History Of Follicular Lymphoma Research Articles

5131 Vanishing Act: Uncommon Case Of Pheochromocytoma With Positive Biochemical Work-up With Absence Of Tumor And Medullary Tissue

Abstract Disclosure: N. Chan: None. R. Kaufman: None. N. Farhat: None. G.Y. Kim: None. Pheochromocytomas are rare neuroendocrine tumors derived from adrenal chromaffin cells that result in hyperactivity of the sympathetic nervous system. In the United States, they occur in about 0.05% to 0.1% patients with sustained hypertension. We are presenting a case of a patient with biochemical evidence of pheochromocytoma, but surgical pathology revealed absence of tumor and residual normal medulla.80-year-old female with a history of follicular lymphoma and hypertension presented for evaluation of an incidental right-sided adrenal nodule noted on a PET-CT. She had a history of hypertension managed on lisinopril 40 mg, amlodipine 10 mg and atenolol 100 mg daily. She denied a history of weakness, dizziness, headaches, palpitations, or easy bruising. Workup was negative for primary aldosteronism and Cushing’s Syndrome. Plasma normetanephrines was high at 675.7 pg/mL (0-285.2 pg/mL). 24-hour urinary normetanephrine was also elevated at 562 ug/g (0-400 ug/g). CT abdomen and pelvis with and without contrast revealed a 1.4 cm right adrenal nodule approximately 16 Hounsfield units. These findings were suggestive of pheochromocytoma. She was pre-treated with alpha blockade and subsequently had a robotically assisted laparoscopic right adrenalectomy. Postoperatively, the patient was hypotensive and required vasopressors. She was eventually weaned off vasopressors and discharged on lisinopril 20 mg daily. Soon after discharge, the patient was complaining of hypotension and this dose was halved. 4 weeks postoperatively, laboratory evaluation showed normalization of plasma normetanephrines to 0.83 nmol/L (0-0.89 nmol/L). Surgical pathology revealed an infarcted benign adrenal cortical proliferative lesion with background of cortical hyperplasia, fibrotic adrenal medullary region, and hemosiderin deposition. There was no identifiable medullary neoplasm and no residual medulla.Pheochromocytomas are highly vascular tumors as angiogenesis is a critical step in tumor growth, which can lead to frequent infarcts. This case shows classic biochemical evidence of pheochromocytoma. Interestingly, the resulting clinical examination displayed obliteration of the medullary tissue. Complete disappearance of both tumor and residual normal medulla is extraordinarily rare. The pre-operative hormonal levels in association with findings of complete absence of neoplastic and nonneoplastic medullary tissue cannot be explained. Presentation: 6/1/2024

Diagnosis, management and follow-up of follicular lymphoma: a consensus practice statement from the Australasian Lymphoma Alliance.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma subtype, accounting for 15-20% of all lymphoma diagnoses. Although typically slow-growing and responsive to frontline therapies, advanced-stage FL remains incurable with current treatments and typically follows a chronic relapsing/remitting course with increasingly shorter responses to subsequent lines of therapy. Outcomes are highly variable; some patients experience prolonged first remissions that may approximate a 'functional cure'. By contrast, a significant minority of patients experience disease progression shortly after frontline treatment resulting in high rates of lymphoma-related mortality. Reflecting on the heterogeneous natural history of FL, clinical practice varies widely, particularly in controversial areas, including appropriate disease staging, selection of management strategies and duration of clinical follow-up. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice.

Abstract 16092: Oncology Meets Cardiology: Sustained Ventricular Tachycardia With a Pulse

Introduction: Palpitations are one of the most common presenting symptoms. While usually benign, they can be life-threatening. We present a case of a sustained VT in the setting of a rare transformation of Follicular Lymphoma (FL). Case Description: An 86-year-old female with a history of FL with cardiac involvement, hypothyroidism, and hypertension presented with three episodes of palpitations. The first lasted about 20 minutes and spontaneously resolved. The second occurred a few hours later and was resolved within 15 minutes. Her third did not resolve. On presentation, she was complaining of palpitations and lightheadedness. BP 136/97, HR 193. Physical exam revealed no respiratory distress, rapid rate, clear lung fields, and unremarkable neurological exam with clear mentation. ECG (below) demonstrated sustained VT with rates of ~260 bpm. Amiodarone bolus was started. Cardioversion was attempted, but her VT degenerated into Ventricular Fibrillation. She achieved ROSC and was admitted with sinus rhythm. It was suspected that her FL had transformed into a more aggressive lymphoma, i.e. Diffuse Large B cell Lymphoma (DLBCL). On Cardiac MRI, she had metastasis to the right AV groove consistent with cardiac lymphoma, which was the etiology of her arrhythmia. She elected to enroll in hospice and was discharged in sinus rhythm. Impact/Discussion: Histological transformation (HT) of indolent non-Hodgkin lymphoma subtypes (FL) to clinically aggressive subtypes (DLBCL) is estimated to occur 1-2 %/year. Although there have been studies examining risk factors suggestive of HT, much still needs to be studied to effectively manage patients with cardiac metastasis. In this case, metastasis involved the right AV groove, which was the cause of her arrhythmia. Patients with sustained VT usually present with severe symptoms including cardiac arrest, but can present with mild symptoms, as was the case of this patient. Prompt evaluation and management of palpitations is paramount.

