Venetoclax with azacitidine is the standard of care for patients with AML who are unfit for intensive chemotherapy, however uncertainties remain regarding the treatment schedule, accurate prognostication and outcomes for patients treated outside clinical trials. The option of venetoclax with low-dose cytarabine (LDAC) is also available, however it is not clear for which patients it may be a useful alternative. Here we report a large real-world cohort of 654 patients treated in 53 UK hospitals with either venetoclax and azacitidine (n=587) or LDAC (n=67). Median age was 73 and 59% had de novo AML. Most patients received 100mg of venetoclax with an azole antifungal. In cycle 1 patients spent a median of 14 days in hospital, 85% required red cell and 59% platelet transfusion and 63% required intravenous antibiotics. Supportive care requirements significantly reduced after the first cycle. Patients receiving venetoclax-azacitidine had a CR/CRi rate of 67%, day 30 and day 60 mortality of 5% and 8%, and median overall survival of 13.6 months. Mutations in NPM1, RUNX1, STAG2 and IDH2 were associated with improved survival, while age, secondary and therapy related AML, +8, MECOM rearrangements, complex karyotype, ASXL1 and KIT mutations were associated with poorer survival. Prognostic systems derived specifically for patients treated with venetoclax-azacitidine performed better than the ELN and MRC classifications, however improved risk classifications are still required. In the 149 patients with NPM1 mutated AML, outcomes were similar for those treated with venetoclax-azacitidine and venetoclax-LDAC.

ABSTRACT:Assessment of measurable residual disease (MRD) by quantitative reverse transcription polymerase chain reaction is strongly prognostic in patients with NPM1-mutated acute myeloid leukemia (AML) treated with intensive chemotherapy; however, there are no data regarding its utility in venetoclax-based nonintensive therapy, despite high efficacy in this genotype. We analyzed the prognostic impact of NPM1 MRD in an international real-world cohort of 76 previously untreated patients with NPM1-mutated AML who achieved complete remission (CR)/CR with incomplete hematological recovery following treatment with venetoclax and hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). A total of 44 patients (58%) achieved bone marrow (BM) MRD negativity, and a further 14 (18%) achieved a reduction of ≥4 log10 from baseline as their best response, with no difference between HMAs and LDAC. The cumulative rates of BM MRD negativity by the end of cycles 2, 4, and 6 were 25%, 47%, and 50%, respectively. Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall of 84% compared with 46% if MRD was positive. On multivariable analyses, MRD negativity was the strongest prognostic factor. A total of 22 patients electively stopped therapy in BM MRD-negative remission after a median of 8 cycles, with 2-year treatment-free remission of 88%. In patients with NPM1-mutated AML attaining remission with venetoclax combination therapies, NPM1 MRD provides valuable prognostic information.

Brexucabtagene autoleucel (brexu-cel) is an autologous CD19 CAR T-cell product, approved for relapsed/refractory (r/r) mantle cell lymphoma (MCL). In ZUMA-2, brexu-cel demonstrated impressive responses in patients failing >= 2 lines, including a bruton's tyrosine kinase inhibitor, with an overall and complete response rate of 93% and 67%, respectively. Here, we report our real-world intention-to-treat (ITT) outcomes for brexu-cel in consecutive, prospectively approved patients, from 12 institutions in the United Kingdom between February 2021 and June 2023, with a focus on feasibility, efficacy, and tolerability. Of 119 approved, 104 underwent leukapheresis and 83 received a brexu-cel infusion. Progressive disease (PD) and/or manufacturing (MF) were the most common reasons for failure to reach harvest and/or infusion. For infused patients, best overall and complete response rates were 87% and 81%, respectively. At a median follow-up of 13.3 months, median progression-free survival (PFS) for infused patients was 21 months (10.1-NA) with a 6- and 12-month PFS of 82% (95% confidence interval [CI], 71-89) and 62% (95% CI, 49-73), respectively. >= Grade 3 cytokine release syndrome and neurotoxicity occurred in 12% and 22%, respectively. On multivariate analysis, inferior PFS was associated with male sex, bulky disease, ECOG PS > 1 and previous MF. Cumulative incidence of non-relapse mortality (NRM) was 6%, 15%, and 25% at 6, 12, and 24 months, respectively, and mostly attributable to infection. Outcomes for infused patients in the UK are comparable to ZUMA-2 and other real-world reports. However, ITT analysis highlights a significant dropout due to PD and/or MF. NRM events warrant further attention.

