Abstract: In a Plenary Paper, Middleton and colleagues describe important transcriptional and translational changes in murine and human platelets during sepsis, elucidating the emerging role of platelets in the complications of systemic inflammatory illness.

Abstract: Background: While most patients (pts) with follicular lymphoma (FL) have excellent outcomes with frontline chemoimmunotherapy (CIT), a subset of pts will experience early progression, which is associated with inferior survival. Earlier identification of high-risk FL pts could allow for intervention with novel treatments to forestall early progression. Current prognostic tools are imperfect, particularly for pts receiving bendamustine-based regimens, and novel biomarkers are needed. In Hodgkin lymphoma, interim positron emission tomography (iPET) evaluated based on Deauville score (DS) is highly prognostic and is used to guide response-adapted therapy. The prognostic value of iPET using DS has not yet been assessed in a large population of FL pts receiving frontline CIT. We hypothesized that iPET would predict progression-free survival (PFS) in this population which could support PET-guided treatment approaches. Methods: We retrospectively identified pts with a diagnosis of FL (grade 1-3B) who initiated frontline CIT at Dana-Farber Cancer Institute from 1/2005-3/2019 and underwent an iPET after 2-4 cycles of CIT. Pts who received radiation (XRT) prior to CIT were included. Baseline, interim, and (when available) end-of-treatment (EOT) PET scans were reviewed by a nuclear medicine radiologist in a blinded fashion and assigned a DS of 1-5. Results: 118 pts were identified. The median age was 55 (range 26-82). 73 pts (62%) had grade 1-2 FL, 17 pts (14%) grade 3A, 15 pts (13%) grade 3B, 12 pts (10%) grade 3 NOS, and 1 pt (1%) grade not reported. FLIPI score was low for 32%, intermediate for 42% and high for 26%. In total, 5 pts (4%) received XRT before CIT. The most common CIT regimens were RCHOP (54%) and BR (42%) (Table 1). 107 pts (91%) received 6 cycles of CIT and 4 pts (3%) received 8 cycles, while 7 pts (6%) discontinued CIT after 4-5 cycles due to cytopenias (4), heart failure (1), infection (1), or pt decision (1). 88% of iPETs were performed after 3 cycles. iPET DS was 1 for 18%, 2 for 57%, 3 for 13%, 4 for 9%, and 5 for 3%. EOT PET was available for review for 112 pts (95%) and demonstrated DS of 1 for 32%, 2 for 56%, 3 for 3%, 4 for 4%, and 5 for 5%. After CIT, 29 pts (25%) received a median of 9 doses (range 1-13) of rituximab maintenance (RM) and 2 pts (2%) received consolidative XRT. With a median follow-up of 54 months (range 5-186), the 4-year (yr) PFS and overall survival (OS) for the entire cohort were 69% (95% CI 58-77%) and 94% (95% CI 87-98%), respectively. iPET was a significant predictor of PFS (p=0.0011 for 5 categories). Compared to pts with an iPET DS of 1-2, pts with a DS of 3 (HR 3.0, p=0.006) or a DS of 4-5 (HR 3.4, p=0.004) had inferior PFS (Figure 1) and were grouped together in a +iPET group (n=30) for all analyses. The 4-yr PFS for DS 1-2 and DS 3-5 pts were 77% and 46%, respectively (HR 3.2, p & lt;0.001). iPET had similar prognostic value among pts receiving BR (HR 3.3 p=0.033) or RCHOP (HR 3.6, p=0.005) and retained significance when pts with grade 3B FL were excluded (HR 2.6, p=0.007). iPET was not predictive of OS (HR 1.6, p=0.48). EOT PET was also a significant predictor of PFS (p & lt;0.0001 for 5 categories). 3 pts with a DS of 3 on EOT PET had favorable outcomes and were grouped with DS 1-2 pts. A positive EOT PET (defined as DS 4-5) was observed more frequently among pts with an iPET DS of 3-5 (9/29 pts; 31%) compared to an iPET DS of 1-2 (1/83 pts; 1%) (p & lt;0.001). To determine if iPET provides additional prognostic information beyond EOT PET, we sorted pts into 4 groups based on iPET/EOT PET status (i.e. -/-, +/-, -/+, and +/+). Compared to -/- pts, +/- pts (HR 2.4, p=0.039), -/+ pts (HR 3.6, p=0.045) and +/+ pts (HR 9.1, p= & lt;0.001) all had inferior PFS (Figure 2). A multivariable analysis confirmed that iPET (HR 2.9, p=0.017), EOT PET (HR 7.6, P & lt;0.001), high FLIPI (HR 2.5, p=0.011), and RM (HR 0.3, p=0.015) were significant predictors of PFS, while CIT regimen (p=0.94) and grade (p=0.21) were not. Conclusions: Our study suggests that iPET may be a useful prognostic marker in FL. Additionally, iPET interpretation may be different in FL compared to other lymphomas. In this cohort, pts with a DS of 3 on iPET had inferior PFS with outcomes similar to those of pts with a DS of 4-5. A DS of 3-5 on iPET appears to predict earlier progression independent of EOT PET while providing response-driven prognostic information earlier in a patient's treatment course. If validated, these results suggest that iPET could be investigated as a tool for response-adapted treatment strategies in FL. Disclosures Salles: BMS/Celgene: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; Epizyme: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; Genmab: Honoraria, Other; Karyopharm: Honoraria; Takeda: Honoraria. Zelenetz:MEI Pharma: Research Funding; Celgene: Research Funding; Sandoz: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Celgene: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Consultancy; MorphoSys: Research Funding; Gilead: Consultancy; Genentech/Roche: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Roche: Research Funding. Brown:Janssen, Teva: Speakers Bureau; Gilead, Loxo, Sun, Verastem: Research Funding; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy. Crombie:AbbVie: Research Funding; Bayer: Research Funding. Davids:Ascentage Pharma: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Merck: Consultancy; Research to Practice: Honoraria; Syros Pharmaceuticals: Consultancy; Zentalis: Consultancy; Sunesis: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Fisher:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Jacobsen:Merck: Consultancy; Acerta: Consultancy; Astra-Zeneca: Consultancy; Pharmacyclics: Research Funding; F. Hoffmann-LaRoche: Research Funding; Novartis: Research Funding; Takeda: Honoraria. LaCasce:BMS: Consultancy; Research to Practice: Speakers Bureau; UptoDate: Patents & Royalties. Armand:Sigma Tau: Research Funding; Tensha: Research Funding; Pfizer: Consultancy; Affimed: Consultancy, Research Funding; IGM: Research Funding; Adaptive: Consultancy, Research Funding; Celgene: Consultancy; Merck & Co., Inc.: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Infinity: Consultancy; ADC Therapeutics: Consultancy; Genentech: Research Funding.