Co-Occurrence of Clonally Related Follicular Lymphoma and Histiocytic Sarcoma

Histiocytic sarcoma (HS) is an extremely rare and aggressive malignancy thought to be derived from mononuclear phagocytic cells. HS may occur as primary tumor or may be clonally related to a hematologic malignancy. Rare cases of HS have been reported in patients with follicular lymphoma (FL). Prior reports have demonstrated a common clonal origin of FL and HS in many cases via demonstration of identical BCL2/IGH [t(14;18)] translocations in both malignancies. As this is likely the earliest event in FL pathogenesis, the mechanisms by which HL may arise from FL remain unknown. A greater understanding of how a B cell malignancy can transdifferentiate into a myeloid one would yield insights into the fundamental underlying biology. From a patient with long-standing history of FL and subsequent diagnosis of HS, we collected tumor biopsies from a tumor site harboring both FL and HS. Tumor biopsies were subjected to standard histopathological assays, as well as targeted hybrid-capture DNA sequencing of 164 genes commonly mutated in hematologic malignancies and cytogenetic assays for the BCL2 rearrangement (Figure 1). Additionally, we performed single cell RNA sequencing (scRNA-seq) using the 10X chromium followed by single cell long read sequencing using Nanopore Oxford Technologies (Figure 1). Two tumor populations were evident in the scRNAseq data - FL tumor cells, identified by homogeneity of BCR light chain variable gene expression and expression of FL marker genes, and a separate cluster of cells expressing CD68, CD163 and S100A8, characteristic for HS cells. Gene expression profiles of the two tumor populations revealed high expression of the targetable “don´t eat me” signal CD47 on both populations. HS also expressed BCL2, hinting at a common clonal origin of FL and HS neoplasms. Indeed, fluorescent in situ hybridization (FISH) studies demonstrated the presence of t(14;18) in both the FL and HS tumor cells. To understand if similar transcription factors (TFs) were active in the two malignancies, we inferred the top 10 enriched TF for each tumor subpopulation and found that while TFs like IRF8 and REL were enriched in FL cells, HS cells showed a higher expression of MYC, STAT2 and CEBPD. Bulk targeted hybrid-capture DNA sequencing of the tumor sample revealed mutations in genes frequently altered in FL ( e.g. CREBBP, BIRC3, and PIM1) as well as in a gene commonly mutated in HS ( MAP2K1). To gain deeper insight into the clonal relationship between the two malignancies within the same tumor, we conducted long read sequencing on the barcoded single cell-cDNA. We are currently analyzing the data in two ways. First, we are searching for the mutations identified in bulk sequencing now in the single cell long read data from the FL and HS cells, using microenvironmental immune cells from the same tumor as a negative control. We have confirmed that these genes are all expressed in the FL, HS, and immune cells, providing transcripts for us to analyze for mutations. Second, we are employing an unbiased approach for identifying genetic variants, again comparing FL and HS cells. This data will be available by the annual meeting. By applying single cell genomics analyses to a combined FL/HS biopsy, our study aims to understand the evolutionary relationship of HS arising from FL, particularly whether the HS arose from an early dormant clone (branched evolution) or from a late, prevalent Fl clone (linear evolution). Evidence of the former would strengthen the view that common progenitor cells (CPCs) in FL are capable of differentiating into myeloid and lymphoid malignancies.

Lymph node location and retention properties of DC‐SIGN engagement with the Immunoglobulin Oligomannoses of Follicular Lymphoma

Introduction: The oligomannose-type glycans occupying the surface immunoglobulin antigen-binding site (sIg-Mann) are a tumor-founding post-translational requirement of classic follicular lymphoma (FL). These are universally acquired and a clonal necessity during the entire natural history of FL from the early stages throughout transformation into EZB-DLBCL (Chiodin G, Blood 2021, Odabashian M, Blood 2020). The low-affinity interaction of sIg-Mann with its specific ligand DC-SIGN distinguishes from conventional high-affinity antigen:Ig protein interactions for promoting prolonged low-level growth and prosurvival signals via PI3K/AKT and not endocytosis (Linley A, Blood 2015). However, the location and function of DC-SIGN remains to be further elucidated. Here, we investigated the hypothesis that the specific DC-SIGN:Ig-Mann interaction functions to promote retention of FL cells in tissue niches maintaining selective survival advantage. Methods: Immunofluorescence imaging was used to determine DC-SIGN histological location in primary FL lymph nodes. In WSU-FSCCL cells, DC-SIGN effects on sIg redistribution were measured by dSTORM; adhesion to VCAM-1 in presence/absence of inhibitors was measured by flow cytometry. Results: Immunofluorescence of lymph nodes from FL patients revealed that DC-SIGN was expressed on interfollicular CD163+ macrophages and, remarkably, on CD23+ follicular dendritic cells (FDC), claiming an influence on FL cell retention and survival. dSTORM revealed that DC-SIGN induced less dense and more diffuse surface Ig clusters compared to anti-Ig, reflecting an immature sIg redistribution unable to promote endocytosis and death. However, DC-SIGN efficiently induced adhesion of sIg-Mann+ve lymphoma cells to VCAM-1, known to be expressed on both lymph node macrophages and FDC, and inhibited migration towards SDF-1 in vitro. Blocking of DC-SIGN carbohydrate-recognition domain completely abrogated DC-SIGN-induced adhesion. Although intracellular signals were significantly lower, DC-SIGN induced levels of adhesion similar to those induced by anti-Ig. Adhesion to VCAM-1 was observed at concentrations from 20 µg/ml down to 20 ng/ml, even when AKT and ERK phosphorylation was not detectable. Either proximal inhibition of the PI3K/AKT pathway, or distal inhibition of ARP2/3, formin, and Cdc42 for lamellipodium formation at the surface membrane, suppressed adhesion. Conclusions: These results reveal an important mechanism of the DC-SIGN:sIg-Mann interaction that fine-tunes signals for membrane adaptation towards tumor cell adhesion, without promotion of cell death. This possibly facilitates FL cell retention in the lymph node protected tumor niche where selective growth and survival signals are maintained. Interrupting this interaction will be a novel way towards tumour-specific targeted therapy in FL patients. The research was funded by: This research was funded by Blood Cancer UK (grant 18009), Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, program C2750/A23669, and BTERP project C36811/A29101). D.T. was funded by the Eyles Cancer Immunology PhD scholarship, G.C. was funded by the Eyles Cancer Immunology Fellowship and the Southampton Cancer Immunology Centre Pump-priming award 2021). Keywords: Indolent non-Hodgkin lymphoma, Microenvironment, Targeting the Tumor Microenvironment Conflicts of interests pertinent to the abstract. F. Forconi Employment or leadership position: University of Siena Consultant or advisory role: Beigene Honoraria: Abbvie, Janssen-cilag, Beigene, Astra-Zeneca Research funding: Cancer Research UK Educational grants: Beigene, Abbvie Other remuneration: BC Platform

