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Bendamustine and rituximab (BR) therapy is commonly used in the treatment of Waldenström Macroglobulinemia (WM). The impact dose of Bendamustine dose on response and survival outcomes is not well-established, and the impact of its use in different treatment settings is not clear. We aimed to report response rates and survival outcomes following BR, and clarify the impact of depth of response and bendamustine dose on survival. A total of 250 WM patients treated with BR in the frontline or relapsed settings were included in this multicenter, retrospective cohort analysis. Rates of partial response (PR) or better differed significantly between the frontline and relapsed cohorts (91.4% vs 73.9%, respectively; p < 0.001). Depth of response impacted survival outcomes: two-year predicted PFS rates after achieving CR/VGPR vs PR were 96% versus 82%, respectively (p = 0.002). Total bendamustine dose was predictive of PFS: in the frontline setting, PFS was superior in the group receiving ≥1000 mg/m2 compared with those receiving 800–999 mg/m2 (p = 0.04). In the relapsed cohort, those who received doses of

International audience; Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 mu g/dose, or 20 mu g/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 mu g/dose expansion. Adverse events grade >= 3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 mu g (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.

Background Hodgkin lymphoma survivors (HLS) are at excess risk of lung cancer as a consequence of HL treatment. HLS without a heavy smoking history are currently unable to access lung cancer screening (LCS) programmes aimed at ever smokers, and there is an unmet need to develop a targeted LCS programme. In this study we prospectively explored HLS perspectives on a future LCS programme, including motivating factors and potential barriers to participation, with the aim of identifying ways to optimise uptake in a future programme. Methods Semistructured telephone interviews were conducted with HLS, aged 18–80 and lymphoma‐free for ≥5 years, selected from a clinical database (ADAPT). Participants provided informed consent. Data were analysed using inductive thematic analysis. Results Despite awareness of other late effects, most participants were unaware of their excess risk of lung cancer. Most were willing to participate in a future LCS programme, citing the potential curability of early‐stage lung cancer and reassurance as motivating factors, whilst prior experience of healthcare was a facilitator. Whilst the screening test (a low dose CT scan) was considered acceptable, radiation risk was a concern for some and travel and time off work were potential barriers to participation. Conclusions Our results suggest that most HLS would participate in a future LCS programme, motivated by perceived benefits. Their feedback identified a need to develop educational materials addressing lung cancer risk and concerns about screening, including radiation risk. Such materials could be provided upon an invitation to LCS. Uptake in a future programme may be further optimized by offering flexible screening appointments close to home.

Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.

Purpose: Marginal zone lymphoma (MZL) is an uncommon non–Hodgkin lymphoma with malignant cells that exhibit a consistent dependency on B-cell receptor signaling. We evaluated the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/refractory (R/R) MZL. Patients and Methods: Patients with R/R MZL were enrolled in the phase II MAGNOLIA (BGB-3111–214) study. The primary endpoint was overall response rate (ORR) as determined by an independent review committee (IRC) based on the Lugano 2014 classification. Results: Sixty-eight patients were enrolled. After a median follow-up of 15.7 months (range, 1.6 to 21.9 months), the IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%. The ORR by investigator assessment was 74.2%, and the CR rate was 25.8%. The median duration of response (DOR) and median progression-free survival (PFS) by independent review was not reached. The IRC-assessed DOR rate at 12 months was 93.0%, and IRC-assessed PFS rate was 82.5% at both 12 and 15 months. Treatment was well tolerated with the majority of adverse events (AE) being grade 1 or 2. The most common AEs were diarrhea (22.1%), contusion (20.6%), and constipation (14.7%). Atrial fibrillation/flutter was reported in 2 patients; 1 patient had grade 3 hypertension. No patient experienced major hemorrhage. In total, 4 patients discontinued treatment due to AEs, none of which were considered treatment-related by the investigators. Conclusions: Zanubrutinib demonstrated high ORR and CR rate with durable disease control and a favorable safety profile in patients with R/R MZL.

