL) study stressed the need to identify cellular pathways associated with poor clinical outcomes and to develop novel therapeutic strategies for DLBCL. We previously demonstrated that over-expression of HKII contribute to the acquirement of resistance to rituximab and chemotherapy agents in DLBCL B-cell lymphoma in pre-clinical models. Using gene expression profiling, we also demonstrated that higher mRNA levels of HKII correlated with a shorter progression free survival (PFS) and overall survival (OS) in previously untreated DLBCL in the pre- and post-rituximab era. In current study, we aimed to assess HKII expression by immunohistochemistry (IHC) and analyze the prognostic significance in 97 diffuse large B cell lymphoma patients pre- and post-rituximab era treated in a different Country/Institution. Methods: We retrospectively identified 97 newly diagnosed DLBCL treated at Fudan University Shanghai Cancer Center, Shanghai, China from March 2009 to December 2012. Clinical, demographic and pathological characteristics for each patient were collected. Patients were treated with standard doses of CHOP (N=41) or rituximab and CHOP (N=56). Pathological archived material was submitted for immunohistochemistry (IHC) for the determination of cell of origin (COO) (Han's algorithm) and HKII levels. Co-relation between HKII expression and COO or impact on overall response rate (ORR), PFS and OS were analyzed. Result: Demographic and clinical characteristic of gender, stage and IPI score distribution were similar between patients treated with CHOP or R+CHOP. As expected, the clinical outcome of DLBCL patients treated with R+CHOP was superior than those treated with CHOP. HKII expression was observed in 62 DLBCL patients (63.9%). There was a correlation between HKII expression and COO. Expression of HKII was observer in 84.6% of non-germinal center B-cell (non-GCB) DLBCL and 60% of GCB DLBCL (P=0.027). There was no correlation between HKII expression and ORR or PFS in DLBCL patients treated with CHOP or R-CHOP. In patients treated with CHOP chemotherapy, HKII expression was associated with an inferior OS, 100% (HKII negative) vs. 67% (HKII positive) (P=0.025). In rituximab era, additionally rituximab to CHOP results significantly improved OS in HKII positive patient compared to CHOP only patients (91% vs 67%, P=0.05), but R+CHOP did not change OS between HKII negative patients. Conclusion: As previously observed, HKII expression is more prevalent in non-GCB DLBCL patients. In pre-rituximab era, HKII expression was associated with a poor clinical outcome after CHOP chemotherapy. The negative effect of HKII expression appears to be overcome by the addition of rituximab to CHOP. (This work was supported by National Natural Science Foundation of China (81670177 and 81773203)). Disclosures No relevant conflicts of interest to declare.

Hematopoietic-cell transplantation for lymphoma in the era of genetically engineered cellular therapy: it's not quite time to scrap the old vehicle for the new car.

Second-line platinum-based salvage chemotherapy followed by high-dose chemotherapy and autologous hematopoietic-cell transplantation (AHCT) has remained the standard of care (SOC) for relapsed and primary refractory (r/r) diffuse large B-cell lymphoma (DLBCL) for greater than 2 decades. In the postrituximab era, this strategy has yielded disappointing outcomes for r/r patients with curability in less one-quarter of the patients by intention-to-treat. Given the Food and Drug Administration (FDA) approval of chimeric antigen receptor (CAR) modified T cells directed against CD19 (CD19 CAR T) for DLBCL following two lines of therapy and/or failed AHCT, encouragement with this therapy in the second line for r/r patients has naturally prompted randomized phase III studies against the aforementioned SOC. The predominant hurdle to procession to AHCT is chemotherapy sensitivity after platinum-based salvage therapy. In this review, we will discuss recent investigations to improve response rates in r/r DLBCL with the intent of proceeding to potentially curative AHCT, as well as investigations to decrease progression post-AHCT. In addition, data regarding currently FDA approved CD19 CAR T cells will be reviewed. Within 2-3 years, we will know if the multicenter/multinational studies of CD19 CAR T will replace SOC salvage therapy and AHCT in the second-line. The role of allogeneic HCT will also be briefly reviewed in the context of these therapies.

S819 PET AFTER 2 CYCLES OF ABVD IN PATIENTS WITH EARLY-STAGE FAVORABLE HODGKIN LYMPHOMA TREATED WITHIN THE PHASE 3 GHSG HD16 STUDY