Pooled Safety Analysis from Phase I-III Studies for Patients with Hematological Malignancies Treated with the PI3K Inhibitor Copanlisib

Introduction: As of 2021, four phosphatidylinositol 3-kinase (PI3K) inhibitors had received accelerated approval by the FDA for treatment of patients (pts) with indolent follicular lymphoma (FL) having received ≥2 systemic therapies. Recently, during confirmatory studies, three of the PI3K inhibitors have been voluntarily withdrawn over concerns for toxicities impacting overall survival and this issue was the focus of an Oncologic Drugs Advisory Committee (ODAC) meeting in April 2022. Copanlisib is the only PI3K inhibitor currently available for treatment of FL and is distinguished by being administered intravenously on an intermittent schedule. We report here a comprehensive pooled analysis of copanlisib safety with long-term follow-up from 10 completed Phase I-III studies in pts with hematologic malignancies. Methods: Pts with hematologic malignancies treated with copanlisib monotherapy in completed open-label Phase I or II studies and a randomized, placebo-controlled Phase III in combination with rituximab were included. Copanlisib 60 mg (i.v.) was administered intermittently on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. AEs were reported using MedDRA version 24.1 and assessed by duration of treatment in 6-month intervals or time of onset (worst grade or new AEs occurring ≤180 days [d], 181-360 d, 361-540 d, 541-720 d, or ≥721 d). Results: A total of 684 pts received copanlisib and were evaluable for safety (data cut-off Feb 2022). Median age was 64 years (range 22-93). A total of 51% of pts had a history of FL, 14% MZL, and 10% DLBCL. More than half (54%) were treated with copanlisib for less than 6 months, whereas 27% were treated for >12 months and 13% >2 yrs. The mean overall duration of treatment was 10.9 months (range 0.2-80 months). 24% of pts had at least one dose reduction and 73% had at least one dose interruption or delay (mean duration 3 days). Copanlisib-related treatment-emergent AEs (TEAEs) were reported in 92% of pts; 55% of pts had TEAEs of worst grade [g] 3, and 24% had TEAEs of worst g4. The most common reasons for discontinuation were progression (41%), AE not associated with clinical disease progression (29%) and withdrawal by subject (11%). The most common (≥10%) copanlisib-related TEAEs (% all-grade/g3/g4) were hyperglycemia (58/37/6), hypertension (42/33/0), diarrhea (23/4/0), neutrophil count decreased (20/7/7), neutropenia (19/8/7), nausea (17/0.3/0), white blood cell count decreased (13/5/0.6), fatigue (13/1/0), and anemia (11/3/0). Hyperglycemia and hypertension, both of which were infusion related and transient, had the highest incidence in the first 180 days of treatment. For diarrhea, pts treated for longer duration were more likely to have experienced diarrhea, but g3 events were constant per 6-month onset of event interval (2.2/2.5/3.2/0.8/3.3%). For AEs of interest, the incidence of colitis was low (0.9%; 6 pts: 2 g1, 3 g3 and 1 g4) as was the overall incidence of pneumonitis (6/2/0.6; one g5) with all the g4 events occurring <180 days. The occurrence of late onset AEs of increasing severity has been an issue with orally administered PI3K inhibitors. The greater exposure of pts to copanlisib with longer treatment notwithstanding, we examined the incidence and severity of AEs in pts treated ≤6 months, 6-12 months and >12 months, by overall duration of treatment and by interval of onset (Table) to ascertain the timing and severity of AEs. For hyperglycemia and hypertension, the overall incidence rate was similar for pts treated ≤6 months, 6-12 months and >12 months but was mostly accounted for higher rates day 1-180. Diarrhea was higher in pts treated >12 months, but mostly due to low grade events. There was a trend for a higher incidence of neutropenia and/or neutrophil count decrease depending on treatment duration, but infections remained low. A total of 50 (7%) pts died within 35 days of discontinuing copanlisib, with 18 (2.6%) due to progressive disease (PD) and 9 (1.3%) AEs related to PD, and 20 (2.9%) AEs not associated with clinical progression. Copanlisib-related g5 (death) TEAEs were reported in 10 pts (1.5%), with 8 events in pts treated <6 months; infection-related AEs reported in 5 pts. Conclusions: Based on this expanded safety dataset with long-term treatment of copanlisib, there is no evidence of late-onset toxicities or worsening of severity of TEAEs. No new or unexpected safety issues were identified. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 444: COVID-IRIS: Immune reconstitution after G-CSF administration for neutropenia during acute COVID-19 infection

Abstract Background: Immune reconstitution inflammatory syndrome (IRIS) is a rapid inflammatory response with immune recovery, most commonly observed following antiretroviral therapy initiation in people with HIV and underlying opportunistic infections. To date there is one reported case of COVID-associated IRIS in a neutropenic patient treated with granulocyte colony-stimulating factor (G-CSF). Here we describe a second case of COVID-associated IRIS in a patient with history of follicular lymphoma who received G-CSF during acute COVID-19 infection. Case: A 64-year-old woman with history of follicular lymphoma and autologous stem cell transplant one year prior presented with dyspnea, diarrhea, and fever, and tested positive for SARS-CoV-2. She had received three doses of the Pfizer BioNTech vaccine. She was admitted to the hospital for acute hypoxic respiratory failure and treated with remdesivir 100mg, dexamethasone 6mg, and 2 L/min supplemental oxygen via nasal cannula for five days. Twelve days after discharge, the patient returned with persistent diarrhea, fatigue, fever, and an oxygen saturation of 87% on room air. She again tested positive for SARS-CoV-2 by PCR. She was admitted to the intensive care unit for high-flow nasal cannula (HFNC) with oxygen at 30 L/min and 50% FiO2 and treated with methylprednisolone 1 mg/kg daily. On admission, her D-dimer was 3943 ng/mL, C-reactive protein 136 mg/L, absolute neutrophil count (ANC) 767/mcL, platelets 84/mcL. Her chest CT scan was negative for pulmonary embolism but demonstrated bilateral ground glass opacities characteristic of COVID-19 pneumonia. Her ANC reached a nadir of 186 on day 3 at which point G-CSF (filgrastim 300 mcg/day) was administered for three days with subsequent neutrophil recovery. On day 6, in light of a negative test for COVID antibodies, she received high-dose monoclonal antibodies through a compassionate use program. At that time, her oxygen requirements were stable and inflammatory markers had decreased to CRP 25 and D-Dimer 940. However, her oxygen requirements and inflammatory markers rapidly increased thereafter, with HFNC settings up to 60L/80%, D-dimer 27754, and CRP 135. After a repeat chest CT on day 8 showed worsened ground glass opacities throughout all lung fields, her steroid dose was increased to methylprednisolone 2 mg/kg daily out of concern for COVID-associated IRIS following G-CSF administration. Her oxygen requirement and inflammatory markers declined over the following 2-3 days and she was transferred out of the ICU. Discussion: We present here an unusual case of COVID-associated IRIS after G-CSF administration in a transplant patient with COVID-19 pneumonia. Given the increased risk of infection and severe illness in immunosuppressed patients despite vaccination, it is important for providers to be aware of complications associated with adjunct therapies such as G-CSF in this vulnerable population. Citation Format: Chloe S. Lalonde, Tony Z. Zhuang, Amalia A. Aldredge, Max W. Adelman, Abeer N. AbouYabis, Morgan L. McLemore, Sara C. Auld. COVID-IRIS: Immune reconstitution after G-CSF administration for neutropenia during acute COVID-19 infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 444.