Mantle cell lymphoma (MCL) after relapse is associated with poor prognosis. No standard of care exists and available evidence for treatments is limited, particularly in patients who fail Bruton tyrosine kinase inhibitor (BTKi) therapy. This multicentre retrospective chart review study, SCHOLAR-2, addresses this knowledge gap and reports on data collected from 240 patients with relapsed/refractory MCL in Europe who were treated with BTKi-based therapy between July 2012 and July 2018, and had experienced disease progression while on BTKi therapy or discontinued BTKi therapy due to intolerance. The median overall survival (OS) from initiation of first BTKi therapy was 14.6 months (95% confidence interval [CI] 11.6-20.0) in the overall cohort, 5.5 months (95% CI 3.9-8.2) in 91 patients without post-BTKi therapy, and 23.8 months (95% CI 18.9-30.1) in 149 patients who received post-BTKi therapy (excluding chimeric antigen receptor T-cell treatment). In the latter group, patients received a median of one (range, one to seven) line of post-BTKi therapy, with lenalidomide-containing regimens and bendamustine plus rituximab being the most frequently administered; the median OS from initiation of first post-BTKi therapy was 9.7 months (95% CI 6.3-12.7). These results provide a benchmark for survival in patients with R/R MCL receiving salvage therapy after BTKi failure.

Introduction Brentuximab vedotin (BV)-CHP is the new standard regimen for first-line treatment of systemic anaplastic large cell lymphoma (sALCL). We undertook a retrospective analysis of consecutive patients diagnosed with sALCL, treated in routine practice, to serve as a benchmark analysis for comparison BV-CHP efficacy in routine practice. Methods Patients aged 16 years or older with sALCL treated in seven UK and Australian centres and from 14 additional centres from the UK Haematological Malignancy Research Network database (n = 214). Treatment allocation was clinician choice and included best supportive care (BSC). Main outcomes were time to treatment failure (TTF) and overall survival (OS). Multivariable analysis for predictors of both TTF and OS was also undertaken. Results The median age 52 years (range 16–93), 18% ECOG ≥ 3 and 40% of cases were ALK positive. CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) was employed in 152 (71%) of patients and CHOEP (CHOP + etoposide) in 4% of patients. For CHOP-treated patients overall response rate (ORR) was 65% and complete response (CR) 47%. Only 9% of patients underwent autologous stem cell transplant (ASCT). With 57 months median follow-up, 4-year TTF and OS were 41.2% (95% CI 33.1–49.1) and 58.9% (95% CI 50.3–66.5) respectively. Multivariable analysis showed ALK+ status was independently associated with superior TTF (HR 0.36, 95% CI 0.21–0.63) but not OS (0.44, 95% CI 0.18–1.07). Discussion We present a retrospective analysis with mature follow-up of one of the largest multicentre populations of sALCL available, comparable to similar large retrospective studies. ALK status remains a strong predictor of outcomes. Conclusion These data serve as a robust benchmark for BV-CHP as the new standard of care for sALCL. Similar real-world evidence with BV-CHP will be desirable to confirm the findings of ECHELON-2. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01764-0.

Background Follicular lymphoma (FL) prognosis is influenced by the composition of the tumour microenvironment. We tested an automated approach to quantitatively assess the phenotypic and spatial immune infiltrate diversity as a prognostic biomarker for FL patients. Methods Diagnostic biopsies were collected from 127 FL patients initially treated with rituximab-based therapy (52%), radiotherapy (28%), or active surveillance (20%). Tissue microarrays were constructed and stained using multiplex immunofluorescence (CD4, CD8, FOXP3, CD21, PD-1, CD68, and DAPI). Subsequently, sections underwent automated cell scoring and analysis of spatial interactions, defined as cells co-occurring within 30 μm. Shannon’s entropy, a metric describing species biodiversity in ecological habitats, was applied to quantify immune infiltrate diversity of cell types and spatial interactions. Immune infiltrate diversity indices were tested in multivariable Cox regression and Kaplan–Meier analysis for overall (OS) and progression-free survival (PFS). Results Increased diversity of cell types (HR = 0.19 95% CI 0.06–0.65, p = 0.008) and cell spatial interactions (HR = 0.39, 95% CI 0.20–0.75, p = 0.005) was associated with favourable OS, independent of the Follicular Lymphoma International Prognostic Index. In the rituximab-treated subset, the favourable trend between diversity and PFS did not reach statistical significance. Conclusion Multiplex immunofluorescence and Shannon’s entropy can objectively quantify immune infiltrate diversity and generate prognostic information in FL. This automated approach warrants validation in additional FL cohorts, and its applicability as a pre-treatment biomarker to identify high-risk patients should be further explored. The multiplex image dataset generated by this study is shared publicly to encourage further research on the FL microenvironment.