Abstract Introduction: Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is uncommon but is associated with poor outcomes. In selected high risk patients (pts), high dose methotrexate (HDMTX) is often used as CNS prophylaxis with frontline (1L) DLBCL therapy despite uncertain efficacy, optimum dose and timing of delivery. A recent UK study (Wilson et al 2020) showed that intercalated HDMTX (i-HDMTX) was associated with increased toxicity and R-CHOP delays compared to end of treatment (EOT) delivery. Although hypothesis generating, the study size was insufficient to determine whether EOT was non-inferior in terms of CNS relapse risk. Methods: We conducted an international, multicentre retrospective analysis of consecutive DLBCL or high grade BCL pts between 2007-20 from 47 centers in Europe, Australia and N. America. Pts were included if they received R-CHOP or R-CHOP-like 1L therapy with curative intent as well as HDMTX CNS prophylaxis (≥1 cycle). Concurrent intrathecal (IT) prophylaxis was permitted. Pts with known CNS involvement at baseline and those treated with more intensive protocols (e.g. R-DA-EPOCH) were excluded. i-HDMTX was defined as any pt receiving a HD-MTX cycle before the final R-CHOP cycle. CNS relapse events were excluded if occurring after first systemic lymphoma relapse/progression. Time to event endpoints were measured from diagnosis to first event or censor and analysed using Kaplan-Meier and Cox regression methods. Time to CNS relapse was analysed using competing risk Fine and Gray method (for death and non-synchronous systemic relapse). To mitigate for possible immortality bias in the EOT arm, a landmark analysis for pts alive and free from progression at 6 months was conducted. We aimed to exclude a 5% difference in 2-year (y) CNS relapse rates. Results: 1,384 pts were analysed. 750 received i-HDMTX and 634 received EOT HDMTX. Key baseline characteristics are summarised in Table 1. Median follow up was 37.9 months. 44.2% had high CNS IPI (4-6) with no significant difference between i-HDMTX and EOT groups (45.1% vs 43.1%, p=0.087). ≥2 cycles of HDMTX were used in 86.6% with no difference between groups (85.6% vs 87.9%, p=0.22). Concurrent IT prophylaxis use was higher for EOT pts (55.6% vs 38.1% p<0.0001). 78 CNS relapses (42 i-HDMTX, 36 EOT) were observed: parenchymal in 41 (53%), parenchymal and leptomeningeal in 16 (21%) and isolated leptomeningeal in 21 (27%). There was no significant difference in 2y CNS relapse rates between i-HDMTX and EOT in all pts: 5.2% vs 3.9%, adjusted hazard ratio (HR) 0.92 (95% CI 0.58-1.47), p=0.74, 2y difference -0.2% (-2.0-2.5) or landmark analysis: 2.8% vs 4.1%, HR: 0.93 (0.56-1.55), p=0.79, 2y difference: -0.3% (-1.8-2.2%) (Fig 1a/b). Exploratory analyses focusing on pts with isolated CNS relapse (n=57) demonstrated similar results (2y rates 3.6% vs 3.0%, p=0.99). On multivariable analysis (MVA) of risk factors for CNS relapse, renal/adrenal involvement was the only variable associated with increased CNS relapse risk (adjusted HR 1.74 (1.03-2.92), p=0.038). Notably, IT prophylaxis was not associated with reduction in CNS relapse. In 600 high CNS IPI (4-6) pts, there was no difference in CNS relapse risk between i-HD-MTX and EOT (3y rates 9.4% vs 8.6%, HR 0.92 (95% CI 0.52-1.62)). In a composite high risk group including CNS IPI 4-6 and/or any of the following: ≥3 extranodal sites, renal, adrenal, testicular or breast involvement (n=885) there was no difference in 3y CNS relapse rates between groups (i-HDMTX 7.6% vs EOT 7.4%, HR 0.94 (0.58-1.53)). Progression-free survival (PFS) and overall survival (OS) in the i-HDMTX and EOT groups were as follows: 3y PFS 70.7% vs 76.7% (p=0.098), 3y OS 79.9% vs 87.0% (p=0.0016). However, there were no PFS/OS differences between groups on landmark analysis (n=1259) (Fig 1c). On analysis of pts experiencing ≥1 R-CHOP delay of ≥7 days, use of i-HDMTX was the only