Clinical Management and Operative Decision-Making in a Patient With a History of Follicular Lymphoma.

Clinical Management and Operative Decision-Making in a Patient With a History of Follicular Lymphoma.

EBV+ high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: a multi-institutional study.

It is unknown whether Epstein-Barr virus (EBV) infection can occur in high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double- or triple-hit lymphoma (DHL/THL). Here we report 16 cases of EBV+ DHL/THL from screening 846 cases of DHL/THL and obtaining additional EBV+ cases through multi-institutional collaboration: eight MYC and BCL2 DHL, six MYC and BCL6 DHL and two THL. There were eight men and eight women, with a median age of 65 years (range = 32-86). Two patients had a history of follicular lymphoma and one had AIDS. Nine of 14 patients had an International Prognostic Index of ≥3. Half of the cases showed high-grade/Burkitt-like morphology and the other half diffuse large B cell lymphoma morphology. Using immunohistochemistry, the lymphoma cells were positive for MYC (n = 14 of 16), BCL2 (n = 12 of 16), BCL6 (n = 14 of 16), CD10 (n = 13 of 16) and MUM1 (n = six of 14). Using Hans' algorithm, 13 cases were classified as germinal centre B cell (GCB) and three as non-GCB. The lymphomas frequently showed an EBV latency Type I with a median EBV-encoded small RNAs of 80% positive cells (range = 20-100%). After a median follow-up of 36.3 months (range = 2.0-41.6), seven patients died, with a median survival of 15.4 months (range = 3.4-47.3) after diagnosis of EBV+ DHL/THL. Five of six patients with MYC and BCL6 DHL were alive, including four in complete remission. In contrast, only four of 10 patients with MYC and BCL2 DHL or THL were alive, including two in complete remission. The median survival in patients with MYC and BCL6 DHL was unreached and was 21.6 months in patients with MYC and BCL2 DHL or THL. EBV infection in DHL/THL is rare (~1.5%). Cases of EBV+ DHL/THL are largely similar to their EBV- counterparts clinicopathologically. Our findings expand the spectrum of EBV+ B cell lymphomas currently recognised in the World Health Organisation classification and suggest differences between EBV+ MYC and BCL2 DHL versus EBV+MYC and BCL6 DHL that may have therapeutic implications.

A Comprehensive and Systematic Analysis of Minimal Residual Disease (MRD) Monitoring in Follicular Lymphoma: Results from the Fondazione Italiana Linfomi (FIL) FOLL12 Trial

A Comprehensive and Systematic Analysis of Minimal Residual Disease (MRD) Monitoring in Follicular Lymphoma: Results from the Fondazione Italiana Linfomi (FIL) FOLL12 Trial

A Prospective Study of Clonal Evolution in Follicular Lymphoma: Circulating Tumor DNA Correlates with Overall Tumor Burden and Fluctuates over Time without Therapy