Background Fulfilling the promise of cancer immunotherapy requires novel predictive biomarkers to characterise the host immune microenvironment. Deciphering the complexity of immune cell interactions requires an automated multiplex approach to histological analysis of tumour sections. We tested a new automatic approach to select tissue and quantify the frequencies of cell-cell spatial interactions occurring in the PD1/PD-L1 pathway, hypothesised to reflect immune escape in oropharyngeal squamous cell carcinoma (OPSCC). Methods Single sections of diagnostic biopsies from 72 OPSCC patients were stained using multiplex immunofluorescence (CD8, PD1, PD-L1, CD68). Following multispectral scanning and automated regions-of-interest selection, the Hypothesised Interaction Distribution (HID) method quantified spatial proximity between cells. Method applicability was tested by investigating the prognostic significance of co-localised cells (within 30 μm) in patients stratified by HPV status. Results High frequencies of proximal CD8+ and PD-L1+ (HR 2.95, p = 0.025) and PD1+ and PD-L1+ (HR 2.64, p = 0.042) cells were prognostic for poor overall survival in patients with HPV negative OPSCC (n = 31). Conclusion The HID method can quantify spatial interactions considered to reflect immune escape and generate prognostic information in OPSCC. The new automated approach is ready to test in additional cohorts and its applicability should be explored in research and clinical studies.

Background Many Hodgkin lymphoma (HL) survivors are at increased risk of subsequent malignant neoplasms (SMN), including lung cancer, due to previous treatment for HL. Lung cancer screening (LCS) detects early-stage lung cancers in ever smokers but HL survivors without a heavy smoking history are ineligible for screening. There is a rationale to develop a targeted LCS. The aim of this study was to investigate levels of willingness to undergo LCS in HL survivors, and to identify the psycho-social factors associated with screening hesitancy. Methods A postal questionnaire was sent to 281 HL survivors registered in a long-term follow-up database and at increased risk of SMNs. Demographic, lung cancer risk factors, psycho-social and LCS belief variables were measured. Multivariable logistic regression analysis was performed to determine the factors associated with lung cancer screening hesitancy, defined as those who would ‘probably’ or ‘probably not’ participate. Results The response rate to the questionnaire was 58% (n=165). Participants were more likely to be female, older and living in a less deprived area than non-participants. Uptake (at any time) of breast and bowel cancer screening among those previously invited was 99% and 77% respectively. 159 participants were at excess risk of lung cancer. The following results refer to these 159. Around half perceived themselves to be at greater risk of lung cancer than their peers. Only 6% were eligible for lung cancer screening pilots aimed at ever smokers in the UK. 98% indicated they would probably or definitely participate in LCS were it available. Psycho-social variables associated with LCS hesitancy on multivariable analysis were male gender (OR 5.94 CI 1.64-21.44, p

BackgroundDecisions aids (DA) can support patients to make informed decisions about screening tests. This study describes the development and initial evaluation of a lung cancer screening (LCS) DA targeted towards survivors of Hodgkin lymphoma (HL).MethodsA prototype decision aid booklet was developed and subsequently reviewed by a steering group who provided feedback. Revisions were made to produce the DA tested in this study. HL survivors were recruited to an online survey and/or focus groups. Lymphoma practitioners were invited to an interview study. In the online survey, decisional conflict scales and knowledge scales were completed before and after accessing the DA. The focus groups and interviews explored acceptability and comprehensibility and the decisional needs of stakeholders. Focus groups and interviews were audio recorded. The framework method was used to analyse qualitative data. Results38 HL survivors completed the online survey. Following exposure to the DA, knowledge of LCS and risk factors and decisional conflict scores (total score and subscale scores) improved significantly. 11 HL survivors took part in two focus groups (n=5 and n=6) and 11 practitioners were interviewed. Focus group and interview results: The language, format and length were considered acceptable. Both groups felt the DA was balanced and presented a choice. Icon arrays were felt to aid comprehension of absolute risk values and for some survivors, they reduced affective risk perceptions. Among survivors, the impact of radiation risk on decision making varied according to gender and screening interval, whilst practitioners did not anticipate it to be a major concern for patients. Both groups expressed that a screening offer could mitigate anxiety about lung cancer risk. As anticipated by practitioners, survivors expressed a desire to seek advice from their clinical team. Practitioners thought the DA would meet their informational needs regarding lung cancer screening when supporting survivors. ConclusionsThe DA tested in this study is considered acceptable by HL survivors and their practitioners. The DA reduces decisional conflict and improves knowledge in HL survivors, suggesting that it would support HL survivors to make informed decisions when considering lung cancer screening in a future clinical trial.

BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have few treatment options. We aimed to establish the safety and recommended phase 2 dose of epcoritamab, a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells.METHODS: For the dose-escalation part of this phase 1/2 study, we enrolled adults (aged ≥18 years) with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma at ten sites across four countries (Denmark, the Netherlands, the UK, and Spain). Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0·0128-60 mg). The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. This study is registered with ClinicalTrials.gov, NCT03625037, with the dose-expansion part ongoing.FINDINGS: Between June 26, 2018, and July 14, 2020, we enrolled 73 patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin lymphoma. 68 patients received escalating full doses (0·0128-60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase 2 dose. All 68 patients received at least one dose of epcoritamab and were included in safety analyses: common adverse events were pyrexia (47 patients [69%]), primarily associated with cytokine release syndrome (CRS; 40 [59%], all grade 1-2), and injection site reactions (32 [47%]; 31 grade 1). There were no grade 3 or higher CRS events. No discontinuations occurred due to treatment-related adverse events or treatment-related deaths. Overall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45-86), with 45% achieving a complete response at full doses of 12-60 mg. At 48 mg, the overall response rate was 88% (47-100), with 38% achieving a complete response. Patients with relapsed or refractory follicular lymphoma had an overall response rate of 90% (55-100), with 50% achieving a complete response at full doses of 0·76-48 mg. Epcoritamab induced robust and sustained B-cell depletion, and CD4+ and CD8+ T-cell activation and expansion, with modest increases in cytokine levels.INTERPRETATION: Single-agent subcutaneous epcoritamab for treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma merits investigation in ongoing phase 2 and phase 3 studies.FUNDING: Genmab and AbbVie.