factor on MVA associated with increased delays (p<0.0001). Discussion: We found no evidence that EOT delivery increases CNS relapse risk when compared to i-HDMTX in this large analysis of pts treated with 1L R-CHOP. Delays to R-CHOP cycles were increased with i-HDMTX. Findings in a high risk subgroup were unchanged and rates of CNS relapse in this HDMTX treated group were similar to published comparable high risk cohorts receiving infrequent CNS prophylaxis. Where HDMTX prophylaxis is used, delivery could be deferred until R-CHOP completion. Figure 1 Figure 1. Disclosures Wilson: Takeda: Other: Conference fees; Janssen: Other: Conference fees; Abbvie: Honoraria. Eyre: Janssen: Honoraria; Secura Bio: Consultancy, Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Beigene: Honoraria, Research Funding. Ahearne: Pfizer: Research Funding; Takeda: Honoraria; Roche: Honoraria. Schorb: Roche: Research Funding; Riemser Pharma GmbH: Honoraria, Research Funding; AbbVie: Research Funding. Ku: Antegene: Consultancy; Roche: Consultancy; Genor Biopharma: Consultancy. Narkhede: Genentech/Roche: Research Funding; Gilead: Research Funding; Genmab: Other: Medical writing support, Research Funding; TG Therapeautics: Research Funding. Lewis: AstraZeneca: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties; Novartis: Patents & Royalties; Roche: Consultancy, Honoraria. Øvlisen: Abbvie: Other: Travel expenses. Santarsiere: Janssen: Honoraria. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roulin: Janssen: Other: Travel and meetings. Manos: Bristol-Myers Squibb: Other: Travel and meetings. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lopez-Garcia: Roche: Other: Speaker Honoraria, Travel and accommodation grants; Janssen: Other: Speaker Honoraria, Advisor, Travel and accommodation grants, Research Funding; Abbvie: Other: Speaker Honoraria, Advisor, Travel and accommodation grants; Celgene: Other: Speaker Honoraria; Fresenius: Other: Speaker Honoraria; Novonordisk: Other: Speaker Honoraria. El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee. Cheah: Beigene: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory. Ferreri: Gilead, Novartis, Juno, PletixaPharm, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; BMS, Beigene, Pharmacyclics, Hutchison Medipharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis, Pfizer: Research Funding. Fox: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: speaker fees. Cwynarski: Gilead: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Atara: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Other: Travel Support; KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Janssen: Honoraria, Other: Travel Support; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background Early data suggest that patients undergoing salvage chemotherapy for relapsed or refractory (R/R) acute myeloid leukaemia (AML) have poor outcomes if infected with SARS-CoV-2, and nosocomial transmission has been a major problem worldwide. Gilteritinib is effective in R/R FLT3 mutated AML, is significantly less immunosuppressive and does not require hospital admission, however at the start of the pandemic this was not yet approved for routine use in all countries. In the United Kingdom, the National Health Service (NHS) made gilteritinib available as an emergency measure from late April 2020 to patients aged >16y with R/R FLT3 mutated AML, with the aim of reducing both mortality and healthcare resource use. We report a health-system-wide real world data collection for toxicity and patient outcomes across 27 NHS Hospitals. Methods Each patient was registered on a central NHS database, with clinicians certifying that their patient met the above criteria. Anonymised data were retrospectively collected by treating physicians. Gilteritinib dose, duration and toxicity information was requested for the first 4 cycles of therapy. Response definitions were