Background: Follicular lymphoma (FL) shows marked variation in clinical course including spontaneous regression and histologic transformation (HT). Watchful waiting (W&W) is routinely applied to pts with newly diagnosed FL, but monitoring strategies are not standardized. Pts with progression within 1-2y of diagnosis have worse outcomes, but the biologic basis is unclear and biologic-based classifiers are not routinely applied at diagnosis. Circulating tumor DNA (ctDNA) is a highly tumor-specific biomarker that is prognostic in aggressive B-cell lymphomas, but its ability to serially monitor FL remains undefined. We applied a next-generation sequencing assay to identify tumor clonotypes for serial monitoring of peripheral blood in pts with untreated FL as part of an ongoing prospective clinical trial [NCT03190928].Methods: Pts with grade I-II or 3A FL are eligible if evaluable disease on CT or FDG-PET, age ≥18, ECOG ≤2, no evidence of HT, and no prior systemic therapy. Pts undergo W&W until they meet uniform protocol-defined treatment criteria and remain on study until second-line therapy. Baseline testing includes labs, peripheral blood flow cytometry, BM biopsy/aspirate, CT and FDG-PET scans, and research biopsy. Pt have clinic visits every 4m for 2y, every 6m in years 3-5, then annually. CT scans are every 8m for 2y, then annually. FDG-PET scans are at baseline, at 2y, and any time of suspected progression. Peripheral blood samples including Streck tubes (plasma) and PBMCs are drawn at each clinic visit and stored. For ctDNA analysis, tumor DNA was amplified from FFPE using locus-specific primer sets for the Ig heavy-chain and light-chain loci along with BCL1/BCL2 translocations (Adaptive Biotechnologies). Amplified products were sequenced and tumor clonotypes were identified in plasma and PBMCs. Serial tracking of ctDNA was done in plasma and blinded to clinical outcomes.Results: 77 pts enrolled between July 2017 and July 2021. Median age was 57 (range 24-83) including 14 (18%) low-risk, 29 (38%) intermediate-risk, and 34 (44%) high-risk by FLIPI. Fourteen (18%) pts had stage I-II disease. Forty-three (56%) pts had monoclonal B-cells on peripheral blood flow cytometry. Twenty-nine (38%) pts progressed requiring frontline therapy including 7 (9%) pts with HT. Twenty-five (32%) pts were monitored ≥2y with no progression including 10 (13%) pts with evidence of at least some spontaneous regression by CT. Twenty (26%) pts were on study for <2y and 3 (4%) pts were unevaluable. Of 36 pts with FFPE analyzed, 35 (97%) had ≥1 dominant tumor clonotype identified for tracking. Of these, 32 (91%) had ≥1 dominant clonotype identified in plasma suitable for tracking. Three pts without available FFPE had the dominant clonotype identified from plasma that was used for tracking. In 28 pts, plasma was compared to PBMCs, and ≥1 clonotype was identified in both compartments in 21 (75%), plasma only in 5 (18%), and neither in 2 (7%). The median overall levels of baseline plasma ctDNA was 104.7 counts/mL (range 4-2096); progressors had median levels of 136.0 counts/mL (range 4-1493) compared to 40.9 count/mL (32-2096)(p=0.85) for non-progressors (Figure 1A). Baseline ctDNA correlated with the total metabolic tumor volume (TMTV) on FDG-PET scan (r=0.49, p=<0.006)(Figure 1B). Pts who required immediate treatment often had very high baseline levels of ctDNA (black dots, Figure 1C) and serial monitoring prior to progression demonstrated patterns of sharp increases in ctDNA prior to progression or relatively stable levels in others (Figure 1C). Notably, significant fluctuations were noted in ctDNA for non-progressing pts with an overall trend for decreasing values including four pts with evidence of spontaneous regression by CT with corresponding decreases in ctDNA over time (Figure 1D). As a notable examples, FL_14 had baseline ctDNA level of 2096 counts/mL with decreases to 101 counts/mL after 4 months, 14 counts/mL at 16 months, and no detectable ctDNA at 2 years.Conclusions: ctDNA quantified from plasma in FL mirrors TMTV. Serial monitoring of ctDNA in patients without therapy demonstrated various patterns of fluctuation, including some patients in which ctDNA became undetectable coincident with spontaneous clinical regressions. ctDNA thus provides a non-invasive platform to monitor the natural history of FL, enabling future studies of tumor immune surveillance in this disease. [Display omitted] DisclosuresJacob: Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Bagaev: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Meerson: BostonGene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Postovalova: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Kudryashova: BostonGene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Kotlov: BostonGene Corp: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Fowler: BostonGene: Current Employment, Current holder of stock options in a privately-held company.

S2395 A Series of Unfortunate Events: A Unique Case of Multiple Small Bowel Malignancies in the Setting of Inflammatory Bowel Disease

Introduction: Crohn’s disease (CD) is known to increase malignancy risk. Both large and small bowel adenocarcinoma and intestinal carcinoid tumors have been reported at increased rates in patients with CD but rarely concurrently. Additionally, there is an association between Non-Hodgkin Lymphoma and CD, however this is attributed to the use of immunosuppressive medications. We present a patient with a history of follicular lymphoma and ileal CD who later developed two separate small bowel malignancies. Case description/methods: The patient is a 63-year-old male with hypertension, chronic kidney disease, pulmonary embolism, and follicular lymphoma. His follicular lymphoma was diagnosed in 2009 by axillary lymph node biopsy after presenting with lower extremity swelling, night sweats, and weight loss. Staging CT scans prior to treatment demonstrated thickening of the ileum. He was treated with chemotherapy for two years and then remained on maintenance therapy. Five years after diagnosis, the patient was evaluated for 20 years of intermittent diarrhea. Endoscopic evaluation revealed CD of his ileum as well as a duodenal nodule. Elevated serum gastrin and chromogranin A levels, a positive octreotide scan, and EUS fine needle aspiration confirmed the nodule as a stage 1 duodenal carcinoid tumor which was subsequently resected. The following year, he developed fatigue and was noted to have iron deficiency anemia. Repeat EGD and colonoscopy was unrevealing thus he had a video capsule study which demonstrated narrowing of his ileum. CT enteroclysis revealed inflammation in his ileum. He underwent a small bowel resection and surgical pathology confirmed intestinal-type moderately differentiated adenocarcinoma of the ileum. Discussion: This case describes a unique course of a patient with follicular lymphoma and CD developing two small bowel malignancies related to underlying CD. While there are reports of CD developing as a treatment related complication of NHL and NHL developing as a treatment related complication of CD, our patient likely had untreated CD at time of his lymphoma diagnosis. This untreated CD likely led to the development of adenocarcinoma and his carcinoid is also likely associated with his CD. While it is rare to develop multiple small bowel malignancies, this case highlights the importance of maintaining a high index of suspicion of symptom changes in CD patients as they may be indicative of treatment specific and/or CD complications which may ultimately change management.

High-risk follicular lymphoma: Treatment options.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. The natural history of FL appears to have been favorably impacted by the introduction of rituximab. Randomized clinical trials have demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Maintenance rituximab strategies can improve progression-free survival (PFS). Obinutuzumab was superior to rituximab for PFS in the GALLIUM study, although the benefit was small and required more drug. Chemotherapy platforms have changed in the past decade, as bendamustine combined with rituximab has become commonly utilized frontline strategy in North America and parts of Europe, although there is certainly no one standard treatment. However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, the development of novel combinations, and strategies to reduce the risk of transformation. A multitude of novel therapies are under investigation in both the frontline and relapsed/refractory settings. It will be critical to identify the most appropriate populations for new agents and to develop validated surrogate endpoints, so that novel agents can be tested (and adopted, if appropriate) efficiently.

Histiocytic and dendritic cell neoplasms: Reappraisal of a Japanese series based on t(14;18) and neoplastic PD-L1 expression.