Background: Marginal zone lymphoma (MZL) is rare and heterogeneous and it has been difficult to define optimal therapeutic strategies. Like other indolent non-Hodgkin lymphomas, advanced stage disease is considered incurable, with most patients experiencing a continuing pattern of relapse and remission. MZL is typically dependent on B-cell receptor (BCR) signaling suggesting a role for BCR pathway targeting via inhibition of Bruton's tyrosine kinase (BTK). The utility of this approach was confirmed by the pivotal phase 2 study demonstrating a 48% objective response rate (ORR) to ibrutinib in patients with relapsed/refractory (R/R) MZL (Noy et al. Blood. 2017;129:2224-2232). Zanubrutinib (BGB-3111) is a potent, highly specific, and irreversible next-generation BTK inhibitor. It was specifically designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases, which are thought to be related to atrial fibrillation, thrombocytopenia, and bleeding events. In an early-phase study (BGB-3111-AU-003) of 20 patients with R/R MZL treated with zanubrutinib, at a median follow-up of 27.1 months, the ORR was 80%, with a complete response (CR) rate of 15%, and partial response (PR) rate of 65% (Tedeschi et al. EHA 2020, abstract 2804). Presented here are initial efficacy and safety data in patients with R/R MZL enrolled in the MAGNOLIA trial (BGB-3111-214). Methods: MAGNOLIA is a phase 2, multicenter, single-arm study of adult patients requiring systemic treatment for R/R MZL who had previously received one or more lines of therapy including at least one CD20-directed regimen. All patients were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary end point was ORR as determined by an independent review committee in accordance with the Lugano classification. Secondary end points include ORR by investigator assessment, duration of response (DOR), progression-free survival (PFS), and safety. Results: In total, 68 patients were enrolled and treated. The median age was 70 years (range, 37-95), with 28% aged ≥75 years. MZL subtypes included extranodal (mucosa-associated lymphoid tissue) in 38%, nodal in 38%, splenic in 18%, and unknown in 6% of patients. The median number of prior therapies was 2 (range, 1-6), and 35% of patients had disease refractory to last therapy. At a median follow-up of 6.8 months (range, 1.6-12.8), 67 patients were evaluable for efficacy. Investigator-assessed ORR (CR + PR) was 60% (CR 15%, PR 45%, stable disease 27%). Responses were observed in all MZL subtypes, with an ORR of 58%, 64%, 58%, and 50% in extranodal, nodal, splenic, and unknown subtypes, respectively. CR rate was 23% for extranodal MZL, 12% for nodal, and 50% for unknown subtype. CR was not observed in patients with splenic MZL. The median DOR and median PFS were not reached. Twenty-one (30.9%) patients discontinued study treatment. Treatment discontinuation was mainly due to disease progression (16 patients; 23.5%); 1 withdrew consent, 2 required prohibited medications, and 2 due to adverse events (AEs) - 1 from pyrexia (later attributed to disease transformation) and 1 from myocardial infarction. The most common treatment-emergent AEs reported in ≥10% of patients were diarrhea (19.1%), bruising (17.6%), constipation (13.2%), pyrexia (10.3%), upper respiratory tract infection (10.3%), and nausea (10.3%). Most AEs were low grade. Neutropenia was the most common grade ≥3 AE (7.3%). Treatment-related serious AEs included atrial flutter, pyrexia, pneumonia, and thrombocytopenia (1 patient each). One patient with pre-existing coronary artery disease died from myocardial infarction, which was assessed as unrelated to zanubrutinib. All-grade AEs of interest included neutropenia (10.3%), thrombocytopenia (10.3%), and atrial flutter (1.5%). To date, no major hemorrhage, serious opportunistic infection, or tumor lysis syndrome have been reported. Conclusion: Preliminary results of this phase 2 study suggest that zanubrutinib is active in R/R MZL, with a favorable safety profile. (NCT03846427) Disclosures Opat: Beigene: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Epizyme: Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tedeschi:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Department of Hematology Niguarda Hospital Milano: Current Employment; Sunesis: Consultancy. Linton:The Christie NHS Foundation Trust and The University of Manchester: Current Employment; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Conference/travel support; Roche: Consultancy, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hartley-Taylor: Honoraria. McKay:Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; TAKEDA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Beatson West of Scotland Cancer Centre: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Gilead, Takeda, and Janssen: Other: For lectures etc. Hu:Kite: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectar: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Beigene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Chan:Celgene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Amgen: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company). Jin:The First Affiliated Hospital of Zhejiang University: Current Employment. Zinzani:Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Browett:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; University of Auckland: Current Employment; BeiGene: Research Funding. Coleman:BeiGene: Research Funding; Acerta: Research Funding; Innocare: Research Funding. Sobieraj-Teague:Flinders Medical Centre: Current Employment; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Ke:Peking University Third Hospital: Current Employment. Sun:Institute of Hematology and Blood Disease Hospital,Chinese Academy of Medical Sciences and Peking Union of Medical College: Current Employment. Marcus:Gilead: Consultancy; Roche: Honoraria; Janssen: Honoraria, Speakers Bureau. Portell:Xencor: Research Funding; Roche/Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; TG Therapeutics: Research Funding; Infinity: Research Funding. Zhou:Henan Cancer Hospital: Current Employment. Thieblemont:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Hospira: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Co:BeiGene: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Wang:BeiGene: Current Employment. Tankersley:Clovis Oncology, Inc: Ended employment in the past 24 months; BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Zhou:BeiGene: Current Employment, Current equity holder in publicly-traded company; Beth Israel Deaconess Medical Center: Ended employment in the past 24 months. Cappellini:BeiGene Ltd.: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; BeiGene Aus Pty. Ltd.: Current Employment. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Trotman:BeiGene: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Roche: Other: Travel/accommodations/expenses, Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for MZL in the US