Background: NLPHL is a rare, distinct and indolent subtype of Hodgkin lymphoma. At present, evidence to guide treatment decision-making in NLPHL comes from a paucity of prospective and retrospective studies performed over the past decades. Population-based studies—which are very scarce in NLPHL—can lend support to examine how treatment practices over time affected population-level survival of patients with NLPHL Aims: The aim of this nationwide population-based study was to assess trends in primary treatment and relative survival (RS) among NLPHL patients diagnosed in the Netherlands. Methods: We selected all adult (≥18 years) NLPHL patients diagnosed between 1993–2016 from the nationwide Netherlands Cancer Registry (NCR), with survival follow-up through 2018. Data on primary therapy—i.e. no anti-neoplastic therapy, radiotherapy (RT) alone, and therapy with a chemotherapeutic backbone—were available in the NCR. Patients were categorized into two calendar periods (1993–2002 and 2003–2016), sex, age categories (18–39, 40–59, and ≥60 years), and stage (I-II and III-IV). The time periods represent the pre- and post-rituximab era, respectively. We calculated RS and excess mortality ratios up to ten years after diagnosis to estimate disease-specific survival. Also, overall survival (OS) was calculated up to ten years after diagnosis to present outcomes according to primary therapy. Results: Our analytical cohort included 616 NLPHL patients (median age, 44 years; 74% males; 72% stage I-II disease). The overall age-standardized incidence rate increased from 1.0/1,000,000 to 2.2/1,000,000 person-years between 1993–2002 and 2003–2016, respectively. This was a result of an increasing incidence in all three age groups across both sexes. There were no noteworthy trends in primary therapy over time. Overall, RT alone was the preferred treatment in stage I-II disease (56%), whereas therapy with a chemotherapeutic backbone was preferred in stage III-IV disease (77%). This was independent of age. Between 2007–2016, 40% and 57% of the chemotherapy recipients with stage I-II and III-IV disease received chemotherapy with rituximab (P = .095). The application of rituximab remained comparatively steady during this period. Rituximab use in earlier periods was not registered in the NCR. Ten-year OS (95% confidence intervals) was 99% (96%–100%) and 80% (67%–88%) for patients with stage I-II and III-IV disease who received first-line RT alone and first-line therapy with a chemotherapeutic backbone, respectively. RS was generally excellent across the various subgroups studied (Fig 1). Interestingly, patients age 18–39 experienced no excess mortality (EM) as compared to the general population. Also, EM was comparatively low among patients age 40–59 and ≥60. The multivariable model demonstrated that EM was similar between the two calendar periods (P = 0.891) and sexes (P = .477), whereas there was a poor prognostic effect of older age (P = .005) and advanced stage (P < .001; Fig 1). Interestingly, EM was similar between patients age 40–59 and ≥60 (P = .674; Fig 1).Summary/Conclusion: In this large, nationwide population-based study, survival among various subgroups of patients with NLPHL during a 23-year period was largely comparable to the survival of the general population. Further, we noted no improved survival after the introduction of rituximab into the therapeutic arsenal of NLPHL since 2003. Future prospective studies in NLPHL are necessary to establish evidence-based treatment recommendations that consider the delicate balance between efficacy, toxicity, and quality of life.

Effects of center type and socioeconomic factors on early mortality and overall survival of diffuse large B-cell lymphoma.

Aim: To examine whether the center type and socioeconomic factors significantly impact 1-month mortality and overall survival (OS) of patients with diffuse large B-cell lymphoma (DLBCL). Methods: National Cancer Database (NCDB) was used to identify patients diagnosed with diffuse large B-cell lymphoma from 2006 to 2012 (postrituximab era). Results: Among 185,183 patients, 33% were treated at academic centers. The receipt of therapy at larger volume centers was associated with improved 1-month mortality. Academic centers had better OS than nonacademic centers in univariable analysis. Younger age, private insurance, lower Charlson comorbidity score and lower lymphoma stage were associated with improved 1-month mortality and OS. Conclusion: The receipt of therapy at larger volume centers and socioeconomic factors were associated with improved survival.

A phase 1 study of ibrutinib in combination with R-ICE in patients with relapsed or primary refractory DLBCL

AbstractIn the postrituximab era, approximately half of the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response to standard salvage therapy, and are thus ineligible to proceed to autologous stem cell transplantation with curative intent. The Bruton tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, particularly of non–germinal center (non-GC) cell of origin. We conducted a single-center phase 1 study evaluating dose-escalated ibrutinib, in a 3-by-3 design, in combination with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in physiologically transplant-eligible rel/ref DLBCL patients. Twenty-one patients have been treated and are evaluable for toxicity with no dose-limiting toxicities observed through expansion with ibrutinib at 840 mg daily at dose level 3. Of the 20 patients evaluable for response, per modern International Conference on Malignant Lymphoma criteria, 11 patients achieved complete remission (CR) and 7 patients achieved partial remission for an overall response rate of 90%. All evaluable patients with non-GC DLBCL achieved a metabolic CR. Ibrutinib in combination with R-ICE demonstrates tolerability and efficacy in rel/ref DLBCL, particularly of non-GC phenotype. This treatment program warrants further investigation in later-phase studies. This trial was registered at www.clinicaltrials.gov as #NCT02219737.

Concurrent Abdominal and Thyroid Lymphoma: A Case Report

ABSTRACT Objective: Thyroid lymphoma constitutes a rare presentation of extranodal, diffuse, large B-cell lymphoma (DLBCL) and represents a small proportion of thyroid cancers. In this article, we present a case report of extranodal DLBCL presenting with simultaneous thyroid, abdominal, and retroperitoneal involvement. We also review the relevant epidemiologic literature and treatment modalities of thyroid lymphoma as well as providing a potential pathophysiologic mechanism. Methods: A literature search was conducted using the databases PubMed and Google Scholar for primary thyroid lymphoma and extranodal lymphoma involving the thyroid. Publications were selected based upon size of patient cohorts, treatment modalities investigated, quality of the data, as well as subsequent citation frequency. Articles most recently published, and therefore belonging to the post-rituximab era, were favored. Results: Thyroid lymphoma in the presence of concurrent abdominal disease usually presents with goiter with or with...