Histiocytic and dendritic cell (H/DC) neoplasms are heterogeneous, originating from myeloid- or stromal-derived cells. Multiple reports describe the cross-lineage transdifferentiation of neoplastic B cells into H/DC neoplasms. Most such cases are from Western countries, and rarely from Japan or East Asia. Here we report 17 cases of H/DC neoplasms in Japanese patients, with analysis of t(14;18) by fluorescence in situ hybridization, and of neoplastic programmed death-ligand 1 (PD-L1) expression by immunostaining (clones SP142, E1J2J, and 28-8). These 17 cases were diagnosed according to the 2017 World Health Organization (WHO) classification, and included two histiocytic sarcomas (HS), two interdigitating cell (IDC) sarcomas, one Langerhans cell sarcoma, two dendritic cell sarcomas, and 10 follicular dendritic cell (FDC) sarcomas. No case had any past history of follicular lymphoma (FL). Two cases of HS and one IDC sarcoma, all of which were myeloid-driven, were found to exhibit t(14;18). In the latter case, at 30 months after IDC sarcoma diagnosis, FL development was detected. Three (30%) FDC sarcoma cases exhibited neoplastic PD-L1 expression with all the three PD-L1 antibody clones. This is the first report of t(14;18) and neoplastic PD-L1 expression on H/DC neoplasms among Japanese patients, each of which appeared to be associated with HS and FDC sarcoma, respectively.

Updates in treatment strategies for follicular lymphoma

Follicular lymphoma (FL) is incurable with the current standard therapeutic strategy despite improvements of the natural history of FL in the last few decades. For advanced-stage patients with low-tumor burden, watchful waiting remains the standard treatment. The optimal timing of rituximab monotherapy has not been elucidated. For advanced-stage patients with high-tumor burden, anti-CD20 monoclonal antibody and chemotherapy are the standard care. A subset of FL patients who had early progression of relapse within 24 months has a significantly poor prognosis. Among the early progression of the disease group, more early progression and transformation are important factors. Recently, genomic analysis suggests that high-risk biology may depend on the type of chemotherapy. Therefore, the genomic profile could help develop appropriate treatment selection in the future. This review includes the current FL treatment strategy and prognostic factors.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS TRIGGERED BY ADENOVIRUS PNEUMONIA: A RARE COMPLICATION OF A COMMON DISEASE

SESSION TITLE: Monday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: Adenovirus (ADV) pneumonia is a common disease with many extrapulmonary complications. We report a case of a 71-year old lady with history of follicular lymphoma who developed ADV pneumonia triggering hemophagocytic lymphohistiocytosis (HLH) CASE PRESENTATION: A 71-year-old female presented to our hospital with fever and cough. Chest X-ray revealed pneumonia. Additional labs upon admission showed pancytopenia. Six months prior to presentation, she was diagnosed with follicular lymphoma and she completed six cycles of R-CHOP (last cycle being four weeks prior to presentation). A PET-CT scan performed five days prior to admission revealed complete metabolic response, and a complete blood count was normal. Empiric antibiotics did not result in improvement prompting a CT scan of the chest that showed dense consolidation in the left lower lobe, ground glass opacities in upper lobes and trace pleural effusions. Bronchoscopy was performed. Bronchial wash cultures grew ADV. Other bacterial, fungal and viral serology/cultures were all negative. ADV was also isolated from serum. Patient remained febrile and had progressive pancytopenia with counts reaching a nadir of 0.0K/uL neutrophils, 5.8 g/dL hemoglobin and 34K/uL platelets. Further labs showed elevated ferritin at >40,000ng/ml , elevated soluble IL-2 receptor alpha and transaminitis. HLH was suspected and steroids were started empirically. Bone Marrow biopsy confirmed HLH without evidence of lymphoma or metastatic carcinoma. Patient continued to decline, she developed rectus sheath hematoma, hypotension, acute kidney injury and delirium. Family decided to withdraw all active treatments and take the route of comfort care which eventually lead to her unfortunate demise on day nine of admission. DISCUSSION: ADV pneumonia can occur in both immunocompetent and immunocompromised hosts(1). Both outbreaks and sporadic cases have been described. ADV-pneumonia can be fatal with poor prognostic factors including: viremia, multilobar infiltrates and parapneumonic effusions(2, 3). CT commonly shows dens consolidation with surrounding ground glass opacities. ADV infection induced HLH has been well described in children. This phenomenon is rare in adults with only a few reported cases, mostly described in hematopoietic stem cell transplant recipients. Older age, markedly elevated ferritin and underlying lymphoma are considered poor prognostic factors in HLH. Our patient’s history of follicular lymphoma had probably put her at higher risk for developing this immunological catastrophe. She had all of the aforementioned poor prognostic of both ADV-pneumonia and HLH. CONCLUSIONS: Our case signifies that HLH should be suspected in the setting of ADV infection and pancytopenia. Early diagnosis and treatment might be associated with better outcomes in this rare-life threatening- hematological complication. Reference #1: Shen CF, Wang SM, Ho TS, Liu CC. Clinical features of community acquired adenovirus pneumonia during the 2011 community outbreak in Southern Taiwan: role of host immune response. BMC infectious diseases. 2017;17(1):196. Reference #2: Gu L, Qu J, Sun B, Yu X, Li H, Cao B. Sustained Viremia and High Viral Load in Respiratory Tract Secretions Are Predictors for Death in Immunocompetent Adults with Adenovirus Pneumonia. PloS one. 2016;11(8):e0160777. Reference #3: Yoon H, Jhun BW, Kim SJ, Kim K. Clinical characteristics and factors predicting respiratory failure in adenovirus pneumonia. Respirology (Carlton, Vic). 2016;21(7):1243-50. DISCLOSURES: No relevant relationships by Muhammad Hamza, source=Web Response No relevant relationships by Khalid Mohamed Ahmed, source=Web Response No relevant relationships by Mahum Shahid, source=Web Response No relevant relationships by Qazi Ahmed Waqas, source=Web Response

Theraputic Approaches to High Grade B-Cell Lymphoma Double-Hit and Follicular Lymphoma with C -MYC, BCL2 and/or BCL6 rearrangements. Single Center Expirience