7518 Background: Epcoritamab is a CD20xCD3 bispecific antibody that induces T-cell–mediated killing of CD20–positive malignant B-cells. We present updated data, including progression-free survival (PFS) from the dose escalation part of the first-in-human phase 1/2 study of epcoritamab in pts with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL; NCT03625037). Methods: Adults with R/R CD20+ B-NHL received flat-dose 1 mL SC epcoritamab (step-up dosing approach) in 28-day cycles (q1w: cycles 1–2; q2w: cycles 3–6; q4w thereafter) until disease progression or unacceptable toxicity. Step-up dosing and standard prophylaxis were used to mitigate severity of cytokine release syndrome (CRS). Results: At data cut off (1/31/2021), 68 pts with B-NHL were enrolled across histologies including diffuse large B-cell lymphoma (DLBCL; n = 46 [67.6%]; de novo and transformed), follicular lymphoma (FL; 12 [17.6%]), mantle cell lymphoma (MCL; 4 [5.9%]), and others (6 [8.8%]). Majority were heavily pretreated (median [range] prior lines: DLBCL, 3 [1–6]; FL, 4.5 [1–18]); including prior CAR-T (n = 6) and prior ASCT (n = 10). At median follow-up of 14.1 mo (DLBCL, 10.2 mo; FL, 15.2 mo), treatment was ongoing in 15 (22%) pts. Most common treatment-emergent adverse events (AEs) were pyrexia (69%), CRS (59%), and injection site reaction (47%). CRS events were all grade 1 or 2 and most occurred in cycle 1; neurotoxicity was limited (6%; grade 1: 3%; grade 3: 3%; all transient). One case of tumor lysis syndrome was observed (1.5%; grade 3); there were no cases of febrile neutropenia or treatment-related death. Overall response is shown for DLBCL ≥12 mg and ≥48 mg and FL ≥12 mg, corresponding to the minimal efficacy threshold (Table). Responses deepened over time (PR converted to CR: DLBCL, 6 pts; FL, 3 pts). Median time to response was 1.4 mo (DLBCL) and 1.9 mo (FL). Among DLBCL pts achieving CR with ≥6 mg (n = 11), none relapsed while on treatment. The median PFS for pts with DLBCL ≥12 mg (n = 22) was 9.1 mo (95% CI: 1.6, NE; median follow-up 9.3 mo) and for pts with DLBCL ≥48 mg (n = 11) median PFS was not reached (median follow-up 8.8 mo). Updated analyses will be presented. Conclusions: With longer follow-up, SC epcoritamab demonstrated substantial single-agent activity, inducing deep and durable clinically meaningful responses, with a consistent safety profile. Notably no severe (grade ≥3) CRS events, no febrile neutropenia, and limited neurotoxicity was observed. Clinical trial information: NCT03625037. [Table: see text]

3115 Background: Tumours rely on lactate transporters (MCT1-4) to maintain glycolytic flux and avoid intracellular acidification. In haematological tumours the MCT1 transporter acts as a lactate and pyruvate exporter. AZD3965 is a potent and specific inhibitor of MCT1 causing intracellular lactate accumulation. In vivo efficacy was observed in xenografts of DLBCL and BL, expressing high levels of MCT1 and no or low levels of MCT4. In the AZD3965 phase I (NCT01791595) dose-escalation an oral recommended phase 2 dose (RP2D) of 10mg twice-daily (bd) was determined. Pharmacokinetic (PK) showed exposure estimated to produce a minimum MCT1 occupancy of 90% (based on modelling). DLTs were primarily on-target dose-dependent, reversible, asymptomatic alterations in retinal function seen on ERG. Methods: This expansion cohort enrolled patients with relapsed/refractory DLBCL and BL. Expression of MCT1/MCT4 was assessed by immunohistochemistry. Pharmacokinetic (PK) sampling was performed and pharmacodynamic assessments included [18F]FDG-PET/CT imaging and plasma/urine metabolomics. Results: 11 DLBCL patients were treated with AZD3965 10mg bd. PK showed exposure to be broadly in line with the escalation cohort. No significant ERG changes were observed. One patient experienced a dose-limiting SUSAR of Troponin I increase. MCT1 is expressed in erythrocytes, however no serious events of anaemia were seen, with one non-clinically significant episode of grade 3 anaemia reported. Urine analysis showed increased excretion of lactate and ketone bodies post AZD3965 treatment consistent with renal target engagement. No alteration was detected in plasma. Ongoing stable disease at cycle 5 was observed in one patient and an additional patient had a confirmed complete response (CR) lasting 15 months, with no significant toxicity. In the patient showing CR a reduction in tumour FDG uptake was observed on day 3 of cycle 1. The other four patients who consented to research imaging did not have a clinical response and no changes were observed on FDG-PET. Conclusions: AZD3965 can be safely administered at 10mg bd. In one DLBCL patient monotherapy activity was observed with changes in FDG-PET providing evidence indicative of proof of mechanism. These changes in FDG uptake as early as on day 3 in the responding patient warrant further investigation of FDG-PET as a predictive biomarker. Further biomarker analysis and preclinical studies are ongoing to understand the biology and explore effective combinations with other agents targeting tumour cell metabolism Clinical trial information: NCT01791595.