as per European Leukaemia Network (ELN) guidelines. A total of 81 patients have been registered on the scheme, with outcomes reported here for those with follow-up information at a data cut on 1st August 2021. Results Fifty patients were included with a median age of 59y (range 19 - 77) and 50% male. The majority (83%) had an ECOG performance status of 0-1. AML was secondary to a previous haematological disorder in 12%, therapy-related in 4% and de novo in the remaining 84%. The disease was refractory to the last therapy in 38%. Most patients had previously received 1 (65%) or 2 (33%) lines of therapy, including intensive chemotherapy in a majority (86%). A FLT3 inhibitor had previously been administered to 45% and 35% were post allogeneic transplant. The FLT3 mutation was an internal tandem duplication (ITD) in 80% and tyrosine kinase domain (TKD) mutation in 22%. NPM1 mutations were detected in 34%. Next-generation sequencing results were available for 94% of patients, with mutations in IDH1 or IDH2 in 12.5%, ASXL1 in 2%, RUNX1 in 21% and no TP53 mutations. Patients spent a median 3.5 days in hospital in cycle 1, 0 days in cycles 2 and 3 and 1 day in cycle 4. In cycles 1, 2, 3 and 4, the median number of days of grade 4 neutropenia was 18, 7, 7.5, and 6.5 respectively, and the grade 4 thrombocytopenia was 2, 7, 0.5 and 0.5. The composite complete remission (CR) / CR with incomplete haematological recovery (CRi) rate was 27%. MRD data is being collected. The best response was morphological leukaemia free state (MLFS) in 4%, partial remission (PR) in 25% and refractory disease in 38%. The rate of combined CR/CRi did not differ in those with previous exposure to FLT3 inhibitors (23% vs 32%, p=0.6) or with past allogeneic transplant (29% vs 27%, p=0.3). There were no CR/CRi in patients with adverse cytogenetic risk. Median follow-up was 10.5 months (95%CI 7.3 - 12.3) with median overall survival (OS) 6.7 months (95%CI 4.5 - not reached). Mortality at day 30 was 0% and day 60 was 14%. 12-month overall survival was 38%. Patients who achieved a CR/CRi had a 12-month OS of 83%, and for PR this was 35%. Survival did not differ in those with previous FLT3 inhibitor exposure (HR 1.0, p>0.9) or allogeneic transplant (HR 0.63, p=0.3). Seven patients (14%) so far have been bridged with gilteritinib to allogeneic transplant. Conclusion Our data demonstrate that gilteritinib is well tolerated and clinically active in adults with relapsed FLT3 mutated AML. Importantly, during the COVID-19 pandemic, its availability has permitted the great majority of treatment to be delivered as an outpatient with significant resource saving at a time of critically constrained inpatient resources. Patients who achieve CR/CRi have good short-term outcomes and are able to proceed to a potentially curative allogeneic stem cell transplant. Figure 1 Figure 1. Disclosures Belsham: Celgene: Other: meeting attendance; Abbvie: Other: meeting attendance. Byrne: Incyte: Honoraria. Khan: Abbvie: Honoraria; Astellas: Honoraria; Takeda: Honoraria; Jazz: Honoraria; Gilead: Honoraria; Novartis: Honoraria. Khwaja: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Latif: Kite: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Takeda UK: Speakers Bureau. Loke: Amgen: Honoraria; Daichi Sankyo: Other: Travel Support; Janssen: Honoraria; Novartis: Other: Travel Support; Pfizer: Honoraria. Munisamy: Jazz Pharmaceuticals: Speakers Bureau; Roche: Speakers Bureau. Murthy: Abbvie: Other: support to attend educational conferences.. Smith: Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Honoraria. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dillon: Amgen: Other: Research support (paid to institution); Astellas: Consultancy, Other: Educational Events , Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events; Jazz: Other: Education events; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events.