Abstract: Fibrin αC389-402 binds a cleft in the β-sandwich domain of FXIII-A2* exposed only after cleavage of the activation peptide. Binding of fibrin αC389-402 to FXIII-A2* regulates fibrin cross-linking and thus clot stabilization and fibrinolysis.

Abstract: Fibrinogen αC residues 242-424 have been shown to have a major regulatory role in the activation of factor XIII-A2B2 (FXIII-A2B2); however, the interactions underpinning this enhancing effect have not been determined. Here, we have characterized the binding of recombinant (r)FXIII-A subunit and FXIII-A2B2 with fibrin(ogen) and fibrin αC residues 233-425. Using recombinant truncations of the fibrin αC region 233-425 and surface plasmon resonance, we found that activated rFXIII-A bound αC 233-425 (Kd of 2.35 ± 0.09μM) which was further localized to αC 389-403. Site-directed mutagenesis of this region highlighted Glu396 as a key residue for binding of activated rFXIII-A. The interaction was specific for activated rFXIII-A and depended on the calcium-induced conformational change known to occur in rFXIII-A during activation. Furthermore, nonactivated FXIII-A2B2, thrombin-cleaved FXIII-A2B2, and activated FXIII-A2B2 each bound fibrin(ogen) and specifically αC region 371-425 with high affinity (Kd 〈 35nM and Kd 〈 31nM, respectively), showing for the first time the potential involvement of the αC region in binding to FXIII-A2B2. These results suggest that in addition to fibrinogen γ′ chain binding, the fibrin αC region also provides a platform for the binding of FXIII-A2B2 and FXIII-A subunit.

Abstract: Improved biomarkers are required to guide the optimal use of autologous stem cell transplantation (ASCT) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples, post-ASCT peripheral blood mononuclear cell (PBMC), and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples. After a median post-ASCT follow-up of 60 months, the 5-year progression-free survival (PFS) was 48%. MRD was detected in of 23/98 (23%) ASC samples and was associated with very poor PFS (5-year PFS 13% vs 53%, P  & lt; .001) and inferior overall survival (52% vs 68%, P = .05). The sensitivity and specificity of ASC MRD positivity for progression and death were 36% and 93%, respectively. Positive ASC MRD remained a significant predictor of PFS in multivariable analysis (hazard ratio [HR], 3.7; P  & lt; .001). Post-ASCT surveillance MRD testing of plasma, but not PBMC samples, reliably identified patients with an impending relapse. A positive plasma MRD result was associated with inferior PFS (HR, 3.0; P = .016) in a multivariable analysis. The median lead time from MRD detection to relapse was 62 days (range, 0-518 days). In conclusion, the detection of MRD in ASC samples is associated with a very high risk of relapse, justifying alternative treatment strategies or trials of novel consolidation options in these patients. Furthermore, post-ASCT MRD monitoring may facilitate the evaluation of the early initiation of treatment at molecular relapse. This trial has been registered at www.clinicaltrials.gov as #NCT02362997.

