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 & lt;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 & lt;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: Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (−2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Abstract: Introduction: Double-unit CBT (DCBT) in adult patients (pts) with hematologic malignancies has been associated with high rates of disease-free survival (DFS) but its role in children is controversial. Methods: We investigated DCBT in children with high-risk acute leukemia following TBI or chemotherapy-based myeloablative cytoreduction. Outcomes of consecutive DCBT pts transplanted 10/2005-2/2013 as their first allograft were evaluated. Results: Thirty-five pts [median age 7.5 yrs (range 0.8-18), median weight 28 kg (range 8-75)] were transplanted. Seventeen had acute myelogenous or biphenotypic leukemia (AML): 6 in CR1 (one each with M7, secondary 5q- MDS, FLT-3 ITD mutation, Ph+, Down syndrome with positive MRD, or germline mutation CEBPa), 8 in CR2 (one with MLL positive MRD), 2 in aplasia, and one in CR3. Seventeen pts had ALL: 10 in CR1 [3 Ph+ (one with MRD), 2 T-cell ALL, one MLL, one L3 disease, and 3 multiple inductions] , 4 in CR2, and 3 in CR3. One pt had CML (imantinib resistant, accelerated phase with MRD). Thirty-one percent were CMV seropositive and 69% had non-European ancestry. Conditioning was cyclophosphamide/fludarabine/TBI 1375 cGy (N=21, 60%), or in the very young or those with prior radiation a chemotherapy-based regimen was used (N=14, 40%, 10 with clofarabine/thiotepa/melphalan and 4 with busulfan/melphalan/thiotepa). GVHD prophylaxis was with calcineurin-inhibitor/mycophenolate mofetil. Units had a donor-recipient 4-6/6 HLA-A,-B antigen,-DRB1 allele match, a cryopreserved total nucleated cell (TNC) dose 〉 1.5 x 107/kg/unit, and were albumin reconstituted for pts 〉 20 kg or washed for smaller pts. The cumulative incidence of sustained donor neutrophil engraftment was 94% (95%CI:78-98, median 21 days, range 12-33) and hematopoiesis was mediated by a single unit. Day 180 platelet engraftment 〉 50 x 109/l was 82% (95%CI: 64-92). The median platelet recovery in 31 evaluable pts was 51 days (range 39-299). Immune recovery was prompt with a mean absolute CD4+ count of 201 (SD:+/-180) at day +60, and 250 (SD:+/-150) at day +120. The engrafting unit had a median infused TNC dose of 3.9 x 107/kg (range 0.9-12.8) and 10/33 (30%) pts engrafted with a unit that had a pre-cryopreservation TNC 〈 2.5x107/kg. In addition, the majority (17/33, 51%) of pts engrafted with a unit that was 〈 5/8 HLA-allele matched to the recipient (range 2-5/8). The cumulative incidence of day 100 grade II-IV acute GVHD was 46% (95%CI:29-61) and 23% (95%CI:11-38) of pts had grade III-IV acute GVHD. The 3-year incidence of chronic GVHD was 14% (95%CI:5-28). With a median survivor follow-up of 58 months (range 20-105), the 3-year cumulative incidences of transplant-related mortality (TRM) and relapse were 11% (95%CI:4-24) and 20% (95%CI:9-35), respectively. Transplant-related causes of death were 2 graft failures, 1 HHV-6 encephalitis (day +53) and 1 RSV/metapneumovirus pneumonia (day +28). While some pts with GVHD required prolonged immunosuppressive therapy, none died of GVHD. Of the 7 children with relapse, 2 had AML in CR1 (one FLT-3 ITD mutation, one M7 AML), one had primary refractory AML transplanted in aplasia, and 4 had ALL (2 CR1, 1 CR2, 1 CR3). None of the 4 pts transplanted with MRD relapsed. Three-year DFS was 68% (95%CI:50-81). There was no difference based on diagnosis (3-yr DFS 77% in AML and 59% in ALL, p = 0.25, Figure), TBI-based cytoreduction (p = 0.68), or European vs non-European ancestry (p = 0.24). Positive recipient CMV serostatus was associated with lower DFS in univariate analysis (p = 0.005) with 5/11 CMV+ pts relapsing. Conclusions: Despite high-risk disease and grafts with a very high degree of donor-recipient HLA-allele mismatch, the low TRM and relapse rates after pediatric DCBT are striking. Although many of the younger children could have had “adequate” single unit grafts based on the recently published CIBMTR definition (cryopreserved TNC 〉 3.0 x 107/kg and 6-8/8 allele HLA-match), a significant minority will not. Therefore, despite the lack of benefit of DCBT in the BMT CTN randomized study, DCBT remains an important consideration in children, especially in those of non-European ancestry. Finally, chemotherapy-only-based conditioning is an effective alternative to high-dose radiation, an approach that further extends transplant access to pts unsuitable for TBI. Figure: 3-yr DFS after DCBT in children with high-risk acute leukemia Figure:. 3-yr DFS after DCBT in children with high-risk acute leukemia Disclosures Boulad: Genzyme Sanofi: Trials partially funded by Genzyme Sanofi Other.