7511 Background: Zandelisib, a PI3Kδ inhibitor with high target-binding affinity, is administered by intermittent dosing (ID) on days 1-7 of 28-day cycles to potentially enable regulatory T-cell repopulation and lower the risk of immune adverse events (irAEs) seen with continuous PI3Kδ inhibition. In a phase 1b study in 37 patients (pts) with R/R FL, zandelisib daily for two 28-day cycles for tumor debulking then on ID achieved an overall response rate (ORR) of 87% (78% single agent and 95% with rituximab) with < 10% irAEs (Pagel et al. ICML 2021; #113). We conducted the TIDAL study to further evaluate zandelisib in R/R indolent lymphomas (NCT03768505). Methods: Eligible pts ≥18 years with FL Grade I-IIIA, progressive disease after ≥2 prior therapies, and no prior PI3K inhibitor, gave consent and received zandelisib 60 mg daily for 2 cycles then on ID. Not reported here are an arm randomizing pts to zandelisib daily continuously, closed to enrollment early, and an actively enrolling arm in R/R marginal zone lymphoma (MZL). The planned FL sample size was 120 pts on ID, with the primary efficacy population (PEP) pre-defined as the first 91 pts treated. The primary efficacy endpoint was ORR by the Lugano criteria in the PEP as assessed by independent review and analyzed after a minimum 6-month follow-up. Results: 121 FL pts were enrolled. In the PEP (N = 91), the median number of prior therapies was 3 (range 2-8), 21 pts (23%) had received prior stem cell transplant, 42 (46%) had disease refractory to last therapy, 31 (34%) had tumors ≥5 cm, and 51 (56%) were POD24. Overall response rate was 70.3% (n = 64) (95% CI 59.8-79.5%) and complete response rate was 35.2% (n = 32) (95% CI 25.4-45.9%). Responses occurred early with 87.5% (n = 56) of responses observed at the end of Cycle 2 and 75% (n = 24) of CRs at the end of Cycle 4. The data are still immature to estimate accurately the duration of response (DOR). With a median follow-up of 9.4 months (range 0.8-24) for all 121 pts, 12 pts (9.9%) discontinued therapy due to any drug-related AE. Grade 3 AEs of special interest (AESI) were diarrhea in 6 pts (5%), colitis in 2 (1.7%), rash in 4 (3.3%), stomatitis in 3 (2.5%), and 1 (0.8%) each for AST and ALT elevation, and non-infectious pneumonitis. Grade 3 AESIs primarily (15 of 18, 83%) occurred in cycles 1-3, during daily dosing. Conclusions: Zandelisib on ID achieved high ORR and CR rate in heavily pretreated FL pts, and was associated with < 10% of discontinuations due to drug-related AEs and grade 3 AESI, results comparable to the Phase 1b study. Longer follow-up is needed to estimate median DOR. This profile supports evaluation of zandelisib alone and in combination in various B-cell malignancies, both in relapsed disease and earlier lines of therapy. Zandelisib plus rituximab vs chemoimmunotherapy is being studied in the phase 3 trial COASTAL in R/R FL and MZL (NCT 04745832). Clinical trial information: NCT03768505.

Scope: This guideline is aimed at providing healthcare professionals with clear guidance on the diagnosis and management of primary central nervous system lymphoma (PCNSL), defined as diffuse large B‐cell lymphoma (DLBCL) solely confined to the central nervous system (CNS): brain, spinal cord, cranial nerves, eyes and meninges. Secondary CNS lymphoma, immunodeficiency‐associated lymphoma and rare forms of non‐DLBCL CNS lymphoma are outside the scope of this guideline. It is not the intention of this guideline to provide treatment recommendations for all situations and clinicians are advised to take individual patient circumstances into account when making management decisions.

Background: Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma. Methods: This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18–70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m2, intravenous infusion, day 0; methotrexate 3·5 g/m2, the first 0·5 g/m2 in 15 min followed by 3 g/m2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m2, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m2, day 1; etoposide 100 mg/m2 per day in 500–1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m2 in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine–thiotepa and autologous HSCT (carmustine 400 mg/m2 in 500 mL glucose 5% solution in a 1–2 h infusion, day −6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days −5 and −4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019. Findings: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55–61). 49 patients (65%; 95% CI 54–76) had an objective response after MATRix–RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51–71) had an objective response, with a median duration of objective response of 26 months (IQR 16–37). At a median follow-up of 29 months (IQR 20–40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39–53). Grade 3–4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07–9·93). Interpretation: MATRix–RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile. Funding: Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.