Aim:To explore the utility of [18F] Fluoro-2-deoxyglucose (18-FDG) positron emission tomography computed tomography (PET/CT) in lymphoblastic lymphoma (LBL). Background: LBL is a rare, malignant disorder of precursor T- or B- cells, which forms the lymphoma variant of acute lymphoblastic leukaemia (ALL). Whilst morphologically and immunophenotypically similar to ALL, distinction is made on degree of bone marrow infiltration (typically less than 25% in LBL). Due to the rarity of the condition, investigations at diagnosis, treatment approach and methods to evaluate disease response are not standardised. Bone marrow examination with MRD determination is the gold standard modality for disease monitoring in ALL yet the utility of this investigation is limited in LBL due to the low levels of marrow involvement at presentation. Computed tomography (CT) scanning is widely used in the diagnosis and assessment of lymphomas, however the criteria for disease are based purely on size of a lesion. Difficulties in distinguishing inflammatory from malignant lesions on CT have been widely reported (Elstrom et al. Blood. 2003;101(10):3875-6). 18-FDG PET/CT has been shown to be sensitive for staging high grade non-Hodgkin's lymphoma and is better at differentiating inflammatory from malignant lesions compared to CT alone (Ngeow et al, Ann Oncol. 2009;20(9):1543-7). Normalisation of the SUV to a suitable reference region such as the tumor-to-liver ratio (TLR), has reduced issues with inter-scanner variability. Retrospective data on the use of PET/CT in LBL is limited. In most series, few patients underwent PET/CT at diagnosis making interpretation of subsequent scans difficult thus PET/CT is currently only used at physician discretion in LBL. Methods: Patients with a diagnosis of T- or B-cell LBL managed at University College London Hospital, a large tertiary haematology unit in the UK since 2011 were identified. Data on timing of PET/CT scans in patients with a diagnosis of LBL were collected retrospectively and correlated with clinical outcome data. SUVmax values within the lesion(s) and within the liver, spleen and mediastinal (aortic) blood pool were collected and the TLR calculated. Results:20 patients were identified (14 T-LBL, 6 B-LBL), median age 24.5 years (range 13-66). Ten patients aged 13-24 years were treated using the UKALL 2011 protocol and 10 patients aged >24, years were treated using the UKALL 14 protocol. Sixteen of 20 (80%) of patients had a PET/CT scan at diagnosis before commencing treatment. The remaining 4 patients presented in extremis, requiring intensive care support and immediate empirical treatment. Of the 16 patients who had a PET/CT at diagnosis, all but one had significant FDG avid disease (mean SUVmax 8.6, range 2.7-17.1, TLR >1). Overall survival (OS) for the whole cohort was 70% (median follow up 31 months, range 6-91 months). Consistent with previous published data, OS was superior in the younger patients (90% in the 13-24 year age group vs 50% in those aged >24 years) although due to different patient characteristics and therapy these groups are not comparable. Regardless of age, all patients with a negative PET/CT scan after cycle 1 of chemotherapy survived, disease free (see table 1). Patients with a positive PET/CT after course 2 of treatment or at the end of treatment had a much poorer OS (60% and 0% respectively). In keeping with data from other high-grade lymphomas, SUVmax>10 at presentation may predict an aggressive clinical course, with average SUVmax of 11.9 (TLR4.23) in the patients who died of their disease compared to 6.225 (TLR2.33) in patients who survived. PET/CT had 100% sensitivity and specificity for detecting relapsed disease in this small series. In 8 patients who presented with symptoms suggestive of disease progression or relapse PET/CT detected all 6 patients with true positive disease and excluded relapse in 2 patients with inflammatory lesions. Conclusions: Our data suggests that PET/CT is useful in the diagnosis and response assessment of LBL particularly if the clinical scenario permits a scan at diagnosis. Although patient numbers are small, these data suggest that a high lesion SUVmax at diagnosis correlates with an aggressive subtype and patients with a negative scan after their first cycle of chemotherapy appear to have an excellent prognosis. Further investigation of the utility of PET/CT in risk stratification in LBL is warranted. Disclosures Fielding: Incyte: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Consultancy.

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.