Abstract Introduction. An appearance of secondary c-MYC gene rearrangement in patients with follicular lymphoma (FL) can predispose to histologic transformation of FL and aggressive clinical course of disease. Approaches to follicular lymphoma with с -MYC, BCL2 and/or BCL6 rearrangements treatment are not clearly defined. Aim. To compare clinical characteristics and treatment efficacy in groups of patients with FL histologic transformation or blastoid variant of FL with c-MYC, BCL2 and/or BCL6 genes rearrangements and HGBL double-hit (DH). Patients and methods. We analyzed data (since 2004 to 2017 years) from a single-center observation of 12 pts with high grade B-cell lymphoma (HGBL) DH, and 5 FL pts with c-MYC, BCL2 and/or BCL6 rearrangements (2 with histologic transformation into DLBCL, 2 cases of FL grade 3A with blastoid morphology and 1 FL grade 3B). Median follow-up was 9,3 (from 0,6 to 71,1) months. These groups did not have significant differences in clinical parameters such as age, ratio between men and women. In both groups majority of patients had ECOG≥2, III-IV stage of disease according to Ann-Arbor classification, high frequency of extranodal involvement (over 80%), bone marrow involvement (40-55%), high activity of LDH. In pts with HGBL DH Ki-67 expression level was significantly higher (median 93% (from 80 to 100%)) than in FL pts (median 70% (from 35% to 80%)), p=0,0037. Three pts with HGBL DH underwent CHOP-21±R, 2 pts - R-(DA)-EPOCH with lenalidomide maintenance, 7 pts - BL-M-04+R. 4 pts with HGBL DH achieved complete remission (CR) (2 - after BL-M-04+R, 1 - after R-DA-EPOCH, 1 - after CHOP), 2 pts achieved partial remission (PR) (1 after R-EPOCH), 7 pts had progressive disease (PD) (6 - after BL-M-04+R, 1 - after R-CHOP). 4 patients underwent autologous stem cell transplantation (autosSCT) 2 - in CR, 2 - in PR. Two pts transplanted in PR had PD 1-3 months later. Three pts with anamnesis or current diagnosis of FL underwent R-(DA)-EPOCH (1 with transformed FL, 2 - with blastoid variant of FL), 2 - R-CHOP-21 (1 pt with transformed FL, 1 pt - with 3B FL). From 3 pts after R-DA-EPOCH - 1 pt with blastoid variant of FL had CR (Ki-67 was 40%), 1 pt with blastoid variant of FL had stable disease (SD) (Ki-67 was 70%), she achieved CR after 3 R-DHAP, autoSCT now is planning. 1 pt with transformed FL had PR after R-DA-EPOCH and after 2 R-DHAP had PD (Ki-67 was 80%), subsequently died at 12,4 months. One pt is alive taking R-CHOP-21 (FL3B), one pts died due to PD after 6 R-CHOP-21 (with transformed FL, Ki-67 was 80%). Median overall survival in pts with HGBL, DH, was 9,6 (0,6-71,1) months; in pts with diagnosis or history of FL - 7,0 (2,4-19) months, p=0,99. Median time to progression (TTP) was 5,8 (0,3-71,1) months in first group and 7,0 (2,4-19) months in second group, respectively (p=0,98). Conclusion. Pts with de novo HGBL DH have a similarly poor prognosis as pts with histologic transformation of FL with c-MYC, BCL2 and/or BCL6 rearrangements. Cases corresponding to morphological criteria of FL with c-MYC and BCL2 rearrangements can differ in clinical course from indolent to highly aggressive depending on proliferative potential of tumor cells. Majority of FL cases with c-MYC and BCL2 rearrangements are characterized by aggressive clinical behavior and require more intensive approach than R-CHOP-21. We suggest that FL pts with c-MYC, BCL2 and/or BCL6 rearrangements could have benefit from R-(DA)-EPOCH. It is reasonable to consider FL pts with c-MYC, BCL2 and/or BCL6 rearrangements as candidates for consequent high dose therapy following autosSCT, if partial remission or stable disease is achieved on the first line of treatment. Download : Download high-res image (82KB) Download : Download full-size image Figure . Disclosures No relevant conflicts of interest to declare.

Diffuse Large B-Cell Lymphomas Transformed from or with Concurrent Follicular Lymphoma Demonstrate Similar Clinical Outcomes As De-Novo Diffuse Large B-Cell Lymphomas, Except for Cases Harboring Double Hit Rearrangements