Content: Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can have serious complications. In this disorder, autoantibodies bind to antigens on red blood cells leading to phagocytosis and destruction of the cells. This is mediated by Fcg receptors on macrophages through a spleen tyrosine kinase (SYK)-dependent pathway. Fostamatinib is a potent, oral SYK inhibitor approved for the treatment of chronic immune thrombocytopenia. Fostamatinib prevents platelet destruction by inhibition of platelet phagocytosis mediated through Fcg receptor and SYK in macrophages. Fostamatinib was evaluated for wAIHA in an open-label, multicenter, phase 2 study (NCT02612558). This study demonstrated markedly improved hemoglobin levels in 11 of 25 patients (44%) after fostamatinib treatment. Adverse events (AEs) were consistent with the safety database (>4000 patients across multiple diseases). Based on this phase 2 study, a randomized, double-blind, placebo-controlled, global phase 3 study (NCT03764618) was initiated in wAIHA patients to investigate the safety and efficacy of fostamatinib. The phase 3 study began enrolling patients at 103 sites in 22 countries (North America, Europe and Australia) in 2020 with a goal of enrolling approximately 90 patients. This is the first phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA. Inclusion criteria include: age ?18;documented diagnosis of primary or secondary wAIHA;failure of ?1 prior wAIHA treatment;haptoglobin below normal or total bilirubin above normal or lactate dehydrogenase above normal;and baseline hemoglobin ?9 g/dl or, if hemoglobin >9 g/dl and 1.5 x normal. Randomization of eligible patients will be 1:1 to fostamatinib or placebo for 24 weeks. Randomized patients will be stratified by concomitant steroid use and baseline anemia severity. Fostamatinib is started at 100 mg BID and increased to 150 mg BID at Week 4, if tolerated. The dose may be reduced for AEs. Patients may continue selected concurrent wAIHA therapies (maximum of 2) throughout the study. A steroid taper will be allowed in patients with a hemoglobin response. Rescue therapy will also be allowed. Patients who complete the study can rollover to an open-label extension. Efficacy endpoints will include hemoglobin response, ( ?10 g/dl with a ?2 g/dl increase from baseline without rescue therapy);duration of hemoglobin response;and the need for rescue therapy. Safety endpoints will be the recording of AEs. Patients will be evaluated in the clinic at two-week intervals. Using the Cochran Mantel Haenszel test at a two-sided significance level of 0.05, to detect a difference in response between the active and placebo groups with 80% power would require 90 subjects randomized 1:1. The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. As of 11 January 2021, 62 sites are open to screening (subject to local COVID-19 regulations), and 64 patients have been randomized.

Diffuse large B-cell lymphoma (DLBCL) and osteoporotic fracture are both more common in older patients. Exposure to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is likely to increase the risk of fracture, but evidence is lacking to define fracture incidence in this group. Data on consecutive patients with DLBCL aged ≥70 years treated with 1 to 8 cycles of full or attenuated R-CHOP were retrospectively collected across 10 UK centers (2009-2019). Patients were followed up from starting R-CHOP for a minimum of 6 months and censored at 18 months; at last follow-up if

High-dose methotrexate (HD-MTX) is increasingly used as prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse. However, there is limited evidence to guide whether to intercalate HD-MTX (i-HD-MTX) between R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone given at 21-day intervals) or to give it at the end of treatment (EOT) with R-CHOP-21. We conducted a retrospective, multicenter analysis of 334 patients with DLBCL who received CNS prophylaxis with i-HD-MTX (n = 204) or EOT HD-MTX (n = 130). Primary end points were R-CHOP delay rates and HD-MTX toxicity. Secondary end points were CNS relapse rate, progression-free survival, and overall survival. The EOT group had more patients with a high CNS international prognostic index (58% vs 39%; P < .001) and more concurrent intrathecal prophylaxis (56% vs 34%; P < .001). Of the 409 cycles of i-HD-MTX given, 82 (20%) were associated with a delay of next R-CHOP (median, 7 days). Delays were significantly increased when i-HD-MTX was given after day 9 post–R-CHOP (26% vs 16%; P = .01). On multivariable analysis, i-HD-MTX was independently associated with increased R-CHOP delays. Increased mucositis, febrile neutropenia, and longer median inpatient stay were recorded with i-HD-MTX delivery. Three-year cumulative CNS relapse incidence was 5.9%, with no differences between groups. There was no difference in survival between groups. We report increased toxicity and R-CHOP delay with i-HD-MTX compared with EOT delivery but no difference in CNS relapse or survival. Decisions on HD-MTX timing should be individualized and, where i-HD-MTX is favored, we recommend scheduling before day 10 of R-CHOP cycles.