Abstract: Background: Induction chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for transplant eligible (TE) patients (pts) with untreated mantle cell lymphoma (uMCL); however, there is no consensus on the optimal induction regimen. The addition of rituximab + high-dose cytarabine (RC) to an RCHOP-like regimen is associated with better outcomes. In addition, two randomized trials have demonstrated superior efficacy and tolerability for rituximab/bendamustine (RB) compared to RCHOP for uMCL. Based on this, we conducted a phase 2 trial of 3 cycles of RB followed by 3 cycles of RC in 23 TE pts with uMCL, with encouraging preliminary results (Armand, BJH 2016). Pts continued to be followed for relapse and survival. Meanwhile, RB/RC became the standard frontline regimen at Dana-Farber Cancer Institute (DFCI). Simultaneously, investigators at Washington University in St. Louis (WUSTL) initiated a similar study of alternating cycles of RB/RC for uMCL. Herein, we report the results of both phase 2 trials as well as the off-trial experience. Methods: In the DFCI trial, TE pts (age 18-69) with uMCL were treated with 3 cycles of RB (R 375 mg/m2 d1, B 90 mg/m2 d1-2) followed by 3 cycles of RC (R 375 mg/m2 d1, C 3gm/m2 BID d1-2 with dose reductions for age, renal dysfunction, or pre-existing neurotoxicity). Off-trial pts treated with RB/RC at DFCI or in consulting community practices were retrospectively identified using clinical and pharmacy databases. In the WUSTL trial, TE pts (age 18-65) received alternating cycles of RB (cycles 1, 3, 5) and RC (cycles 2, 4, 6) (same dosing as above). Response assessments were made using CT scans for the DFCI trial and PET/CT for the WUSTL trial and DFCI off-trial pts. Results: In total, 86 pts (23 DFCI trial, 49 DFCI off-trial, 14 WUSTL trial) were treated with RB/RC. The median age was 57 (range 30-72). Pts in the WUSTL cohort were more likely to be male, have a high MIPI score, and have blastoid variant (Table). 94% of pts completed 6 cycles of RB/RC therapy. Off-trial pts were more likely to receive a lower starting dose (≤ 2gm/m2) of cytarabine (76%) compared to trial pts (38%). At the EOI, the overall response rate and CRR were 98% and 92%, respectively, with similar response rates across cohorts (Table). 73 pts (85%) subsequently underwent ASCT and 4 additional pts (5%) have ASCTs planned. 9 pts did not undergo ASCT because of persistent or PD (n=3), prolonged cytopenias (n=3), an incidentally identified ASXL1 mutation without cytopenias (n=1), pt preference (n=1), and inadequate stem cell collection (n=1). Delayed platelet engraftment after ASCT was seen for pts receiving alternating cycles of RB/RC compared to sequential RB/RC at day 30 (plts 〈 50: 70% vs 16%, p=0.001) and at day 100 (plts 〈 100: 60% vs 21%, p=0.017). An initial cytarabine dose 〉 2gm/m2 was also associated with reduced 30-day platelet count (plts 〈 50: 41% vs 8%, p=0.004). There was 1 treatment-related death from respiratory failure and RSV infection (Day 56 after ASCT). Median follow-up was 32m (range 4-69m) among survivors overall (54m for DFCI trial, 28m for DFCI off-trial, 19m for WUSTL trial). The 24m and 48m PFS for the entire cohort were 88% (95CI 77-93) and 80% (95CI 66-89), respectively (Figure, panel A); the 24m and 48m OS were 96% (95CI 89-99) and 92% (95CI 81-97), respectively. PFS and OS were similar across cohorts with a trend towards inferior PFS in the higher-risk WUSTL cohort (Figure, panel B). PFS was similar among non-trial pts treated at DFCI (n=32) and in community centers (n=17). In univariate analyses, a higher cytarabine dose ( 〉 2gm/m2) was not associated with improved PFS, while blastoid or pleomorphic variant (HR 4.5, p=0.016) and high-risk MIPI score (HR 4.0, p=0.034) were both associated with inferior PFS. Conclusions: Induction therapy with RB/RC followed by ASCT achieved high rates of durable remissions in two phase 2 clinical trials. Similarly favorable outcomes were observed with off-trial use of this regimen both at an academic center and in community practices. RB/RC is therefore an excellent choice of induction therapy for TE pts with uMCL, and could be further tested in comparative prospective trials. Sequential, rather than alternating, RB/RC cycles and lower dose cytarabine may reduce the risk of prolonged thrombocytopenia post-ASCT. Figure 1. Figure 1. Disclosures Kahl: Juno: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Acerta: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy. LaCasce:Research to Practice: Speakers Bureau; Bristol-Myers Squibb: Other: Data safety and monitoring board; Seattle Genetics: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria. Jacobson:Bayer: Consultancy; Novartis: Consultancy; Precision Bioscience: Consultancy; Humanigen: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Davids:Gilead: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Merck: Consultancy; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Brown:Sun Pharmaceutical Industries: Research Funding; Roche/Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Research Funding; Genentech: Consultancy; Celgene: Consultancy; Boehringer: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Verastem: Consultancy, Research Funding; Loxo: Consultancy; TG Therapeutics: Consultancy; Sunesis: Consultancy. Bartlett:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Pharmacyclics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Novartis: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Bristol-Meyers Squibb: Research Funding; Immune Design: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Novartis: Research Funding; Millennium: Research Funding. Armand:Merck: Consultancy, Research Funding; Adaptive: Research Funding; Otsuka: Research Funding; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Jacobsen:Seattle Genetics: Consultancy; Merck: Consultancy.