▪Introduction:Follicular lymphoma (FL) is characterized by an indolent clinical course, but patients with this disease bear a risk of transformation to diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL). DLBCL transformed from FL (tDLBCL) traditionally has been associated with an aggressive course and a post-transformation survival of 0.6-1.7 years. However, a more recent study showed longer survivals in these patients, challenging the notion that transformation universally portends a poor prognosis in the immunotherapy era. Presence of concurrent FL at the time of diagnosis of DLBCL (cDLBCL/FL) also raises the possibility of transformation, but its clinical significance has not been elucidated in the literature. In this study, we analyzed and compared outcomes of tDLBCL, cDLBCL/FL, and de novo DLBCL. We also characterized the prevalence of MYC/BCL2/BCL6 gene rearrangements in tDLBCL and cDLBCL/FL cohorts and evaluated the impact of dual rearrangements (double hit, DH) on clinical outcomes.Methods:Patients diagnosed with DLBCL or B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma, also known as HGBL (BCLU/HGBL), treated at Northwestern University or University of Pennsylvania from 1/2010 to 7/2016 were included. Patients with Burkitt lymphoma, primary CNS and HIV-associated lymphoma were excluded. Transformation was defined as presence of DLBCL/ BCLU/HGBL in cases with an antecedent diagnosis of FL by at least 6 months. We divided our cohort into three groups: 1. De novo DLBCL or BCLU/HGBL with no prior history of FL (dDLBCL) 2. Transformed FL (tDLBCL) and 3. DLBCL or BCLU/HGBL with concurrent FL (cDLBCL/FL). Progression free survival (PFS) was defined as time from diagnosis to radiographic progression, regimen change, death or last follow-up. Overall survival (OS) was defined as time from diagnosis to death or last follow-up. Kaplan-Meier (KM) survival analyses, using a log-rank p-values were performed for PFS and OS to compare the three diagnosis groups (dDLBCL, tDLBCL, and cDLBCL; alpha=0.05) and pairwise comparisons of combinations of diagnosis (dDLBCL and tDLBCL+cDLBCL) and double hit status (accounting for multiple comparisons with a Bonferroni corrected alpha=0.013). Fluorescence in situ hybridization for MYC, BCL2 and BCL6 rearrangements was performed using break-apart probes per the policy of each institution.Results:A total of 293 pts, including 233 dDLBCL, 37 tDLBCL, and 23 cDLBCL/FL were included. 50% of the tDLBCL received at cytotoxic chemotherapy before transformation for precedent FL. Age and sex distribution, as well as clinical characteristics including stage, ECOG performance status, IPI score, and primary refractoriness were similar amongst the three groups. LDH was more likely to be elevated in dDLBCL (75%), as compared to tDLBCL(63%) and cDLBCL/FL (47%)(p=0.02%). Additionally, non-bone marrow extra-nodal disease was seen more often in dDLBCL (72%), as compared with tDLBCL (53%) and cDLBCL/FL (43%)(p <0.01). DH were seen more often in tDLBCL(32%) and cDLBCL/FL (30%), compared with the dDLBCL (11%)(p <0.01). The cell of origin was germinal-center type in 92% of the tDLBCL and 91% cDLBCL/FL, compared with 64% of dDLBCL (p <0.01). Intensive chemotherapy regimens (R-EPOCH or R-hyperCVAD) and autologous stem cell transplantation was used more often in tDLBCL (43% and 19%, respectively), compared with dDLBCL (30% and 3%, respectively) and cDLBCL/FL (28% and 8% respectively). For all pts, the median length of follow-up was 13.8 months (range 0.2-59.2). OS and PFS were similar in the three subgroups (p=0.90 and p=0.77, respectively; Figure 1). We then analyzed the survival based on the presence of DH in two separate subgroups: 1) dDLBCL and 2) tDLBCL + cDLBCL/FL (combined as one group given low number of cases). OS was significantly shorter in lymphomas with DH, compared to non-DH in both subgroups (p <0.001 for dDLBCL and p=0.004 for tDLBCL + cDLBCL/FL). Comparison of the OS in DH of dDLBCL versus DH of tDLBCL + cDLBCL/FL showed no statistical difference (p=0.15), similar to the OS of non-DH cases the two groups(p=0.31).Conclusions:DLBCLs transformed from FL or with concurrent diagnosis of FL (composite lymphoma) demonstrated similar clinical outcomes in our study. However, dual rearrangements are more prevalent in these patients and drive inferior survival similar to DH status in de novo DLBCL. [Display omitted] DisclosuresLandsburg:Curis: Consultancy, Research Funding; Takeda: Research Funding. Winter:Merck: Research Funding; Glaxo-Smith-Kline: Research Funding. Pro:Seattle Genetics: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Gordon:Janssen: Other: Data Monitoring Committee. Karmali:Celgene: Speakers Bureau. Kaplan:Millennium: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding.

MYC/BCL2/BCL6 triple hit lymphoma: A study of 33 patients who had an aggressive clinical course similar to patients with double hit lymphomas.

7559 Background: Large B cell lymphomas with MYC, BCL2, and BCL6 rearrangements, designated as triple hit lymphoma (THL), are uncommon. Large series studies of THL are scant and studies comparing THL to different types of double hit lymphoma (DHL) are lacking. Methods: We studied the clinicopathologic features and prognosis of 33 patients with THL and compared them to 83 patients with MYC/BCL2 DHL and 13 patients with MYC/BCL6DHL. Results: There were 21 men and 12 women, with a median age of 63 years (range, 34-85). Six patients had a history of low-grade B cell lymphoma and 27 had de novo lymphoma. These tumors were classified histologically as: 21 DLBCL, 10 high grade B-cell lymphoma, one concurrent DLBCL and follicular lymphoma (FL), and one concurrent DLBCL and mantle cell lymphoma. Immunohistochemical analysis showed that these tumors were positive for CD10 (94%), BCL6 (80%), BCL2 (93%), and MYC (69%, 40% as cutoff). 62% of tumors (8/13) with available data showed coexpression of MYC and BCL2. Using the Hans algorithm, 30 of 33 (91%) tumors had a germinal center B cell like (GCB) immunophenotype. All 7 cases tested by conventional cytogenetics showed a complex karyotype. Although BCL2 was always translocated with IGH, BCL6 translocated to MYC in 2of 7 cases of THL. Twenty-nine patients had treatment information available and all received immune-chemotherapy induction, including 11 with R-CHOP, 14 with R-EPOCH, 3 with R-HyperCVAD, and one with RICE (patient had a history of FL). The clinicopathological features of THL including induction chemotherapy were very similar to both the MYC/BCL2 DHL and MYC/BCL6 DHL (all P&gt;0.05). There was no significant difference in median overall survival (OS) between patients with de novo lymphoma and those with a history of low-grade lymphoma (P=0.99). The OS in THL patients was 17.9 months, similar to the OS (17.2 months) of patients with MYC/BCL6 DHL and those with MYC/BCL2DHL (19.9 months) (P=0.60). Conclusions: MYC/BCL2/BCL6 THL is an aggressive B cell lymphoma and &gt;90% of cases have a GCB immunophenotype. THL patients usually have an aggressive clinical course and a poor prognosis, similar to patients with double hit lymphomas.

Management strategy for follicular lymphoma.

Follicular lymphoma (FL) is incurable with the current standard therapeutic strategy, although the natural history of FL has improved in the last few decades. Treatment strategy for FL is considered by stage and tumor burden. For advanced-stage FL patients with low tumor burden, monitoring remains an appropriate approach. Single agent rituximab is also suggested as a good alternative. The addition of rituximab to chemotherapy has improved overall survival in advanced-stage FL patients with high tumor burden. The optimal chemotherapy to partner with rituximab might be CHOP or bendamustine. Rituximab maintenance after successful induction rituximab-based chemotherapy prolongs PFS. Recently, progression within 24 months of first-line chemotherapy has been established as a predictor of inferior outcome, with a 50% risk of death in 5 years. Addressing this high-risk group is important for optimal future treatment strategies.